Patrice Wendling

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – The traditional Chinese herbal medicine tongxinluo added to guideline-directed therapy improves clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the CTS-AMI study suggests.

Compared with those assigned to placebo, Chinese patients assigned to tongxinluo had lower rates of 30-day and 1-year major adverse cardiovascular and cerebrovascular events (MACCE), driven by fewer cardiac deaths. Severe STEMI complications were also lower.

Tongxinluo, which contains 10 or more potential active herbs and insects, did not result in severe adverse effects, including major bleeding.

The results were presented at the American Heart Association scientific sessions by Yuejin Yang, MD, PhD, a professor of cardiology at Fuwai Hospital, National Center for CV Disease, Beijing.

He noted that despite reperfusion and optimal medical therapy, patients with STEMI still face high in-hospital mortality, myocardial no-flow, and reperfusion injury, which have no targeted drugs so far worldwide. In addition, “inadequate implementation of timely revascularization for STEMI in China (50-70%) and other developing countries leaves a substantial infarct size in many patients.”

Tongxinluo has been approved for angina and stroke since 1996 in China. Previous preclinical studies and the investigators’ proof-of-concept ENLEAT trial in STEMI suggested tongxinluo could reduce myocardial no-flow and infarction size and protect the cardiomyocytes, Dr. Yang said.

The CTS-AMI trial was conducted at 124 hospitals in mainland China and evenly randomly assigned 3,797 patients with STEMI or new left bundle-branch block within 24 hours of symptom onset to eight capsules of tongxinluo, 2.08 g, or to placebo plus dual antiplatelet therapy before percutaneous coronary intervention (PCI), thrombolysis, or medical management alone, followed by four capsules thrice daily plus guideline-directed therapy for 12 months.

In the modified intention-to-treat cohort of 1,889 tongxinluo- and 1,888 placebo-treated patients, primary PCI was performed in 94.2% and 92.3%, respectively.

The relative risk of 30-day MACCE was reduced 36% in the tongxinluo group, compared with the placebo group (3.39% vs. 5.24%; RR, 0.64; 95% confidence interval, 0.47-0.88).

Among the primary endpoint components, the relative risk of cardiac death was reduced 30% (2.97% vs. 4.24%; RR, 0.70; 95% CI, 0.50-0.99) and MI reinfarction 65% (0 vs. 9 events; RR, 0.35; 95% CI, 0.13-0.99).

Strokes were similar in the tongxinluo and control groups (4 vs. 9; RR, 0.44; 95% CI, 0.14-1.43) and no patient had emergent coronary revascularization at 30 days.

The benefit of the traditional Chinese compound on the primary endpoint was consistent across subgroups, Dr. Yang reported.

At 30 days, severe STEMI complications (11.79% vs. 14.80%; P = .008) and malignant arrhythmias (7.84% vs. 10.20%; P = .011) were lower in the tongxinluo group, whereas mechanical complications (10 vs. 13; P = .526) and cardiogenic shock (2.37% vs. 3.31%; P =.082) were similar.

At 1 year, hazard ratios favored tongxinluo for MACCE (0.64; 95% CI, 0.49-0.82), cardiac death (0.73; 95% CI, 0.55-0.97), MI reinfarction (0.26; 95% CI, 0.10-0.67), and stroke (0.44; 95% CI, 0.21-0.92).

In terms of safety issues, 41 patients receiving tongxinluo and 52 patients receiving placebo had a serious adverse event (2.17% vs. 2.75%; P = .25).

Except for fewer renal injuries with tongxinluo (3.81% vs. 5.30%; P = .029), there were no significant between-group differences in adverse effects including allergic rash, hepatic injury, prolonged activated partial thromboplastin time or prothrombin time, digestive tract hemorrhage, nausea, diarrhea, and headache or dizziness.

“These findings support the use of tongxinluo as an adjunctive therapy in treating STEMI, at least in China and other developing countries,” Dr. Yang concluded.

Invited discussant Kenneth Mahaffey, MD, associate dean, Stanford (Calif.) University, and director of the Stanford Center for Clinical Research, said the results “likely will support use of tongxinluo in China” but that “more studies are needed in other populations and treatment paradigms.”

Asked for further comment by this news organization, Dr. Mahaffey said, “The surprising thing is where are all the MIs? Where are all the revascularization procedures?”

Usually one would expect MIs in about 1% of patients, or about 40 MIs among the 4,000 patients but, he noted, there were zero MIs in the treatment group and 9 among controls.

“We haven’t seen a 30% reduction in cardiovascular death or overall mortality with a therapy in ages with good background therapy,” Dr. Mahaffey said. “We need to see how they ascertained all those events.”

He noted that the results were based on the modified intention-to-treat cohort, which did not include data on 20 patients allocated to treatment, and showed no difference in ST-segment resolution at 2 hours and only a slight difference at 24 hours.

“So even in this trial, for at least some of the data we’ve gotten already that supports the proposed mechanism, it doesn’t show the benefit on that mechanistic substudy. And that’s why we need to see these echoes, the biomarkers, and probably the angios to see: Did it have any effect on the proposed mechanism?” Dr. Mahaffey said.

Finally, information on background therapy is critical for putting the treatment effect into context for other health systems and populations, he said. “Unfortunately, we need to see some additional information to really understand how this will fit in, even in Chinese therapy for STEMI patients, but definitely not outside of China, particularly in the United States, because I don’t know what their background therapy was.”

The study was funded by the National Key Research and Development Program of China. Tongxinluo and placebo were provided by Yiling Pharmacological. The study was designed, conducted, and analyzed independent of the sponsors. Dr. Yang reports no relevant financial conflicts of interest. Dr. Mahaffey reports research funding from the AHA, Apple, Bayer, CIRM, Eidos, Ferring, Gilead, Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, Sanifit, and Verily; consultancy fees from Amgen, Applied Therapeutics, AstraZeneca, CLS Behring, Elsevier, Fibrogen, Inova, Johnson & Johnson, Lexicon, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Sanofi, and Theravance; and equity in Precordior.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

CHICAGO – Treatment with the investigational CRISPR-Cas9 gene-editing therapy, NTLA-2001, led to rapid responses in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), interim phase 1 results show.

Serum levels of the disease-causing TTR protein were reduced by at least 90% at day 28 with a single infusion of NTLA-2001 at two different doses, with reductions sustained across 4-6 months’ follow-up.

NTLA-2001 was generally well-tolerated, and the results were similar in patients with New York Heart Association (NYHA) class I-III heart failure.

“These data further support and extend the early findings demonstrating the promise of CRISPR-based in vivo genome editing in humans,” said Julian Gillmore, MD, PhD, MBBS, who is leading the study at University College London.

“More specifically, the deep TTR reductions observed in patients with ATTR amyloidosis in this study provide a real possibility of genuine clinical improvement in a condition that has hitherto been ultimately progressive and invariably fatal,” he said.

The results were reported in a late-breaking session at the American Heart Association scientific sessions.

Mutations in the TTR gene and age-related changes in the stability of the TTR protein can cause misfolding of the TTR protein, resulting in amyloid deposits in skin and myocardial tissues.

An estimated 50,000 people worldwide are thought to have hereditary ATTR and up to 500,000 to have wild-type ATTR amyloidosis. Amyloid cardiomyopathy is underdiagnosed and fatal in 3-10 years without treatment. Current treatment options only slow progression and require lifelong administration, he said.

Results reported last year from the polyneuropathy arm of the study were hailed as a breakthrough and further proof-of-concept that CRISPR could be used to treat other diseases

CRISPR gene editing has shown success, for example, in beta-thalassemia and sickle cell disease but involved stem cells extracted from patients’ bone marrow, edited in the lab, and then replaced.

NTLA-2001 (Intellia Therapeutics/Regeneron) is an in vivo treatment that uses lipid nanoparticles containing messenger RNA for Cas9 and a single-guide RNA targeting TTR in the liver, where it’s almost exclusively produced.

The new analysis included 12 patients with heart failure: 3 in NYHA  class I-II and 6 in NYHA class III who received a single dose of NTLA-2001 at 0.7 mg/kg, while the remaining 3 patients in NYHA class I-II received a single dose of 1.0 mg/kg.

During follow-up out to 6 months, TTR reductions averaged:

• 93% in the 0.7 mg/kg NYHA I-II group at 6 months.
• 94% in the 0.7 mg/kg NYHA III group at 4 months.
• 92% in the 1.0 mg/kg NYHA I-II group at 4 months.

Eight patients reported mild or moderate adverse events, and two patients experienced transient infusion reactions, including one grade 3 reaction in the 0.7 mg/kg NYHA class III group that resolved without clinical consequence. This group was expanded to six patients per study protocol. No additional treatment-related adverse events higher than grade 1 were reported, and no further dose escalation was undertaken, Dr. Gillmore reported.

There were no clinically relevant laboratory findings; one patient had a transient grade 1 liver enzyme elevation.

One disadvantage of CRISPR is the potential for off-target effects, but Dr. Gillmore said in an interview that the drug developers went through a “very rigorous process when selecting the guide RNA, which is what really targets the specificity of the TTR gene.”

“That’s a really, really important point,” he said. “When they did various studies using, for example, primary human hepatocytes, they found no evidence of off-target editing at concentrations of NTLA-2001 threefold greater than the EC90, the concentration at which one knocks down the protein by 90%. So, what we can say at the moment, is the specificity of NTLA-2001 for the TTR gene seems to be absolute.”

In terms of other challenges going forward, Dr. Gillmore added, “I think that it’s really to see whether the knockdown that is being achieved is going to translate into greater clinical benefit.”

Invited discussant Kevin M. Alexander, MD, of Stanford (Calif.) University, said therapies that stabilize or reduce TTR have recently emerged that have improved ATTR amyloidosis outcomes, including tafamidis and patisiran.

Nevertheless, there has been an unmet need to develop therapies that can halt or reverse disease, are effective in advanced ATTR, and have an improved route or frequency of administration, given that this is a chronic disease, he said.

Dr. Alexander noted that the reductions of greater than 90% were achieved with higher doses than used in the polyneuropathy arm reported last year but were well tolerated in patients that for the most part had wild-type ATTR (83%) and reflect the wild-type ATTR population in practice. “The data support consideration for subsequent efficacy trials for this compound.”

Unanswered questions in ongoing ATTR trials are whether TTR reductions translate into improved clinical outcomes, the long-term safety of TTR lowering, and the efficacy of NTLA-2001, particularly in higher-risk patients, such as those in NYHA class III and those with hereditary ATTR, Dr. Alexander said.

During a media briefing earlier in the day, invited discussant Kiran Musunuru, MD, University of Pennsylvania, Philadelphia, pointed out that, in the recent APOLLO-B trial of patisiran, patients with ATTR amyloidosis with cardiomyopathy had an average 87% TTR reduction but need intravenous infusions every 3 weeks for the rest of their lives.

“In contrast, gene editing is a one-and-done proposition,” he said. “You receive a single treatment that turns off the TTR gene permanently and the effects are durable and likely last a lifetime.”

Dr. Musunuru noted that patients who received patisiran also had significantly and substantially better functional capacity and quality of life, compared with those who received placebo. “Based on today’s results, we can expect future clinical trials for gene editing to have the same beneficial effects and possibly a mortality benefit as well.”

Today’s study is also important because it is part of the first wave of putting CRISPR into the body for an array of diseases, he commented.

“TTR gene editing stands out because it’s the very first CRISPR trial to show unequivocal success – you see that with a greater than 90% reduction in TTR,” Dr. Musunuru said. “So, in my view that makes it a milestone for modern medicine.”

Dosing at 55 mg, corresponding to a fixed 0.7 mg/kg dose, is ongoing in the dose-expansion portion of the trial, with enrollment across both arms expected to be completed by the end of 2022, Intellia Therapeutics reported.

The study was funded by Intellia Therapeutics and Regeneron Pharmaceuticals. Dr. Gillmore reports receiving consultancy fees from Alnylam, Ionis, AstraZeneca, Pfizer, Intellia, ATTRalus, and Novo Nordisk and has received grant support from Alnylam Pharmaceuticals. Dr. Alexander reports serving on advisory boards for Almylam and Arbor Biotechnologies; has consulted  for Eidos, Ionis, Novo Nordisk, and Pfizer; and has received grants from AHA, Alnylam, Eidos, and the National Institutes of Health.

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

Most hospitals in the United States have yet to transition from conventional to high-sensitivity cardiac troponin (hs-cTn) assays, despite their greater sensitivity for myocardial injury, a new National Cardiovascular Data Registry (NCDR) registry study indicates.

hs-cTn assays have been used in routine clinical practice in Europe, Canada, and Australia since 2010, but the first such assay did not gain approval in the United States until 2017. Although single-center studies have examined their efficacy and potential downstream consequences, few data exist on hs-cTn implementation nationally, explained study author Cian McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston.

The results were published online in the Journal of the American College of Cardiology and will be presented Nov. 5 at the American Heart Association scientific sessions.

For the study, Dr. McCarthy and colleagues examined 550 hospitals participating in the NCDR Chest Pain-MI registry from January 2019 through September 2021.

Of the 251,000 patients included in the analysis (mean age, 64 years; 41.5% female), 155,049 had a non–ST-segment myocardial infarction (NSTEMI), 15,989 had unstable angina, and 79,962 had low-risk chest pain.

The hs-cTn assays included Roche Diagnostic’s Elecsys Gen5 STAT troponin T assay (23%); Abbott’s ARCHITECT STAT (17%); Beckman Coulter’s ACCESS (21%); and Siemens’ Atellica IM (18%), Dimension VISTA (14%), Dimension EXL (4%), and ADVIA Centaur (2%) troponin I assays.

During the study period, 11.5% of patients were evaluated with hs-cTn assays and the remainder were evaluated with conventional troponin assays. These patients were slightly older (65.0 vs. 64.0 years), more commonly White (83.1% vs. 79.9%), less likely to be of Hispanic or Latino ethnicity (8.9% vs. 10.0%), and less likely to be uninsured (6.8% vs. 8.3%; P for all < .001).

A slightly higher proportion of patients evaluated with hs-cTn assays were diagnosed with unstable angina (7.1% vs. 6.3%), a lower proportion with NSTEMI (61.1% vs. 61.9%), and a similar proportion with low-risk chest pain (31.8% vs. 31.9%) compared with those evaluated by conventional troponin assays.

Implementation, defined as at least 25% of patients evaluated by hs-cTn in each quarter, increased from 3.3% in the first quarter of 2019 to 32.6% in the third quarter of 2021 (P trend < .001).

Using higher implementation thresholds of at least 50% and 75% of patients evaluated by hs-cTn, the prevalence in 2021 was 28.9% and 24.7%, respectively.

“So still, the majority of the hospitals by the end of the third quarter 2021 were not using these assays,” Dr. McCarthy said.

Potential explanations for the slow uptake are that prospective comparative effectiveness trials of These assays have predominantly been in international populations and real-world data on U.S. implementation have been limited to integrated health networks at academic institutions.

Approval of several assays was also delayed and the study data cut off just before the October publication of the 2021 AHA/ACC Chest Pain guideline. “So, whether the chest pain guideline with the new class 1 recommendation for hs-cTn will lead to further uptake is something that will need to be looked at in the future,” he said.
 

Downstream testing

In adjusted analyses, hs-cTn use was associated with more echocardiography among patients with non-ST elevation–acute coronary syndrome (NSTE-ACS) (82.4% vs. 75.0%; odds ratio [OR], 1.43; 95% confidence interval [CI], 1.19-1.73), but not among those with low-risk chest pain (19.7% vs. 19.4%; OR, 0.93; 95% CI, 0.71-1.22) compared with conventional cTn assays.

Importantly, hs-cTn was not associated with a difference in stress testing or CT coronary angiography utilization.

Use of hs-cTn was associated with lower use of invasive coronary angiography among patients with low-risk chest pain (3.7% vs. 4.5%; OR, 0.73, 95% CI, 0.58-0.92) but similar use for NSTE-ACS (96.3% vs. 95.8%; OR, 0.99, 95% CI, 0.82-1.19).

Among patients with NSTE-ACS, there also was no difference in revascularization with percutaneous coronary intervention (PCI) (52.7% vs. 52.3%; OR, 0.99; 95% CI, 0.94-1.04) or coronary bypass graft surgery (9.4% vs. 9.1%; OR, 1.06; 95% CI, 0.94-1.18).

PCI (0.1% vs. 0.2%; P = .05) and bypass graft surgery (both 0.1%) were uncommon among patients with low-risk chest pain.

In-hospital mortality was similar among patients with low-risk chest pain evaluated using hs-cTn assays vs. conventional troponin assays (0% vs. 0.02%; P = .16) and among patients with NSTE-ACS (2.8% vs. 3.2%; OR, 0.98, 95% CI, 0.87-1.11).

Length of stay was slightly shorter with hs-cTn use for patients with low-risk chest pain (median, 5.8 vs. 6.2 hours; P < .001) and patients with NSTE-ACS (66.9 vs. 67.8 hours; P = .01).

“There was always a concern that maybe high-sensitivity cardiac troponin would dramatically increase testing and could even increase length of stay, but I think these data are reassuring, in that this study suggests high-sensitivity cardiac troponin is associated with a small reduction in length of stay and possibly more appropriate use of testing with echocardiography in STEMI and a reduction in invasive angiography in low-risk patients,” Dr. McCarthy said. “But the majority of hospitals haven’t implemented the assay.”

The authors pointed out that because registry entry of patients with low-risk chest pain and unstable angina is optional for participating sites, the percentage of patients with NSTEMI is higher than in typical chest pain analyses. This higher pretest probability for MI may thus affect post-test accuracy for a true positive result. “That stated, this is the exact scenario where higher sensitivity might be associated with favorable impact on utilization.”

Among other limitations: There was the potential for unmeasured confounders, the accuracy of diagnoses could not be confirmed, patients with type 2 MI were excluded from the registry, and post-discharge safety was not assessed.

“These data indicate further opportunities to more widely and effectively implement hs-cTn in the U.S. hospitals persist that could optimize care for patients with possible or definitive ACS,” Dr. McCarthy and colleagues concluded.

The study was funded by the American College of Cardiology’s National Cardiovascular Data Registry. Dr. McCarthy is supported by the National Heart, Lung, and Blood Institute and has received consulting income from Abbott Laboratories.

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

Most hospitals in the United States have yet to transition from conventional to high-sensitivity cardiac troponin (hs-cTn) assays, despite their greater sensitivity for myocardial injury, a new National Cardiovascular Data Registry (NCDR) registry study indicates.

hs-cTn assays have been used in routine clinical practice in Europe, Canada, and Australia since 2010, but the first such assay did not gain approval in the United States until 2017. Although single-center studies have examined their efficacy and potential downstream consequences, few data exist on hs-cTn implementation nationally, explained study author Cian McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston.

The results were published online in the Journal of the American College of Cardiology and will be presented Nov. 5 at the American Heart Association scientific sessions.

For the study, Dr. McCarthy and colleagues examined 550 hospitals participating in the NCDR Chest Pain-MI registry from January 2019 through September 2021.

Of the 251,000 patients included in the analysis (mean age, 64 years; 41.5% female), 155,049 had a non–ST-segment myocardial infarction (NSTEMI), 15,989 had unstable angina, and 79,962 had low-risk chest pain.

The hs-cTn assays included Roche Diagnostic’s Elecsys Gen5 STAT troponin T assay (23%); Abbott’s ARCHITECT STAT (17%); Beckman Coulter’s ACCESS (21%); and Siemens’ Atellica IM (18%), Dimension VISTA (14%), Dimension EXL (4%), and ADVIA Centaur (2%) troponin I assays.

During the study period, 11.5% of patients were evaluated with hs-cTn assays and the remainder were evaluated with conventional troponin assays. These patients were slightly older (65.0 vs. 64.0 years), more commonly White (83.1% vs. 79.9%), less likely to be of Hispanic or Latino ethnicity (8.9% vs. 10.0%), and less likely to be uninsured (6.8% vs. 8.3%; P for all < .001).

A slightly higher proportion of patients evaluated with hs-cTn assays were diagnosed with unstable angina (7.1% vs. 6.3%), a lower proportion with NSTEMI (61.1% vs. 61.9%), and a similar proportion with low-risk chest pain (31.8% vs. 31.9%) compared with those evaluated by conventional troponin assays.

Implementation, defined as at least 25% of patients evaluated by hs-cTn in each quarter, increased from 3.3% in the first quarter of 2019 to 32.6% in the third quarter of 2021 (P trend < .001).

Using higher implementation thresholds of at least 50% and 75% of patients evaluated by hs-cTn, the prevalence in 2021 was 28.9% and 24.7%, respectively.

“So still, the majority of the hospitals by the end of the third quarter 2021 were not using these assays,” Dr. McCarthy said.

Potential explanations for the slow uptake are that prospective comparative effectiveness trials of These assays have predominantly been in international populations and real-world data on U.S. implementation have been limited to integrated health networks at academic institutions.

Approval of several assays was also delayed and the study data cut off just before the October publication of the 2021 AHA/ACC Chest Pain guideline. “So, whether the chest pain guideline with the new class 1 recommendation for hs-cTn will lead to further uptake is something that will need to be looked at in the future,” he said.
 

Downstream testing

In adjusted analyses, hs-cTn use was associated with more echocardiography among patients with non-ST elevation–acute coronary syndrome (NSTE-ACS) (82.4% vs. 75.0%; odds ratio [OR], 1.43; 95% confidence interval [CI], 1.19-1.73), but not among those with low-risk chest pain (19.7% vs. 19.4%; OR, 0.93; 95% CI, 0.71-1.22) compared with conventional cTn assays.

Importantly, hs-cTn was not associated with a difference in stress testing or CT coronary angiography utilization.

Use of hs-cTn was associated with lower use of invasive coronary angiography among patients with low-risk chest pain (3.7% vs. 4.5%; OR, 0.73, 95% CI, 0.58-0.92) but similar use for NSTE-ACS (96.3% vs. 95.8%; OR, 0.99, 95% CI, 0.82-1.19).

Among patients with NSTE-ACS, there also was no difference in revascularization with percutaneous coronary intervention (PCI) (52.7% vs. 52.3%; OR, 0.99; 95% CI, 0.94-1.04) or coronary bypass graft surgery (9.4% vs. 9.1%; OR, 1.06; 95% CI, 0.94-1.18).

PCI (0.1% vs. 0.2%; P = .05) and bypass graft surgery (both 0.1%) were uncommon among patients with low-risk chest pain.

In-hospital mortality was similar among patients with low-risk chest pain evaluated using hs-cTn assays vs. conventional troponin assays (0% vs. 0.02%; P = .16) and among patients with NSTE-ACS (2.8% vs. 3.2%; OR, 0.98, 95% CI, 0.87-1.11).

Length of stay was slightly shorter with hs-cTn use for patients with low-risk chest pain (median, 5.8 vs. 6.2 hours; P < .001) and patients with NSTE-ACS (66.9 vs. 67.8 hours; P = .01).

“There was always a concern that maybe high-sensitivity cardiac troponin would dramatically increase testing and could even increase length of stay, but I think these data are reassuring, in that this study suggests high-sensitivity cardiac troponin is associated with a small reduction in length of stay and possibly more appropriate use of testing with echocardiography in STEMI and a reduction in invasive angiography in low-risk patients,” Dr. McCarthy said. “But the majority of hospitals haven’t implemented the assay.”

The authors pointed out that because registry entry of patients with low-risk chest pain and unstable angina is optional for participating sites, the percentage of patients with NSTEMI is higher than in typical chest pain analyses. This higher pretest probability for MI may thus affect post-test accuracy for a true positive result. “That stated, this is the exact scenario where higher sensitivity might be associated with favorable impact on utilization.”

Among other limitations: There was the potential for unmeasured confounders, the accuracy of diagnoses could not be confirmed, patients with type 2 MI were excluded from the registry, and post-discharge safety was not assessed.

“These data indicate further opportunities to more widely and effectively implement hs-cTn in the U.S. hospitals persist that could optimize care for patients with possible or definitive ACS,” Dr. McCarthy and colleagues concluded.

The study was funded by the American College of Cardiology’s National Cardiovascular Data Registry. Dr. McCarthy is supported by the National Heart, Lung, and Blood Institute and has received consulting income from Abbott Laboratories.

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

Most hospitals in the United States have yet to transition from conventional to high-sensitivity cardiac troponin (hs-cTn) assays, despite their greater sensitivity for myocardial injury, a new National Cardiovascular Data Registry (NCDR) registry study indicates.

hs-cTn assays have been used in routine clinical practice in Europe, Canada, and Australia since 2010, but the first such assay did not gain approval in the United States until 2017. Although single-center studies have examined their efficacy and potential downstream consequences, few data exist on hs-cTn implementation nationally, explained study author Cian McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston.

The results were published online in the Journal of the American College of Cardiology and will be presented Nov. 5 at the American Heart Association scientific sessions.

For the study, Dr. McCarthy and colleagues examined 550 hospitals participating in the NCDR Chest Pain-MI registry from January 2019 through September 2021.

Of the 251,000 patients included in the analysis (mean age, 64 years; 41.5% female), 155,049 had a non–ST-segment myocardial infarction (NSTEMI), 15,989 had unstable angina, and 79,962 had low-risk chest pain.

The hs-cTn assays included Roche Diagnostic’s Elecsys Gen5 STAT troponin T assay (23%); Abbott’s ARCHITECT STAT (17%); Beckman Coulter’s ACCESS (21%); and Siemens’ Atellica IM (18%), Dimension VISTA (14%), Dimension EXL (4%), and ADVIA Centaur (2%) troponin I assays.

During the study period, 11.5% of patients were evaluated with hs-cTn assays and the remainder were evaluated with conventional troponin assays. These patients were slightly older (65.0 vs. 64.0 years), more commonly White (83.1% vs. 79.9%), less likely to be of Hispanic or Latino ethnicity (8.9% vs. 10.0%), and less likely to be uninsured (6.8% vs. 8.3%; P for all < .001).

A slightly higher proportion of patients evaluated with hs-cTn assays were diagnosed with unstable angina (7.1% vs. 6.3%), a lower proportion with NSTEMI (61.1% vs. 61.9%), and a similar proportion with low-risk chest pain (31.8% vs. 31.9%) compared with those evaluated by conventional troponin assays.

Implementation, defined as at least 25% of patients evaluated by hs-cTn in each quarter, increased from 3.3% in the first quarter of 2019 to 32.6% in the third quarter of 2021 (P trend < .001).

Using higher implementation thresholds of at least 50% and 75% of patients evaluated by hs-cTn, the prevalence in 2021 was 28.9% and 24.7%, respectively.

“So still, the majority of the hospitals by the end of the third quarter 2021 were not using these assays,” Dr. McCarthy said.

Potential explanations for the slow uptake are that prospective comparative effectiveness trials of These assays have predominantly been in international populations and real-world data on U.S. implementation have been limited to integrated health networks at academic institutions.

Approval of several assays was also delayed and the study data cut off just before the October publication of the 2021 AHA/ACC Chest Pain guideline. “So, whether the chest pain guideline with the new class 1 recommendation for hs-cTn will lead to further uptake is something that will need to be looked at in the future,” he said.
 

Downstream testing

In adjusted analyses, hs-cTn use was associated with more echocardiography among patients with non-ST elevation–acute coronary syndrome (NSTE-ACS) (82.4% vs. 75.0%; odds ratio [OR], 1.43; 95% confidence interval [CI], 1.19-1.73), but not among those with low-risk chest pain (19.7% vs. 19.4%; OR, 0.93; 95% CI, 0.71-1.22) compared with conventional cTn assays.

Importantly, hs-cTn was not associated with a difference in stress testing or CT coronary angiography utilization.

Use of hs-cTn was associated with lower use of invasive coronary angiography among patients with low-risk chest pain (3.7% vs. 4.5%; OR, 0.73, 95% CI, 0.58-0.92) but similar use for NSTE-ACS (96.3% vs. 95.8%; OR, 0.99, 95% CI, 0.82-1.19).

Among patients with NSTE-ACS, there also was no difference in revascularization with percutaneous coronary intervention (PCI) (52.7% vs. 52.3%; OR, 0.99; 95% CI, 0.94-1.04) or coronary bypass graft surgery (9.4% vs. 9.1%; OR, 1.06; 95% CI, 0.94-1.18).

PCI (0.1% vs. 0.2%; P = .05) and bypass graft surgery (both 0.1%) were uncommon among patients with low-risk chest pain.

In-hospital mortality was similar among patients with low-risk chest pain evaluated using hs-cTn assays vs. conventional troponin assays (0% vs. 0.02%; P = .16) and among patients with NSTE-ACS (2.8% vs. 3.2%; OR, 0.98, 95% CI, 0.87-1.11).

Length of stay was slightly shorter with hs-cTn use for patients with low-risk chest pain (median, 5.8 vs. 6.2 hours; P < .001) and patients with NSTE-ACS (66.9 vs. 67.8 hours; P = .01).

“There was always a concern that maybe high-sensitivity cardiac troponin would dramatically increase testing and could even increase length of stay, but I think these data are reassuring, in that this study suggests high-sensitivity cardiac troponin is associated with a small reduction in length of stay and possibly more appropriate use of testing with echocardiography in STEMI and a reduction in invasive angiography in low-risk patients,” Dr. McCarthy said. “But the majority of hospitals haven’t implemented the assay.”

The authors pointed out that because registry entry of patients with low-risk chest pain and unstable angina is optional for participating sites, the percentage of patients with NSTEMI is higher than in typical chest pain analyses. This higher pretest probability for MI may thus affect post-test accuracy for a true positive result. “That stated, this is the exact scenario where higher sensitivity might be associated with favorable impact on utilization.”

Among other limitations: There was the potential for unmeasured confounders, the accuracy of diagnoses could not be confirmed, patients with type 2 MI were excluded from the registry, and post-discharge safety was not assessed.

“These data indicate further opportunities to more widely and effectively implement hs-cTn in the U.S. hospitals persist that could optimize care for patients with possible or definitive ACS,” Dr. McCarthy and colleagues concluded.

The study was funded by the American College of Cardiology’s National Cardiovascular Data Registry. Dr. McCarthy is supported by the National Heart, Lung, and Blood Institute and has received consulting income from Abbott Laboratories.

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

A new study shows that Black Americans received ventricular assist devices (VADs) and heart transplants about half as often as White Americans, even when receiving care at an advanced heart failure (HF) center.

The analysis, drawn from 377 patients treated at one of 21 VAD centers in the United States as part of the RIVIVAL study, found that 22.3% of White adults received a heart transplant or VAD, compared with 11% of Black adults.

“That’s what is so concerning to us, that we’re seeing this pattern within this select population. I think it would be too reasonable to hypothesize that it very well could be worse in the general population,” study author Thomas Cascino, MD, MSc, University of Michigan, Ann Arbor, commented.

The study was published online in Circulation: Heart Failure, and it builds on previous work by the researchers, showing that patient preference for early VAD therapy is associated with higher New York Heart Association (NYHA) class and lower income level but not race.

In the present analysis, the number of Black and White participants who said they “definitely or probably” wanted VAD therapy was similar (27% vs. 29%), as was the number wanting “any and all life-sustaining therapies” (74% vs. 65%).

Two-thirds of the cohort was NYHA class III, the average EuroQoL visual analog scale (EQ-VAS) score was 64.6 among the 100 participants who identified as Black and 62.1 in the 277 White participants, and the average age was 58 and 61 years, respectively.

Death rates were also similar during the 2-year follow-up: 18% of Black patients and 13% of White patients.

After controlling for multiple clinical and social determinants of health, including age, Interagency Registry for Mechanically Assisted Circulator Support (INTERMACS) patient profile, EQ-VAS score, and level of education, Black participants had a 55% lower rate of VAD or transplant, compared with White participants (hazard ratio, 0.45; 95% confidence interval, 0.23-0.85). Adding VAD preference to the model did not affect the association.

“Our study suggests that we as providers may be making decisions differently,” Dr. Cascino said. “We can’t say for sure what the reasons are but certainly structural racism, discrimination, and provider biases are the things I worry about.”

“There’s an absolute need for us to look inwards, reflect, and acknowledge that we are likely playing a role in this and then start to be part of the change,” he added.

“The lives disabled or lost are simply too many,” coauthor Wendy Taddei-Peters, PhD, a clinical trials project official at the National Heart, Lung, and Blood Institute, said in an NIH statement. “An immediate step could be to require implicit bias training, particularly for transplant and VAD team members.”

Other suggestions are better tracking of underserved patients and the reasons why they do not receive VAD or become listed for transplant; inclusion of psychosocial components into decision-making about advanced therapy candidacy; and having “disparity experts” join in heart team meetings to help identify biases in real time.

Commenting on the study, Khadijah Breathett, MD, HF/transplant cardiologist and tenured associate professor of medicine, Indiana University Bloomington, said, “I’m glad there’s more push for awareness, because there’s still a population of people that don’t believe this is a real problem.”

Breathett_Khadijah_AZ_web.jpg

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

A new study shows that Black Americans received ventricular assist devices (VADs) and heart transplants about half as often as White Americans, even when receiving care at an advanced heart failure (HF) center.

The analysis, drawn from 377 patients treated at one of 21 VAD centers in the United States as part of the RIVIVAL study, found that 22.3% of White adults received a heart transplant or VAD, compared with 11% of Black adults.

“That’s what is so concerning to us, that we’re seeing this pattern within this select population. I think it would be too reasonable to hypothesize that it very well could be worse in the general population,” study author Thomas Cascino, MD, MSc, University of Michigan, Ann Arbor, commented.

The study was published online in Circulation: Heart Failure, and it builds on previous work by the researchers, showing that patient preference for early VAD therapy is associated with higher New York Heart Association (NYHA) class and lower income level but not race.

In the present analysis, the number of Black and White participants who said they “definitely or probably” wanted VAD therapy was similar (27% vs. 29%), as was the number wanting “any and all life-sustaining therapies” (74% vs. 65%).

Two-thirds of the cohort was NYHA class III, the average EuroQoL visual analog scale (EQ-VAS) score was 64.6 among the 100 participants who identified as Black and 62.1 in the 277 White participants, and the average age was 58 and 61 years, respectively.

Death rates were also similar during the 2-year follow-up: 18% of Black patients and 13% of White patients.

After controlling for multiple clinical and social determinants of health, including age, Interagency Registry for Mechanically Assisted Circulator Support (INTERMACS) patient profile, EQ-VAS score, and level of education, Black participants had a 55% lower rate of VAD or transplant, compared with White participants (hazard ratio, 0.45; 95% confidence interval, 0.23-0.85). Adding VAD preference to the model did not affect the association.

“Our study suggests that we as providers may be making decisions differently,” Dr. Cascino said. “We can’t say for sure what the reasons are but certainly structural racism, discrimination, and provider biases are the things I worry about.”

“There’s an absolute need for us to look inwards, reflect, and acknowledge that we are likely playing a role in this and then start to be part of the change,” he added.

“The lives disabled or lost are simply too many,” coauthor Wendy Taddei-Peters, PhD, a clinical trials project official at the National Heart, Lung, and Blood Institute, said in an NIH statement. “An immediate step could be to require implicit bias training, particularly for transplant and VAD team members.”

Other suggestions are better tracking of underserved patients and the reasons why they do not receive VAD or become listed for transplant; inclusion of psychosocial components into decision-making about advanced therapy candidacy; and having “disparity experts” join in heart team meetings to help identify biases in real time.

Commenting on the study, Khadijah Breathett, MD, HF/transplant cardiologist and tenured associate professor of medicine, Indiana University Bloomington, said, “I’m glad there’s more push for awareness, because there’s still a population of people that don’t believe this is a real problem.”

Breathett_Khadijah_AZ_web.jpg

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

A new study shows that Black Americans received ventricular assist devices (VADs) and heart transplants about half as often as White Americans, even when receiving care at an advanced heart failure (HF) center.

The analysis, drawn from 377 patients treated at one of 21 VAD centers in the United States as part of the RIVIVAL study, found that 22.3% of White adults received a heart transplant or VAD, compared with 11% of Black adults.

“That’s what is so concerning to us, that we’re seeing this pattern within this select population. I think it would be too reasonable to hypothesize that it very well could be worse in the general population,” study author Thomas Cascino, MD, MSc, University of Michigan, Ann Arbor, commented.

The study was published online in Circulation: Heart Failure, and it builds on previous work by the researchers, showing that patient preference for early VAD therapy is associated with higher New York Heart Association (NYHA) class and lower income level but not race.

In the present analysis, the number of Black and White participants who said they “definitely or probably” wanted VAD therapy was similar (27% vs. 29%), as was the number wanting “any and all life-sustaining therapies” (74% vs. 65%).

Two-thirds of the cohort was NYHA class III, the average EuroQoL visual analog scale (EQ-VAS) score was 64.6 among the 100 participants who identified as Black and 62.1 in the 277 White participants, and the average age was 58 and 61 years, respectively.

Death rates were also similar during the 2-year follow-up: 18% of Black patients and 13% of White patients.

After controlling for multiple clinical and social determinants of health, including age, Interagency Registry for Mechanically Assisted Circulator Support (INTERMACS) patient profile, EQ-VAS score, and level of education, Black participants had a 55% lower rate of VAD or transplant, compared with White participants (hazard ratio, 0.45; 95% confidence interval, 0.23-0.85). Adding VAD preference to the model did not affect the association.

“Our study suggests that we as providers may be making decisions differently,” Dr. Cascino said. “We can’t say for sure what the reasons are but certainly structural racism, discrimination, and provider biases are the things I worry about.”

“There’s an absolute need for us to look inwards, reflect, and acknowledge that we are likely playing a role in this and then start to be part of the change,” he added.

“The lives disabled or lost are simply too many,” coauthor Wendy Taddei-Peters, PhD, a clinical trials project official at the National Heart, Lung, and Blood Institute, said in an NIH statement. “An immediate step could be to require implicit bias training, particularly for transplant and VAD team members.”

Other suggestions are better tracking of underserved patients and the reasons why they do not receive VAD or become listed for transplant; inclusion of psychosocial components into decision-making about advanced therapy candidacy; and having “disparity experts” join in heart team meetings to help identify biases in real time.

Commenting on the study, Khadijah Breathett, MD, HF/transplant cardiologist and tenured associate professor of medicine, Indiana University Bloomington, said, “I’m glad there’s more push for awareness, because there’s still a population of people that don’t believe this is a real problem.”

Breathett_Khadijah_AZ_web.jpg

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

Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.

COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.

drug_pills_web.jpg

“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.

“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”

The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.

It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.

Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.

“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.

When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.

For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.

Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.

Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.

While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.

“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”

Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.

The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.

Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.

“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.

“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”

The authors reported no relevant financial relationships.

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

Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.

COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.

drug_pills_web.jpg

“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.

“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”

The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.

It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.

Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.

“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.

When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.

For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.

Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.

Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.

While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.

“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”

Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.

The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.

Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.

“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.

“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”

The authors reported no relevant financial relationships.

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

Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.

COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.

drug_pills_web.jpg

“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.

“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”

The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.

It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.

Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.

“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.

When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.

For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.

Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.

Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.

While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.

“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”

Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.

The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.

Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.

“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.

“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”

The authors reported no relevant financial relationships.

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

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

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

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

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

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

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

BOSTON – Despite a promising start, extended follow-up from the SUGAR trial found that the Cre8 EVO drug-eluting stent could not maintain superiority over the Resolute Onyx DES at 2 years in patients with diabetes undergoing revascularization for coronary artery disease.

The Cre8 EVO stent (Alvimedica) is not available in the United States but, as previously reported, caused a stir last year after demonstrating a 35% relative risk reduction in the primary endpoint of target lesion failure (TLF) at 1 year in a prespecified superiority analysis.

At 2 years, however, the TLF rate was 10.4% with the polymer-free Cre8 EVO amphilimus-eluting stent and 12.1% with the durable polymer Resolute Onyx (Medtronic) zotarolimus-eluting stent, which did not achieve superiority (hazard ratio, 0.84; 95% confidence interval, 0.60-1.19).

Rates were numerically lower with the Cre8 EVO stent for the endpoint’s individual components of cardiac death (3.1% vs. 3.4%), target vessel MI (6.6% vs. 7.6%), and target lesion revascularization (4.3% vs. 4.6%).

Results were also similar between the Cre8 EVO and Resolute Onyx stents for all-cause mortality (7.1% vs. 6.8%), any MI (9.0% vs. 9.2%), target vessel revascularization (5.5% vs. 5.1%), all new revascularizations (7.6% vs. 9.4%), definite stent thrombosis (1.0% vs. 1.2%), and major adverse cardiac events (18.3% vs. 20.8%), Pablo Salinas, MD, PhD, of Hospital Clinico San Carlos, Madrid, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

He noted that all-cause mortality was 7% in just 2 years in the diabetic cohort, or twice the number of cardiac deaths. “In other words, these patients had the same chance of dying from cardiac causes and noncardiac causes, so we need a more comprehensive approach to the disease. Also, if you look at all new revascularizations, roughly 50% were off target, so there is disease progression at 2 years in this population.”

Among the 586 Cre8 EVO and 589 Resolute Onyx patients who underwent percutaneous coronary intervention (PCI), roughly half had multivessel coronary artery disease, 83% had hypertension, 81% had dyslipidemia, and 21% were current smokers. Nearly all patients had diabetes type 2 for an average of 10.6 years for Cre8 EVO and 11.4 years for Resolute Onyx, with hemoglobin A1c levels of 7.4% and 7.5%, respectively.

Although there is “insufficient evidence” the Cre8 EVO stent is superior to the Resolute Onyx stent with regard to TLF, Dr. Salinas concluded extended follow-up until 5 years is warranted.

During a discussion of the results, Dr. Salinas said he expects the 5-year results will “probably go parallel” but that it’s worth following this very valuable cohort. “There are not so many trials with 1,000 diabetic patients. We always speak about how complex they are, the results are bad, but we don’t use the diabetic population in trials,” he said at the meeting sponsored by the Cardiovascular Research Foundation.

Asked during a TCT press conference what could have caused the catch-up in TLF at 2 years, Dr. Salinas said there were only 25 primary events from years 1 to 2, driven primarily by periprocedural MI, but that the timing of restenosis was different. Events accrued “drop by drop” with the Cre8 EVO, whereas with the Resolute Onyx there was a “bump in restenosis” after 6 months “but then it is very nice to see it is flat, which means that durable polymers are also safe because we have not seen late events.”

Di Mario_Carlo_Italy_web.jpg

Press conference discussant Carlo Di Mario, MD, from Careggi University Hospital, Florence, Italy, who was not involved in the study, said the reversal of superiority for the Cre8 EVO might be a “bitter note” for the investigators but “maybe it is not bitter for us because overall, the percentage of figures are so low that it’s very difficult to find a difference” between the two stents.

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

BOSTON – Despite a promising start, extended follow-up from the SUGAR trial found that the Cre8 EVO drug-eluting stent could not maintain superiority over the Resolute Onyx DES at 2 years in patients with diabetes undergoing revascularization for coronary artery disease.

The Cre8 EVO stent (Alvimedica) is not available in the United States but, as previously reported, caused a stir last year after demonstrating a 35% relative risk reduction in the primary endpoint of target lesion failure (TLF) at 1 year in a prespecified superiority analysis.

At 2 years, however, the TLF rate was 10.4% with the polymer-free Cre8 EVO amphilimus-eluting stent and 12.1% with the durable polymer Resolute Onyx (Medtronic) zotarolimus-eluting stent, which did not achieve superiority (hazard ratio, 0.84; 95% confidence interval, 0.60-1.19).

Rates were numerically lower with the Cre8 EVO stent for the endpoint’s individual components of cardiac death (3.1% vs. 3.4%), target vessel MI (6.6% vs. 7.6%), and target lesion revascularization (4.3% vs. 4.6%).

Results were also similar between the Cre8 EVO and Resolute Onyx stents for all-cause mortality (7.1% vs. 6.8%), any MI (9.0% vs. 9.2%), target vessel revascularization (5.5% vs. 5.1%), all new revascularizations (7.6% vs. 9.4%), definite stent thrombosis (1.0% vs. 1.2%), and major adverse cardiac events (18.3% vs. 20.8%), Pablo Salinas, MD, PhD, of Hospital Clinico San Carlos, Madrid, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

He noted that all-cause mortality was 7% in just 2 years in the diabetic cohort, or twice the number of cardiac deaths. “In other words, these patients had the same chance of dying from cardiac causes and noncardiac causes, so we need a more comprehensive approach to the disease. Also, if you look at all new revascularizations, roughly 50% were off target, so there is disease progression at 2 years in this population.”

Among the 586 Cre8 EVO and 589 Resolute Onyx patients who underwent percutaneous coronary intervention (PCI), roughly half had multivessel coronary artery disease, 83% had hypertension, 81% had dyslipidemia, and 21% were current smokers. Nearly all patients had diabetes type 2 for an average of 10.6 years for Cre8 EVO and 11.4 years for Resolute Onyx, with hemoglobin A1c levels of 7.4% and 7.5%, respectively.

Although there is “insufficient evidence” the Cre8 EVO stent is superior to the Resolute Onyx stent with regard to TLF, Dr. Salinas concluded extended follow-up until 5 years is warranted.

During a discussion of the results, Dr. Salinas said he expects the 5-year results will “probably go parallel” but that it’s worth following this very valuable cohort. “There are not so many trials with 1,000 diabetic patients. We always speak about how complex they are, the results are bad, but we don’t use the diabetic population in trials,” he said at the meeting sponsored by the Cardiovascular Research Foundation.

Asked during a TCT press conference what could have caused the catch-up in TLF at 2 years, Dr. Salinas said there were only 25 primary events from years 1 to 2, driven primarily by periprocedural MI, but that the timing of restenosis was different. Events accrued “drop by drop” with the Cre8 EVO, whereas with the Resolute Onyx there was a “bump in restenosis” after 6 months “but then it is very nice to see it is flat, which means that durable polymers are also safe because we have not seen late events.”

Di Mario_Carlo_Italy_web.jpg

Press conference discussant Carlo Di Mario, MD, from Careggi University Hospital, Florence, Italy, who was not involved in the study, said the reversal of superiority for the Cre8 EVO might be a “bitter note” for the investigators but “maybe it is not bitter for us because overall, the percentage of figures are so low that it’s very difficult to find a difference” between the two stents.

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

BOSTON – Despite a promising start, extended follow-up from the SUGAR trial found that the Cre8 EVO drug-eluting stent could not maintain superiority over the Resolute Onyx DES at 2 years in patients with diabetes undergoing revascularization for coronary artery disease.

The Cre8 EVO stent (Alvimedica) is not available in the United States but, as previously reported, caused a stir last year after demonstrating a 35% relative risk reduction in the primary endpoint of target lesion failure (TLF) at 1 year in a prespecified superiority analysis.

At 2 years, however, the TLF rate was 10.4% with the polymer-free Cre8 EVO amphilimus-eluting stent and 12.1% with the durable polymer Resolute Onyx (Medtronic) zotarolimus-eluting stent, which did not achieve superiority (hazard ratio, 0.84; 95% confidence interval, 0.60-1.19).

Rates were numerically lower with the Cre8 EVO stent for the endpoint’s individual components of cardiac death (3.1% vs. 3.4%), target vessel MI (6.6% vs. 7.6%), and target lesion revascularization (4.3% vs. 4.6%).

Results were also similar between the Cre8 EVO and Resolute Onyx stents for all-cause mortality (7.1% vs. 6.8%), any MI (9.0% vs. 9.2%), target vessel revascularization (5.5% vs. 5.1%), all new revascularizations (7.6% vs. 9.4%), definite stent thrombosis (1.0% vs. 1.2%), and major adverse cardiac events (18.3% vs. 20.8%), Pablo Salinas, MD, PhD, of Hospital Clinico San Carlos, Madrid, reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

He noted that all-cause mortality was 7% in just 2 years in the diabetic cohort, or twice the number of cardiac deaths. “In other words, these patients had the same chance of dying from cardiac causes and noncardiac causes, so we need a more comprehensive approach to the disease. Also, if you look at all new revascularizations, roughly 50% were off target, so there is disease progression at 2 years in this population.”

Among the 586 Cre8 EVO and 589 Resolute Onyx patients who underwent percutaneous coronary intervention (PCI), roughly half had multivessel coronary artery disease, 83% had hypertension, 81% had dyslipidemia, and 21% were current smokers. Nearly all patients had diabetes type 2 for an average of 10.6 years for Cre8 EVO and 11.4 years for Resolute Onyx, with hemoglobin A1c levels of 7.4% and 7.5%, respectively.

Although there is “insufficient evidence” the Cre8 EVO stent is superior to the Resolute Onyx stent with regard to TLF, Dr. Salinas concluded extended follow-up until 5 years is warranted.

During a discussion of the results, Dr. Salinas said he expects the 5-year results will “probably go parallel” but that it’s worth following this very valuable cohort. “There are not so many trials with 1,000 diabetic patients. We always speak about how complex they are, the results are bad, but we don’t use the diabetic population in trials,” he said at the meeting sponsored by the Cardiovascular Research Foundation.

Asked during a TCT press conference what could have caused the catch-up in TLF at 2 years, Dr. Salinas said there were only 25 primary events from years 1 to 2, driven primarily by periprocedural MI, but that the timing of restenosis was different. Events accrued “drop by drop” with the Cre8 EVO, whereas with the Resolute Onyx there was a “bump in restenosis” after 6 months “but then it is very nice to see it is flat, which means that durable polymers are also safe because we have not seen late events.”

Di Mario_Carlo_Italy_web.jpg

Press conference discussant Carlo Di Mario, MD, from Careggi University Hospital, Florence, Italy, who was not involved in the study, said the reversal of superiority for the Cre8 EVO might be a “bitter note” for the investigators but “maybe it is not bitter for us because overall, the percentage of figures are so low that it’s very difficult to find a difference” between the two stents.

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

The Amplatzer Amulet (Abbott) and first-generation Watchman 2.5 (Boston Scientific) devices provide relatively comparable results out to 3 years after left atrial appendage occlusion (LAAO), longer follow-up from the Amplatzer Amulet Left Atrial Appendage Occluder Versus Watchman Device for Stroke Prophylaxis (Amulet IDE) trial shows.

Lakkireddy_Dhanunjaya_KAN_web.jpg

“The dual-seal Amplatzer Amulet left atrial appendage occluder continued to demonstrate safety and effectiveness through 3 years,” principal investigator Dhanunjaya Lakkireddy, MD, said in a late-breaking session at the recent Transcatheter Cardiovascular Therapeutics annual meeting.

Preliminary results, reported last year, showed that procedural complications were higher with the Amplatzer but that it provided superior closure of the left atrial appendage (LAA) at 45 days and was noninferior with respect to safety at 12 months and efficacy at 18 months.

Amulet IDE is the largest head-to-head comparison of the two devices, enrolling 1,878 high-risk patients with nonvalvular atrial fibrillation undergoing LAA closure to reduce the risk of stroke.

Three-year follow-up was higher with the Amulet device than with the Watchman, at 721 vs. 659 patients, driven by increased deaths (85 vs. 63) and withdrawals (50 vs. 23) in the Watchman group within 18 months, noted Dr. Lakkireddy, Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kan.

Use of oral anticoagulation was higher in the Watchman group at 6 months (2.8% vs. 4.7%; P = .04), 18 months (3.1% vs. 5.6%; P = .01), and 3 years (3.7% vs. 7.3%; P < .01).

This was primarily driven by more late device-related thrombus (DRT) after 6 months with the Watchman device than with the Amulet occluder (23 vs. 10). “Perhaps the dual-closure mechanism of the Amulet explains this fundamental difference, where you have a nice smooth disc that covers the ostium,” he posited.

At 3 years, rates of cardiovascular death trended lower with Amulet than with Watchman (6.6% vs. 8.5%; P = .14), as did all-cause deaths (14.6% vs. 17.9%; P = .07).

Most cardiovascular deaths in the Amulet group were not preceded by a device factor, whereas DRT (1 vs. 4) and peridevice leak 3 mm or more (5 vs. 15) frequently preceded these deaths in the Watchman group, Dr. Lakkireddy observed. No pericardial effusion-related deaths occurred in either group.

Major bleeding, however, trended higher for the Amulet, at 16.1%, compared with 14.7% for the Watchman (P = .46). Ischemic stroke and systemic embolic rates also trended higher for Amulet, at 5%, and 4.6% for Watchman.

The protocol recommended aspirin only for both groups after 6 months. None of the 29 Amulet and 3 of the 29 Watchman patients with an ischemic stroke were on oral anticoagulation at the time of the stroke.

Device factors, however, frequently preceded ischemic strokes in the Watchman group, Dr. Lakkireddy said. DRT occurred in 1 patient with Amulet and 2 patients with Watchman and peridevice leak in 3 with Amulet and 15 with Watchman. “Again, the peridevice leak issue really stands out as an important factor,” he said at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Based on “data from the large trials, it’s clearly evident that the presence of peridevice leak significantly raises the risk of stroke in follow-up,” he said. “So, attention has to be paid to the choice of the device and how we can mitigate the risk of peridevice leaks in these patients.”

The composite of stroke, systemic embolism, and cardiovascular death occurred in 11.1% of patients with Amulet and 12.7% with Watchman (P = .31).

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

The Amplatzer Amulet (Abbott) and first-generation Watchman 2.5 (Boston Scientific) devices provide relatively comparable results out to 3 years after left atrial appendage occlusion (LAAO), longer follow-up from the Amplatzer Amulet Left Atrial Appendage Occluder Versus Watchman Device for Stroke Prophylaxis (Amulet IDE) trial shows.

Lakkireddy_Dhanunjaya_KAN_web.jpg

“The dual-seal Amplatzer Amulet left atrial appendage occluder continued to demonstrate safety and effectiveness through 3 years,” principal investigator Dhanunjaya Lakkireddy, MD, said in a late-breaking session at the recent Transcatheter Cardiovascular Therapeutics annual meeting.

Preliminary results, reported last year, showed that procedural complications were higher with the Amplatzer but that it provided superior closure of the left atrial appendage (LAA) at 45 days and was noninferior with respect to safety at 12 months and efficacy at 18 months.

Amulet IDE is the largest head-to-head comparison of the two devices, enrolling 1,878 high-risk patients with nonvalvular atrial fibrillation undergoing LAA closure to reduce the risk of stroke.

Three-year follow-up was higher with the Amulet device than with the Watchman, at 721 vs. 659 patients, driven by increased deaths (85 vs. 63) and withdrawals (50 vs. 23) in the Watchman group within 18 months, noted Dr. Lakkireddy, Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kan.

Use of oral anticoagulation was higher in the Watchman group at 6 months (2.8% vs. 4.7%; P = .04), 18 months (3.1% vs. 5.6%; P = .01), and 3 years (3.7% vs. 7.3%; P < .01).

This was primarily driven by more late device-related thrombus (DRT) after 6 months with the Watchman device than with the Amulet occluder (23 vs. 10). “Perhaps the dual-closure mechanism of the Amulet explains this fundamental difference, where you have a nice smooth disc that covers the ostium,” he posited.

At 3 years, rates of cardiovascular death trended lower with Amulet than with Watchman (6.6% vs. 8.5%; P = .14), as did all-cause deaths (14.6% vs. 17.9%; P = .07).

Most cardiovascular deaths in the Amulet group were not preceded by a device factor, whereas DRT (1 vs. 4) and peridevice leak 3 mm or more (5 vs. 15) frequently preceded these deaths in the Watchman group, Dr. Lakkireddy observed. No pericardial effusion-related deaths occurred in either group.

Major bleeding, however, trended higher for the Amulet, at 16.1%, compared with 14.7% for the Watchman (P = .46). Ischemic stroke and systemic embolic rates also trended higher for Amulet, at 5%, and 4.6% for Watchman.

The protocol recommended aspirin only for both groups after 6 months. None of the 29 Amulet and 3 of the 29 Watchman patients with an ischemic stroke were on oral anticoagulation at the time of the stroke.

Device factors, however, frequently preceded ischemic strokes in the Watchman group, Dr. Lakkireddy said. DRT occurred in 1 patient with Amulet and 2 patients with Watchman and peridevice leak in 3 with Amulet and 15 with Watchman. “Again, the peridevice leak issue really stands out as an important factor,” he said at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Based on “data from the large trials, it’s clearly evident that the presence of peridevice leak significantly raises the risk of stroke in follow-up,” he said. “So, attention has to be paid to the choice of the device and how we can mitigate the risk of peridevice leaks in these patients.”

The composite of stroke, systemic embolism, and cardiovascular death occurred in 11.1% of patients with Amulet and 12.7% with Watchman (P = .31).

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

The Amplatzer Amulet (Abbott) and first-generation Watchman 2.5 (Boston Scientific) devices provide relatively comparable results out to 3 years after left atrial appendage occlusion (LAAO), longer follow-up from the Amplatzer Amulet Left Atrial Appendage Occluder Versus Watchman Device for Stroke Prophylaxis (Amulet IDE) trial shows.

Lakkireddy_Dhanunjaya_KAN_web.jpg

“The dual-seal Amplatzer Amulet left atrial appendage occluder continued to demonstrate safety and effectiveness through 3 years,” principal investigator Dhanunjaya Lakkireddy, MD, said in a late-breaking session at the recent Transcatheter Cardiovascular Therapeutics annual meeting.

Preliminary results, reported last year, showed that procedural complications were higher with the Amplatzer but that it provided superior closure of the left atrial appendage (LAA) at 45 days and was noninferior with respect to safety at 12 months and efficacy at 18 months.

Amulet IDE is the largest head-to-head comparison of the two devices, enrolling 1,878 high-risk patients with nonvalvular atrial fibrillation undergoing LAA closure to reduce the risk of stroke.

Three-year follow-up was higher with the Amulet device than with the Watchman, at 721 vs. 659 patients, driven by increased deaths (85 vs. 63) and withdrawals (50 vs. 23) in the Watchman group within 18 months, noted Dr. Lakkireddy, Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kan.

Use of oral anticoagulation was higher in the Watchman group at 6 months (2.8% vs. 4.7%; P = .04), 18 months (3.1% vs. 5.6%; P = .01), and 3 years (3.7% vs. 7.3%; P < .01).

This was primarily driven by more late device-related thrombus (DRT) after 6 months with the Watchman device than with the Amulet occluder (23 vs. 10). “Perhaps the dual-closure mechanism of the Amulet explains this fundamental difference, where you have a nice smooth disc that covers the ostium,” he posited.

At 3 years, rates of cardiovascular death trended lower with Amulet than with Watchman (6.6% vs. 8.5%; P = .14), as did all-cause deaths (14.6% vs. 17.9%; P = .07).

Most cardiovascular deaths in the Amulet group were not preceded by a device factor, whereas DRT (1 vs. 4) and peridevice leak 3 mm or more (5 vs. 15) frequently preceded these deaths in the Watchman group, Dr. Lakkireddy observed. No pericardial effusion-related deaths occurred in either group.

Major bleeding, however, trended higher for the Amulet, at 16.1%, compared with 14.7% for the Watchman (P = .46). Ischemic stroke and systemic embolic rates also trended higher for Amulet, at 5%, and 4.6% for Watchman.

The protocol recommended aspirin only for both groups after 6 months. None of the 29 Amulet and 3 of the 29 Watchman patients with an ischemic stroke were on oral anticoagulation at the time of the stroke.

Device factors, however, frequently preceded ischemic strokes in the Watchman group, Dr. Lakkireddy said. DRT occurred in 1 patient with Amulet and 2 patients with Watchman and peridevice leak in 3 with Amulet and 15 with Watchman. “Again, the peridevice leak issue really stands out as an important factor,” he said at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Based on “data from the large trials, it’s clearly evident that the presence of peridevice leak significantly raises the risk of stroke in follow-up,” he said. “So, attention has to be paid to the choice of the device and how we can mitigate the risk of peridevice leaks in these patients.”

The composite of stroke, systemic embolism, and cardiovascular death occurred in 11.1% of patients with Amulet and 12.7% with Watchman (P = .31).

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

Patients with a rheumatic immune-mediated inflammatory disease (IMID) had worse outcomes, especially for mortality, after a myocardial infarction than those without an IMID, in a large propensity-matched analysis.

At a median of 2 years after their MI, Medicare beneficiaries with an IMID had adjusted risks that were:

• 15% higher for all-cause death (hazard ratio, 1.15);
• 12% higher for heart failure (HR, 1.12);
• 8% higher for recurrent MI (HR, 1.08); and
• 6% higher risk for coronary reintervention (HR, 1.06; P < .05 for all).

In addition, interventions known to improve outcomes in this context, such as coronary revascularization, were less common in patients with IMID.

“This could be because they usually are sicker and have more risk factors when they present, like kidney disease, so maybe they’re not eligible for the therapy. But by itself, it was surprising they’re not offered these interventions as common[ly] as people who don’t have the disease,” Amgad Mentias, MD, a clinical cardiologist at the Cleveland Clinic, said in an interview.

The study was published Sept. 14 in the Journal of the American Heart Association, with Dr. Mentias as senior author and Heba Wassif, MD, MPH, also with Cleveland Clinic, as first author.

IMIDs, such as rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease, are known to be associated with significantly higher cardiovascular disease (CVD) risk due to a greater prevalence of traditional CVD risk factors and chronic systemic inflammation.

Certain disease-modifying agents may also increase patients’ cardiovascular risk. This has been a long-simmering issue for the arthritis and ulcerative colitis drug tofacitinib (Xeljanz, Xeljanz XR), resulting in an updated boxed warning in 2021.

Many of these patients also have joint disease, pain, and fatigue, which can limit physical activity, Dr. Mentias said. “So these small nuances of how to manage these patients, or balance between controlling the inflammation but also improv[ing] cardiac risk factors, is not an easy task.”

Evidence regarding post-MI events has been inconsistent and limited to smaller single-center studies, he said. After propensity-score matching, the present study included 59,820 patients with and 178,547 patients without rheumatic IMIDs followed for a maximum of 6 years.

They were drawn from a cohort of 1.6 million persons aged 65 or older in the Medicare Provider Analysis and Review (MedPAR) file who had been admitted for an MI between 2014 and 2019. Of these, 60,072 had a prior history of rheumatic IMIDs, most commonly rheumatoid arthritis (77.8%), followed by systemic lupus erythematosus (12.2%), psoriasis (5.1%), systemic sclerosis (2.8%), and myositis/dermatomyositis (1.8%).

Patients with an IMID were more often women; had a higher prevalence of valve disease, pulmonary hypertension, hypothyroidism, and anemia; and were more likely to present with non–ST-segment MI (NSTEMI).

Rates of coronary angiography (46.1% vs. 51.5%), percutaneous coronary intervention (31.6% vs. 33.6%), and coronary artery bypass grafting (7.7% vs. 10.7%) were significantly lower in patients with IMIDs who had NSTEMI, compared with patients without an IMID who had NSTEMI. Rates of these interventions were also lower in patients with IMIDs who presented with STEMI versus their peers without an IMID, at 78.2% vs. 80.7%, 70.2% vs. 71.5%, and 4.9% vs. 6.4%, respectively.

Dr. Mentias pointed out that the emerging subspecialty of cardiorheumatology is gaining traction, especially at large hospitals and academic centers, but that less than one-third of persons in the United States with an IMID are likely to be under the care of such specialists.

“It’s important before developing an MI to try and control the different risk factors and improve the risk profile for these patients as much as possible by both specialties, and then, after an unfortunate event like MI happens, it’s important to make sure we offer therapies and treatments that are known to improve outcomes,” he said.

Commenting for this article, Jon Tyler Giles, MD, a clinical researcher who focuses on cardiovascular diseases in rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York, said that “at least for rheumatoid arthritis, this is something that we already knew. People with rheumatic arthritis, when they have a heart attack, are less likely to get the standard kind of treatments and have worse outcomes. This is a little larger sample, but it’s not a surprise, not a surprise at all.”

He noted that the study could have answered questions regarding potential drivers, but “they didn’t dig down into any of the factors that were associated with the poorer outcomes in the patients with rheumatoid arthritis and lupus and scleroderma.”

Indeed, the investigators acknowledge that the study lacked information on coronary anatomy, duration and severity of the autoimmune disease, imaging data, and medications such as anti-inflammatory or immune-targeted therapies.

Dr. Giles highlighted several factors that can contribute to a poorer post-MI prognosis in patients with rheumatic diseases; these include frailty, being more hypercoaguable, increased rates of myocardial dysfunction and other heart and blood vessel diseases, and chronic treatment with steroids and nonsteroidal anti-inflammatory drugs that often interferes with anticoagulation after a MI or when putting in a stent. “So, there’s lot of moving parts, and not one single thing that is likely the answer.”

In addition, he said, “there’s always going to be a portion of these patients who, despite doing the best that we can with treatment, are going to have very severe disease. That may or may not be the subset of patients that did the worst, but likely they’re overrepresented in those patients.”

Finally, the inability to move the needle may lie with the lack of evidence-based screening and management guidelines for cardiovascular disease in any rheumatic disease, Dr. Giles observed. “There’s no guideline for us to use to decide who needs screening over and above what’s recommended for the general population, and then, even if you do screen, what do you do other than what you would normally?”

Rheumatologists are often reluctant to take up the cardiovascular screening side of things because visits are short, and a lot of that time is spent trying to manage the inflammatory components of a patient’s disease, he said. There’s also a barrier in getting some patients to add a cardiologist to the mix of physicians they already see, especially if they don’t have any symptoms.

“If someone has had an event, it’s a lot easier for people to be convinced to go see the cardiologist, obviously, but prior to having an event, the preventative side of things is something that often gets missed or goes to the wayside,” Dr. Giles said.

The study was partly funded by philanthropic gifts by the Haslam family, Bailey family, and Khouri family to the Cleveland Clinic for coauthor Dr. Milind Desai’s research. Dr. Desai is a consultant for Medtronic and Bristol Myers Squibb and serves on an executive steering committee of a BMS-sponsored trial. The remaining authors report having no relevant disclosures. Dr. Giles is a consultant on drug cardiovascular safety for Pfizer, AbbVie, and Eli Lilly.

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

Patients with a rheumatic immune-mediated inflammatory disease (IMID) had worse outcomes, especially for mortality, after a myocardial infarction than those without an IMID, in a large propensity-matched analysis.

At a median of 2 years after their MI, Medicare beneficiaries with an IMID had adjusted risks that were:

• 15% higher for all-cause death (hazard ratio, 1.15);
• 12% higher for heart failure (HR, 1.12);
• 8% higher for recurrent MI (HR, 1.08); and
• 6% higher risk for coronary reintervention (HR, 1.06; P < .05 for all).

In addition, interventions known to improve outcomes in this context, such as coronary revascularization, were less common in patients with IMID.

“This could be because they usually are sicker and have more risk factors when they present, like kidney disease, so maybe they’re not eligible for the therapy. But by itself, it was surprising they’re not offered these interventions as common[ly] as people who don’t have the disease,” Amgad Mentias, MD, a clinical cardiologist at the Cleveland Clinic, said in an interview.

The study was published Sept. 14 in the Journal of the American Heart Association, with Dr. Mentias as senior author and Heba Wassif, MD, MPH, also with Cleveland Clinic, as first author.

IMIDs, such as rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease, are known to be associated with significantly higher cardiovascular disease (CVD) risk due to a greater prevalence of traditional CVD risk factors and chronic systemic inflammation.

Certain disease-modifying agents may also increase patients’ cardiovascular risk. This has been a long-simmering issue for the arthritis and ulcerative colitis drug tofacitinib (Xeljanz, Xeljanz XR), resulting in an updated boxed warning in 2021.

Many of these patients also have joint disease, pain, and fatigue, which can limit physical activity, Dr. Mentias said. “So these small nuances of how to manage these patients, or balance between controlling the inflammation but also improv[ing] cardiac risk factors, is not an easy task.”

Evidence regarding post-MI events has been inconsistent and limited to smaller single-center studies, he said. After propensity-score matching, the present study included 59,820 patients with and 178,547 patients without rheumatic IMIDs followed for a maximum of 6 years.

They were drawn from a cohort of 1.6 million persons aged 65 or older in the Medicare Provider Analysis and Review (MedPAR) file who had been admitted for an MI between 2014 and 2019. Of these, 60,072 had a prior history of rheumatic IMIDs, most commonly rheumatoid arthritis (77.8%), followed by systemic lupus erythematosus (12.2%), psoriasis (5.1%), systemic sclerosis (2.8%), and myositis/dermatomyositis (1.8%).

Patients with an IMID were more often women; had a higher prevalence of valve disease, pulmonary hypertension, hypothyroidism, and anemia; and were more likely to present with non–ST-segment MI (NSTEMI).

Rates of coronary angiography (46.1% vs. 51.5%), percutaneous coronary intervention (31.6% vs. 33.6%), and coronary artery bypass grafting (7.7% vs. 10.7%) were significantly lower in patients with IMIDs who had NSTEMI, compared with patients without an IMID who had NSTEMI. Rates of these interventions were also lower in patients with IMIDs who presented with STEMI versus their peers without an IMID, at 78.2% vs. 80.7%, 70.2% vs. 71.5%, and 4.9% vs. 6.4%, respectively.

Dr. Mentias pointed out that the emerging subspecialty of cardiorheumatology is gaining traction, especially at large hospitals and academic centers, but that less than one-third of persons in the United States with an IMID are likely to be under the care of such specialists.

“It’s important before developing an MI to try and control the different risk factors and improve the risk profile for these patients as much as possible by both specialties, and then, after an unfortunate event like MI happens, it’s important to make sure we offer therapies and treatments that are known to improve outcomes,” he said.

Commenting for this article, Jon Tyler Giles, MD, a clinical researcher who focuses on cardiovascular diseases in rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York, said that “at least for rheumatoid arthritis, this is something that we already knew. People with rheumatic arthritis, when they have a heart attack, are less likely to get the standard kind of treatments and have worse outcomes. This is a little larger sample, but it’s not a surprise, not a surprise at all.”

He noted that the study could have answered questions regarding potential drivers, but “they didn’t dig down into any of the factors that were associated with the poorer outcomes in the patients with rheumatoid arthritis and lupus and scleroderma.”

Indeed, the investigators acknowledge that the study lacked information on coronary anatomy, duration and severity of the autoimmune disease, imaging data, and medications such as anti-inflammatory or immune-targeted therapies.

Dr. Giles highlighted several factors that can contribute to a poorer post-MI prognosis in patients with rheumatic diseases; these include frailty, being more hypercoaguable, increased rates of myocardial dysfunction and other heart and blood vessel diseases, and chronic treatment with steroids and nonsteroidal anti-inflammatory drugs that often interferes with anticoagulation after a MI or when putting in a stent. “So, there’s lot of moving parts, and not one single thing that is likely the answer.”

In addition, he said, “there’s always going to be a portion of these patients who, despite doing the best that we can with treatment, are going to have very severe disease. That may or may not be the subset of patients that did the worst, but likely they’re overrepresented in those patients.”

Finally, the inability to move the needle may lie with the lack of evidence-based screening and management guidelines for cardiovascular disease in any rheumatic disease, Dr. Giles observed. “There’s no guideline for us to use to decide who needs screening over and above what’s recommended for the general population, and then, even if you do screen, what do you do other than what you would normally?”

Rheumatologists are often reluctant to take up the cardiovascular screening side of things because visits are short, and a lot of that time is spent trying to manage the inflammatory components of a patient’s disease, he said. There’s also a barrier in getting some patients to add a cardiologist to the mix of physicians they already see, especially if they don’t have any symptoms.

“If someone has had an event, it’s a lot easier for people to be convinced to go see the cardiologist, obviously, but prior to having an event, the preventative side of things is something that often gets missed or goes to the wayside,” Dr. Giles said.

The study was partly funded by philanthropic gifts by the Haslam family, Bailey family, and Khouri family to the Cleveland Clinic for coauthor Dr. Milind Desai’s research. Dr. Desai is a consultant for Medtronic and Bristol Myers Squibb and serves on an executive steering committee of a BMS-sponsored trial. The remaining authors report having no relevant disclosures. Dr. Giles is a consultant on drug cardiovascular safety for Pfizer, AbbVie, and Eli Lilly.

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

Patients with a rheumatic immune-mediated inflammatory disease (IMID) had worse outcomes, especially for mortality, after a myocardial infarction than those without an IMID, in a large propensity-matched analysis.

At a median of 2 years after their MI, Medicare beneficiaries with an IMID had adjusted risks that were:

• 15% higher for all-cause death (hazard ratio, 1.15);
• 12% higher for heart failure (HR, 1.12);
• 8% higher for recurrent MI (HR, 1.08); and
• 6% higher risk for coronary reintervention (HR, 1.06; P < .05 for all).

In addition, interventions known to improve outcomes in this context, such as coronary revascularization, were less common in patients with IMID.

“This could be because they usually are sicker and have more risk factors when they present, like kidney disease, so maybe they’re not eligible for the therapy. But by itself, it was surprising they’re not offered these interventions as common[ly] as people who don’t have the disease,” Amgad Mentias, MD, a clinical cardiologist at the Cleveland Clinic, said in an interview.

The study was published Sept. 14 in the Journal of the American Heart Association, with Dr. Mentias as senior author and Heba Wassif, MD, MPH, also with Cleveland Clinic, as first author.

IMIDs, such as rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease, are known to be associated with significantly higher cardiovascular disease (CVD) risk due to a greater prevalence of traditional CVD risk factors and chronic systemic inflammation.

Certain disease-modifying agents may also increase patients’ cardiovascular risk. This has been a long-simmering issue for the arthritis and ulcerative colitis drug tofacitinib (Xeljanz, Xeljanz XR), resulting in an updated boxed warning in 2021.

Many of these patients also have joint disease, pain, and fatigue, which can limit physical activity, Dr. Mentias said. “So these small nuances of how to manage these patients, or balance between controlling the inflammation but also improv[ing] cardiac risk factors, is not an easy task.”

Evidence regarding post-MI events has been inconsistent and limited to smaller single-center studies, he said. After propensity-score matching, the present study included 59,820 patients with and 178,547 patients without rheumatic IMIDs followed for a maximum of 6 years.

They were drawn from a cohort of 1.6 million persons aged 65 or older in the Medicare Provider Analysis and Review (MedPAR) file who had been admitted for an MI between 2014 and 2019. Of these, 60,072 had a prior history of rheumatic IMIDs, most commonly rheumatoid arthritis (77.8%), followed by systemic lupus erythematosus (12.2%), psoriasis (5.1%), systemic sclerosis (2.8%), and myositis/dermatomyositis (1.8%).

Patients with an IMID were more often women; had a higher prevalence of valve disease, pulmonary hypertension, hypothyroidism, and anemia; and were more likely to present with non–ST-segment MI (NSTEMI).

Rates of coronary angiography (46.1% vs. 51.5%), percutaneous coronary intervention (31.6% vs. 33.6%), and coronary artery bypass grafting (7.7% vs. 10.7%) were significantly lower in patients with IMIDs who had NSTEMI, compared with patients without an IMID who had NSTEMI. Rates of these interventions were also lower in patients with IMIDs who presented with STEMI versus their peers without an IMID, at 78.2% vs. 80.7%, 70.2% vs. 71.5%, and 4.9% vs. 6.4%, respectively.

Dr. Mentias pointed out that the emerging subspecialty of cardiorheumatology is gaining traction, especially at large hospitals and academic centers, but that less than one-third of persons in the United States with an IMID are likely to be under the care of such specialists.

“It’s important before developing an MI to try and control the different risk factors and improve the risk profile for these patients as much as possible by both specialties, and then, after an unfortunate event like MI happens, it’s important to make sure we offer therapies and treatments that are known to improve outcomes,” he said.

Commenting for this article, Jon Tyler Giles, MD, a clinical researcher who focuses on cardiovascular diseases in rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York, said that “at least for rheumatoid arthritis, this is something that we already knew. People with rheumatic arthritis, when they have a heart attack, are less likely to get the standard kind of treatments and have worse outcomes. This is a little larger sample, but it’s not a surprise, not a surprise at all.”

He noted that the study could have answered questions regarding potential drivers, but “they didn’t dig down into any of the factors that were associated with the poorer outcomes in the patients with rheumatoid arthritis and lupus and scleroderma.”

Indeed, the investigators acknowledge that the study lacked information on coronary anatomy, duration and severity of the autoimmune disease, imaging data, and medications such as anti-inflammatory or immune-targeted therapies.

Dr. Giles highlighted several factors that can contribute to a poorer post-MI prognosis in patients with rheumatic diseases; these include frailty, being more hypercoaguable, increased rates of myocardial dysfunction and other heart and blood vessel diseases, and chronic treatment with steroids and nonsteroidal anti-inflammatory drugs that often interferes with anticoagulation after a MI or when putting in a stent. “So, there’s lot of moving parts, and not one single thing that is likely the answer.”

In addition, he said, “there’s always going to be a portion of these patients who, despite doing the best that we can with treatment, are going to have very severe disease. That may or may not be the subset of patients that did the worst, but likely they’re overrepresented in those patients.”

Finally, the inability to move the needle may lie with the lack of evidence-based screening and management guidelines for cardiovascular disease in any rheumatic disease, Dr. Giles observed. “There’s no guideline for us to use to decide who needs screening over and above what’s recommended for the general population, and then, even if you do screen, what do you do other than what you would normally?”

Rheumatologists are often reluctant to take up the cardiovascular screening side of things because visits are short, and a lot of that time is spent trying to manage the inflammatory components of a patient’s disease, he said. There’s also a barrier in getting some patients to add a cardiologist to the mix of physicians they already see, especially if they don’t have any symptoms.

“If someone has had an event, it’s a lot easier for people to be convinced to go see the cardiologist, obviously, but prior to having an event, the preventative side of things is something that often gets missed or goes to the wayside,” Dr. Giles said.

The study was partly funded by philanthropic gifts by the Haslam family, Bailey family, and Khouri family to the Cleveland Clinic for coauthor Dr. Milind Desai’s research. Dr. Desai is a consultant for Medtronic and Bristol Myers Squibb and serves on an executive steering committee of a BMS-sponsored trial. The remaining authors report having no relevant disclosures. Dr. Giles is a consultant on drug cardiovascular safety for Pfizer, AbbVie, and Eli Lilly.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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