Heart Failure

Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.

The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.

The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.

Wikimedia Commons/FitzColinGerald/Creative Commons License

A version of this article first appeared on Medscape.com.

Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.

The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.

The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.

Wikimedia Commons/FitzColinGerald/Creative Commons License

A version of this article first appeared on Medscape.com.

Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.

The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.

The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.

Wikimedia Commons/FitzColinGerald/Creative Commons License

A version of this article first appeared on Medscape.com.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.

The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.

The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.

Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.

Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.

More recent experience has calmed AKI concerns, however.

Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.

The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).

Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk

“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.

Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.

Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.

One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.

Early AKI concern has diminished

Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.

In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.

Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.

The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.

During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.

The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.

He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.

The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.

A version of this article originally appeared on Medscape.com.

Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.

The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.

The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.

Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.

Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.

More recent experience has calmed AKI concerns, however.

Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.

The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).

Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk

“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.

Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.

Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.

One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.

Early AKI concern has diminished

Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.

In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.

Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.

The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.

During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.

The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.

He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.

The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.

A version of this article originally appeared on Medscape.com.

Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.

The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.

The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.

Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.

Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.

More recent experience has calmed AKI concerns, however.

Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.

The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).

Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk

“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.

Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.

Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.

One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.

Early AKI concern has diminished

Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.

In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.

Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.

The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.

During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.

The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.

He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.

The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.

A version of this article originally appeared on Medscape.com.

NEW ORLEANS – A wearable device that monitors thoracic fluid and can signal elevated levels can improve outcomes after heart failure hospitalization, according to a comparative but nonrandomized trial.

In this study, management adjustments made in response to a threshold alert from the device led to several improvements in outcome at 90 days, including a significant 38% reduction in the primary outcome of rehospitalization, relative to controls (P = .02), reported John P. Boehmer, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

The same relative risk reduction at 90 days was observed for a composite outcome of time to first hospitalization, visit to an emergency room, or death (hazard ratio, 0.62; P = .03).

Quality of life, as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), improved steadily in both the experimental and control arm over the 90-day study, but the curves separated at about 30 days, Dr. Boehmer reported. By the end of the study, the mean KCCQ difference was 12 points favoring the experimental arm on a scale in which 5 points is considered clinically meaningful.
 

70% report improved quality of life

“Responder analysis revealed that nearly 70% of patients in the arm managed with the monitor reported a clinically meaningful improvement in quality of life, compared to 50% of patients in the control arm,” said Dr. Boehmer, professor of medicine and surgery at Penn State Health, Hershey.

Fluid overload is an indication of worsening disease and a frequent cause of heart failure hospitalization. The Zoll Heart Failure Monitoring System (HFMS) that was tested in this study already has regulatory approval. It is equipped to monitor several biomarkers, including heart rate and respiration rate, but its ability to measure lung fluid through low electromagnetic radiofrequency pulses was the function of interest for this study.

In this nonrandomized study, called Benefits of Microcor in Ambulatory

Decompensated Heart Failure (BMAD), a control arm was enrolled first. By monitoring the initial patients enrolled in the control arm, the investigators established a threshold of thoracic fluid that would be used to trigger an alert in the intervention arm. This ultimately was defined as 3 standard deviations from the population mean.

Patients were eligible for this study if they were discharged from a hospital with heart failure in the previous 10 days. Of exclusion criteria, a short life expectancy (< 1 year) and a wearable cardiac defibrillator were notable. Left ventricular ejection fraction (LVEF) was not considered for inclusion or exclusion.

All subjects participated in weekly phone calls and monthly office visits. However, both investigators and patients were blinded to the device data in the control arm. Conversely, subjects and investigators in the intervention arm were able to access data generated by the device through a secure website.

Of the 245 eligible patients in the control arm, 168 were available for evaluation at 90 days. Among the 249 eligible patients in the intervention arm, 176 were included in the 90-day evaluation. Of those who were not available, the most common reason was study withdrawal. About 20% died before the 90-day evaluation.

The majority of patients in both arms were in class III or IV heart failure. About half had LVEF less than 40%, and more than 40% of patients in each group had chronic kidney disease (CKD). Roughly 55% of patients were at least 65 years of age.

At 90 days, the absolute risk reduction in rehospitalization was 7%, producing a number to treat with the device of 14.3 to prevent one rehospitalization. In a subgroup stratification, the benefit was similar by age, sex, presence or absence of CKD, LVEF greater or lower than 40%, Black or non-Black race, and ischemic or nonischemic etiology.
 

Patient access to data considered a plus

If lack of randomization is a weakness of this study, the decision to unblind the data for both investigators and patients might not be, according to Lynne Stevenson, MD, director of the cardiomyopathy program, Vanderbilt University Medical Center, Nashville, Tenn.

“You might be criticized for this [allowing patients to monitor their data], but I actually think this is a strength of the study,” said Dr. Stevenson, who believes the growing trend to involve heart failure patients in self-management has been a positive direction in clinical care.

She indicated that, despite the potential bias derived from being aware of fluid fluctuations, this information might also be contributing to patient motivation for adherence and appropriate lifestyle modifications.

Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, made a similar point but for a different reason. She expressed concern about the work that monitoring the wearable device creates for clinicians. Despite the positive data generated by this study, Dr. Bozkurt said the device as used in the study demanded “a lot of clinical time and effort” when these are both in short supply.

Mitchel L. Zoler/MDedge News

While she called for a larger and randomized study to corroborate the results of this investigation, she also thinks that it would make sense to compare the clinical value of this device against alternative methods for monitoring heart failure, including other wearable devices. Dr. Bozkurt asserted that some of the most helpful devices from a clinical perspective might be those that patients monitor themselves.

“Hopefully in the future, we will be offering tools that provide patients information they can use without the immediate need of a clinician,” she said.

Dr. Boehmer reports financial relationships with Abbott, Boston Scientific, Medtronic, and Zoll Medical Corporation, which provided the funding for this study. Dr. Stevenson reports no potential conflicts of interest. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

NEW ORLEANS – A wearable device that monitors thoracic fluid and can signal elevated levels can improve outcomes after heart failure hospitalization, according to a comparative but nonrandomized trial.

In this study, management adjustments made in response to a threshold alert from the device led to several improvements in outcome at 90 days, including a significant 38% reduction in the primary outcome of rehospitalization, relative to controls (P = .02), reported John P. Boehmer, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

The same relative risk reduction at 90 days was observed for a composite outcome of time to first hospitalization, visit to an emergency room, or death (hazard ratio, 0.62; P = .03).

Quality of life, as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), improved steadily in both the experimental and control arm over the 90-day study, but the curves separated at about 30 days, Dr. Boehmer reported. By the end of the study, the mean KCCQ difference was 12 points favoring the experimental arm on a scale in which 5 points is considered clinically meaningful.
 

70% report improved quality of life

“Responder analysis revealed that nearly 70% of patients in the arm managed with the monitor reported a clinically meaningful improvement in quality of life, compared to 50% of patients in the control arm,” said Dr. Boehmer, professor of medicine and surgery at Penn State Health, Hershey.

Fluid overload is an indication of worsening disease and a frequent cause of heart failure hospitalization. The Zoll Heart Failure Monitoring System (HFMS) that was tested in this study already has regulatory approval. It is equipped to monitor several biomarkers, including heart rate and respiration rate, but its ability to measure lung fluid through low electromagnetic radiofrequency pulses was the function of interest for this study.

In this nonrandomized study, called Benefits of Microcor in Ambulatory

Decompensated Heart Failure (BMAD), a control arm was enrolled first. By monitoring the initial patients enrolled in the control arm, the investigators established a threshold of thoracic fluid that would be used to trigger an alert in the intervention arm. This ultimately was defined as 3 standard deviations from the population mean.

Patients were eligible for this study if they were discharged from a hospital with heart failure in the previous 10 days. Of exclusion criteria, a short life expectancy (< 1 year) and a wearable cardiac defibrillator were notable. Left ventricular ejection fraction (LVEF) was not considered for inclusion or exclusion.

All subjects participated in weekly phone calls and monthly office visits. However, both investigators and patients were blinded to the device data in the control arm. Conversely, subjects and investigators in the intervention arm were able to access data generated by the device through a secure website.

Of the 245 eligible patients in the control arm, 168 were available for evaluation at 90 days. Among the 249 eligible patients in the intervention arm, 176 were included in the 90-day evaluation. Of those who were not available, the most common reason was study withdrawal. About 20% died before the 90-day evaluation.

The majority of patients in both arms were in class III or IV heart failure. About half had LVEF less than 40%, and more than 40% of patients in each group had chronic kidney disease (CKD). Roughly 55% of patients were at least 65 years of age.

At 90 days, the absolute risk reduction in rehospitalization was 7%, producing a number to treat with the device of 14.3 to prevent one rehospitalization. In a subgroup stratification, the benefit was similar by age, sex, presence or absence of CKD, LVEF greater or lower than 40%, Black or non-Black race, and ischemic or nonischemic etiology.
 

Patient access to data considered a plus

If lack of randomization is a weakness of this study, the decision to unblind the data for both investigators and patients might not be, according to Lynne Stevenson, MD, director of the cardiomyopathy program, Vanderbilt University Medical Center, Nashville, Tenn.

“You might be criticized for this [allowing patients to monitor their data], but I actually think this is a strength of the study,” said Dr. Stevenson, who believes the growing trend to involve heart failure patients in self-management has been a positive direction in clinical care.

She indicated that, despite the potential bias derived from being aware of fluid fluctuations, this information might also be contributing to patient motivation for adherence and appropriate lifestyle modifications.

Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, made a similar point but for a different reason. She expressed concern about the work that monitoring the wearable device creates for clinicians. Despite the positive data generated by this study, Dr. Bozkurt said the device as used in the study demanded “a lot of clinical time and effort” when these are both in short supply.

Mitchel L. Zoler/MDedge News

While she called for a larger and randomized study to corroborate the results of this investigation, she also thinks that it would make sense to compare the clinical value of this device against alternative methods for monitoring heart failure, including other wearable devices. Dr. Bozkurt asserted that some of the most helpful devices from a clinical perspective might be those that patients monitor themselves.

“Hopefully in the future, we will be offering tools that provide patients information they can use without the immediate need of a clinician,” she said.

Dr. Boehmer reports financial relationships with Abbott, Boston Scientific, Medtronic, and Zoll Medical Corporation, which provided the funding for this study. Dr. Stevenson reports no potential conflicts of interest. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

NEW ORLEANS – A wearable device that monitors thoracic fluid and can signal elevated levels can improve outcomes after heart failure hospitalization, according to a comparative but nonrandomized trial.

In this study, management adjustments made in response to a threshold alert from the device led to several improvements in outcome at 90 days, including a significant 38% reduction in the primary outcome of rehospitalization, relative to controls (P = .02), reported John P. Boehmer, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

The same relative risk reduction at 90 days was observed for a composite outcome of time to first hospitalization, visit to an emergency room, or death (hazard ratio, 0.62; P = .03).

Quality of life, as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), improved steadily in both the experimental and control arm over the 90-day study, but the curves separated at about 30 days, Dr. Boehmer reported. By the end of the study, the mean KCCQ difference was 12 points favoring the experimental arm on a scale in which 5 points is considered clinically meaningful.
 

70% report improved quality of life

“Responder analysis revealed that nearly 70% of patients in the arm managed with the monitor reported a clinically meaningful improvement in quality of life, compared to 50% of patients in the control arm,” said Dr. Boehmer, professor of medicine and surgery at Penn State Health, Hershey.

Fluid overload is an indication of worsening disease and a frequent cause of heart failure hospitalization. The Zoll Heart Failure Monitoring System (HFMS) that was tested in this study already has regulatory approval. It is equipped to monitor several biomarkers, including heart rate and respiration rate, but its ability to measure lung fluid through low electromagnetic radiofrequency pulses was the function of interest for this study.

In this nonrandomized study, called Benefits of Microcor in Ambulatory

Decompensated Heart Failure (BMAD), a control arm was enrolled first. By monitoring the initial patients enrolled in the control arm, the investigators established a threshold of thoracic fluid that would be used to trigger an alert in the intervention arm. This ultimately was defined as 3 standard deviations from the population mean.

Patients were eligible for this study if they were discharged from a hospital with heart failure in the previous 10 days. Of exclusion criteria, a short life expectancy (< 1 year) and a wearable cardiac defibrillator were notable. Left ventricular ejection fraction (LVEF) was not considered for inclusion or exclusion.

All subjects participated in weekly phone calls and monthly office visits. However, both investigators and patients were blinded to the device data in the control arm. Conversely, subjects and investigators in the intervention arm were able to access data generated by the device through a secure website.

Of the 245 eligible patients in the control arm, 168 were available for evaluation at 90 days. Among the 249 eligible patients in the intervention arm, 176 were included in the 90-day evaluation. Of those who were not available, the most common reason was study withdrawal. About 20% died before the 90-day evaluation.

The majority of patients in both arms were in class III or IV heart failure. About half had LVEF less than 40%, and more than 40% of patients in each group had chronic kidney disease (CKD). Roughly 55% of patients were at least 65 years of age.

At 90 days, the absolute risk reduction in rehospitalization was 7%, producing a number to treat with the device of 14.3 to prevent one rehospitalization. In a subgroup stratification, the benefit was similar by age, sex, presence or absence of CKD, LVEF greater or lower than 40%, Black or non-Black race, and ischemic or nonischemic etiology.
 

Patient access to data considered a plus

If lack of randomization is a weakness of this study, the decision to unblind the data for both investigators and patients might not be, according to Lynne Stevenson, MD, director of the cardiomyopathy program, Vanderbilt University Medical Center, Nashville, Tenn.

“You might be criticized for this [allowing patients to monitor their data], but I actually think this is a strength of the study,” said Dr. Stevenson, who believes the growing trend to involve heart failure patients in self-management has been a positive direction in clinical care.

She indicated that, despite the potential bias derived from being aware of fluid fluctuations, this information might also be contributing to patient motivation for adherence and appropriate lifestyle modifications.

Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, made a similar point but for a different reason. She expressed concern about the work that monitoring the wearable device creates for clinicians. Despite the positive data generated by this study, Dr. Bozkurt said the device as used in the study demanded “a lot of clinical time and effort” when these are both in short supply.

Mitchel L. Zoler/MDedge News

While she called for a larger and randomized study to corroborate the results of this investigation, she also thinks that it would make sense to compare the clinical value of this device against alternative methods for monitoring heart failure, including other wearable devices. Dr. Bozkurt asserted that some of the most helpful devices from a clinical perspective might be those that patients monitor themselves.

“Hopefully in the future, we will be offering tools that provide patients information they can use without the immediate need of a clinician,” she said.

Dr. Boehmer reports financial relationships with Abbott, Boston Scientific, Medtronic, and Zoll Medical Corporation, which provided the funding for this study. Dr. Stevenson reports no potential conflicts of interest. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.

The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.

The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.

Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.

“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.

“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented. 

“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.  

Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.

Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.

“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.

On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”

He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”

David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”

“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”

Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”

In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.

The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.  

The current 3-year results suggest the benefit appears to be maintained out for another year. 

The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).

In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.

Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.

Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.

However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.

On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.

Quality-of-life results looked good in both groups.

“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”

Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”

Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.

Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”

Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.

Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”

He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.

“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.    

Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.  

Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”

Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”

But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”

The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.

A version of this article first appeared on Medscape.com.

Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.

The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.

The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.

Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.

“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.

“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented. 

“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.  

Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.

Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.

“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.

On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”

He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”

David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”

“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”

Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”

In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.

The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.  

The current 3-year results suggest the benefit appears to be maintained out for another year. 

The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).

In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.

Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.

Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.

However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.

On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.

Quality-of-life results looked good in both groups.

“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”

Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”

Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.

Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”

Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.

Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”

He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.

“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.    

Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.  

Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”

Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”

But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”

The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.

A version of this article first appeared on Medscape.com.

Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.

The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.

The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.

Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.

“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.

“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented. 

“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.  

Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.

Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.

“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.

On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”

He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”

David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”

“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”

Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”

In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.

The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.  

The current 3-year results suggest the benefit appears to be maintained out for another year. 

The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).

In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.

Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.

Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.

However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.

On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.

Quality-of-life results looked good in both groups.

“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”

Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”

Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.

Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”

Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.

Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”

He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.

“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.    

Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.  

Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”

Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”

But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”

The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.

A version of this article first appeared on Medscape.com.

In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.

These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.

“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.

Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
 

The needle mover: LDL lowering

“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.

“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.

“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.

Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.

Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.

That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.

“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”

At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.

Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.

And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.

Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.

“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”


 

Other important successes and equally important failures

Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.

There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.

Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.

“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
 

The rise and fall of CVOTs

Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).

It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.

His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.

“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.

Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.

In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.

Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.

“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”

Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.

“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.

“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”

Clinical research for the next 20 years

Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.

Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.

RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.

“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.

RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.

Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.

“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
 

Time to be inclusive

Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.

“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.

“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”

In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”

The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
 

Stick with randomization

Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.

“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.

“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”

Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.

“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”

Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”

In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.

These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.

“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.

Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
 

The needle mover: LDL lowering

“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.

“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.

“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.

Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.

Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.

That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.

“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”

At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.

Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.

And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.

Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.

“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”


 

Other important successes and equally important failures

Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.

There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.

Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.

“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
 

The rise and fall of CVOTs

Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).

It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.

His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.

“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.

Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.

In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.

Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.

“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”

Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.

“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.

“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”

Clinical research for the next 20 years

Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.

Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.

RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.

“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.

RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.

Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.

“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
 

Time to be inclusive

Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.

“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.

“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”

In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”

The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
 

Stick with randomization

Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.

“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.

“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”

Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.

“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”

Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”

In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.

These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.

“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.

Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
 

The needle mover: LDL lowering

“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.

“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.

“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.

Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.

Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.

That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.

“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”

At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.

Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.

And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.

Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.

“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”


 

Other important successes and equally important failures

Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.

There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.

Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.

“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
 

The rise and fall of CVOTs

Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).

It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.

His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.

“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.

Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.

In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.

Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.

“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”

Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.

“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.

“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”

Clinical research for the next 20 years

Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.

Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.

RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.

“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.

RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.

Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.

“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
 

Time to be inclusive

Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.

“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.

“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”

In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”

The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
 

Stick with randomization

Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.

“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.

“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”

Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.

“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”

Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”

Patients with degenerative mitral valve (MV) regurgitation that calls for surgery may, for the most part, safely choose either a standard procedure requiring a midline sternotomy or one performed through a minithoracotomy, suggests a randomized comparison of the two techniques.

Still, the minimally invasive approach showed some advantages in the study. Patients’ quality of recovery was about the same with both procedures at 12 weeks, but those who had the minimally invasive thoracoscopy-guided surgery had shown greater improvement 6 weeks earlier.

Also in the UK Mini Mitral Trial, hospital length of stay (LOS) was significantly shorter for patients who underwent the mini-thoracotomy procedure, and that group spent fewer days in the hospital over the following months.

But neither procedure had an edge in terms of postoperative clinical risk in the study. Rates of clinical events, such as death or hospitalization for heart failure (HHF), were about the same over 1 year.

Patients in this trial had been deemed suitable for either of the two surgeries, which were always performed by surgeons specially chosen by the steering committee for their experience and expertise.

This first randomized head-to-head comparison of the two approaches in such patients should make both patients and clinicians more confident about choosing the minimally invasive surgery for degenerative MV disease, said Enoch Akowuah, MD, Newcastle (England) University, United Kingdom.

Dr. Akowuah presented the UK Mini-Mitral Trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

A “main takeaway” for clinical practice from the trial would be that minithoracotomy MV repair “is as safe and effective as conventional sternotomy for degenerative mitral regurgitation,” said discussant Amy E. Simone, PA-C, following Dr. Akowuah’s presentation.

“I think this study is unique in that its focus is on delivering high-quality, cost-efficient care for mitral regurgitation, but also with an emphasis on patients’ goals and wishes,” said Ms. Simone, who directs the Marcus Heart Valve Center of the Piedmont Heart Institute, Atlanta.

Cardiac surgeon Thomas MacGillivray, MD, another discussant, agreed that the data presented from at least this study suggest neither the minithoracotomy nor sternotomy approach is better than the other. But he questioned whether that would hold true if applied to broader clinical practice.

Dr. MacGillivray, of MedStar Washington Hospital Center, Washington, observed that only 330 patients were randomly assigned among a total of 1,167 candidates for candidates for MV repair surgery.

Indeed, he noted, more than 200 declined and about 600 were declared ineligible for the study, “even though it had seemed as if all were appropriate for mitral valve repair. That could be viewed as a significant limitation in terms of scalability in the real world.”

Some of those patients weren’t randomly assigned because they ultimately were not considered appropriate for both procedures, and some expressed a preference for one or the other approach, Dr. Akowuah replied. Those were the most common reasons. Many others did not enter the study, he said, because their mitral regurgitation was functional, not degenerative.

The two randomization groups fared similarly for the primary endpoint reflecting recovery from surgery, so the trial was actually “negative,” Dr. Akowuah said in an interview. However, “I see it as very much a win for minithoracotomy. The outstanding questions for clinicians and patients have been about the clinical efficacy and safety of the technique. And we’ve shown in this trial that minithoracotomy is safe and effective.”

If the minithoracotomy procedure is available, he continued, “and it’s just as clinically effective and safe – and we weren’t sure that was the case until we did this trial – and the repair is almost as durable, then why have a sternotomy?”

The researchers assigned 330 patients with degenerative MV disease who were deemed suitable for either type of surgery to undergo the standard operation via sternotomy or the minithoracotomy procedure at 10 centers in the United Kingdom. The steering committee had hand-selected its 28 experienced surgeons, each of whom performed only one of the two surgeries consistently for the trial’s patients.

The technically more demanding minithoracotomy procedure took longer to perform by a mean of 44 minutes,  it prolonged cross-clamp time by 11 minutes, and it required 30 minutes more cardiopulmonary bypass support, Dr. Akowuah reported.

The two patient groups showed no significant differences in the primary endpoint of physical function and ability to return to usual activity levels at 12 weeks, as assessed by scores on the 36-Item Short Form Survey and wrist-worn accelerometer monitoring. At 6 weeks, however, the mini-thoracotomy patients had shown a significant early but temporary advantage for those recovery measures.

The minithoracotomy group clearly fared better, however, on some secondary endpoints. For example, their median hospital LOS was 5 days, compared with 6 days for the sternotomy group (P = .003), and 33.1% of the mini-thoracotomy patients were discharged within 4 days of the surgery, compared with only 15.3% of patients who had the standard procedure (P < .001).

The minithoracotomy group also had marginally more days alive out of the hospital at both 30 days (23.6 days vs. 22.4 days in the sternotomy group) and 90 days (82.7 days and 80.5 days, respectively) after the surgery (P = .03 for both differences).

Safety outcomes at 12 weeks were similar, with no significant differences in rate of death, strokes, MI, or renal impairment, or in ICU length of stay or need for more than 48 hours of mechanical ventilation, Dr. Akowuah reported.

Safety outcomes at 1 year were also similar. Mortality by then was 2.4% for the minithoracotomy patients and 2.5% for the sternotomy group, nor were there significant differences in HHF rates or need for repeat MV surgical repair.

Dr. Akowuah said the patients will be followed for up to 5 years for the primary outcomes, echocardiographic changes, and clinical events.

The minithoracotomy surgery’s longer operative times and specialized equipment make it more a expensive procedure than the standard surgery, he said. “So we need to work out in a cost-effectiveness analysis whether that is offset by the benefits,” such as shorter hospital stays or perhaps fewer transfusions or readmissions.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reported no relevant financial relationships with industry.

A version of this article first appeared on Medscape.com.

Patients with degenerative mitral valve (MV) regurgitation that calls for surgery may, for the most part, safely choose either a standard procedure requiring a midline sternotomy or one performed through a minithoracotomy, suggests a randomized comparison of the two techniques.

Still, the minimally invasive approach showed some advantages in the study. Patients’ quality of recovery was about the same with both procedures at 12 weeks, but those who had the minimally invasive thoracoscopy-guided surgery had shown greater improvement 6 weeks earlier.

Also in the UK Mini Mitral Trial, hospital length of stay (LOS) was significantly shorter for patients who underwent the mini-thoracotomy procedure, and that group spent fewer days in the hospital over the following months.

But neither procedure had an edge in terms of postoperative clinical risk in the study. Rates of clinical events, such as death or hospitalization for heart failure (HHF), were about the same over 1 year.

Patients in this trial had been deemed suitable for either of the two surgeries, which were always performed by surgeons specially chosen by the steering committee for their experience and expertise.

This first randomized head-to-head comparison of the two approaches in such patients should make both patients and clinicians more confident about choosing the minimally invasive surgery for degenerative MV disease, said Enoch Akowuah, MD, Newcastle (England) University, United Kingdom.

Dr. Akowuah presented the UK Mini-Mitral Trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

A “main takeaway” for clinical practice from the trial would be that minithoracotomy MV repair “is as safe and effective as conventional sternotomy for degenerative mitral regurgitation,” said discussant Amy E. Simone, PA-C, following Dr. Akowuah’s presentation.

“I think this study is unique in that its focus is on delivering high-quality, cost-efficient care for mitral regurgitation, but also with an emphasis on patients’ goals and wishes,” said Ms. Simone, who directs the Marcus Heart Valve Center of the Piedmont Heart Institute, Atlanta.

Cardiac surgeon Thomas MacGillivray, MD, another discussant, agreed that the data presented from at least this study suggest neither the minithoracotomy nor sternotomy approach is better than the other. But he questioned whether that would hold true if applied to broader clinical practice.

Dr. MacGillivray, of MedStar Washington Hospital Center, Washington, observed that only 330 patients were randomly assigned among a total of 1,167 candidates for candidates for MV repair surgery.

Indeed, he noted, more than 200 declined and about 600 were declared ineligible for the study, “even though it had seemed as if all were appropriate for mitral valve repair. That could be viewed as a significant limitation in terms of scalability in the real world.”

Some of those patients weren’t randomly assigned because they ultimately were not considered appropriate for both procedures, and some expressed a preference for one or the other approach, Dr. Akowuah replied. Those were the most common reasons. Many others did not enter the study, he said, because their mitral regurgitation was functional, not degenerative.

The two randomization groups fared similarly for the primary endpoint reflecting recovery from surgery, so the trial was actually “negative,” Dr. Akowuah said in an interview. However, “I see it as very much a win for minithoracotomy. The outstanding questions for clinicians and patients have been about the clinical efficacy and safety of the technique. And we’ve shown in this trial that minithoracotomy is safe and effective.”

If the minithoracotomy procedure is available, he continued, “and it’s just as clinically effective and safe – and we weren’t sure that was the case until we did this trial – and the repair is almost as durable, then why have a sternotomy?”

The researchers assigned 330 patients with degenerative MV disease who were deemed suitable for either type of surgery to undergo the standard operation via sternotomy or the minithoracotomy procedure at 10 centers in the United Kingdom. The steering committee had hand-selected its 28 experienced surgeons, each of whom performed only one of the two surgeries consistently for the trial’s patients.

The technically more demanding minithoracotomy procedure took longer to perform by a mean of 44 minutes,  it prolonged cross-clamp time by 11 minutes, and it required 30 minutes more cardiopulmonary bypass support, Dr. Akowuah reported.

The two patient groups showed no significant differences in the primary endpoint of physical function and ability to return to usual activity levels at 12 weeks, as assessed by scores on the 36-Item Short Form Survey and wrist-worn accelerometer monitoring. At 6 weeks, however, the mini-thoracotomy patients had shown a significant early but temporary advantage for those recovery measures.

The minithoracotomy group clearly fared better, however, on some secondary endpoints. For example, their median hospital LOS was 5 days, compared with 6 days for the sternotomy group (P = .003), and 33.1% of the mini-thoracotomy patients were discharged within 4 days of the surgery, compared with only 15.3% of patients who had the standard procedure (P < .001).

The minithoracotomy group also had marginally more days alive out of the hospital at both 30 days (23.6 days vs. 22.4 days in the sternotomy group) and 90 days (82.7 days and 80.5 days, respectively) after the surgery (P = .03 for both differences).

Safety outcomes at 12 weeks were similar, with no significant differences in rate of death, strokes, MI, or renal impairment, or in ICU length of stay or need for more than 48 hours of mechanical ventilation, Dr. Akowuah reported.

Safety outcomes at 1 year were also similar. Mortality by then was 2.4% for the minithoracotomy patients and 2.5% for the sternotomy group, nor were there significant differences in HHF rates or need for repeat MV surgical repair.

Dr. Akowuah said the patients will be followed for up to 5 years for the primary outcomes, echocardiographic changes, and clinical events.

The minithoracotomy surgery’s longer operative times and specialized equipment make it more a expensive procedure than the standard surgery, he said. “So we need to work out in a cost-effectiveness analysis whether that is offset by the benefits,” such as shorter hospital stays or perhaps fewer transfusions or readmissions.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reported no relevant financial relationships with industry.

A version of this article first appeared on Medscape.com.

Patients with degenerative mitral valve (MV) regurgitation that calls for surgery may, for the most part, safely choose either a standard procedure requiring a midline sternotomy or one performed through a minithoracotomy, suggests a randomized comparison of the two techniques.

Still, the minimally invasive approach showed some advantages in the study. Patients’ quality of recovery was about the same with both procedures at 12 weeks, but those who had the minimally invasive thoracoscopy-guided surgery had shown greater improvement 6 weeks earlier.

Also in the UK Mini Mitral Trial, hospital length of stay (LOS) was significantly shorter for patients who underwent the mini-thoracotomy procedure, and that group spent fewer days in the hospital over the following months.

But neither procedure had an edge in terms of postoperative clinical risk in the study. Rates of clinical events, such as death or hospitalization for heart failure (HHF), were about the same over 1 year.

Patients in this trial had been deemed suitable for either of the two surgeries, which were always performed by surgeons specially chosen by the steering committee for their experience and expertise.

This first randomized head-to-head comparison of the two approaches in such patients should make both patients and clinicians more confident about choosing the minimally invasive surgery for degenerative MV disease, said Enoch Akowuah, MD, Newcastle (England) University, United Kingdom.

Dr. Akowuah presented the UK Mini-Mitral Trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

A “main takeaway” for clinical practice from the trial would be that minithoracotomy MV repair “is as safe and effective as conventional sternotomy for degenerative mitral regurgitation,” said discussant Amy E. Simone, PA-C, following Dr. Akowuah’s presentation.

“I think this study is unique in that its focus is on delivering high-quality, cost-efficient care for mitral regurgitation, but also with an emphasis on patients’ goals and wishes,” said Ms. Simone, who directs the Marcus Heart Valve Center of the Piedmont Heart Institute, Atlanta.

Cardiac surgeon Thomas MacGillivray, MD, another discussant, agreed that the data presented from at least this study suggest neither the minithoracotomy nor sternotomy approach is better than the other. But he questioned whether that would hold true if applied to broader clinical practice.

Dr. MacGillivray, of MedStar Washington Hospital Center, Washington, observed that only 330 patients were randomly assigned among a total of 1,167 candidates for candidates for MV repair surgery.

Indeed, he noted, more than 200 declined and about 600 were declared ineligible for the study, “even though it had seemed as if all were appropriate for mitral valve repair. That could be viewed as a significant limitation in terms of scalability in the real world.”

Some of those patients weren’t randomly assigned because they ultimately were not considered appropriate for both procedures, and some expressed a preference for one or the other approach, Dr. Akowuah replied. Those were the most common reasons. Many others did not enter the study, he said, because their mitral regurgitation was functional, not degenerative.

The two randomization groups fared similarly for the primary endpoint reflecting recovery from surgery, so the trial was actually “negative,” Dr. Akowuah said in an interview. However, “I see it as very much a win for minithoracotomy. The outstanding questions for clinicians and patients have been about the clinical efficacy and safety of the technique. And we’ve shown in this trial that minithoracotomy is safe and effective.”

If the minithoracotomy procedure is available, he continued, “and it’s just as clinically effective and safe – and we weren’t sure that was the case until we did this trial – and the repair is almost as durable, then why have a sternotomy?”

The researchers assigned 330 patients with degenerative MV disease who were deemed suitable for either type of surgery to undergo the standard operation via sternotomy or the minithoracotomy procedure at 10 centers in the United Kingdom. The steering committee had hand-selected its 28 experienced surgeons, each of whom performed only one of the two surgeries consistently for the trial’s patients.

The technically more demanding minithoracotomy procedure took longer to perform by a mean of 44 minutes,  it prolonged cross-clamp time by 11 minutes, and it required 30 minutes more cardiopulmonary bypass support, Dr. Akowuah reported.

The two patient groups showed no significant differences in the primary endpoint of physical function and ability to return to usual activity levels at 12 weeks, as assessed by scores on the 36-Item Short Form Survey and wrist-worn accelerometer monitoring. At 6 weeks, however, the mini-thoracotomy patients had shown a significant early but temporary advantage for those recovery measures.

The minithoracotomy group clearly fared better, however, on some secondary endpoints. For example, their median hospital LOS was 5 days, compared with 6 days for the sternotomy group (P = .003), and 33.1% of the mini-thoracotomy patients were discharged within 4 days of the surgery, compared with only 15.3% of patients who had the standard procedure (P < .001).

The minithoracotomy group also had marginally more days alive out of the hospital at both 30 days (23.6 days vs. 22.4 days in the sternotomy group) and 90 days (82.7 days and 80.5 days, respectively) after the surgery (P = .03 for both differences).

Safety outcomes at 12 weeks were similar, with no significant differences in rate of death, strokes, MI, or renal impairment, or in ICU length of stay or need for more than 48 hours of mechanical ventilation, Dr. Akowuah reported.

Safety outcomes at 1 year were also similar. Mortality by then was 2.4% for the minithoracotomy patients and 2.5% for the sternotomy group, nor were there significant differences in HHF rates or need for repeat MV surgical repair.

Dr. Akowuah said the patients will be followed for up to 5 years for the primary outcomes, echocardiographic changes, and clinical events.

The minithoracotomy surgery’s longer operative times and specialized equipment make it more a expensive procedure than the standard surgery, he said. “So we need to work out in a cost-effectiveness analysis whether that is offset by the benefits,” such as shorter hospital stays or perhaps fewer transfusions or readmissions.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reported no relevant financial relationships with industry.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).

Ted Bosworth/MDedge News

Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.

The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
 

Causal AI trained on nearly 2 million patients

This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.

To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.

When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.

Providing examples, Dr. Ference explained that a PGS in the 80^th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80^th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.

Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80^th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.

Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.

Even though family history is equivalent to having PGS above the 95^th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.

Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.

According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
 

Treatments become understandable to patients

“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.

A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.

Ted Bosworth/MDedge News

Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.

By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.

With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.

She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.

Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.

NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).

Ted Bosworth/MDedge News

Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.

The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
 

Causal AI trained on nearly 2 million patients

This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.

To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.

When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.

Providing examples, Dr. Ference explained that a PGS in the 80^th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80^th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.

Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80^th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.

Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.

Even though family history is equivalent to having PGS above the 95^th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.

Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.

According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
 

Treatments become understandable to patients

“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.

A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.

Ted Bosworth/MDedge News

Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.

By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.

With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.

She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.

Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.

NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).

Ted Bosworth/MDedge News

Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.

The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
 

Causal AI trained on nearly 2 million patients

This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.

To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.

When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.

Providing examples, Dr. Ference explained that a PGS in the 80^th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80^th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.

Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80^th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.

Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.

Even though family history is equivalent to having PGS above the 95^th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.

Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.

According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
 

Treatments become understandable to patients

“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.

A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.

Ted Bosworth/MDedge News

Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.

By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.

With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.

She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.

Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.

Two types of electronically delivered letter strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination and a repeat reminder letter – increased flu shot uptake, compared with usual care alone, in a national study of seniors in Denmark.

And in a prespecified subanalysis focusing on older adults with cardiovascular disease, these two strategies were also effective in boosting vaccine uptake in those with or without CVD.

The findings are from the Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU) trial, which compared usual care alone with one of nine different electronic letter “behavioral nudge” strategies during the 2022-2023 flu season in people aged 65 years and older.  

Pix by Marti/Fotolia

Niklas Dyrby Johansen, MD, Hospital–Herlev and Gentofte and Copenhagen University, presented the main study findings in a late-breaking clinical trial session at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, and the article was simultaneously published in The Lancet

The subanalysis in patients with CVD was published online March 5 in Circulation.

“Despite modest effect sizes, the results may have important implications when translated to a population level,” Dr. Dyrby Johansen concluded during his presentation. Still, the authors write, “the low-touch (no person-to-person interaction), inexpensive, and highly scalable nature of these electronic letters might have important population-level public health implications.”  

They note that, among approximately 63 million Medicare beneficiaries in the United States, a 0.89–percentage point absolute increase in vaccination rate achieved through the most successful electronic letter in NUDGE-FLU, the one highlighting cardiovascular gain, would be expected to lead to 500,000 additional vaccinations and potentially prevent 7,849 illnesses, 4,395 medical visits, 714 hospitalizations, and 66 deaths each year.

Electronic letter systems similar to the one used in this trial are already in place in several European countries, including Sweden, Norway, and Ireland, the researchers note.

In countries such as the United States, where implementing a nationwide government electronic letter system might not be feasible, nudges could be done via email, text message, or other systems, but whether this would be as effective remains to be seen.

Commenting on the findings, David Cho, MD, UCLA Health and chair of the ACC Health Care Innovation Council, commended the researchers on engaging patients with more than a million separate nudges sent out during one flu season, and randomly assigning participants to 10 different types of nudges, calling it “impressive.”

“I think the concept that the nudge is to plant an idea that leads to an action is pretty much the basis of a lot of these health care interventions, which seems like a small way to have a big impact at outcome,” Dr. Cho noted. “The behavioral science aspects of the nudges are also fascinating to me personally, and I think to a lot of the cardiologists in the audience – about how you actually get people to act. I think it’s been a lifelong question for people in general, how do you get people to follow through on an action?”

“So I found the fact that secondary gain from a cardiovascular health standpoint, but also the repeated nudges were sort of simple ways that you could have people take ownership and get their flu vaccination,” he said.

“This is ACC, this is a cardiovascular conference, but the influence of vaccine is not just a primary care problem, it is also directly affecting cardiovascular disease,” Dr. Cho concluded.

‘Small but important effect’

In an accompanying editorial (Lancet. 2023 Mar 5. doi: 10.1016/S0140-6736(23)00453-1), Melissa Stockwell, MD, Columbia University, New York, writes, “The study by Johansen and colleagues highlights the small but still important effect of scalable, digital interventions across an entire at-risk population.”

A difference of 0.89% in the entire study population of over 960,000 adults age 65 years or older would be more than 8,500 additional adults protected, she notes. “That increase is important for a scalable intervention that has a low cost per letter.”

Moreover, “that the cardiovascular gain–framed messages worked best in those who had not been vaccinated in the previous season further highlights the potential impact on a more vaccine-hesitant population,” Dr. Stockwell notes. 

However, with the mandatory government electronic notification system in Denmark, “notifications are sent via regular email and SMS message, and recipients log in through a portal or smartphone app to view the letter.” Similar studies in the United States that included this extra step of needing to sign in online have not been effective in older populations.

Another limitation is that the intervention may have a different effect in populations for which there is a digital divide between people with or without Internet access of sufficient data on their mobile phones.

First-of-its kind, nationwide pragmatic trial

The NUDGE-FLU protocol was previously published in the American Heart Journal. NUDGE-FLU is a first-of-its kind nationwide, pragmatic, registry-based, cluster-randomized implementation trial of electronically delivered nudges to increase influenza vaccination uptake, the researchers note.

They identified 964,870 individuals who were 65 years or older (or would turn 65 by Jan. 15, 2023) who lived in one of 691,820 households in Denmark.

This excluded individuals who lived in a nursing home or were exempt from the government’s mandatory electronic letter system that is used for official communications.

Households were randomly assigned 9:1:1:1:1:1:1:1:1:1 to receive usual care alone or to one of nine electronic letter strategies based on different behavioral science approaches to encourage influenza vaccination uptake:

• Standard electronic letter
• Standard electronic letter sent at randomization and again 14 days later (repeated letter)
• Depersonalized letter without the recipient’s name
• Gain-framing nudge (“Vaccinations help end pandemics, like COVID-19 and the flu. Protect yourself and your loved ones.”)
• Loss-framing nudge (“When too few people get vaccinated, pandemics from diseases like COVID-19 and the flu can spread and place you and your loved ones at risk.”)
• Collective-goal nudge (“78% of Danes 65 and above were vaccinated against influenza last year. Help us achieve an even higher goal this year.”)  
• Active choice or implementation-intention prompt (“We encourage you to record your appointment time here.”)
• Cardiovascular gain–framing nudge (“In addition to its protection against influenza infection, influenza vaccination also seems to protect against cardiovascular disease such as heart attacks and heart failure.”)
• Expert-authority statement (“I recommend everyone over the age of 65 years to get vaccinated against influenza – Tyra Grove Krause, Executive Vice President, Statens Serum Institut.”)

The electronic letters were sent out Sept. 16, 2022, and the primary endpoint was vaccine receipt on or before Jan. 1, 2023.

All individuals received an informative vaccination encouragement letter from the Danish Health Authority (usual care) delivered via the same electronic letter system during Sept. 17 through Sept. 21, 2022. 

The individuals had a mean age of 73.8 years, 51.5% were women, and 27.4% had chronic cardiovascular disease.

The analyses were done in one randomly selected individual per household.

Influenza vaccination rates were significantly higher in the cardiovascular gain–framing nudge group vs. usual care (81.00% vs. 80.12%; difference, 0.89 percentage points; P < .0001) and in the repeat-letter group vs. usual care (80.85% vs 80.12%; difference, 0.73 percentage points; P = .0006).

These two strategies also improved vaccination rates across major subgroups.

The cardiovascular gain–framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season.

The seven other letter strategies did not increase flu shot uptake.

Subanalysis in CVD

In the prespecified subanalysis of the NUDGE-FLU trial of patients aged 65 and older that focused on patients with CVD, Daniel Modin, MB, and colleagues report that 83.1% of patients with CVD vs. 79.2% of patients without CVD received influenza vaccination within the requested time (P < .0001).

The two nudging strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination or a repeat letter – that were effective in boosting flu shot rates in the main analysis were also effective in all major CVD subgroups (ischemic heart disease, pulmonary heart disease, heart failure, atrial fibrillation, cerebrovascular disease, atherosclerotic CVD, embolic or thrombotic disease, and congenital heart disease).

Despite strong guideline endorsement, “influenza vaccination rates remain suboptimal in patients with high-risk cardiovascular disease,” Dr. Morin and colleagues write, possibly because of “insufficient knowledge among patients and providers of potential clinical benefits, concerns about vaccine safety, and other forms of vaccine hesitancy.”

Their findings suggest that “select digital behaviorally informed nudges delivered in advance of vaccine availability might be utilized to increase influenza vaccinate uptake in individuals with cardiovascular disease.”

NUDGE-HF was funded by Sanofi. Dr. Johansen and Dr. Modin have no disclosures. The disclosures of the other authors are listed with the articles. Dr. Stockwell has no disclosures.

A version of this article first appeared on Medscape.com.

Two types of electronically delivered letter strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination and a repeat reminder letter – increased flu shot uptake, compared with usual care alone, in a national study of seniors in Denmark.

And in a prespecified subanalysis focusing on older adults with cardiovascular disease, these two strategies were also effective in boosting vaccine uptake in those with or without CVD.

The findings are from the Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU) trial, which compared usual care alone with one of nine different electronic letter “behavioral nudge” strategies during the 2022-2023 flu season in people aged 65 years and older.  

Pix by Marti/Fotolia

Niklas Dyrby Johansen, MD, Hospital–Herlev and Gentofte and Copenhagen University, presented the main study findings in a late-breaking clinical trial session at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, and the article was simultaneously published in The Lancet

The subanalysis in patients with CVD was published online March 5 in Circulation.

“Despite modest effect sizes, the results may have important implications when translated to a population level,” Dr. Dyrby Johansen concluded during his presentation. Still, the authors write, “the low-touch (no person-to-person interaction), inexpensive, and highly scalable nature of these electronic letters might have important population-level public health implications.”  

They note that, among approximately 63 million Medicare beneficiaries in the United States, a 0.89–percentage point absolute increase in vaccination rate achieved through the most successful electronic letter in NUDGE-FLU, the one highlighting cardiovascular gain, would be expected to lead to 500,000 additional vaccinations and potentially prevent 7,849 illnesses, 4,395 medical visits, 714 hospitalizations, and 66 deaths each year.

Electronic letter systems similar to the one used in this trial are already in place in several European countries, including Sweden, Norway, and Ireland, the researchers note.

In countries such as the United States, where implementing a nationwide government electronic letter system might not be feasible, nudges could be done via email, text message, or other systems, but whether this would be as effective remains to be seen.

Commenting on the findings, David Cho, MD, UCLA Health and chair of the ACC Health Care Innovation Council, commended the researchers on engaging patients with more than a million separate nudges sent out during one flu season, and randomly assigning participants to 10 different types of nudges, calling it “impressive.”

“I think the concept that the nudge is to plant an idea that leads to an action is pretty much the basis of a lot of these health care interventions, which seems like a small way to have a big impact at outcome,” Dr. Cho noted. “The behavioral science aspects of the nudges are also fascinating to me personally, and I think to a lot of the cardiologists in the audience – about how you actually get people to act. I think it’s been a lifelong question for people in general, how do you get people to follow through on an action?”

“So I found the fact that secondary gain from a cardiovascular health standpoint, but also the repeated nudges were sort of simple ways that you could have people take ownership and get their flu vaccination,” he said.

“This is ACC, this is a cardiovascular conference, but the influence of vaccine is not just a primary care problem, it is also directly affecting cardiovascular disease,” Dr. Cho concluded.

‘Small but important effect’

In an accompanying editorial (Lancet. 2023 Mar 5. doi: 10.1016/S0140-6736(23)00453-1), Melissa Stockwell, MD, Columbia University, New York, writes, “The study by Johansen and colleagues highlights the small but still important effect of scalable, digital interventions across an entire at-risk population.”

A difference of 0.89% in the entire study population of over 960,000 adults age 65 years or older would be more than 8,500 additional adults protected, she notes. “That increase is important for a scalable intervention that has a low cost per letter.”

Moreover, “that the cardiovascular gain–framed messages worked best in those who had not been vaccinated in the previous season further highlights the potential impact on a more vaccine-hesitant population,” Dr. Stockwell notes. 

However, with the mandatory government electronic notification system in Denmark, “notifications are sent via regular email and SMS message, and recipients log in through a portal or smartphone app to view the letter.” Similar studies in the United States that included this extra step of needing to sign in online have not been effective in older populations.

Another limitation is that the intervention may have a different effect in populations for which there is a digital divide between people with or without Internet access of sufficient data on their mobile phones.

First-of-its kind, nationwide pragmatic trial

The NUDGE-FLU protocol was previously published in the American Heart Journal. NUDGE-FLU is a first-of-its kind nationwide, pragmatic, registry-based, cluster-randomized implementation trial of electronically delivered nudges to increase influenza vaccination uptake, the researchers note.

They identified 964,870 individuals who were 65 years or older (or would turn 65 by Jan. 15, 2023) who lived in one of 691,820 households in Denmark.

This excluded individuals who lived in a nursing home or were exempt from the government’s mandatory electronic letter system that is used for official communications.

Households were randomly assigned 9:1:1:1:1:1:1:1:1:1 to receive usual care alone or to one of nine electronic letter strategies based on different behavioral science approaches to encourage influenza vaccination uptake:

• Standard electronic letter
• Standard electronic letter sent at randomization and again 14 days later (repeated letter)
• Depersonalized letter without the recipient’s name
• Gain-framing nudge (“Vaccinations help end pandemics, like COVID-19 and the flu. Protect yourself and your loved ones.”)
• Loss-framing nudge (“When too few people get vaccinated, pandemics from diseases like COVID-19 and the flu can spread and place you and your loved ones at risk.”)
• Collective-goal nudge (“78% of Danes 65 and above were vaccinated against influenza last year. Help us achieve an even higher goal this year.”)  
• Active choice or implementation-intention prompt (“We encourage you to record your appointment time here.”)
• Cardiovascular gain–framing nudge (“In addition to its protection against influenza infection, influenza vaccination also seems to protect against cardiovascular disease such as heart attacks and heart failure.”)
• Expert-authority statement (“I recommend everyone over the age of 65 years to get vaccinated against influenza – Tyra Grove Krause, Executive Vice President, Statens Serum Institut.”)

The electronic letters were sent out Sept. 16, 2022, and the primary endpoint was vaccine receipt on or before Jan. 1, 2023.

All individuals received an informative vaccination encouragement letter from the Danish Health Authority (usual care) delivered via the same electronic letter system during Sept. 17 through Sept. 21, 2022. 

The individuals had a mean age of 73.8 years, 51.5% were women, and 27.4% had chronic cardiovascular disease.

The analyses were done in one randomly selected individual per household.

Influenza vaccination rates were significantly higher in the cardiovascular gain–framing nudge group vs. usual care (81.00% vs. 80.12%; difference, 0.89 percentage points; P < .0001) and in the repeat-letter group vs. usual care (80.85% vs 80.12%; difference, 0.73 percentage points; P = .0006).

These two strategies also improved vaccination rates across major subgroups.

The cardiovascular gain–framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season.

The seven other letter strategies did not increase flu shot uptake.

Subanalysis in CVD

In the prespecified subanalysis of the NUDGE-FLU trial of patients aged 65 and older that focused on patients with CVD, Daniel Modin, MB, and colleagues report that 83.1% of patients with CVD vs. 79.2% of patients without CVD received influenza vaccination within the requested time (P < .0001).

The two nudging strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination or a repeat letter – that were effective in boosting flu shot rates in the main analysis were also effective in all major CVD subgroups (ischemic heart disease, pulmonary heart disease, heart failure, atrial fibrillation, cerebrovascular disease, atherosclerotic CVD, embolic or thrombotic disease, and congenital heart disease).

Despite strong guideline endorsement, “influenza vaccination rates remain suboptimal in patients with high-risk cardiovascular disease,” Dr. Morin and colleagues write, possibly because of “insufficient knowledge among patients and providers of potential clinical benefits, concerns about vaccine safety, and other forms of vaccine hesitancy.”

Their findings suggest that “select digital behaviorally informed nudges delivered in advance of vaccine availability might be utilized to increase influenza vaccinate uptake in individuals with cardiovascular disease.”

NUDGE-HF was funded by Sanofi. Dr. Johansen and Dr. Modin have no disclosures. The disclosures of the other authors are listed with the articles. Dr. Stockwell has no disclosures.

A version of this article first appeared on Medscape.com.

Two types of electronically delivered letter strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination and a repeat reminder letter – increased flu shot uptake, compared with usual care alone, in a national study of seniors in Denmark.

And in a prespecified subanalysis focusing on older adults with cardiovascular disease, these two strategies were also effective in boosting vaccine uptake in those with or without CVD.

The findings are from the Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU) trial, which compared usual care alone with one of nine different electronic letter “behavioral nudge” strategies during the 2022-2023 flu season in people aged 65 years and older.  

Pix by Marti/Fotolia

Niklas Dyrby Johansen, MD, Hospital–Herlev and Gentofte and Copenhagen University, presented the main study findings in a late-breaking clinical trial session at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, and the article was simultaneously published in The Lancet

The subanalysis in patients with CVD was published online March 5 in Circulation.

“Despite modest effect sizes, the results may have important implications when translated to a population level,” Dr. Dyrby Johansen concluded during his presentation. Still, the authors write, “the low-touch (no person-to-person interaction), inexpensive, and highly scalable nature of these electronic letters might have important population-level public health implications.”  

They note that, among approximately 63 million Medicare beneficiaries in the United States, a 0.89–percentage point absolute increase in vaccination rate achieved through the most successful electronic letter in NUDGE-FLU, the one highlighting cardiovascular gain, would be expected to lead to 500,000 additional vaccinations and potentially prevent 7,849 illnesses, 4,395 medical visits, 714 hospitalizations, and 66 deaths each year.

Electronic letter systems similar to the one used in this trial are already in place in several European countries, including Sweden, Norway, and Ireland, the researchers note.

In countries such as the United States, where implementing a nationwide government electronic letter system might not be feasible, nudges could be done via email, text message, or other systems, but whether this would be as effective remains to be seen.

Commenting on the findings, David Cho, MD, UCLA Health and chair of the ACC Health Care Innovation Council, commended the researchers on engaging patients with more than a million separate nudges sent out during one flu season, and randomly assigning participants to 10 different types of nudges, calling it “impressive.”

“I think the concept that the nudge is to plant an idea that leads to an action is pretty much the basis of a lot of these health care interventions, which seems like a small way to have a big impact at outcome,” Dr. Cho noted. “The behavioral science aspects of the nudges are also fascinating to me personally, and I think to a lot of the cardiologists in the audience – about how you actually get people to act. I think it’s been a lifelong question for people in general, how do you get people to follow through on an action?”

“So I found the fact that secondary gain from a cardiovascular health standpoint, but also the repeated nudges were sort of simple ways that you could have people take ownership and get their flu vaccination,” he said.

“This is ACC, this is a cardiovascular conference, but the influence of vaccine is not just a primary care problem, it is also directly affecting cardiovascular disease,” Dr. Cho concluded.

‘Small but important effect’

In an accompanying editorial (Lancet. 2023 Mar 5. doi: 10.1016/S0140-6736(23)00453-1), Melissa Stockwell, MD, Columbia University, New York, writes, “The study by Johansen and colleagues highlights the small but still important effect of scalable, digital interventions across an entire at-risk population.”

A difference of 0.89% in the entire study population of over 960,000 adults age 65 years or older would be more than 8,500 additional adults protected, she notes. “That increase is important for a scalable intervention that has a low cost per letter.”

Moreover, “that the cardiovascular gain–framed messages worked best in those who had not been vaccinated in the previous season further highlights the potential impact on a more vaccine-hesitant population,” Dr. Stockwell notes. 

However, with the mandatory government electronic notification system in Denmark, “notifications are sent via regular email and SMS message, and recipients log in through a portal or smartphone app to view the letter.” Similar studies in the United States that included this extra step of needing to sign in online have not been effective in older populations.

Another limitation is that the intervention may have a different effect in populations for which there is a digital divide between people with or without Internet access of sufficient data on their mobile phones.

First-of-its kind, nationwide pragmatic trial

The NUDGE-FLU protocol was previously published in the American Heart Journal. NUDGE-FLU is a first-of-its kind nationwide, pragmatic, registry-based, cluster-randomized implementation trial of electronically delivered nudges to increase influenza vaccination uptake, the researchers note.

They identified 964,870 individuals who were 65 years or older (or would turn 65 by Jan. 15, 2023) who lived in one of 691,820 households in Denmark.

This excluded individuals who lived in a nursing home or were exempt from the government’s mandatory electronic letter system that is used for official communications.

Households were randomly assigned 9:1:1:1:1:1:1:1:1:1 to receive usual care alone or to one of nine electronic letter strategies based on different behavioral science approaches to encourage influenza vaccination uptake:

• Standard electronic letter
• Standard electronic letter sent at randomization and again 14 days later (repeated letter)
• Depersonalized letter without the recipient’s name
• Gain-framing nudge (“Vaccinations help end pandemics, like COVID-19 and the flu. Protect yourself and your loved ones.”)
• Loss-framing nudge (“When too few people get vaccinated, pandemics from diseases like COVID-19 and the flu can spread and place you and your loved ones at risk.”)
• Collective-goal nudge (“78% of Danes 65 and above were vaccinated against influenza last year. Help us achieve an even higher goal this year.”)  
• Active choice or implementation-intention prompt (“We encourage you to record your appointment time here.”)
• Cardiovascular gain–framing nudge (“In addition to its protection against influenza infection, influenza vaccination also seems to protect against cardiovascular disease such as heart attacks and heart failure.”)
• Expert-authority statement (“I recommend everyone over the age of 65 years to get vaccinated against influenza – Tyra Grove Krause, Executive Vice President, Statens Serum Institut.”)

The electronic letters were sent out Sept. 16, 2022, and the primary endpoint was vaccine receipt on or before Jan. 1, 2023.

All individuals received an informative vaccination encouragement letter from the Danish Health Authority (usual care) delivered via the same electronic letter system during Sept. 17 through Sept. 21, 2022. 

The individuals had a mean age of 73.8 years, 51.5% were women, and 27.4% had chronic cardiovascular disease.

The analyses were done in one randomly selected individual per household.

Influenza vaccination rates were significantly higher in the cardiovascular gain–framing nudge group vs. usual care (81.00% vs. 80.12%; difference, 0.89 percentage points; P < .0001) and in the repeat-letter group vs. usual care (80.85% vs 80.12%; difference, 0.73 percentage points; P = .0006).

These two strategies also improved vaccination rates across major subgroups.

The cardiovascular gain–framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season.

The seven other letter strategies did not increase flu shot uptake.

Subanalysis in CVD

In the prespecified subanalysis of the NUDGE-FLU trial of patients aged 65 and older that focused on patients with CVD, Daniel Modin, MB, and colleagues report that 83.1% of patients with CVD vs. 79.2% of patients without CVD received influenza vaccination within the requested time (P < .0001).

The two nudging strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination or a repeat letter – that were effective in boosting flu shot rates in the main analysis were also effective in all major CVD subgroups (ischemic heart disease, pulmonary heart disease, heart failure, atrial fibrillation, cerebrovascular disease, atherosclerotic CVD, embolic or thrombotic disease, and congenital heart disease).

Despite strong guideline endorsement, “influenza vaccination rates remain suboptimal in patients with high-risk cardiovascular disease,” Dr. Morin and colleagues write, possibly because of “insufficient knowledge among patients and providers of potential clinical benefits, concerns about vaccine safety, and other forms of vaccine hesitancy.”

Their findings suggest that “select digital behaviorally informed nudges delivered in advance of vaccine availability might be utilized to increase influenza vaccinate uptake in individuals with cardiovascular disease.”

NUDGE-HF was funded by Sanofi. Dr. Johansen and Dr. Modin have no disclosures. The disclosures of the other authors are listed with the articles. Dr. Stockwell has no disclosures.

A version of this article first appeared on Medscape.com.