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ISCHEMIA trial revisited: Some MAY benefit from invasive strategy
The landmark ISCHEMIA trial rattled the cardiology world with its message that clinical outcomes weren’t significantly better with a routine initial invasive strategy than with medical therapy alone in patients with stable coronary artery disease and moderate or severe myocardial ischemia on noninvasive testing. But
ISCHEMIA participants in the sweet spot for an initial invasive strategy were the ones with a baseline history of mild to moderate heart failure symptoms and a left ventricular ejection fraction (LVEF) of 35%-45%, Renato Lopes, MD, PhD, reported at the virtual annual congress of the European Society of Cardiology.
“An invasive approach may be beneficial in this subgroup of high-risk patients with moderate to severe ischemia and a history of heart failure and left ventricular dysfunction,” declared Dr. Lopes, professor of medicine at Duke University, Durham, N.C.
He was quick to add, however, that this finding from ISCHEMIA should be considered hypothesis generating in light of the small sample size in the subgroup analysis.
The ISCHEMIA trial randomized 5,179 patients with stable CAD and at least moderate myocardial ischemia on noninvasive testing to a routine invasive or conservative management strategy. At 4 years of follow-up there was no significant between-group difference in cardiovascular outcomes (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Patients with a baseline LVEF below 35% weren’t eligible for enrollment in ISCHEMIA. That’s because the prior Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) showed patients with ischemic cardiomyopathy and an LVEF below 35% had a significantly lower cardiovascular death rate with surgical revascularization plus medical therapy than optimal medical therapy alone at 10 years of follow-up (N Engl J Med. 2016 Apr 21;374[16]:1511-20).
But what about the impact of immediate revascularization as compared with medical management alone in patients with milder impairment of LVEF in the 35%-45% range and/or a history of symptomatic heart failure? Theoretically, the improved blood flow to ischemic myocardium obtained via revascularization in such patients might activate hibernating myocardium and reduce ventricular dysfunction, thereby reducing the risk of cardiovascular events. The ISCHEMIA trial provided a unique opportunity to prospectively examine this question in 398 affected study participants, Dr. Lopes explained.
This 398-patient subgroup with a baseline history of heart failure and/or left ventricular dysfunction (HF/LVD) was at higher risk than patients without those features. Indeed, the primary outcome in ISCHEMIA – a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest – occurred in 22.7% of the HF/LVD group at 4 years of follow-up, compared with 13.8% of the much larger group without HF/LVD. The HF/LVD group also had significantly higher rates of the secondary composite endpoints of cardiovascular death or MI (19.7% vs. 12.3%) and all-cause mortality or heart failure (15% vs. 6.9%).
The provocative central finding in this new subanalysis was that patients in the HF/LVD subgroup fared significantly better in terms of cardiovascular events if randomized to the initial invasive approach. Indeed, their 4-year rate of the primary outcome was 17.2%, compared with 29.3% with an initial conservative approach. The various secondary outcomes followed suit. In contrast, the primary outcome occurred in 13% of patients without HF/LVD who were randomized to the invasive strategy, not significantly different from the 14.6% rate with conservative management.
Drilling deeper into the data, Dr. Lopes and coinvestigators found that the enhanced event-free survival benefit of an initial invasive strategy was restricted to the 28 patients having both a baseline history of symptomatic heart failure and an LVEF of 35%-45%. There was no significant difference in outcomes with an invasive versus conservative strategy in the 177 patients with a history of heart failure whose LVEF was greater than 50% – that is, patients with heart failure with preserved ejection fraction – nor in the 193 participants with an LVEF of 35%-45% but no history of symptomatic heart failure.
In an interview, Mark H. Drazner, MD, commented, “this is an interesting hypothesis, for sure, that warrants further study to confirm whether it’s valid. And if it is valid, there could be real implications. If this is true, I think there could be a decent number of patients out there that this would have implications for.
“The ISCHEMIA trial was a heroic effort. While there are certainly logistical hurdles involved in anybody doing an ISCHEMIA 2 trial based on this small subgroup analysis, other people could start looking at retrospective datasets and see if they can confirm these findings to build momentum to study this further,” said Dr. Drazner, professor of medicine and chief of clinical cardiology at the University of Texas Southwestern Medical Center, Dallas, as well as an associate editor at Circulation.
Dr. Lopes reported receiving research grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis as well as serving as a consultant to a handful of pharmaceutical companies, none relevant to his presentation.
Simultaneous with his presentation at ESC Congress 2020, Dr. Lopes’ study was published online in Circulation.
SOURCE: Lopes R et al. Circulation. 2020 Aug 29. doi: 10.1161/CIRCULATIONAHA.120.050304.
The landmark ISCHEMIA trial rattled the cardiology world with its message that clinical outcomes weren’t significantly better with a routine initial invasive strategy than with medical therapy alone in patients with stable coronary artery disease and moderate or severe myocardial ischemia on noninvasive testing. But
ISCHEMIA participants in the sweet spot for an initial invasive strategy were the ones with a baseline history of mild to moderate heart failure symptoms and a left ventricular ejection fraction (LVEF) of 35%-45%, Renato Lopes, MD, PhD, reported at the virtual annual congress of the European Society of Cardiology.
“An invasive approach may be beneficial in this subgroup of high-risk patients with moderate to severe ischemia and a history of heart failure and left ventricular dysfunction,” declared Dr. Lopes, professor of medicine at Duke University, Durham, N.C.
He was quick to add, however, that this finding from ISCHEMIA should be considered hypothesis generating in light of the small sample size in the subgroup analysis.
The ISCHEMIA trial randomized 5,179 patients with stable CAD and at least moderate myocardial ischemia on noninvasive testing to a routine invasive or conservative management strategy. At 4 years of follow-up there was no significant between-group difference in cardiovascular outcomes (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Patients with a baseline LVEF below 35% weren’t eligible for enrollment in ISCHEMIA. That’s because the prior Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) showed patients with ischemic cardiomyopathy and an LVEF below 35% had a significantly lower cardiovascular death rate with surgical revascularization plus medical therapy than optimal medical therapy alone at 10 years of follow-up (N Engl J Med. 2016 Apr 21;374[16]:1511-20).
But what about the impact of immediate revascularization as compared with medical management alone in patients with milder impairment of LVEF in the 35%-45% range and/or a history of symptomatic heart failure? Theoretically, the improved blood flow to ischemic myocardium obtained via revascularization in such patients might activate hibernating myocardium and reduce ventricular dysfunction, thereby reducing the risk of cardiovascular events. The ISCHEMIA trial provided a unique opportunity to prospectively examine this question in 398 affected study participants, Dr. Lopes explained.
This 398-patient subgroup with a baseline history of heart failure and/or left ventricular dysfunction (HF/LVD) was at higher risk than patients without those features. Indeed, the primary outcome in ISCHEMIA – a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest – occurred in 22.7% of the HF/LVD group at 4 years of follow-up, compared with 13.8% of the much larger group without HF/LVD. The HF/LVD group also had significantly higher rates of the secondary composite endpoints of cardiovascular death or MI (19.7% vs. 12.3%) and all-cause mortality or heart failure (15% vs. 6.9%).
The provocative central finding in this new subanalysis was that patients in the HF/LVD subgroup fared significantly better in terms of cardiovascular events if randomized to the initial invasive approach. Indeed, their 4-year rate of the primary outcome was 17.2%, compared with 29.3% with an initial conservative approach. The various secondary outcomes followed suit. In contrast, the primary outcome occurred in 13% of patients without HF/LVD who were randomized to the invasive strategy, not significantly different from the 14.6% rate with conservative management.
Drilling deeper into the data, Dr. Lopes and coinvestigators found that the enhanced event-free survival benefit of an initial invasive strategy was restricted to the 28 patients having both a baseline history of symptomatic heart failure and an LVEF of 35%-45%. There was no significant difference in outcomes with an invasive versus conservative strategy in the 177 patients with a history of heart failure whose LVEF was greater than 50% – that is, patients with heart failure with preserved ejection fraction – nor in the 193 participants with an LVEF of 35%-45% but no history of symptomatic heart failure.
In an interview, Mark H. Drazner, MD, commented, “this is an interesting hypothesis, for sure, that warrants further study to confirm whether it’s valid. And if it is valid, there could be real implications. If this is true, I think there could be a decent number of patients out there that this would have implications for.
“The ISCHEMIA trial was a heroic effort. While there are certainly logistical hurdles involved in anybody doing an ISCHEMIA 2 trial based on this small subgroup analysis, other people could start looking at retrospective datasets and see if they can confirm these findings to build momentum to study this further,” said Dr. Drazner, professor of medicine and chief of clinical cardiology at the University of Texas Southwestern Medical Center, Dallas, as well as an associate editor at Circulation.
Dr. Lopes reported receiving research grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis as well as serving as a consultant to a handful of pharmaceutical companies, none relevant to his presentation.
Simultaneous with his presentation at ESC Congress 2020, Dr. Lopes’ study was published online in Circulation.
SOURCE: Lopes R et al. Circulation. 2020 Aug 29. doi: 10.1161/CIRCULATIONAHA.120.050304.
The landmark ISCHEMIA trial rattled the cardiology world with its message that clinical outcomes weren’t significantly better with a routine initial invasive strategy than with medical therapy alone in patients with stable coronary artery disease and moderate or severe myocardial ischemia on noninvasive testing. But
ISCHEMIA participants in the sweet spot for an initial invasive strategy were the ones with a baseline history of mild to moderate heart failure symptoms and a left ventricular ejection fraction (LVEF) of 35%-45%, Renato Lopes, MD, PhD, reported at the virtual annual congress of the European Society of Cardiology.
“An invasive approach may be beneficial in this subgroup of high-risk patients with moderate to severe ischemia and a history of heart failure and left ventricular dysfunction,” declared Dr. Lopes, professor of medicine at Duke University, Durham, N.C.
He was quick to add, however, that this finding from ISCHEMIA should be considered hypothesis generating in light of the small sample size in the subgroup analysis.
The ISCHEMIA trial randomized 5,179 patients with stable CAD and at least moderate myocardial ischemia on noninvasive testing to a routine invasive or conservative management strategy. At 4 years of follow-up there was no significant between-group difference in cardiovascular outcomes (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Patients with a baseline LVEF below 35% weren’t eligible for enrollment in ISCHEMIA. That’s because the prior Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) showed patients with ischemic cardiomyopathy and an LVEF below 35% had a significantly lower cardiovascular death rate with surgical revascularization plus medical therapy than optimal medical therapy alone at 10 years of follow-up (N Engl J Med. 2016 Apr 21;374[16]:1511-20).
But what about the impact of immediate revascularization as compared with medical management alone in patients with milder impairment of LVEF in the 35%-45% range and/or a history of symptomatic heart failure? Theoretically, the improved blood flow to ischemic myocardium obtained via revascularization in such patients might activate hibernating myocardium and reduce ventricular dysfunction, thereby reducing the risk of cardiovascular events. The ISCHEMIA trial provided a unique opportunity to prospectively examine this question in 398 affected study participants, Dr. Lopes explained.
This 398-patient subgroup with a baseline history of heart failure and/or left ventricular dysfunction (HF/LVD) was at higher risk than patients without those features. Indeed, the primary outcome in ISCHEMIA – a composite of cardiovascular death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest – occurred in 22.7% of the HF/LVD group at 4 years of follow-up, compared with 13.8% of the much larger group without HF/LVD. The HF/LVD group also had significantly higher rates of the secondary composite endpoints of cardiovascular death or MI (19.7% vs. 12.3%) and all-cause mortality or heart failure (15% vs. 6.9%).
The provocative central finding in this new subanalysis was that patients in the HF/LVD subgroup fared significantly better in terms of cardiovascular events if randomized to the initial invasive approach. Indeed, their 4-year rate of the primary outcome was 17.2%, compared with 29.3% with an initial conservative approach. The various secondary outcomes followed suit. In contrast, the primary outcome occurred in 13% of patients without HF/LVD who were randomized to the invasive strategy, not significantly different from the 14.6% rate with conservative management.
Drilling deeper into the data, Dr. Lopes and coinvestigators found that the enhanced event-free survival benefit of an initial invasive strategy was restricted to the 28 patients having both a baseline history of symptomatic heart failure and an LVEF of 35%-45%. There was no significant difference in outcomes with an invasive versus conservative strategy in the 177 patients with a history of heart failure whose LVEF was greater than 50% – that is, patients with heart failure with preserved ejection fraction – nor in the 193 participants with an LVEF of 35%-45% but no history of symptomatic heart failure.
In an interview, Mark H. Drazner, MD, commented, “this is an interesting hypothesis, for sure, that warrants further study to confirm whether it’s valid. And if it is valid, there could be real implications. If this is true, I think there could be a decent number of patients out there that this would have implications for.
“The ISCHEMIA trial was a heroic effort. While there are certainly logistical hurdles involved in anybody doing an ISCHEMIA 2 trial based on this small subgroup analysis, other people could start looking at retrospective datasets and see if they can confirm these findings to build momentum to study this further,” said Dr. Drazner, professor of medicine and chief of clinical cardiology at the University of Texas Southwestern Medical Center, Dallas, as well as an associate editor at Circulation.
Dr. Lopes reported receiving research grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis as well as serving as a consultant to a handful of pharmaceutical companies, none relevant to his presentation.
Simultaneous with his presentation at ESC Congress 2020, Dr. Lopes’ study was published online in Circulation.
SOURCE: Lopes R et al. Circulation. 2020 Aug 29. doi: 10.1161/CIRCULATIONAHA.120.050304.
FROM ESC CONGRESS 2020
REALITY trial supports restrictive transfusion in anemic MI
in the landmark REALITY trial.
Randomized trial data already support a restrictive transfusion strategy in patients undergoing cardiac and noncardiac surgery, as well as in other settings. Those trials deliberately excluded patients with acute myocardial ischemia.
Cardiologists have been loath to adopt a restrictive strategy in the absence of persuasive supporting evidence because of a theoretic concern that low hemoglobin might be particularly harmful to ischemic myocardium. Anemia occurs in 5%-10% patients with MI, and clinicians have been eager for evidence-based guidance on how to best manage it.
“Blood is a precious resource and transfusion is costly, logistically cumbersome, and has side effects,” Philippe Gabriel Steg, MD, chair of the REALITY trial, noted in presenting the study results at the virtual annual congress of the European Society of Cardiology.
REALITY was the first-ever large randomized trial of a restrictive versus liberal transfusion strategy in acute MI. The study, which featured a noninferiority design, included 668 stable patients with acute MI and anemia with a hemoglobin of 7-10 g/dL at 35 hospitals in France and Spain. Participants were randomized to a restrictive strategy in which transfusion was withheld unless the hemoglobin dropped to 8 g/dL or less, or to a conventional liberal strategy triggered by a hemoglobin of 10 g/dL or lower. The transfusion target was a hemoglobin level of 8-10 g/dL in the restrictive strategy group and greater than 11 g/dL in the liberal transfusion group. In the restrictive transfusion group, 36% received at least one RBC transfusion, as did 87% in the liberal transfusion study arm. The restrictive strategy group used 414 fewer units of blood.
The two coprimary endpoints were 30-day major adverse cardiovascular events and cost-effectiveness. The 30-day composite of all-cause mortality, reinfarction, stroke, and emergency percutaneous coronary intervention for myocardial ischemia occurred in 11% of the restrictive transfusion group and 14% of the liberal transfusion group. The resultant 21% relative risk reduction established that the restrictive strategy was noninferior. Of note, all of the individual components of the composite endpoint numerically favored the restrictive approach.
In terms of safety, patients in the restrictive transfusion group were significantly less likely to develop an infection, by a margin of 0% versus 1.5%. The rate of acute lung injury was also significantly lower in the restrictive group: 0.3%, compared with 2.2%. The median hospital length of stay was identical at 7 days in both groups.
The cost-effectiveness analysis concluded that the restrictive transfusion strategy had an 84% probability of being both less expensive and more effective.
Patients were enrolled in REALITY regardless of whether they had active bleeding, as long as the bleeding wasn’t deemed massive and life-threatening. Notably, there was no difference in the results of restrictive versus liberal transfusion regardless of whether active bleeding was present, nor did baseline hemoglobin or the presence or absence of preexisting anemia affect the results.
Dr. Steg noted that a much larger randomized trial of restrictive versus liberal transfusion in the setting of acute MI with anemia is underway in the United States and Canada. The 3,000-patient MINT trial, sponsored by the National Institutes of Health, is testing the superiority of restrictive transfusion, rather than its noninferiority, as in REALITY. Results are a couple of years away.
“I think that will be an important piece of additional evidence,” he said.
Discussant Marco Roffi, MD, didn’t mince words.
“I really love the REALITY trial,” declared Dr. Roffi, professor and vice chairman of the cardiology department and director of the interventional cardiology unit at University Hospital of Geneva.
He ticked off a series of reasons: The trial addressed a common clinical dilemma about which there has been essentially no prior high-quality evidence, it provided convincing results, and it carried important implications for responsible stewardship of the blood supply.
“REALITY allows clinicians to comfortably refrain from transfusing anemic patients presenting with myocardial infarction, and this should lead to a reduction in the consumption of blood products,” Dr. Roffi said.
He applauded the investigators for their success in obtaining public funding for a study lacking a commercial hook. And as a clinical investigator, he was particularly impressed by one of the technical details about the REALITY trial: “I was amazed by the fact that the observed event rates virtually corresponded to the estimated ones used for the power calculations. This is rarely the case in such a trial.”
Dr. Roffi said the REALITY findings should have an immediate impact on clinical practice, as well as on the brand new 2020 ESC guidelines on the management of non–ST-elevation ACS issued during the ESC virtual congress.
The freshly inked guidelines state: “Based on inconsistent study results and the lack of adequately powered randomized, controlled trials, a restrictive policy of transfusion in anemic patients with MI may be considered.” As of today, Dr. Roffi argued, the phrase “may be considered” ought to be replaced by the stronger phrase “should be considered.”
During the discussion period, he was asked if it’s appropriate to extrapolate the REALITY results to patients undergoing transcatheter aortic valve replacement, among whom anemia is highly prevalent.
“I think this is a different patient population. Nevertheless, the concept of being restrictive is one that in my opinion now remains until proven otherwise. So we are being very restrictive in these patients,” he replied.
Asked about possible mechanisms by which liberal transfusion might have detrimental effects in acute MI patients, Dr. Steg cited several, including evidence that transfusion may not improve oxygen delivery to as great an extent as traditionally thought. There is also the risk of volume overload, increased blood viscosity, and enhanced platelet aggregation and activation, which could promote myocardial ischemia.
The REALITY trial was funded by the French Ministry of Health and the Spanish Ministry of Economy and Competitiveness with no commercial support. Outside the scope of the trial, Dr. Steg reported receiving research grants from Bayer, Merck, Servier, and Sanofi as well as serving as a consultant to numerous pharmaceutical companies.
in the landmark REALITY trial.
Randomized trial data already support a restrictive transfusion strategy in patients undergoing cardiac and noncardiac surgery, as well as in other settings. Those trials deliberately excluded patients with acute myocardial ischemia.
Cardiologists have been loath to adopt a restrictive strategy in the absence of persuasive supporting evidence because of a theoretic concern that low hemoglobin might be particularly harmful to ischemic myocardium. Anemia occurs in 5%-10% patients with MI, and clinicians have been eager for evidence-based guidance on how to best manage it.
“Blood is a precious resource and transfusion is costly, logistically cumbersome, and has side effects,” Philippe Gabriel Steg, MD, chair of the REALITY trial, noted in presenting the study results at the virtual annual congress of the European Society of Cardiology.
REALITY was the first-ever large randomized trial of a restrictive versus liberal transfusion strategy in acute MI. The study, which featured a noninferiority design, included 668 stable patients with acute MI and anemia with a hemoglobin of 7-10 g/dL at 35 hospitals in France and Spain. Participants were randomized to a restrictive strategy in which transfusion was withheld unless the hemoglobin dropped to 8 g/dL or less, or to a conventional liberal strategy triggered by a hemoglobin of 10 g/dL or lower. The transfusion target was a hemoglobin level of 8-10 g/dL in the restrictive strategy group and greater than 11 g/dL in the liberal transfusion group. In the restrictive transfusion group, 36% received at least one RBC transfusion, as did 87% in the liberal transfusion study arm. The restrictive strategy group used 414 fewer units of blood.
The two coprimary endpoints were 30-day major adverse cardiovascular events and cost-effectiveness. The 30-day composite of all-cause mortality, reinfarction, stroke, and emergency percutaneous coronary intervention for myocardial ischemia occurred in 11% of the restrictive transfusion group and 14% of the liberal transfusion group. The resultant 21% relative risk reduction established that the restrictive strategy was noninferior. Of note, all of the individual components of the composite endpoint numerically favored the restrictive approach.
In terms of safety, patients in the restrictive transfusion group were significantly less likely to develop an infection, by a margin of 0% versus 1.5%. The rate of acute lung injury was also significantly lower in the restrictive group: 0.3%, compared with 2.2%. The median hospital length of stay was identical at 7 days in both groups.
The cost-effectiveness analysis concluded that the restrictive transfusion strategy had an 84% probability of being both less expensive and more effective.
Patients were enrolled in REALITY regardless of whether they had active bleeding, as long as the bleeding wasn’t deemed massive and life-threatening. Notably, there was no difference in the results of restrictive versus liberal transfusion regardless of whether active bleeding was present, nor did baseline hemoglobin or the presence or absence of preexisting anemia affect the results.
Dr. Steg noted that a much larger randomized trial of restrictive versus liberal transfusion in the setting of acute MI with anemia is underway in the United States and Canada. The 3,000-patient MINT trial, sponsored by the National Institutes of Health, is testing the superiority of restrictive transfusion, rather than its noninferiority, as in REALITY. Results are a couple of years away.
“I think that will be an important piece of additional evidence,” he said.
Discussant Marco Roffi, MD, didn’t mince words.
“I really love the REALITY trial,” declared Dr. Roffi, professor and vice chairman of the cardiology department and director of the interventional cardiology unit at University Hospital of Geneva.
He ticked off a series of reasons: The trial addressed a common clinical dilemma about which there has been essentially no prior high-quality evidence, it provided convincing results, and it carried important implications for responsible stewardship of the blood supply.
“REALITY allows clinicians to comfortably refrain from transfusing anemic patients presenting with myocardial infarction, and this should lead to a reduction in the consumption of blood products,” Dr. Roffi said.
He applauded the investigators for their success in obtaining public funding for a study lacking a commercial hook. And as a clinical investigator, he was particularly impressed by one of the technical details about the REALITY trial: “I was amazed by the fact that the observed event rates virtually corresponded to the estimated ones used for the power calculations. This is rarely the case in such a trial.”
Dr. Roffi said the REALITY findings should have an immediate impact on clinical practice, as well as on the brand new 2020 ESC guidelines on the management of non–ST-elevation ACS issued during the ESC virtual congress.
The freshly inked guidelines state: “Based on inconsistent study results and the lack of adequately powered randomized, controlled trials, a restrictive policy of transfusion in anemic patients with MI may be considered.” As of today, Dr. Roffi argued, the phrase “may be considered” ought to be replaced by the stronger phrase “should be considered.”
During the discussion period, he was asked if it’s appropriate to extrapolate the REALITY results to patients undergoing transcatheter aortic valve replacement, among whom anemia is highly prevalent.
“I think this is a different patient population. Nevertheless, the concept of being restrictive is one that in my opinion now remains until proven otherwise. So we are being very restrictive in these patients,” he replied.
Asked about possible mechanisms by which liberal transfusion might have detrimental effects in acute MI patients, Dr. Steg cited several, including evidence that transfusion may not improve oxygen delivery to as great an extent as traditionally thought. There is also the risk of volume overload, increased blood viscosity, and enhanced platelet aggregation and activation, which could promote myocardial ischemia.
The REALITY trial was funded by the French Ministry of Health and the Spanish Ministry of Economy and Competitiveness with no commercial support. Outside the scope of the trial, Dr. Steg reported receiving research grants from Bayer, Merck, Servier, and Sanofi as well as serving as a consultant to numerous pharmaceutical companies.
in the landmark REALITY trial.
Randomized trial data already support a restrictive transfusion strategy in patients undergoing cardiac and noncardiac surgery, as well as in other settings. Those trials deliberately excluded patients with acute myocardial ischemia.
Cardiologists have been loath to adopt a restrictive strategy in the absence of persuasive supporting evidence because of a theoretic concern that low hemoglobin might be particularly harmful to ischemic myocardium. Anemia occurs in 5%-10% patients with MI, and clinicians have been eager for evidence-based guidance on how to best manage it.
“Blood is a precious resource and transfusion is costly, logistically cumbersome, and has side effects,” Philippe Gabriel Steg, MD, chair of the REALITY trial, noted in presenting the study results at the virtual annual congress of the European Society of Cardiology.
REALITY was the first-ever large randomized trial of a restrictive versus liberal transfusion strategy in acute MI. The study, which featured a noninferiority design, included 668 stable patients with acute MI and anemia with a hemoglobin of 7-10 g/dL at 35 hospitals in France and Spain. Participants were randomized to a restrictive strategy in which transfusion was withheld unless the hemoglobin dropped to 8 g/dL or less, or to a conventional liberal strategy triggered by a hemoglobin of 10 g/dL or lower. The transfusion target was a hemoglobin level of 8-10 g/dL in the restrictive strategy group and greater than 11 g/dL in the liberal transfusion group. In the restrictive transfusion group, 36% received at least one RBC transfusion, as did 87% in the liberal transfusion study arm. The restrictive strategy group used 414 fewer units of blood.
The two coprimary endpoints were 30-day major adverse cardiovascular events and cost-effectiveness. The 30-day composite of all-cause mortality, reinfarction, stroke, and emergency percutaneous coronary intervention for myocardial ischemia occurred in 11% of the restrictive transfusion group and 14% of the liberal transfusion group. The resultant 21% relative risk reduction established that the restrictive strategy was noninferior. Of note, all of the individual components of the composite endpoint numerically favored the restrictive approach.
In terms of safety, patients in the restrictive transfusion group were significantly less likely to develop an infection, by a margin of 0% versus 1.5%. The rate of acute lung injury was also significantly lower in the restrictive group: 0.3%, compared with 2.2%. The median hospital length of stay was identical at 7 days in both groups.
The cost-effectiveness analysis concluded that the restrictive transfusion strategy had an 84% probability of being both less expensive and more effective.
Patients were enrolled in REALITY regardless of whether they had active bleeding, as long as the bleeding wasn’t deemed massive and life-threatening. Notably, there was no difference in the results of restrictive versus liberal transfusion regardless of whether active bleeding was present, nor did baseline hemoglobin or the presence or absence of preexisting anemia affect the results.
Dr. Steg noted that a much larger randomized trial of restrictive versus liberal transfusion in the setting of acute MI with anemia is underway in the United States and Canada. The 3,000-patient MINT trial, sponsored by the National Institutes of Health, is testing the superiority of restrictive transfusion, rather than its noninferiority, as in REALITY. Results are a couple of years away.
“I think that will be an important piece of additional evidence,” he said.
Discussant Marco Roffi, MD, didn’t mince words.
“I really love the REALITY trial,” declared Dr. Roffi, professor and vice chairman of the cardiology department and director of the interventional cardiology unit at University Hospital of Geneva.
He ticked off a series of reasons: The trial addressed a common clinical dilemma about which there has been essentially no prior high-quality evidence, it provided convincing results, and it carried important implications for responsible stewardship of the blood supply.
“REALITY allows clinicians to comfortably refrain from transfusing anemic patients presenting with myocardial infarction, and this should lead to a reduction in the consumption of blood products,” Dr. Roffi said.
He applauded the investigators for their success in obtaining public funding for a study lacking a commercial hook. And as a clinical investigator, he was particularly impressed by one of the technical details about the REALITY trial: “I was amazed by the fact that the observed event rates virtually corresponded to the estimated ones used for the power calculations. This is rarely the case in such a trial.”
Dr. Roffi said the REALITY findings should have an immediate impact on clinical practice, as well as on the brand new 2020 ESC guidelines on the management of non–ST-elevation ACS issued during the ESC virtual congress.
The freshly inked guidelines state: “Based on inconsistent study results and the lack of adequately powered randomized, controlled trials, a restrictive policy of transfusion in anemic patients with MI may be considered.” As of today, Dr. Roffi argued, the phrase “may be considered” ought to be replaced by the stronger phrase “should be considered.”
During the discussion period, he was asked if it’s appropriate to extrapolate the REALITY results to patients undergoing transcatheter aortic valve replacement, among whom anemia is highly prevalent.
“I think this is a different patient population. Nevertheless, the concept of being restrictive is one that in my opinion now remains until proven otherwise. So we are being very restrictive in these patients,” he replied.
Asked about possible mechanisms by which liberal transfusion might have detrimental effects in acute MI patients, Dr. Steg cited several, including evidence that transfusion may not improve oxygen delivery to as great an extent as traditionally thought. There is also the risk of volume overload, increased blood viscosity, and enhanced platelet aggregation and activation, which could promote myocardial ischemia.
The REALITY trial was funded by the French Ministry of Health and the Spanish Ministry of Economy and Competitiveness with no commercial support. Outside the scope of the trial, Dr. Steg reported receiving research grants from Bayer, Merck, Servier, and Sanofi as well as serving as a consultant to numerous pharmaceutical companies.
REPORTING FROM ESC CONGRESS 2020
HOME-PE trial clarifies which pulmonary embolism patients to treat at home
The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.
“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.
The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).
The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).
HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.
However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.
Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.
Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”
“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).
In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.
The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.
Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.
“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.
The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).
The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).
HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.
However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.
Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.
Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”
“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).
In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.
The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.
Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
The pragmatic Hestia criteria proved as safe as the more structured, points-based simplified Pulmonary Embolism Severity Index (sPESI) score for selection of patients with acute pulmonary embolism for outpatient care in the large, randomized HOME-PE trial presented at the virtual annual congress of the European Society of Cardiology.
“These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for the physician-in-charge to override the decision. In hospitals organized for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications,” Pierre-Marie Roy, MD, said in presenting the HOME-PE findings.
The study clarifies a transatlantic controversy regarding how best to triage patients with acute pulmonary embolism (PE) for outpatient care. The answer? It’s basically a tie between the points-based sPESI score recommended in the current ESC guidelines (Eur Respir J. 2019 Oct 9;54[3]:1901647) and the Hestia method endorsed in the American College of Chest Physician guidelines (Chest. 2016 Feb;149[2]:315-52).
The sPESI is a validated tool that grants 1 point each for age over 80 years, background cardiopulmonary disease, a systolic blood pressure below 100 mm Hg, cancer, a heart rate of 110 bpm or more, and an oxygen saturation level below 90%. A patient needs a score of zero to be eligible for outpatient management. In contrast, the Hestia method relies upon 11 simple bedside criteria rather than a points system, explained Dr. Roy of University Hospital of Angers, France (J Thromb Haemost. 2011 Aug;9[8]:1500-7).
HOME-PE was a randomized, open-label, noninferiority trial conducted at 26 hospitals in France, Belgium, Switzerland, and the Netherlands. The study included 1,974 patients presenting to the emergency department with non–high-risk acute PE as defined by hemodynamic stability. About 39% of patients in the Hestia group were eligible for outpatient care on the basis of ‘no’ answers regarding all 11 criteria, while 48% of patients had an sPESI score of 0 and were thus initially considered appropriate for outpatient management.
However, the investigators recognized that no scoring system for acute PE is perfect, and that the judgment of a physician with extensive experience in managing this life-threatening condition counts for a lot. So they stipulated that a patient’s physician-in-charge could overrule a decision for early discharge. This happened 29% of the time in patients with a sPESI score of 0, as compared with a 3% overrule rate with the Hestia rule. The physician-in-charge also moved small numbers of patients who were Hestia or sPESI positive into the outpatient care group. As a result, a similar proportion of patients in both groups were discharged home within 24 hours for outpatient treatment: 38% of the total Hestia group and 37% in the sPESI arm.
Major adverse event rates were reassuringly low in both groups managed on an outpatient basis. The composite of recurrent venous thromboembolism, bleeding, or death within 30 days occurred in 1.3% of Hestia outpatients and 1.1% of sPESI outpatients. Among patients managed in the hospital, these rates were 5.6% in the Hestia group and 4.7% in the sPESI group.
Discussant Stavros V. Konstantinides, MD, who chaired the ESC guideline committee, asked rhetorically, “who’s happy with the HOME-PE trial? I think everybody.”
“The Hestia criteria integrate the feasibility of family support of the individual patient. This is a good thing. And eligibility based on the Hestia criteria, unlike sPESI, does not require age younger than 80 years or no cancer, and it appears from the HOME-PE study that this is okay,” observed Dr. Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz (Germany).
In an interview, Hadley Wilson, MD, called the HOME-PE trial “transformative” and predicted it will change clinical practice. He was particularly impressed with the high quality of the trial, noting that 87% of participants managed as outpatients received a direct oral anticoagulant.
The Hestia rule is simpler and more user-friendly. And greater use of this triaging strategy might have advantages in terms of economics and health care utilization by potentially encouraging movement of decision-making regarding outpatient management of acute PE out of the hospital wards and into emergency departments, said Dr. Wilson, executive vice chair of the Sanger Heart and Vascular Institute and a cardiologist at the University of North Carolina at Chapel Hill.
Dr. Roy reported receiving research grants to conduct HOME-PE from the French Ministry of Health, the study sponsor. In addition, he is on scientific advisory boards and/or speakers’ panels for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi Aventis.
REPORTING FROM ESC CONGRESS 2020
RATE-AF trial boosts digoxin for rate control in permanent AFib
Digoxin now deserves to be considered first-line therapy for long-term heart rate control in older patients with permanent atrial fibrillation and symptoms of heart failure, Dipak Kotecha, MBChB, PhD, MSc, declared at the virtual annual congress of the European Society of Cardiology.
He presented the 12-month results of RATE-AF (Rate Control Therapy Evaluation in Permanent Atrial Fibrillation), in which 160 seniors (mean age, 76 years) with moderate or severe symptoms caused by permanent atrial fibrillation (AFib) as well as heart failure symptoms were randomized to low-dose digoxin or the beta-blocker bisoprolol for rate control.
The open-label trial was designed to address a centuries-old unmet need: “Although digoxin has been in use since 1785, we have no longer-term clinical trials of digoxin in patients with AFib or AFib with heart failure,” noted Dr. Kotecha, professor of cardiology at the University of Birmingham (England).
Not only is digoxin greatly understudied in AFib, but permanent AFib – the most common form of the arrhythmia – has received only a tiny fraction of the research attention that’s been devoted to paroxysmal or persistent AFib, he added.
In RATE-AF, digoxin and bisoprolol proved similarly effective at reducing heart rate, from about 100 bpm at baseline to the mid-70s at 6 and 12 months. Notably, only a handful of study participants required an additional rate control drug during the 12-month study. Nor did the two drugs differ in terms of their impact on patient-reported quality of life at 6 months as reflected by their Short Form–36 physical component score, the primary study endpoint. And both drugs were well tolerated, with 96% of patients in the digoxin group still on the drug at a mean of 161 mcg/day at 6 months, and 89% still on their beta-blocker.
But that’s pretty much where the similarities in outcomes ended.
For example, at 12 months, the digoxin group scored significantly higher than the beta-blocker group on several domains of the Short Form–36 physical component score, including vitality, physical function, and global health. More than half of the digoxin group had a two-class improvement in modified European Heart Rhythm Association AFib-related symptoms at 6 months, compared with 10% of the beta-blocker group. At 12 months, nearly 70% of the digoxin group had a two-class improvement, as did 30% on bisoprolol.
Heart failure symptoms in the digoxin group improved from a mean baseline New York Heart Association class of 2.4 to 1.5 at both 6 and 12 months; the improvement was more modest in the beta-blocker group, going from NYHA 2.4 at baseline to 2.0 at both 6 and 12 months. And while N-terminal of the prohormone brain natriuretic peptide levels improved in the digoxin group from a baseline of 1,095 pg/mL to 1,058 at 6 months and 960 at 12 months, NT-proBNP actually went up in the beta-blocker group, from 1,041 to 1,209-1,250 pg/mL at 12 months.
Moreover, Dr. Kotecha continued, while RATE-AF was underpowered to assess clinical events, it’s nevertheless noteworthy that a total of 29 adverse events occurred in 12 months in the digoxin group, compared with 142 with beta-blocker therapy. There were 12 unplanned hospital admissions in the digoxin group and 28 in the beta-blocker group, and 22 primary care visits for either AFib or cardiovascular symptoms in patients on digoxin versus 64 in the beta-blocker group.
“Our results suggest a wider use of digoxin for stable patients with permanent AFib,” Dr. Kotecha concluded. However, in an interview, Jonathan Piccini, MD, had a different take on the study results.
“I don’t think this study should widely impact clinical practice in the U.S.,” according to Dr. Piccini, director of cardiac electrophysiology at Duke University, Durham, N.C.
His reservations included RATE-AF’s modest sample size as well as uncertainty as to the trial’s generalizability, given that bisoprolol isn’t much used in the United States. Also, these were elderly patients with shortness of breath, and it’s unclear how effective digoxin would be for rate control in patients with permanent AFib who are more active.
“The classic teaching is that digoxin is great for rate control at rest, but when people are active it’s not nearly as good as beta-blockers or calcium-channel blockers,” the cardiologist said.
“A beta-blocker is still going to be my first-line rate control agent. But the results of RATE-AF do open my mind that for an older sedentary patient I may very well think twice now about using digoxin, because in that situation it looks like it achieves similar goals as a beta-blocker,” Dr. Piccini added.
On the plus side for RATE-AF: “I am very pleased to see that we have a randomized controlled trial focused on rate control in permanent AFib. It also tickles me pink to see a randomized, controlled study of digoxin. And I’m really excited to see a clinical trial that focuses on quality of life. It should give some confidence to know that from a quality of life perspective clinicians can consider using either digoxin or a beta-blocker for rate control,” he said.
American College of Cardiology vice president Dipti Itchhaporia, MD, said she’d need to see a much larger randomized trial including a calcium-channel blocker as a third-rate control arm before she’d consider digoxin as first-line rate control therapy in patients with AFib with or without heart failure. Also, she has reservations about drawing definitive conclusions from an open, unblinded study in which patient-reported outcomes are the primary endpoint.
“I think these were surprising findings given what we all think about digoxin in this country. In general, digoxin fell out of favor for rate control, mainly because of observational studies showing increased mortality. So most of us choose a beta-blocker,” she observed in an interview.
But of course, a randomized trial, even a 160-patient randomized trial, constitutes a higher level of evidence.
“I don’t think I’m going to convert tomorrow and make digoxin my first-line rate control therapy without more data. But RATE-AF does makes me stop and think about using it more than I did before in some of my permanent AFib patients,” said Dr. Itchhaporia, director of disease management at Hoag Memorial Hospital in Newport Beach, Calif.
Dr. Kotecha reported having no financial conflicts regarding the study, which was funded by the U.K. National Institute for Health Research, the British Heart Foundation, and the European Union.
Digoxin now deserves to be considered first-line therapy for long-term heart rate control in older patients with permanent atrial fibrillation and symptoms of heart failure, Dipak Kotecha, MBChB, PhD, MSc, declared at the virtual annual congress of the European Society of Cardiology.
He presented the 12-month results of RATE-AF (Rate Control Therapy Evaluation in Permanent Atrial Fibrillation), in which 160 seniors (mean age, 76 years) with moderate or severe symptoms caused by permanent atrial fibrillation (AFib) as well as heart failure symptoms were randomized to low-dose digoxin or the beta-blocker bisoprolol for rate control.
The open-label trial was designed to address a centuries-old unmet need: “Although digoxin has been in use since 1785, we have no longer-term clinical trials of digoxin in patients with AFib or AFib with heart failure,” noted Dr. Kotecha, professor of cardiology at the University of Birmingham (England).
Not only is digoxin greatly understudied in AFib, but permanent AFib – the most common form of the arrhythmia – has received only a tiny fraction of the research attention that’s been devoted to paroxysmal or persistent AFib, he added.
In RATE-AF, digoxin and bisoprolol proved similarly effective at reducing heart rate, from about 100 bpm at baseline to the mid-70s at 6 and 12 months. Notably, only a handful of study participants required an additional rate control drug during the 12-month study. Nor did the two drugs differ in terms of their impact on patient-reported quality of life at 6 months as reflected by their Short Form–36 physical component score, the primary study endpoint. And both drugs were well tolerated, with 96% of patients in the digoxin group still on the drug at a mean of 161 mcg/day at 6 months, and 89% still on their beta-blocker.
But that’s pretty much where the similarities in outcomes ended.
For example, at 12 months, the digoxin group scored significantly higher than the beta-blocker group on several domains of the Short Form–36 physical component score, including vitality, physical function, and global health. More than half of the digoxin group had a two-class improvement in modified European Heart Rhythm Association AFib-related symptoms at 6 months, compared with 10% of the beta-blocker group. At 12 months, nearly 70% of the digoxin group had a two-class improvement, as did 30% on bisoprolol.
Heart failure symptoms in the digoxin group improved from a mean baseline New York Heart Association class of 2.4 to 1.5 at both 6 and 12 months; the improvement was more modest in the beta-blocker group, going from NYHA 2.4 at baseline to 2.0 at both 6 and 12 months. And while N-terminal of the prohormone brain natriuretic peptide levels improved in the digoxin group from a baseline of 1,095 pg/mL to 1,058 at 6 months and 960 at 12 months, NT-proBNP actually went up in the beta-blocker group, from 1,041 to 1,209-1,250 pg/mL at 12 months.
Moreover, Dr. Kotecha continued, while RATE-AF was underpowered to assess clinical events, it’s nevertheless noteworthy that a total of 29 adverse events occurred in 12 months in the digoxin group, compared with 142 with beta-blocker therapy. There were 12 unplanned hospital admissions in the digoxin group and 28 in the beta-blocker group, and 22 primary care visits for either AFib or cardiovascular symptoms in patients on digoxin versus 64 in the beta-blocker group.
“Our results suggest a wider use of digoxin for stable patients with permanent AFib,” Dr. Kotecha concluded. However, in an interview, Jonathan Piccini, MD, had a different take on the study results.
“I don’t think this study should widely impact clinical practice in the U.S.,” according to Dr. Piccini, director of cardiac electrophysiology at Duke University, Durham, N.C.
His reservations included RATE-AF’s modest sample size as well as uncertainty as to the trial’s generalizability, given that bisoprolol isn’t much used in the United States. Also, these were elderly patients with shortness of breath, and it’s unclear how effective digoxin would be for rate control in patients with permanent AFib who are more active.
“The classic teaching is that digoxin is great for rate control at rest, but when people are active it’s not nearly as good as beta-blockers or calcium-channel blockers,” the cardiologist said.
“A beta-blocker is still going to be my first-line rate control agent. But the results of RATE-AF do open my mind that for an older sedentary patient I may very well think twice now about using digoxin, because in that situation it looks like it achieves similar goals as a beta-blocker,” Dr. Piccini added.
On the plus side for RATE-AF: “I am very pleased to see that we have a randomized controlled trial focused on rate control in permanent AFib. It also tickles me pink to see a randomized, controlled study of digoxin. And I’m really excited to see a clinical trial that focuses on quality of life. It should give some confidence to know that from a quality of life perspective clinicians can consider using either digoxin or a beta-blocker for rate control,” he said.
American College of Cardiology vice president Dipti Itchhaporia, MD, said she’d need to see a much larger randomized trial including a calcium-channel blocker as a third-rate control arm before she’d consider digoxin as first-line rate control therapy in patients with AFib with or without heart failure. Also, she has reservations about drawing definitive conclusions from an open, unblinded study in which patient-reported outcomes are the primary endpoint.
“I think these were surprising findings given what we all think about digoxin in this country. In general, digoxin fell out of favor for rate control, mainly because of observational studies showing increased mortality. So most of us choose a beta-blocker,” she observed in an interview.
But of course, a randomized trial, even a 160-patient randomized trial, constitutes a higher level of evidence.
“I don’t think I’m going to convert tomorrow and make digoxin my first-line rate control therapy without more data. But RATE-AF does makes me stop and think about using it more than I did before in some of my permanent AFib patients,” said Dr. Itchhaporia, director of disease management at Hoag Memorial Hospital in Newport Beach, Calif.
Dr. Kotecha reported having no financial conflicts regarding the study, which was funded by the U.K. National Institute for Health Research, the British Heart Foundation, and the European Union.
Digoxin now deserves to be considered first-line therapy for long-term heart rate control in older patients with permanent atrial fibrillation and symptoms of heart failure, Dipak Kotecha, MBChB, PhD, MSc, declared at the virtual annual congress of the European Society of Cardiology.
He presented the 12-month results of RATE-AF (Rate Control Therapy Evaluation in Permanent Atrial Fibrillation), in which 160 seniors (mean age, 76 years) with moderate or severe symptoms caused by permanent atrial fibrillation (AFib) as well as heart failure symptoms were randomized to low-dose digoxin or the beta-blocker bisoprolol for rate control.
The open-label trial was designed to address a centuries-old unmet need: “Although digoxin has been in use since 1785, we have no longer-term clinical trials of digoxin in patients with AFib or AFib with heart failure,” noted Dr. Kotecha, professor of cardiology at the University of Birmingham (England).
Not only is digoxin greatly understudied in AFib, but permanent AFib – the most common form of the arrhythmia – has received only a tiny fraction of the research attention that’s been devoted to paroxysmal or persistent AFib, he added.
In RATE-AF, digoxin and bisoprolol proved similarly effective at reducing heart rate, from about 100 bpm at baseline to the mid-70s at 6 and 12 months. Notably, only a handful of study participants required an additional rate control drug during the 12-month study. Nor did the two drugs differ in terms of their impact on patient-reported quality of life at 6 months as reflected by their Short Form–36 physical component score, the primary study endpoint. And both drugs were well tolerated, with 96% of patients in the digoxin group still on the drug at a mean of 161 mcg/day at 6 months, and 89% still on their beta-blocker.
But that’s pretty much where the similarities in outcomes ended.
For example, at 12 months, the digoxin group scored significantly higher than the beta-blocker group on several domains of the Short Form–36 physical component score, including vitality, physical function, and global health. More than half of the digoxin group had a two-class improvement in modified European Heart Rhythm Association AFib-related symptoms at 6 months, compared with 10% of the beta-blocker group. At 12 months, nearly 70% of the digoxin group had a two-class improvement, as did 30% on bisoprolol.
Heart failure symptoms in the digoxin group improved from a mean baseline New York Heart Association class of 2.4 to 1.5 at both 6 and 12 months; the improvement was more modest in the beta-blocker group, going from NYHA 2.4 at baseline to 2.0 at both 6 and 12 months. And while N-terminal of the prohormone brain natriuretic peptide levels improved in the digoxin group from a baseline of 1,095 pg/mL to 1,058 at 6 months and 960 at 12 months, NT-proBNP actually went up in the beta-blocker group, from 1,041 to 1,209-1,250 pg/mL at 12 months.
Moreover, Dr. Kotecha continued, while RATE-AF was underpowered to assess clinical events, it’s nevertheless noteworthy that a total of 29 adverse events occurred in 12 months in the digoxin group, compared with 142 with beta-blocker therapy. There were 12 unplanned hospital admissions in the digoxin group and 28 in the beta-blocker group, and 22 primary care visits for either AFib or cardiovascular symptoms in patients on digoxin versus 64 in the beta-blocker group.
“Our results suggest a wider use of digoxin for stable patients with permanent AFib,” Dr. Kotecha concluded. However, in an interview, Jonathan Piccini, MD, had a different take on the study results.
“I don’t think this study should widely impact clinical practice in the U.S.,” according to Dr. Piccini, director of cardiac electrophysiology at Duke University, Durham, N.C.
His reservations included RATE-AF’s modest sample size as well as uncertainty as to the trial’s generalizability, given that bisoprolol isn’t much used in the United States. Also, these were elderly patients with shortness of breath, and it’s unclear how effective digoxin would be for rate control in patients with permanent AFib who are more active.
“The classic teaching is that digoxin is great for rate control at rest, but when people are active it’s not nearly as good as beta-blockers or calcium-channel blockers,” the cardiologist said.
“A beta-blocker is still going to be my first-line rate control agent. But the results of RATE-AF do open my mind that for an older sedentary patient I may very well think twice now about using digoxin, because in that situation it looks like it achieves similar goals as a beta-blocker,” Dr. Piccini added.
On the plus side for RATE-AF: “I am very pleased to see that we have a randomized controlled trial focused on rate control in permanent AFib. It also tickles me pink to see a randomized, controlled study of digoxin. And I’m really excited to see a clinical trial that focuses on quality of life. It should give some confidence to know that from a quality of life perspective clinicians can consider using either digoxin or a beta-blocker for rate control,” he said.
American College of Cardiology vice president Dipti Itchhaporia, MD, said she’d need to see a much larger randomized trial including a calcium-channel blocker as a third-rate control arm before she’d consider digoxin as first-line rate control therapy in patients with AFib with or without heart failure. Also, she has reservations about drawing definitive conclusions from an open, unblinded study in which patient-reported outcomes are the primary endpoint.
“I think these were surprising findings given what we all think about digoxin in this country. In general, digoxin fell out of favor for rate control, mainly because of observational studies showing increased mortality. So most of us choose a beta-blocker,” she observed in an interview.
But of course, a randomized trial, even a 160-patient randomized trial, constitutes a higher level of evidence.
“I don’t think I’m going to convert tomorrow and make digoxin my first-line rate control therapy without more data. But RATE-AF does makes me stop and think about using it more than I did before in some of my permanent AFib patients,” said Dr. Itchhaporia, director of disease management at Hoag Memorial Hospital in Newport Beach, Calif.
Dr. Kotecha reported having no financial conflicts regarding the study, which was funded by the U.K. National Institute for Health Research, the British Heart Foundation, and the European Union.
REPORTING FROM ESC CONGRESS 2020
Early rhythm control in AFib gains new life
Initiation of rhythm control with antiarrhythmic drugs and/or ablation in patients with early, recently diagnosed atrial fibrillation (AFib) led to a significantly lower risk of major adverse cardiovascular outcomes, compared with a rate-control strategy, during more than 5 years of follow-up in the large randomized EAST-AFNET 4 trial, Paulus Kirchhof, MD, said at the virtual annual congress of the European Society of Cardiology.
Previous trials of rate versus rhythm control in AFib, such as AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), failed to show an advantage for rhythm over rate control in terms of clinical outcomes. Why was EAST-AFNET 4 different? Dr. Kirchhof offered two major reasons: The study incorporated AFib ablation as an option in the rhythm control strategy, and treatment started soon after diagnosis of the arrhythmia. Indeed, nearly 40% of patients had their first-ever AFib episode at the time of randomization, and the median time from diagnosis to randomization was just 36 days.
“Once you are in AFib for a few months, the atrium suffers severe damage, some of it irreversible, so it becomes more difficult to restore and maintain sinus rhythm when you wait longer,” explained Dr. Kirchhof, director of the department of cardiology at the University Heart and Vascular Center in Hamburg (Ger.) and professor of cardiovascular medicine at the University of Birmingham, England.
Also, epidemiologic studies show that the risk of cardiovascular complications is heightened in the first year following diagnosis of AFib. “So there’s a window of opportunity to prevent complications,” he added.
The impetus for conducting EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial ) was straightforward, according to the cardiologist: “The question of whether rhythm control is beneficial or not has been in the field for several decades. Most people, like me, always believed that maintaining sinus rhythm would help, but we didn’t have the data to show it.”
Early rhythm control shows sustained benefits
EAST-AFNET 4 was a prospective, open, blinded-outcome-assessement trial. It included 2,789 patients with early AFib and an average CHA2DS2-VASc score of 3.4 who were randomized at 135 sites in 11 European countries to early rhythm control or guideline-recommended rate control. At a median 5.1 years of follow-up, the primary outcome – a composite of cardiovascular death, stroke, acute coronary syndrome, or hospitalization for worsening heart failure – occurred at a pace of 3.9% per year in the rhythm control group and 5% per year with rate control. This translated to a statistically significant and clinically meaningful 21% relative risk reduction favoring early rhythm control.
The 28% reduction in cardiovascular death with rhythm control was statistically significant, as was the 35% reduction in stroke. However, the 19% reduction in heart failure hospitalizations and 17% decrease in hospitalizations for acute coronary syndrome were not.
The co–primary endpoint – the mean number of nights spent in the hospital per year, which served as a proxy for the cost of treatment to a health care system – didn’t differ between the two treatment arms, at roughly 5 nights per year.
The clinical benefit of early rhythm control was consistent across all 19 prespecified patient subgroups, including those who were asymptomatic and patients with or without heart failure.
Serious adverse events related to rhythm control therapy – most often drug-related bradycardia – occurred in 4.9% of patients over the course of 5.1 years, compared to a 1.4% serious event rate in patients assigned to rate control. Dr. Kirchhof called the roughly 1% per year serious event rate in the rhythm control group quite acceptable.
“To put that in perspective, the annualized rate of severe bleeds on oral anticoagulation – a very beneficial therapy used by more than 90% of participants at 2 years – is about 2%,” the cardiologist noted.
Only 8% of patients randomized to rhythm control received AFib ablation as initial therapy, consistent with current clinical practice. By 2 years, 19.4% of the rhythm control group had undergone AFib ablation. Also at that time, 15% of the rate control group was receiving rhythm control therapy to help manage AFib-related symptoms.
One of the big surprises in the study, he said, was that nearly three-quarters of patients in both groups were asymptomatic at 2 years.
“I think that shows how well we control symptoms, even without rhythm control,” he observed.
Results ‘move the field forward’
Dr. Kirchhof stressed that this was a trial of two different treatment strategies, and it’s not yet possible to single out any specific component of the rhythm control strategy as being responsible for the improved outcomes.
“I cannot tell you whether the outcome difference was due to AFib ablation or early treatment or the fact that we’re now better at using antiarrhythmic drugs than we were 20 years ago,” he said.
Asked if the EAST-AFNET 4 findings warrant more aggressive screening for AFib in order to detect and intervene early in the arrhythmia, Dr. Kirchhof replied with an unambiguous yes.
“My conclusion is that every patient with newly diagnosed AFib and a CHA2DS2-VASc score of 2 or more should not only receive anticoagulation and rate control, but should also be offered rhythm control therapy at the time of diagnosis, which also means that all of these people have to be seen by a cardiologist who has expertise in the domain of AFib management. It’s a big clinical challenge, but it leads to a 21% improvement in outcomes, and I think we have to do what’s best for our patients,” he said.
In an interview, Kalyanam Shivkumar, MD, PhD, called EAST-AFNET 4 “a very important study.”
“It moves the field forward, for sure. I think it will change clinical practice, and it should,” commented Dr. Shivkumar, who was not involved in the study.
“Now there are so many wearable technologies out there – the Apple Watch and others – which will enable rhythm abnormalities to be detected early on. This bodes well for the field,” said Dr. Shivkumar, who is editor-in-chief of JACC: Clinical Electrophysiology. He is also professor of medicine, radiology, and bioengineering at the University of California, Los Angeles, and director of the UCLA Cardiac Arrhythmia Center.
Dr. Kirchhof reported receiving research grants to conduct the EAST-AFNET 4 trial from the German Ministry of Education and Research, the German Center for Cardiovascular Research, the Atrial Fibrillation Network, the European Heart Rhythm Association, St. Jude Medical, Abbott, Sanofi, the German Heart Foundation, the European Union, the British Heart Foundation, and the Leducq Foundation.
Simultaneous with his presentation at ESC Congress 2020, the study results were published online at NEJM.org.
SOURCE: Kirchhof P. ESC Congress 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2019422.
Initiation of rhythm control with antiarrhythmic drugs and/or ablation in patients with early, recently diagnosed atrial fibrillation (AFib) led to a significantly lower risk of major adverse cardiovascular outcomes, compared with a rate-control strategy, during more than 5 years of follow-up in the large randomized EAST-AFNET 4 trial, Paulus Kirchhof, MD, said at the virtual annual congress of the European Society of Cardiology.
Previous trials of rate versus rhythm control in AFib, such as AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), failed to show an advantage for rhythm over rate control in terms of clinical outcomes. Why was EAST-AFNET 4 different? Dr. Kirchhof offered two major reasons: The study incorporated AFib ablation as an option in the rhythm control strategy, and treatment started soon after diagnosis of the arrhythmia. Indeed, nearly 40% of patients had their first-ever AFib episode at the time of randomization, and the median time from diagnosis to randomization was just 36 days.
“Once you are in AFib for a few months, the atrium suffers severe damage, some of it irreversible, so it becomes more difficult to restore and maintain sinus rhythm when you wait longer,” explained Dr. Kirchhof, director of the department of cardiology at the University Heart and Vascular Center in Hamburg (Ger.) and professor of cardiovascular medicine at the University of Birmingham, England.
Also, epidemiologic studies show that the risk of cardiovascular complications is heightened in the first year following diagnosis of AFib. “So there’s a window of opportunity to prevent complications,” he added.
The impetus for conducting EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial ) was straightforward, according to the cardiologist: “The question of whether rhythm control is beneficial or not has been in the field for several decades. Most people, like me, always believed that maintaining sinus rhythm would help, but we didn’t have the data to show it.”
Early rhythm control shows sustained benefits
EAST-AFNET 4 was a prospective, open, blinded-outcome-assessement trial. It included 2,789 patients with early AFib and an average CHA2DS2-VASc score of 3.4 who were randomized at 135 sites in 11 European countries to early rhythm control or guideline-recommended rate control. At a median 5.1 years of follow-up, the primary outcome – a composite of cardiovascular death, stroke, acute coronary syndrome, or hospitalization for worsening heart failure – occurred at a pace of 3.9% per year in the rhythm control group and 5% per year with rate control. This translated to a statistically significant and clinically meaningful 21% relative risk reduction favoring early rhythm control.
The 28% reduction in cardiovascular death with rhythm control was statistically significant, as was the 35% reduction in stroke. However, the 19% reduction in heart failure hospitalizations and 17% decrease in hospitalizations for acute coronary syndrome were not.
The co–primary endpoint – the mean number of nights spent in the hospital per year, which served as a proxy for the cost of treatment to a health care system – didn’t differ between the two treatment arms, at roughly 5 nights per year.
The clinical benefit of early rhythm control was consistent across all 19 prespecified patient subgroups, including those who were asymptomatic and patients with or without heart failure.
Serious adverse events related to rhythm control therapy – most often drug-related bradycardia – occurred in 4.9% of patients over the course of 5.1 years, compared to a 1.4% serious event rate in patients assigned to rate control. Dr. Kirchhof called the roughly 1% per year serious event rate in the rhythm control group quite acceptable.
“To put that in perspective, the annualized rate of severe bleeds on oral anticoagulation – a very beneficial therapy used by more than 90% of participants at 2 years – is about 2%,” the cardiologist noted.
Only 8% of patients randomized to rhythm control received AFib ablation as initial therapy, consistent with current clinical practice. By 2 years, 19.4% of the rhythm control group had undergone AFib ablation. Also at that time, 15% of the rate control group was receiving rhythm control therapy to help manage AFib-related symptoms.
One of the big surprises in the study, he said, was that nearly three-quarters of patients in both groups were asymptomatic at 2 years.
“I think that shows how well we control symptoms, even without rhythm control,” he observed.
Results ‘move the field forward’
Dr. Kirchhof stressed that this was a trial of two different treatment strategies, and it’s not yet possible to single out any specific component of the rhythm control strategy as being responsible for the improved outcomes.
“I cannot tell you whether the outcome difference was due to AFib ablation or early treatment or the fact that we’re now better at using antiarrhythmic drugs than we were 20 years ago,” he said.
Asked if the EAST-AFNET 4 findings warrant more aggressive screening for AFib in order to detect and intervene early in the arrhythmia, Dr. Kirchhof replied with an unambiguous yes.
“My conclusion is that every patient with newly diagnosed AFib and a CHA2DS2-VASc score of 2 or more should not only receive anticoagulation and rate control, but should also be offered rhythm control therapy at the time of diagnosis, which also means that all of these people have to be seen by a cardiologist who has expertise in the domain of AFib management. It’s a big clinical challenge, but it leads to a 21% improvement in outcomes, and I think we have to do what’s best for our patients,” he said.
In an interview, Kalyanam Shivkumar, MD, PhD, called EAST-AFNET 4 “a very important study.”
“It moves the field forward, for sure. I think it will change clinical practice, and it should,” commented Dr. Shivkumar, who was not involved in the study.
“Now there are so many wearable technologies out there – the Apple Watch and others – which will enable rhythm abnormalities to be detected early on. This bodes well for the field,” said Dr. Shivkumar, who is editor-in-chief of JACC: Clinical Electrophysiology. He is also professor of medicine, radiology, and bioengineering at the University of California, Los Angeles, and director of the UCLA Cardiac Arrhythmia Center.
Dr. Kirchhof reported receiving research grants to conduct the EAST-AFNET 4 trial from the German Ministry of Education and Research, the German Center for Cardiovascular Research, the Atrial Fibrillation Network, the European Heart Rhythm Association, St. Jude Medical, Abbott, Sanofi, the German Heart Foundation, the European Union, the British Heart Foundation, and the Leducq Foundation.
Simultaneous with his presentation at ESC Congress 2020, the study results were published online at NEJM.org.
SOURCE: Kirchhof P. ESC Congress 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2019422.
Initiation of rhythm control with antiarrhythmic drugs and/or ablation in patients with early, recently diagnosed atrial fibrillation (AFib) led to a significantly lower risk of major adverse cardiovascular outcomes, compared with a rate-control strategy, during more than 5 years of follow-up in the large randomized EAST-AFNET 4 trial, Paulus Kirchhof, MD, said at the virtual annual congress of the European Society of Cardiology.
Previous trials of rate versus rhythm control in AFib, such as AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), failed to show an advantage for rhythm over rate control in terms of clinical outcomes. Why was EAST-AFNET 4 different? Dr. Kirchhof offered two major reasons: The study incorporated AFib ablation as an option in the rhythm control strategy, and treatment started soon after diagnosis of the arrhythmia. Indeed, nearly 40% of patients had their first-ever AFib episode at the time of randomization, and the median time from diagnosis to randomization was just 36 days.
“Once you are in AFib for a few months, the atrium suffers severe damage, some of it irreversible, so it becomes more difficult to restore and maintain sinus rhythm when you wait longer,” explained Dr. Kirchhof, director of the department of cardiology at the University Heart and Vascular Center in Hamburg (Ger.) and professor of cardiovascular medicine at the University of Birmingham, England.
Also, epidemiologic studies show that the risk of cardiovascular complications is heightened in the first year following diagnosis of AFib. “So there’s a window of opportunity to prevent complications,” he added.
The impetus for conducting EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial ) was straightforward, according to the cardiologist: “The question of whether rhythm control is beneficial or not has been in the field for several decades. Most people, like me, always believed that maintaining sinus rhythm would help, but we didn’t have the data to show it.”
Early rhythm control shows sustained benefits
EAST-AFNET 4 was a prospective, open, blinded-outcome-assessement trial. It included 2,789 patients with early AFib and an average CHA2DS2-VASc score of 3.4 who were randomized at 135 sites in 11 European countries to early rhythm control or guideline-recommended rate control. At a median 5.1 years of follow-up, the primary outcome – a composite of cardiovascular death, stroke, acute coronary syndrome, or hospitalization for worsening heart failure – occurred at a pace of 3.9% per year in the rhythm control group and 5% per year with rate control. This translated to a statistically significant and clinically meaningful 21% relative risk reduction favoring early rhythm control.
The 28% reduction in cardiovascular death with rhythm control was statistically significant, as was the 35% reduction in stroke. However, the 19% reduction in heart failure hospitalizations and 17% decrease in hospitalizations for acute coronary syndrome were not.
The co–primary endpoint – the mean number of nights spent in the hospital per year, which served as a proxy for the cost of treatment to a health care system – didn’t differ between the two treatment arms, at roughly 5 nights per year.
The clinical benefit of early rhythm control was consistent across all 19 prespecified patient subgroups, including those who were asymptomatic and patients with or without heart failure.
Serious adverse events related to rhythm control therapy – most often drug-related bradycardia – occurred in 4.9% of patients over the course of 5.1 years, compared to a 1.4% serious event rate in patients assigned to rate control. Dr. Kirchhof called the roughly 1% per year serious event rate in the rhythm control group quite acceptable.
“To put that in perspective, the annualized rate of severe bleeds on oral anticoagulation – a very beneficial therapy used by more than 90% of participants at 2 years – is about 2%,” the cardiologist noted.
Only 8% of patients randomized to rhythm control received AFib ablation as initial therapy, consistent with current clinical practice. By 2 years, 19.4% of the rhythm control group had undergone AFib ablation. Also at that time, 15% of the rate control group was receiving rhythm control therapy to help manage AFib-related symptoms.
One of the big surprises in the study, he said, was that nearly three-quarters of patients in both groups were asymptomatic at 2 years.
“I think that shows how well we control symptoms, even without rhythm control,” he observed.
Results ‘move the field forward’
Dr. Kirchhof stressed that this was a trial of two different treatment strategies, and it’s not yet possible to single out any specific component of the rhythm control strategy as being responsible for the improved outcomes.
“I cannot tell you whether the outcome difference was due to AFib ablation or early treatment or the fact that we’re now better at using antiarrhythmic drugs than we were 20 years ago,” he said.
Asked if the EAST-AFNET 4 findings warrant more aggressive screening for AFib in order to detect and intervene early in the arrhythmia, Dr. Kirchhof replied with an unambiguous yes.
“My conclusion is that every patient with newly diagnosed AFib and a CHA2DS2-VASc score of 2 or more should not only receive anticoagulation and rate control, but should also be offered rhythm control therapy at the time of diagnosis, which also means that all of these people have to be seen by a cardiologist who has expertise in the domain of AFib management. It’s a big clinical challenge, but it leads to a 21% improvement in outcomes, and I think we have to do what’s best for our patients,” he said.
In an interview, Kalyanam Shivkumar, MD, PhD, called EAST-AFNET 4 “a very important study.”
“It moves the field forward, for sure. I think it will change clinical practice, and it should,” commented Dr. Shivkumar, who was not involved in the study.
“Now there are so many wearable technologies out there – the Apple Watch and others – which will enable rhythm abnormalities to be detected early on. This bodes well for the field,” said Dr. Shivkumar, who is editor-in-chief of JACC: Clinical Electrophysiology. He is also professor of medicine, radiology, and bioengineering at the University of California, Los Angeles, and director of the UCLA Cardiac Arrhythmia Center.
Dr. Kirchhof reported receiving research grants to conduct the EAST-AFNET 4 trial from the German Ministry of Education and Research, the German Center for Cardiovascular Research, the Atrial Fibrillation Network, the European Heart Rhythm Association, St. Jude Medical, Abbott, Sanofi, the German Heart Foundation, the European Union, the British Heart Foundation, and the Leducq Foundation.
Simultaneous with his presentation at ESC Congress 2020, the study results were published online at NEJM.org.
SOURCE: Kirchhof P. ESC Congress 2020. N Engl J Med. 2020 Aug 29. doi: 10.1056/NEJMoa2019422.
REPORTING FROM ESC CONGRESS 2020
Batten down the hatches for thyroid storm
Thyroid storm is a life-threatening endocrine emergency for which, remarkably, there are no definitive diagnostic tests, and the management of which is supported by a startlingly weak evidence base.
“What’s tricky is there really are no specific biochemical level cutoffs for thyroid storm, and also no unique laboratory abnormalities. So in the end, it’s a clinical diagnosis and a clinical judgment,” Stephanie B. Mayer, MD, MHSc, observed at HM20 Virtual, hosted by the Society of Hospital Medicine.
Moreover, there are no prospective clinical trials addressing the treatment of thyroid storm, and the 2016 American Thyroid Association clinical practice guidelines on the topic are based upon low-quality evidence from case reports and studies dating back to the 1970s and 1980s. UpToDate reached the same conclusion in 2020, noted Dr. Mayer, an endocrinologist at Virginia Commonwealth University, Richmond.
Thinking that perhaps the guideline writing panel had missed something, she asked a university medical research librarian to custom-build a comprehensive search for studies on thyroid storm management. The search proved unrewarding.
“The evidence is, unfortunately, a little disappointing,” Dr. Mayer said.
Thyroid storm is a rare condition, but one that hospitalists must be ready for. She highlighted current best practices in diagnosis and management.
A high-mortality emergency
Thyroid storm is an extreme manifestation of thyrotoxicosis, which is marked by multiorgan dysfunction and rapid decompensation. In a large, first-of-its-kind, national retrospective U.S. study, the incidence of thyroid storm was 0.57-0.76 cases per 100,000 persons per year. Thyroid storm accounted for 16% of the more than 121,000 hospital discharges featuring a primary diagnosis of thyrotoxicosis. The in-hospital mortality rate for patients with thyroid storm was 1.2%-3.6% during the 10-year study period, a rate 12-fold higher than that among patients with thyrotoxicosis without thyroid storm (Thyroid. 2019 Jan;29[1]:36-43).
Dr. Mayer highlighted a multicenter French study that underscored the current hefty morbidity and mortality associated with thyroid storm. Among 92 patients admitted to the ICU for thyroid storm, the in-ICU mortality rate was 17%, and the mortality rate 6 months after admission was 22%. Independent risk factors for in-ICU mortality were multiorgan failure and the occurrence of cardiogenic shock within the first 48 hours in the ICU (Crit Care Med. 2020 Jan;48[1]:83-90).
How to recognize thyroid storm
The most user-friendly system for assistance in diagnosing thyroid storm is the one put forth by the Japan Thyroid Association and the Japan Endocrine Society, in Dr. Mayer’s view. As a prerequisite to the diagnosis a patient must have thyrotoxicosis as evidenced by elevated free thyroxine (free T4) and free or total triiodothyronine (T3), which in the vast majority of cases, is accompanied by low thyroid stimulating hormone (TSH).
The Japanese diagnostic system for thyroid storm relies on five categories of organ system–based clinical features. This approach places greater weight on disturbances of consciousness – restlessness, delirium, agitation, psychosis, lethargy, coma – than the other four components, which consist of fever of at least 100.4° F, tachycardia of 130 or more beats per minute, heart failure signs and symptoms, and gastrointestinal/hepatic involvement as evidenced by nausea, vomiting, hyperdefecation, and/or a total bilirubin level of 3.0 mg/dL or more.
The Japanese approach offers two paths to a definite diagnosis of thyroid storm. One requires at least one CNS manifestation plus symptoms drawn from any one of the other four categories. The other route, for patients without evident CNS symptoms, requires the presence of symptoms from at least three of the other four categories.
A patient is categorized as having suspected rather than definite thyroid storm if the CNS criterion isn’t met but any two of the others are. A patient also qualifies for suspected thyroid storm when CNS manifestations plus symptoms from at least one other category are present, but thyroid hormone levels aren’t available (Endocr J. 2016 Dec 30;63[12]:1025-64).
Management of thyroid storm
There is usually a precipitating event that drives the transition from smoldering thyrotoxicosis to thyroid storm.
“The big thing is to look for and treat the underlying precipitating event,” the endocrinologist stressed.
It’s often a systemic insult: severe infection, trauma, surgery, an acute MI, diabetic ketoacidosis, pulmonary embolism, or perhaps having just gone through labor. Iodine exposure in the form of IV contrast or taking amiodarone, which contains 37% iodine by weight, can also fan thyrotoxicosis into thyroid storm. Abrupt discontinuation of antithyroid medication is another common cause.
Fluid and electrolyte replacement, oxygen if appropriate, cooling blankets, and other supportive measures are also important.
Medical management targets multiple steps in thyroid hormone production and action to quell thyroid storm. The first order of business is to inhibit synthesis of new thyroid hormone by prescribing a thioamide. Dr. Mayer favors propylthiouracil over methimazole for this purpose because, not only does it block the thyroid gland from synthesizing new hormone, it also reduces conversion of T4 to T3. Propylthiouracil is usually given orally as a 500- to 1,000-mg loading dose, then 250 mg every 4 hours. The drug can also be given rectally or by nasogastric tube.
One hour or more after starting the thioamide, inorganic iodine is started to inhibit release of preformed hormone from the thyroid gland. Five drops of saturated solution of potassium iodide given every 6 hours is the recommended dose; it provides 764 mg of iodide per day. Lugol’s solution dosed at four to eight drops every 6-8 hours is an effective alternative.
Simultaneous with starting the patient on inorganic iodine, a low-dose beta blocker is introduced to control adrenergic symptoms.
“Propranolol is first line because it also decreases T4 to T3 conversion and it’s noncardioselective, so it’s better than a cardioselective beta blocker at reducing sympathetic tone-related symptoms, such as agitation, fever, and psychosis,” the endocrinologist explained.
At the same time that propranolol at 60-80 mg is given orally every 4 hours and iodine are started, the patient is placed on glucocorticoids as another means of reducing peripheral conversion of T4 to T3. The options are intravenous hydrocortisone at 100-300 mg/day in divided doses or dexamethasone at 2 mg every 6 hours.
Aspirin and NSAIDs should be avoided as antipyretics because they can actually raise T3 and T4 levels. Acetaminophen is the right fever-lowering agent in the setting of thyroid storm.
Dr. Mayer has occasionally had to reach for one of several backup therapies. Prescribing a bile acid sequestrant – 20-30 g/day of cholestyramine or colestipol – will trap thyroid hormone in the intestine, preventing it from recirculating.
“Be careful to dose it away from the other medications,” she cautioned.
Also, therapeutic plasmapheresis is effective at rapidly removing circulating thyroid hormone in patients who don’t show early clinical improvement in response to multipronged medical therapy.
Dr. Mayer offered a couple of final tips to hospitalists regarding thyroid storm: Know who directs plasmapheresis at your hospital, and keep the American Thyroid Association management guidelines handy (Thyroid. 2016 Oct;26[10]:1343-421).
She reported receiving funding from both NovoNordisk and Astra Zeneca.
Thyroid storm is a life-threatening endocrine emergency for which, remarkably, there are no definitive diagnostic tests, and the management of which is supported by a startlingly weak evidence base.
“What’s tricky is there really are no specific biochemical level cutoffs for thyroid storm, and also no unique laboratory abnormalities. So in the end, it’s a clinical diagnosis and a clinical judgment,” Stephanie B. Mayer, MD, MHSc, observed at HM20 Virtual, hosted by the Society of Hospital Medicine.
Moreover, there are no prospective clinical trials addressing the treatment of thyroid storm, and the 2016 American Thyroid Association clinical practice guidelines on the topic are based upon low-quality evidence from case reports and studies dating back to the 1970s and 1980s. UpToDate reached the same conclusion in 2020, noted Dr. Mayer, an endocrinologist at Virginia Commonwealth University, Richmond.
Thinking that perhaps the guideline writing panel had missed something, she asked a university medical research librarian to custom-build a comprehensive search for studies on thyroid storm management. The search proved unrewarding.
“The evidence is, unfortunately, a little disappointing,” Dr. Mayer said.
Thyroid storm is a rare condition, but one that hospitalists must be ready for. She highlighted current best practices in diagnosis and management.
A high-mortality emergency
Thyroid storm is an extreme manifestation of thyrotoxicosis, which is marked by multiorgan dysfunction and rapid decompensation. In a large, first-of-its-kind, national retrospective U.S. study, the incidence of thyroid storm was 0.57-0.76 cases per 100,000 persons per year. Thyroid storm accounted for 16% of the more than 121,000 hospital discharges featuring a primary diagnosis of thyrotoxicosis. The in-hospital mortality rate for patients with thyroid storm was 1.2%-3.6% during the 10-year study period, a rate 12-fold higher than that among patients with thyrotoxicosis without thyroid storm (Thyroid. 2019 Jan;29[1]:36-43).
Dr. Mayer highlighted a multicenter French study that underscored the current hefty morbidity and mortality associated with thyroid storm. Among 92 patients admitted to the ICU for thyroid storm, the in-ICU mortality rate was 17%, and the mortality rate 6 months after admission was 22%. Independent risk factors for in-ICU mortality were multiorgan failure and the occurrence of cardiogenic shock within the first 48 hours in the ICU (Crit Care Med. 2020 Jan;48[1]:83-90).
How to recognize thyroid storm
The most user-friendly system for assistance in diagnosing thyroid storm is the one put forth by the Japan Thyroid Association and the Japan Endocrine Society, in Dr. Mayer’s view. As a prerequisite to the diagnosis a patient must have thyrotoxicosis as evidenced by elevated free thyroxine (free T4) and free or total triiodothyronine (T3), which in the vast majority of cases, is accompanied by low thyroid stimulating hormone (TSH).
The Japanese diagnostic system for thyroid storm relies on five categories of organ system–based clinical features. This approach places greater weight on disturbances of consciousness – restlessness, delirium, agitation, psychosis, lethargy, coma – than the other four components, which consist of fever of at least 100.4° F, tachycardia of 130 or more beats per minute, heart failure signs and symptoms, and gastrointestinal/hepatic involvement as evidenced by nausea, vomiting, hyperdefecation, and/or a total bilirubin level of 3.0 mg/dL or more.
The Japanese approach offers two paths to a definite diagnosis of thyroid storm. One requires at least one CNS manifestation plus symptoms drawn from any one of the other four categories. The other route, for patients without evident CNS symptoms, requires the presence of symptoms from at least three of the other four categories.
A patient is categorized as having suspected rather than definite thyroid storm if the CNS criterion isn’t met but any two of the others are. A patient also qualifies for suspected thyroid storm when CNS manifestations plus symptoms from at least one other category are present, but thyroid hormone levels aren’t available (Endocr J. 2016 Dec 30;63[12]:1025-64).
Management of thyroid storm
There is usually a precipitating event that drives the transition from smoldering thyrotoxicosis to thyroid storm.
“The big thing is to look for and treat the underlying precipitating event,” the endocrinologist stressed.
It’s often a systemic insult: severe infection, trauma, surgery, an acute MI, diabetic ketoacidosis, pulmonary embolism, or perhaps having just gone through labor. Iodine exposure in the form of IV contrast or taking amiodarone, which contains 37% iodine by weight, can also fan thyrotoxicosis into thyroid storm. Abrupt discontinuation of antithyroid medication is another common cause.
Fluid and electrolyte replacement, oxygen if appropriate, cooling blankets, and other supportive measures are also important.
Medical management targets multiple steps in thyroid hormone production and action to quell thyroid storm. The first order of business is to inhibit synthesis of new thyroid hormone by prescribing a thioamide. Dr. Mayer favors propylthiouracil over methimazole for this purpose because, not only does it block the thyroid gland from synthesizing new hormone, it also reduces conversion of T4 to T3. Propylthiouracil is usually given orally as a 500- to 1,000-mg loading dose, then 250 mg every 4 hours. The drug can also be given rectally or by nasogastric tube.
One hour or more after starting the thioamide, inorganic iodine is started to inhibit release of preformed hormone from the thyroid gland. Five drops of saturated solution of potassium iodide given every 6 hours is the recommended dose; it provides 764 mg of iodide per day. Lugol’s solution dosed at four to eight drops every 6-8 hours is an effective alternative.
Simultaneous with starting the patient on inorganic iodine, a low-dose beta blocker is introduced to control adrenergic symptoms.
“Propranolol is first line because it also decreases T4 to T3 conversion and it’s noncardioselective, so it’s better than a cardioselective beta blocker at reducing sympathetic tone-related symptoms, such as agitation, fever, and psychosis,” the endocrinologist explained.
At the same time that propranolol at 60-80 mg is given orally every 4 hours and iodine are started, the patient is placed on glucocorticoids as another means of reducing peripheral conversion of T4 to T3. The options are intravenous hydrocortisone at 100-300 mg/day in divided doses or dexamethasone at 2 mg every 6 hours.
Aspirin and NSAIDs should be avoided as antipyretics because they can actually raise T3 and T4 levels. Acetaminophen is the right fever-lowering agent in the setting of thyroid storm.
Dr. Mayer has occasionally had to reach for one of several backup therapies. Prescribing a bile acid sequestrant – 20-30 g/day of cholestyramine or colestipol – will trap thyroid hormone in the intestine, preventing it from recirculating.
“Be careful to dose it away from the other medications,” she cautioned.
Also, therapeutic plasmapheresis is effective at rapidly removing circulating thyroid hormone in patients who don’t show early clinical improvement in response to multipronged medical therapy.
Dr. Mayer offered a couple of final tips to hospitalists regarding thyroid storm: Know who directs plasmapheresis at your hospital, and keep the American Thyroid Association management guidelines handy (Thyroid. 2016 Oct;26[10]:1343-421).
She reported receiving funding from both NovoNordisk and Astra Zeneca.
Thyroid storm is a life-threatening endocrine emergency for which, remarkably, there are no definitive diagnostic tests, and the management of which is supported by a startlingly weak evidence base.
“What’s tricky is there really are no specific biochemical level cutoffs for thyroid storm, and also no unique laboratory abnormalities. So in the end, it’s a clinical diagnosis and a clinical judgment,” Stephanie B. Mayer, MD, MHSc, observed at HM20 Virtual, hosted by the Society of Hospital Medicine.
Moreover, there are no prospective clinical trials addressing the treatment of thyroid storm, and the 2016 American Thyroid Association clinical practice guidelines on the topic are based upon low-quality evidence from case reports and studies dating back to the 1970s and 1980s. UpToDate reached the same conclusion in 2020, noted Dr. Mayer, an endocrinologist at Virginia Commonwealth University, Richmond.
Thinking that perhaps the guideline writing panel had missed something, she asked a university medical research librarian to custom-build a comprehensive search for studies on thyroid storm management. The search proved unrewarding.
“The evidence is, unfortunately, a little disappointing,” Dr. Mayer said.
Thyroid storm is a rare condition, but one that hospitalists must be ready for. She highlighted current best practices in diagnosis and management.
A high-mortality emergency
Thyroid storm is an extreme manifestation of thyrotoxicosis, which is marked by multiorgan dysfunction and rapid decompensation. In a large, first-of-its-kind, national retrospective U.S. study, the incidence of thyroid storm was 0.57-0.76 cases per 100,000 persons per year. Thyroid storm accounted for 16% of the more than 121,000 hospital discharges featuring a primary diagnosis of thyrotoxicosis. The in-hospital mortality rate for patients with thyroid storm was 1.2%-3.6% during the 10-year study period, a rate 12-fold higher than that among patients with thyrotoxicosis without thyroid storm (Thyroid. 2019 Jan;29[1]:36-43).
Dr. Mayer highlighted a multicenter French study that underscored the current hefty morbidity and mortality associated with thyroid storm. Among 92 patients admitted to the ICU for thyroid storm, the in-ICU mortality rate was 17%, and the mortality rate 6 months after admission was 22%. Independent risk factors for in-ICU mortality were multiorgan failure and the occurrence of cardiogenic shock within the first 48 hours in the ICU (Crit Care Med. 2020 Jan;48[1]:83-90).
How to recognize thyroid storm
The most user-friendly system for assistance in diagnosing thyroid storm is the one put forth by the Japan Thyroid Association and the Japan Endocrine Society, in Dr. Mayer’s view. As a prerequisite to the diagnosis a patient must have thyrotoxicosis as evidenced by elevated free thyroxine (free T4) and free or total triiodothyronine (T3), which in the vast majority of cases, is accompanied by low thyroid stimulating hormone (TSH).
The Japanese diagnostic system for thyroid storm relies on five categories of organ system–based clinical features. This approach places greater weight on disturbances of consciousness – restlessness, delirium, agitation, psychosis, lethargy, coma – than the other four components, which consist of fever of at least 100.4° F, tachycardia of 130 or more beats per minute, heart failure signs and symptoms, and gastrointestinal/hepatic involvement as evidenced by nausea, vomiting, hyperdefecation, and/or a total bilirubin level of 3.0 mg/dL or more.
The Japanese approach offers two paths to a definite diagnosis of thyroid storm. One requires at least one CNS manifestation plus symptoms drawn from any one of the other four categories. The other route, for patients without evident CNS symptoms, requires the presence of symptoms from at least three of the other four categories.
A patient is categorized as having suspected rather than definite thyroid storm if the CNS criterion isn’t met but any two of the others are. A patient also qualifies for suspected thyroid storm when CNS manifestations plus symptoms from at least one other category are present, but thyroid hormone levels aren’t available (Endocr J. 2016 Dec 30;63[12]:1025-64).
Management of thyroid storm
There is usually a precipitating event that drives the transition from smoldering thyrotoxicosis to thyroid storm.
“The big thing is to look for and treat the underlying precipitating event,” the endocrinologist stressed.
It’s often a systemic insult: severe infection, trauma, surgery, an acute MI, diabetic ketoacidosis, pulmonary embolism, or perhaps having just gone through labor. Iodine exposure in the form of IV contrast or taking amiodarone, which contains 37% iodine by weight, can also fan thyrotoxicosis into thyroid storm. Abrupt discontinuation of antithyroid medication is another common cause.
Fluid and electrolyte replacement, oxygen if appropriate, cooling blankets, and other supportive measures are also important.
Medical management targets multiple steps in thyroid hormone production and action to quell thyroid storm. The first order of business is to inhibit synthesis of new thyroid hormone by prescribing a thioamide. Dr. Mayer favors propylthiouracil over methimazole for this purpose because, not only does it block the thyroid gland from synthesizing new hormone, it also reduces conversion of T4 to T3. Propylthiouracil is usually given orally as a 500- to 1,000-mg loading dose, then 250 mg every 4 hours. The drug can also be given rectally or by nasogastric tube.
One hour or more after starting the thioamide, inorganic iodine is started to inhibit release of preformed hormone from the thyroid gland. Five drops of saturated solution of potassium iodide given every 6 hours is the recommended dose; it provides 764 mg of iodide per day. Lugol’s solution dosed at four to eight drops every 6-8 hours is an effective alternative.
Simultaneous with starting the patient on inorganic iodine, a low-dose beta blocker is introduced to control adrenergic symptoms.
“Propranolol is first line because it also decreases T4 to T3 conversion and it’s noncardioselective, so it’s better than a cardioselective beta blocker at reducing sympathetic tone-related symptoms, such as agitation, fever, and psychosis,” the endocrinologist explained.
At the same time that propranolol at 60-80 mg is given orally every 4 hours and iodine are started, the patient is placed on glucocorticoids as another means of reducing peripheral conversion of T4 to T3. The options are intravenous hydrocortisone at 100-300 mg/day in divided doses or dexamethasone at 2 mg every 6 hours.
Aspirin and NSAIDs should be avoided as antipyretics because they can actually raise T3 and T4 levels. Acetaminophen is the right fever-lowering agent in the setting of thyroid storm.
Dr. Mayer has occasionally had to reach for one of several backup therapies. Prescribing a bile acid sequestrant – 20-30 g/day of cholestyramine or colestipol – will trap thyroid hormone in the intestine, preventing it from recirculating.
“Be careful to dose it away from the other medications,” she cautioned.
Also, therapeutic plasmapheresis is effective at rapidly removing circulating thyroid hormone in patients who don’t show early clinical improvement in response to multipronged medical therapy.
Dr. Mayer offered a couple of final tips to hospitalists regarding thyroid storm: Know who directs plasmapheresis at your hospital, and keep the American Thyroid Association management guidelines handy (Thyroid. 2016 Oct;26[10]:1343-421).
She reported receiving funding from both NovoNordisk and Astra Zeneca.
FROM HM20 VIRTUAL
Heart failure: Practice-changing developments for hospitalists
A recently validated, easy-to-use calculator of predicted 7-day mortality risk in patients presenting with acute decompensated heart failure is well worth incorporating into hospitalist clinical practice, Dustin T. Smith, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
In addition to the EHMRG, other highlights of his wide-ranging update on recent practice-changing developments in heart failure directly relevant to hospitalists included the introduction of a simple, evidence-based tool for differentiating heart failure with preserved ejection fraction from other potential causes of unexplained dyspnea on exertion in euvolemic patients, and a study debunking what has been called the potassium repletion reflex in patients with acute heart failure undergoing diuresis.
The ACUTE study
Heart failure is an area of special interest for Dr. Smith. He has been surprised to find that virtually no hospitalists, emergency medicine physicians, or cardiologists he has spoken with have heard of the EHMRG or its validation in the ACUTE (Acute Congestive Heart Failure Urgent Care Evaluation) study. Yet this is a very handy tool for hospitalists, he observed.
The EHMRG algorithm utilizes nine variables for which data is readily available for every patient who arrives at the emergency department with acute heart failure. The variables are age, arrival by ambulance, heart rate, systolic blood pressure, potassium level, oxygen saturation, troponin, serum creatine, and presence or absence of active cancer. The information is entered into a cell phone app, which spits out the patient’s estimated 7-day mortality risk. The algorithm divides patients into one of five risk groups ranging from very low to very high. With the addition of data input as to the presence or absence of ST-segment depression on the 12-lead ECG, the weighted algorithm will simultaneously generate an estimated 30-day mortality risk.
ACUTE was a prospective, observational, real-world validation study of EHMRG involving 1,983 patients seeking emergency department care for acute heart failure at nine Canadian hospitals. The actual 7-day mortality rate was 0% in the very-low-risk group, 0% in the low-risk group, 0.6% with an intermediate-risk EHMRG, 1.9% with high risk, and 3.9% in the very-high-risk group. The corresponding 30-day mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%.
The University of Toronto investigators also asked participating physicians for their clinical estimates of 7-day mortality risk while blinded to the EHMRG predictions. The algorithm proved more accurate than physician predictions across the board. Indeed, physicians consistently overestimated the mortality risk for all categories except the very-high-risk one, where they underestimated the true risk (Circulation. 2019 Feb 26;139[9]:1146-56).
Given that heart failure remains year after year at the top of the list of most frequent causes for hospital admission, and that there is compelling evidence that many low-risk patients get hospitalized while potentially unsafe early discharges also occur, the EHMRG score fills an important unmet need.
“I think this can help inform us as to who with acute heart failure potentially needs to come into the hospital and who doesn’t,” Dr. Smith said. “I think the sweet spot here is that if you’re in the low- or very-low-risk category, your 7-day mortality is less than 1%; in fact, in this study it’s zero. But once you get to category 3 – the intermediate category – you’re talking about a 7-day mortality of 1%-2%, which I think is high enough to warrant hospital admission for treatment and to watch them, not just send them home.”
The H2FPEF score
Diagnosis of heart failure with preserved ejection fraction (HFpEF) is a challenge in euvolemic patients with clear lungs and dyspnea on exertion. Investigators at the Mayo Clinic have developed and subsequently validated a weighted score known as the H2FPEF score that’s of great assistance in this task. The score is based upon a set of six simple variables universally available in patients undergoing diagnostic workup for the numerous potential causes for dyspnea on exertion. Together these six variables comprise the acronym H2FPEF:
- Heavy: One point for a BMI greater than 30 kg/m2.
- Hypertension: One point for being on two or more antihypertensive drugs.
- Atrial fibrillation: Three points for paroxysmal or persistent AF.
- Pulmonary hypertension: One point for having a Doppler echocardiographic estimated pulmonary artery systolic pressure greater than 35 mm Hg.
- Elder: One point for age greater than 60 years.
- Filling pressure: One point for a Doppler echocardiographic E/e’ ratio above 9.
The total score can range from 0 to 9. (Circulation. 2018 Aug 28;138[9]:861-70).
Each 1-point increase in the score essentially doubled a patient’s risk of having HFpEF as opposed to pulmonary embolism or some other cause for the dyspnea.
“I really like this H2FPEF score. The score works very, very well. Once you get to a score of 6 or above, the probability of HFpEF is more than 90%, which is pretty powerful. I think this is worthwhile,” Dr. Smith said.
In their derivation and validation cohorts, the Mayo Clinic investigators used as their gold standard for diagnosis of HFpEF invasive hemodynamic exercise testing with a pulmonary artery catheter in place to measure pressures. A score that enables hospitalists to lessen the need for that kind of costly invasive testing is most welcome.
“Here’s how I’d use this score: With an H2FPEF score of 0-1, HFpEF is unlikely. With an intermediate score of 2-5, additional testing is warranted. If the score is high, 6-9, I think HFpEF is likely,” the hospitalist said.
Dr. Smith isn’t the only big fan of the H2FPEF score. In an editorial accompanying publication of the score’s validation study, Walter J. Paulus, MD, PhD, hailed the H2FPEF score as “a unique tour de force” which constitutes a major advance beyond the confusing diagnostic recommendations for HFpEF issued by the European Society of Cardiology and the American Society of Echocardiography, which he said have been “met by skepticism qualifying them as overcomplicated and even triggered disbelief in the existence of HFpEF.”
Particularly interesting were the variables rejected for inclusion in the H2FPEF score because they failed to achieve statistical significance as predictors, even though they’re often considered important in defining HFpEF, he noted. These included left atrial volume index, sex, and levels of circulating N-terminal probrain natriuretic peptide, wrote Dr. Paulus, professor of cardiac pathophysiology at VU University, Amsterdam.
Debunking the potassium repletion reflex
Longstanding conventional wisdom holds that patients hospitalized for heart failure need to maintain a serum potassium above 4.0 mEq/L.
“I’m sure you’ve all written orders to keep the potassium greater than 4.0 mEq/L and the magnesium above 2mEq/L about a million times, like I have,” Dr. Smith said.
But it turns out this traditional practice, which involves a huge cost in terms of time, money, and health care resources, is supported by weak evidence – and an important recent study has now debunked what the investigators termed the potassium “repletion reflex.”
The investigators at the University of Massachusetts identified 4,995 patients admitted with exacerbation of acute heart failure and a normal admission serum potassium level of 3.5-5.0 mEq/L. More than 70% received potassium repletion at least once within a 72-hour observation window, during which 2,080 patients maintained a low-normal serum potassium below 4.0 mEq/L, 2,326 had a mid-normal level of 4.0-4.5 mEq/L, and 589 had a high-normal level of more than 4.5 mEq/L but not more than 5.0 mEq/L.
The study had three endpoints: in-hospital mortality, transfer to the intensive care unit, and hospital length of stay. After statistical adjustment for comorbidities, demographics, and severity at admission, there was no difference between the low- and mid-normal serum potassium groups in any of the three endpoints. In contrast, the high-normal potassium group had a significantly longer length of stay, by a median of 0.6 extra days. The high-normal group also had a 78% increased likelihood of ICU transfer and a 51% increased risk of in-hospital mortality, although neither of these differences reached statistical significance (J Hosp Med. 2019 Dec 1;14[12]:729-36).
“A potassium greater than 4.5 mEq/L may be associated with increased risk of worse outcomes,” Dr. Smith observed. “I think the sweet spot may be 3.5-4.5 mEq/L based on this study.”
He reported having no financial conflicts regarding his presentation.
A recently validated, easy-to-use calculator of predicted 7-day mortality risk in patients presenting with acute decompensated heart failure is well worth incorporating into hospitalist clinical practice, Dustin T. Smith, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
In addition to the EHMRG, other highlights of his wide-ranging update on recent practice-changing developments in heart failure directly relevant to hospitalists included the introduction of a simple, evidence-based tool for differentiating heart failure with preserved ejection fraction from other potential causes of unexplained dyspnea on exertion in euvolemic patients, and a study debunking what has been called the potassium repletion reflex in patients with acute heart failure undergoing diuresis.
The ACUTE study
Heart failure is an area of special interest for Dr. Smith. He has been surprised to find that virtually no hospitalists, emergency medicine physicians, or cardiologists he has spoken with have heard of the EHMRG or its validation in the ACUTE (Acute Congestive Heart Failure Urgent Care Evaluation) study. Yet this is a very handy tool for hospitalists, he observed.
The EHMRG algorithm utilizes nine variables for which data is readily available for every patient who arrives at the emergency department with acute heart failure. The variables are age, arrival by ambulance, heart rate, systolic blood pressure, potassium level, oxygen saturation, troponin, serum creatine, and presence or absence of active cancer. The information is entered into a cell phone app, which spits out the patient’s estimated 7-day mortality risk. The algorithm divides patients into one of five risk groups ranging from very low to very high. With the addition of data input as to the presence or absence of ST-segment depression on the 12-lead ECG, the weighted algorithm will simultaneously generate an estimated 30-day mortality risk.
ACUTE was a prospective, observational, real-world validation study of EHMRG involving 1,983 patients seeking emergency department care for acute heart failure at nine Canadian hospitals. The actual 7-day mortality rate was 0% in the very-low-risk group, 0% in the low-risk group, 0.6% with an intermediate-risk EHMRG, 1.9% with high risk, and 3.9% in the very-high-risk group. The corresponding 30-day mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%.
The University of Toronto investigators also asked participating physicians for their clinical estimates of 7-day mortality risk while blinded to the EHMRG predictions. The algorithm proved more accurate than physician predictions across the board. Indeed, physicians consistently overestimated the mortality risk for all categories except the very-high-risk one, where they underestimated the true risk (Circulation. 2019 Feb 26;139[9]:1146-56).
Given that heart failure remains year after year at the top of the list of most frequent causes for hospital admission, and that there is compelling evidence that many low-risk patients get hospitalized while potentially unsafe early discharges also occur, the EHMRG score fills an important unmet need.
“I think this can help inform us as to who with acute heart failure potentially needs to come into the hospital and who doesn’t,” Dr. Smith said. “I think the sweet spot here is that if you’re in the low- or very-low-risk category, your 7-day mortality is less than 1%; in fact, in this study it’s zero. But once you get to category 3 – the intermediate category – you’re talking about a 7-day mortality of 1%-2%, which I think is high enough to warrant hospital admission for treatment and to watch them, not just send them home.”
The H2FPEF score
Diagnosis of heart failure with preserved ejection fraction (HFpEF) is a challenge in euvolemic patients with clear lungs and dyspnea on exertion. Investigators at the Mayo Clinic have developed and subsequently validated a weighted score known as the H2FPEF score that’s of great assistance in this task. The score is based upon a set of six simple variables universally available in patients undergoing diagnostic workup for the numerous potential causes for dyspnea on exertion. Together these six variables comprise the acronym H2FPEF:
- Heavy: One point for a BMI greater than 30 kg/m2.
- Hypertension: One point for being on two or more antihypertensive drugs.
- Atrial fibrillation: Three points for paroxysmal or persistent AF.
- Pulmonary hypertension: One point for having a Doppler echocardiographic estimated pulmonary artery systolic pressure greater than 35 mm Hg.
- Elder: One point for age greater than 60 years.
- Filling pressure: One point for a Doppler echocardiographic E/e’ ratio above 9.
The total score can range from 0 to 9. (Circulation. 2018 Aug 28;138[9]:861-70).
Each 1-point increase in the score essentially doubled a patient’s risk of having HFpEF as opposed to pulmonary embolism or some other cause for the dyspnea.
“I really like this H2FPEF score. The score works very, very well. Once you get to a score of 6 or above, the probability of HFpEF is more than 90%, which is pretty powerful. I think this is worthwhile,” Dr. Smith said.
In their derivation and validation cohorts, the Mayo Clinic investigators used as their gold standard for diagnosis of HFpEF invasive hemodynamic exercise testing with a pulmonary artery catheter in place to measure pressures. A score that enables hospitalists to lessen the need for that kind of costly invasive testing is most welcome.
“Here’s how I’d use this score: With an H2FPEF score of 0-1, HFpEF is unlikely. With an intermediate score of 2-5, additional testing is warranted. If the score is high, 6-9, I think HFpEF is likely,” the hospitalist said.
Dr. Smith isn’t the only big fan of the H2FPEF score. In an editorial accompanying publication of the score’s validation study, Walter J. Paulus, MD, PhD, hailed the H2FPEF score as “a unique tour de force” which constitutes a major advance beyond the confusing diagnostic recommendations for HFpEF issued by the European Society of Cardiology and the American Society of Echocardiography, which he said have been “met by skepticism qualifying them as overcomplicated and even triggered disbelief in the existence of HFpEF.”
Particularly interesting were the variables rejected for inclusion in the H2FPEF score because they failed to achieve statistical significance as predictors, even though they’re often considered important in defining HFpEF, he noted. These included left atrial volume index, sex, and levels of circulating N-terminal probrain natriuretic peptide, wrote Dr. Paulus, professor of cardiac pathophysiology at VU University, Amsterdam.
Debunking the potassium repletion reflex
Longstanding conventional wisdom holds that patients hospitalized for heart failure need to maintain a serum potassium above 4.0 mEq/L.
“I’m sure you’ve all written orders to keep the potassium greater than 4.0 mEq/L and the magnesium above 2mEq/L about a million times, like I have,” Dr. Smith said.
But it turns out this traditional practice, which involves a huge cost in terms of time, money, and health care resources, is supported by weak evidence – and an important recent study has now debunked what the investigators termed the potassium “repletion reflex.”
The investigators at the University of Massachusetts identified 4,995 patients admitted with exacerbation of acute heart failure and a normal admission serum potassium level of 3.5-5.0 mEq/L. More than 70% received potassium repletion at least once within a 72-hour observation window, during which 2,080 patients maintained a low-normal serum potassium below 4.0 mEq/L, 2,326 had a mid-normal level of 4.0-4.5 mEq/L, and 589 had a high-normal level of more than 4.5 mEq/L but not more than 5.0 mEq/L.
The study had three endpoints: in-hospital mortality, transfer to the intensive care unit, and hospital length of stay. After statistical adjustment for comorbidities, demographics, and severity at admission, there was no difference between the low- and mid-normal serum potassium groups in any of the three endpoints. In contrast, the high-normal potassium group had a significantly longer length of stay, by a median of 0.6 extra days. The high-normal group also had a 78% increased likelihood of ICU transfer and a 51% increased risk of in-hospital mortality, although neither of these differences reached statistical significance (J Hosp Med. 2019 Dec 1;14[12]:729-36).
“A potassium greater than 4.5 mEq/L may be associated with increased risk of worse outcomes,” Dr. Smith observed. “I think the sweet spot may be 3.5-4.5 mEq/L based on this study.”
He reported having no financial conflicts regarding his presentation.
A recently validated, easy-to-use calculator of predicted 7-day mortality risk in patients presenting with acute decompensated heart failure is well worth incorporating into hospitalist clinical practice, Dustin T. Smith, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
In addition to the EHMRG, other highlights of his wide-ranging update on recent practice-changing developments in heart failure directly relevant to hospitalists included the introduction of a simple, evidence-based tool for differentiating heart failure with preserved ejection fraction from other potential causes of unexplained dyspnea on exertion in euvolemic patients, and a study debunking what has been called the potassium repletion reflex in patients with acute heart failure undergoing diuresis.
The ACUTE study
Heart failure is an area of special interest for Dr. Smith. He has been surprised to find that virtually no hospitalists, emergency medicine physicians, or cardiologists he has spoken with have heard of the EHMRG or its validation in the ACUTE (Acute Congestive Heart Failure Urgent Care Evaluation) study. Yet this is a very handy tool for hospitalists, he observed.
The EHMRG algorithm utilizes nine variables for which data is readily available for every patient who arrives at the emergency department with acute heart failure. The variables are age, arrival by ambulance, heart rate, systolic blood pressure, potassium level, oxygen saturation, troponin, serum creatine, and presence or absence of active cancer. The information is entered into a cell phone app, which spits out the patient’s estimated 7-day mortality risk. The algorithm divides patients into one of five risk groups ranging from very low to very high. With the addition of data input as to the presence or absence of ST-segment depression on the 12-lead ECG, the weighted algorithm will simultaneously generate an estimated 30-day mortality risk.
ACUTE was a prospective, observational, real-world validation study of EHMRG involving 1,983 patients seeking emergency department care for acute heart failure at nine Canadian hospitals. The actual 7-day mortality rate was 0% in the very-low-risk group, 0% in the low-risk group, 0.6% with an intermediate-risk EHMRG, 1.9% with high risk, and 3.9% in the very-high-risk group. The corresponding 30-day mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%.
The University of Toronto investigators also asked participating physicians for their clinical estimates of 7-day mortality risk while blinded to the EHMRG predictions. The algorithm proved more accurate than physician predictions across the board. Indeed, physicians consistently overestimated the mortality risk for all categories except the very-high-risk one, where they underestimated the true risk (Circulation. 2019 Feb 26;139[9]:1146-56).
Given that heart failure remains year after year at the top of the list of most frequent causes for hospital admission, and that there is compelling evidence that many low-risk patients get hospitalized while potentially unsafe early discharges also occur, the EHMRG score fills an important unmet need.
“I think this can help inform us as to who with acute heart failure potentially needs to come into the hospital and who doesn’t,” Dr. Smith said. “I think the sweet spot here is that if you’re in the low- or very-low-risk category, your 7-day mortality is less than 1%; in fact, in this study it’s zero. But once you get to category 3 – the intermediate category – you’re talking about a 7-day mortality of 1%-2%, which I think is high enough to warrant hospital admission for treatment and to watch them, not just send them home.”
The H2FPEF score
Diagnosis of heart failure with preserved ejection fraction (HFpEF) is a challenge in euvolemic patients with clear lungs and dyspnea on exertion. Investigators at the Mayo Clinic have developed and subsequently validated a weighted score known as the H2FPEF score that’s of great assistance in this task. The score is based upon a set of six simple variables universally available in patients undergoing diagnostic workup for the numerous potential causes for dyspnea on exertion. Together these six variables comprise the acronym H2FPEF:
- Heavy: One point for a BMI greater than 30 kg/m2.
- Hypertension: One point for being on two or more antihypertensive drugs.
- Atrial fibrillation: Three points for paroxysmal or persistent AF.
- Pulmonary hypertension: One point for having a Doppler echocardiographic estimated pulmonary artery systolic pressure greater than 35 mm Hg.
- Elder: One point for age greater than 60 years.
- Filling pressure: One point for a Doppler echocardiographic E/e’ ratio above 9.
The total score can range from 0 to 9. (Circulation. 2018 Aug 28;138[9]:861-70).
Each 1-point increase in the score essentially doubled a patient’s risk of having HFpEF as opposed to pulmonary embolism or some other cause for the dyspnea.
“I really like this H2FPEF score. The score works very, very well. Once you get to a score of 6 or above, the probability of HFpEF is more than 90%, which is pretty powerful. I think this is worthwhile,” Dr. Smith said.
In their derivation and validation cohorts, the Mayo Clinic investigators used as their gold standard for diagnosis of HFpEF invasive hemodynamic exercise testing with a pulmonary artery catheter in place to measure pressures. A score that enables hospitalists to lessen the need for that kind of costly invasive testing is most welcome.
“Here’s how I’d use this score: With an H2FPEF score of 0-1, HFpEF is unlikely. With an intermediate score of 2-5, additional testing is warranted. If the score is high, 6-9, I think HFpEF is likely,” the hospitalist said.
Dr. Smith isn’t the only big fan of the H2FPEF score. In an editorial accompanying publication of the score’s validation study, Walter J. Paulus, MD, PhD, hailed the H2FPEF score as “a unique tour de force” which constitutes a major advance beyond the confusing diagnostic recommendations for HFpEF issued by the European Society of Cardiology and the American Society of Echocardiography, which he said have been “met by skepticism qualifying them as overcomplicated and even triggered disbelief in the existence of HFpEF.”
Particularly interesting were the variables rejected for inclusion in the H2FPEF score because they failed to achieve statistical significance as predictors, even though they’re often considered important in defining HFpEF, he noted. These included left atrial volume index, sex, and levels of circulating N-terminal probrain natriuretic peptide, wrote Dr. Paulus, professor of cardiac pathophysiology at VU University, Amsterdam.
Debunking the potassium repletion reflex
Longstanding conventional wisdom holds that patients hospitalized for heart failure need to maintain a serum potassium above 4.0 mEq/L.
“I’m sure you’ve all written orders to keep the potassium greater than 4.0 mEq/L and the magnesium above 2mEq/L about a million times, like I have,” Dr. Smith said.
But it turns out this traditional practice, which involves a huge cost in terms of time, money, and health care resources, is supported by weak evidence – and an important recent study has now debunked what the investigators termed the potassium “repletion reflex.”
The investigators at the University of Massachusetts identified 4,995 patients admitted with exacerbation of acute heart failure and a normal admission serum potassium level of 3.5-5.0 mEq/L. More than 70% received potassium repletion at least once within a 72-hour observation window, during which 2,080 patients maintained a low-normal serum potassium below 4.0 mEq/L, 2,326 had a mid-normal level of 4.0-4.5 mEq/L, and 589 had a high-normal level of more than 4.5 mEq/L but not more than 5.0 mEq/L.
The study had three endpoints: in-hospital mortality, transfer to the intensive care unit, and hospital length of stay. After statistical adjustment for comorbidities, demographics, and severity at admission, there was no difference between the low- and mid-normal serum potassium groups in any of the three endpoints. In contrast, the high-normal potassium group had a significantly longer length of stay, by a median of 0.6 extra days. The high-normal group also had a 78% increased likelihood of ICU transfer and a 51% increased risk of in-hospital mortality, although neither of these differences reached statistical significance (J Hosp Med. 2019 Dec 1;14[12]:729-36).
“A potassium greater than 4.5 mEq/L may be associated with increased risk of worse outcomes,” Dr. Smith observed. “I think the sweet spot may be 3.5-4.5 mEq/L based on this study.”
He reported having no financial conflicts regarding his presentation.
FROM HM20 VIRTUAL
Mapping melasma management
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
FROM AAD 20
Novel oral drug improves sunlight tolerance in patients with erythropoietic protoporphyria
in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.
Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.
Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.
“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.
Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.
Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.
The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.
The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.
Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.
Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.
The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.
EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.
In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.
Dr. Belangie is employed by the study sponsor.
in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.
Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.
Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.
“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.
Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.
Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.
The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.
The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.
Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.
Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.
The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.
EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.
In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.
Dr. Belangie is employed by the study sponsor.
in a multicenter, phase 2, randomized trial, Kirstine Belongie, PhD, reported at the virtual annual meeting of the American Academy of Dermatology.
Based upon these favorable phase 2 results, a pivotal phase 3 clinical trial is now underway, added Dr. Belongie of Mitsubishi Tanabe Pharma Development America, in Jersey City, N.J., the study sponsor.
Erythropoietic protoporphyria (EPP) is the most common cutaneous porphyria as well as the most common porphyria of any type in children. It’s a rare but devastating disorder, with an incidence estimated at 1 in 75,000-200,000. It involves acute cutaneous photosensitivity to sunlight, which takes the form of incapacitating burning pain that lasts 3-7 days and is then followed by erythema and edema.
“These phototoxic reactions are extremely painful and cause the patients to have extreme fear of the sun. They do everything they can to avoid the sun. It leads to a highly impaired quality of life that’s restricted to the indoors,” she explained.
Current first-line therapy is sun avoidance, the use of zinc oxide sunblock, and protective clothing. It’s inadequate for most patients. “There is a tremendously high unmet medical need for treatment options, especially in the pediatric population,” Dr. Belongie observed.
Patients with EPP experience prodromal symptoms – tingling, itching, and burning – which serve as a signal to get out of the sun immediately. As demonstrated in the phase 2 trial, dersimelagon prolongs the time to onset of these prodromal symptoms by increasing melanin density in the skin in a dose-dependent fashion.
The phase 2 study included 102 EPP patients, with an average age 40 years, at 9 sites, who were randomized double blind to 16 weeks of dersimelagon at 100 mg or 300 mg once daily or placebo. The goal was to increase their pain-free sunlight exposure time.
The primary endpoint was change from baseline to week 16 in the average daily time to first prodromal symptoms. There was a 20-minute increase with placebo, a 74-minute gain with dersimelagon at 100 mg, and an 83-minute gain with dersimelagon at 300 mg. The difference between active medication and placebo became significant at week 6.
Treatment-emergent adverse events leading to study discontinuation occurred in one patient on dersimelagon at 100 mg/day, five patients on the higher dose, and none on placebo. Dr. Belangie said that the drug was well tolerated, with roughly 90% of adverse events being mild or moderate in severity. The frequency of adverse events was dose-related. The most common were headache, nausea, and diarrhea, occurring in 29%, 46%, and 23%, respectively, of patients on dersimelagon at 300 mg/day, compared with 18%, 12% and 12% of those on placebo.
Consistent with the drug’s mechanism of action, there was also a dose-related increase in hyperpigmentation side effects. New freckles were documented in 15% and 31% of patients on low- and high-dose dersimelagon, skin hyperpigmentation in 9% and 31%, and melanocytic nevi in 12% and 20%.
The ongoing double-blind, international, phase 3 trial includes not only patients with EPP, but also individuals with X-linked porphyria, which has similar clinical symptoms. The trial is double blind for the first 26 weeks, followed by another 26 weeks of open-label treatment.
EPP is an inherited metabolic disorder caused by a genetic mutation resulting in deficient activity of the enzyme ferrochelatase. This leads to accumulation of protoporphyrin IX in erythrocytes, skin, and the liver. The excess protoporphyrin is excreted in bile and can cause hepatobiliary disease. Indeed, up to 5% of patients with EPP develop liver failure.
In October 2019, the Food and Drug Administration approved afamelanotide (Scenesse), also a melanocortin-1 receptor agonist, to increase pain-free light exposure in adults with a history of phototoxic reactions EPP; this was the first FDA-approved treatment for helping EPP patients increase their exposure to light, according to the agency. It is administered as an implant every 2 months.
Dr. Belangie is employed by the study sponsor.
FROM AAD 2020
Managing acute pain in inpatients on OUD therapy
“This is something we’re going to see more frequently, and many of us already have,” Theresa E. Vettese, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
The drastic drop in prescriptions for opioid pain medications in the last several years hasn’t curtailed the current opioid epidemic. Instead, the epidemic has to a great extent morphed into expanded use of illicit heroin and fentanyl, noted Dr. Vettese, an internist, hospitalist, and palliative care physician at Emory University and Grady Memorial Hospital in Atlanta.
Mythbusting
Treatment of acute pain in hospitalized patients on opioid agonist therapy for opioid use disorder (OUD) is actually pretty straightforward once a few common myths have been dispelled, she said.
One of these myths –common among both physicians and patients in treatment for OUD – is that prescribing opioids for management of acute pain will place such patients at risk for OUD relapse.
“In fact, the data really strongly suggest this is not the case,” Dr. Vettese said. “It will not worsen addiction. But if we don’t aggressively treat these patients’ acute pain, it puts them at higher risk for bad outcomes.”
Another myth – this one not uncommon among hospital pharmacy departments – is that only physicians with a special certification can prescribe methadone for inpatients.
“The federal laws are clear: Any physician who has a DEA license can prescribe methadone in the hospital acute care setting, not only for pain management, but also for treatment of opioid withdrawal. You can’t prescribe it in the outpatient setting for opioid withdrawal – that has to be dispensed through a federally regulated methadone outpatient treatment program. But in the hospital, we can feel safe that we can do so. You may need to educate your pharmacist about this,” she said.
Hospitalists also can prescribe buprenorphine in the acute care inpatient setting, both for pain and treatment of opioid withdrawal, without need for a DEA waiver.
“It’s useful to get some skills in using buprenorphine in the inpatient setting. You don’t need an X waiver, but I encourage everyone to do the X-waiver training because it’s a terrific educational session. It’s 8 hours for physicians and well worth it,” Dr. Vettese noted.
By federal law the inpatient physician also can prescribe 3 days of buprenorphine at discharge to get the patient to an outpatient provider.
Misconceptions also abound about NSAIDs as a nonopioid component of acute pain management in hospitalized patients. They actually are extremely effective for the treatment of musculoskeletal, orthopedic, procedural, migraine, and some types of cancer pain. The number needed to treat (NNT) for postoperative pain relief for ibuprofen or celecoxib is 2.5, and when used in conjunction with acetaminophen at 325 mg every 4 hours, that NNT drops to 1.5, similar to the NNT of 1.7 for oxycodone at 15 mg. It should be noted, however, that the bar defining effective pain relief in randomized studies is set rather low: A 50% greater reduction in pain than achieved with placebo.
Many hospitalists would like to use NSAIDs more often, but they’re leery of the associated risks of GI bleeding, ischemic cardiovascular events, and worsening kidney function. Dr. Vettese offered several risk-mitigation strategies to increase the use of NSAIDs as opioid-sparing agents for acute pain management.
She has changed her own clinical practice with regard to using NSAIDs in patients with chronic kidney disease in response to a 2019 systematic review by investigators at the University of Ottawa.
“This was a game changer for me because in this review, low-dose NSAIDs were safe in that they didn’t significantly increase the risk of worsening kidney failure even in patients with stage 3 chronic kidney disease. So this has expanded my use of NSAIDs in this population through stage 3 CKD. With a creatinine clearance below 30, however, kidney failure worsened rapidly, so I don’t do it in patients with CKD stage 4,” Dr. Vettese said.
Gastroenterologists categorize patients as being at high risk of GI bleeding related to NSAID use if they have a history of a complicated ulcer or they have at least three of the following risk factors: Age above 65 years, history of an uncomplicated ulcer, being on high-dose NSAID therapy, or concurrent use of aspirin, glucocorticoids, or anticoagulants. Patients are considered at moderate risk if they have one or two of the risk factors, and low risk if they have none. Dr. Vettese said that, while NSAIDs clearly should be avoided in the high-risk group, moderate-risk patients are a different matter.
“Many avoid the use of NSAIDs with moderate risk, but I think we can expand their use if we use the right NSAID and we use protective strategies,” Dr. Vettese said.
Celecoxib is the safest drug in terms of upper GI bleeding risk, but ibuprofen is close. They are associated with a 2.2-fold increased risk of bleeding when compared with risk in patients not on an NSAID. Naproxen or indeomethacin use carries a fourfold to fivefold increased risk.
“Celecoxib with a proton pump inhibitor is safest, followed by celecoxib alone, followed by ibuprofen with a proton pump inhibitor. So I advocate using NSAIDs more frequently in people who are at moderate risk by using them with a PPI,” she said.
There is persuasive evidence of increased cardiovascular risk in association with even short-duration NSAIDs, as the drugs are utilized in the treatment of acute pain in hospitalized patients. That being said, Dr. Vettese believes hospitalists can use these drugs safely in more patients by following a thoughtful cardiovascular risk-mitigation strategy developed by Italian investigators.
Communicating about pain management
“Communication is always the key to effective pain management in every situation,” Dr. Vettese emphasized.
“I talk to the patient about the goals of effective pain management. I’ll discourage the use of the 1-10 pain scale, and instead, I’ll be honest about expectations, saying, ‘You have a problem that will cause acute pain, and it’s unlikely that I will be able to completely relieve your pain. The goal is to improve your function so that you can get up and go the bathroom by yourself, and so that you can sleep for a few hours. That’s how we’re going to measure the efficacy of our pain-management program.’ ”
She explains to the patient that she’ll be using nonopioid medications and nondrug therapies along with oral opioid pain medications, which are less risky than IV opioids. She offers reassurance that this treatment strategy won’t cause an OUD relapse. She lets the patient know up-front that the opioids will be tapered as the acute pain improves.
For the patient who comes into the hospital on buprenorphine for OUD, she immediately checks with the state prescription drug monitoring program to make sure everything is above board and there’s no indication of doctor shopping for prescriptions. For in-hospital acute pain, it’s safe and effective to continue the outpatient dose. On an outpatient basis, however, the drug is given once daily. On that dosing schedule both the euphoric effect as well as the analgesic effect are lost, so for acute pain management in the hospital it’s recommended to split the dose into twice- or thrice-daily doses to achieve an analgesic effect.
Oral NSAIDs are part of the treatment strategy whenever possible. For severe acute pain, Dr. Vettese will prescribe an immediate-release opioid having a high affinity to the mu opioid receptor, such as oral hydromorphone, on an as-needed basis. The drug has onset of effect in 30 minutes, peak effect in 1 hour, and a duration of effect of 4-6 hours, although she recommends going with 4 hours to provide adequate analgesia.
“These patients will require much higher doses than the patients who are opioid naive,” she advised.
For the patient with acute pain who is admitted while on methadone for OUD, it’s important to call the outpatient treatment program to verify the dosage.
“You can split the dose of methadone to try to get better analgesia, although I can tell you that patients who are treated with methadone for OUD frequently don’t want to do that. And if they don’t want to, then I don’t,” the hospitalist said.
As with the patient on buprenorphine for OUD, she’ll use additional oral immediate-release opioids as needed for acute severe pain in a patient on methadone for medication-assisted OUD treatment.
Dr. Vettese reported having no financial conflicts regarding her presentation.
“This is something we’re going to see more frequently, and many of us already have,” Theresa E. Vettese, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
The drastic drop in prescriptions for opioid pain medications in the last several years hasn’t curtailed the current opioid epidemic. Instead, the epidemic has to a great extent morphed into expanded use of illicit heroin and fentanyl, noted Dr. Vettese, an internist, hospitalist, and palliative care physician at Emory University and Grady Memorial Hospital in Atlanta.
Mythbusting
Treatment of acute pain in hospitalized patients on opioid agonist therapy for opioid use disorder (OUD) is actually pretty straightforward once a few common myths have been dispelled, she said.
One of these myths –common among both physicians and patients in treatment for OUD – is that prescribing opioids for management of acute pain will place such patients at risk for OUD relapse.
“In fact, the data really strongly suggest this is not the case,” Dr. Vettese said. “It will not worsen addiction. But if we don’t aggressively treat these patients’ acute pain, it puts them at higher risk for bad outcomes.”
Another myth – this one not uncommon among hospital pharmacy departments – is that only physicians with a special certification can prescribe methadone for inpatients.
“The federal laws are clear: Any physician who has a DEA license can prescribe methadone in the hospital acute care setting, not only for pain management, but also for treatment of opioid withdrawal. You can’t prescribe it in the outpatient setting for opioid withdrawal – that has to be dispensed through a federally regulated methadone outpatient treatment program. But in the hospital, we can feel safe that we can do so. You may need to educate your pharmacist about this,” she said.
Hospitalists also can prescribe buprenorphine in the acute care inpatient setting, both for pain and treatment of opioid withdrawal, without need for a DEA waiver.
“It’s useful to get some skills in using buprenorphine in the inpatient setting. You don’t need an X waiver, but I encourage everyone to do the X-waiver training because it’s a terrific educational session. It’s 8 hours for physicians and well worth it,” Dr. Vettese noted.
By federal law the inpatient physician also can prescribe 3 days of buprenorphine at discharge to get the patient to an outpatient provider.
Misconceptions also abound about NSAIDs as a nonopioid component of acute pain management in hospitalized patients. They actually are extremely effective for the treatment of musculoskeletal, orthopedic, procedural, migraine, and some types of cancer pain. The number needed to treat (NNT) for postoperative pain relief for ibuprofen or celecoxib is 2.5, and when used in conjunction with acetaminophen at 325 mg every 4 hours, that NNT drops to 1.5, similar to the NNT of 1.7 for oxycodone at 15 mg. It should be noted, however, that the bar defining effective pain relief in randomized studies is set rather low: A 50% greater reduction in pain than achieved with placebo.
Many hospitalists would like to use NSAIDs more often, but they’re leery of the associated risks of GI bleeding, ischemic cardiovascular events, and worsening kidney function. Dr. Vettese offered several risk-mitigation strategies to increase the use of NSAIDs as opioid-sparing agents for acute pain management.
She has changed her own clinical practice with regard to using NSAIDs in patients with chronic kidney disease in response to a 2019 systematic review by investigators at the University of Ottawa.
“This was a game changer for me because in this review, low-dose NSAIDs were safe in that they didn’t significantly increase the risk of worsening kidney failure even in patients with stage 3 chronic kidney disease. So this has expanded my use of NSAIDs in this population through stage 3 CKD. With a creatinine clearance below 30, however, kidney failure worsened rapidly, so I don’t do it in patients with CKD stage 4,” Dr. Vettese said.
Gastroenterologists categorize patients as being at high risk of GI bleeding related to NSAID use if they have a history of a complicated ulcer or they have at least three of the following risk factors: Age above 65 years, history of an uncomplicated ulcer, being on high-dose NSAID therapy, or concurrent use of aspirin, glucocorticoids, or anticoagulants. Patients are considered at moderate risk if they have one or two of the risk factors, and low risk if they have none. Dr. Vettese said that, while NSAIDs clearly should be avoided in the high-risk group, moderate-risk patients are a different matter.
“Many avoid the use of NSAIDs with moderate risk, but I think we can expand their use if we use the right NSAID and we use protective strategies,” Dr. Vettese said.
Celecoxib is the safest drug in terms of upper GI bleeding risk, but ibuprofen is close. They are associated with a 2.2-fold increased risk of bleeding when compared with risk in patients not on an NSAID. Naproxen or indeomethacin use carries a fourfold to fivefold increased risk.
“Celecoxib with a proton pump inhibitor is safest, followed by celecoxib alone, followed by ibuprofen with a proton pump inhibitor. So I advocate using NSAIDs more frequently in people who are at moderate risk by using them with a PPI,” she said.
There is persuasive evidence of increased cardiovascular risk in association with even short-duration NSAIDs, as the drugs are utilized in the treatment of acute pain in hospitalized patients. That being said, Dr. Vettese believes hospitalists can use these drugs safely in more patients by following a thoughtful cardiovascular risk-mitigation strategy developed by Italian investigators.
Communicating about pain management
“Communication is always the key to effective pain management in every situation,” Dr. Vettese emphasized.
“I talk to the patient about the goals of effective pain management. I’ll discourage the use of the 1-10 pain scale, and instead, I’ll be honest about expectations, saying, ‘You have a problem that will cause acute pain, and it’s unlikely that I will be able to completely relieve your pain. The goal is to improve your function so that you can get up and go the bathroom by yourself, and so that you can sleep for a few hours. That’s how we’re going to measure the efficacy of our pain-management program.’ ”
She explains to the patient that she’ll be using nonopioid medications and nondrug therapies along with oral opioid pain medications, which are less risky than IV opioids. She offers reassurance that this treatment strategy won’t cause an OUD relapse. She lets the patient know up-front that the opioids will be tapered as the acute pain improves.
For the patient who comes into the hospital on buprenorphine for OUD, she immediately checks with the state prescription drug monitoring program to make sure everything is above board and there’s no indication of doctor shopping for prescriptions. For in-hospital acute pain, it’s safe and effective to continue the outpatient dose. On an outpatient basis, however, the drug is given once daily. On that dosing schedule both the euphoric effect as well as the analgesic effect are lost, so for acute pain management in the hospital it’s recommended to split the dose into twice- or thrice-daily doses to achieve an analgesic effect.
Oral NSAIDs are part of the treatment strategy whenever possible. For severe acute pain, Dr. Vettese will prescribe an immediate-release opioid having a high affinity to the mu opioid receptor, such as oral hydromorphone, on an as-needed basis. The drug has onset of effect in 30 minutes, peak effect in 1 hour, and a duration of effect of 4-6 hours, although she recommends going with 4 hours to provide adequate analgesia.
“These patients will require much higher doses than the patients who are opioid naive,” she advised.
For the patient with acute pain who is admitted while on methadone for OUD, it’s important to call the outpatient treatment program to verify the dosage.
“You can split the dose of methadone to try to get better analgesia, although I can tell you that patients who are treated with methadone for OUD frequently don’t want to do that. And if they don’t want to, then I don’t,” the hospitalist said.
As with the patient on buprenorphine for OUD, she’ll use additional oral immediate-release opioids as needed for acute severe pain in a patient on methadone for medication-assisted OUD treatment.
Dr. Vettese reported having no financial conflicts regarding her presentation.
“This is something we’re going to see more frequently, and many of us already have,” Theresa E. Vettese, MD, said at HM20 Virtual, hosted by the Society of Hospital Medicine.
The drastic drop in prescriptions for opioid pain medications in the last several years hasn’t curtailed the current opioid epidemic. Instead, the epidemic has to a great extent morphed into expanded use of illicit heroin and fentanyl, noted Dr. Vettese, an internist, hospitalist, and palliative care physician at Emory University and Grady Memorial Hospital in Atlanta.
Mythbusting
Treatment of acute pain in hospitalized patients on opioid agonist therapy for opioid use disorder (OUD) is actually pretty straightforward once a few common myths have been dispelled, she said.
One of these myths –common among both physicians and patients in treatment for OUD – is that prescribing opioids for management of acute pain will place such patients at risk for OUD relapse.
“In fact, the data really strongly suggest this is not the case,” Dr. Vettese said. “It will not worsen addiction. But if we don’t aggressively treat these patients’ acute pain, it puts them at higher risk for bad outcomes.”
Another myth – this one not uncommon among hospital pharmacy departments – is that only physicians with a special certification can prescribe methadone for inpatients.
“The federal laws are clear: Any physician who has a DEA license can prescribe methadone in the hospital acute care setting, not only for pain management, but also for treatment of opioid withdrawal. You can’t prescribe it in the outpatient setting for opioid withdrawal – that has to be dispensed through a federally regulated methadone outpatient treatment program. But in the hospital, we can feel safe that we can do so. You may need to educate your pharmacist about this,” she said.
Hospitalists also can prescribe buprenorphine in the acute care inpatient setting, both for pain and treatment of opioid withdrawal, without need for a DEA waiver.
“It’s useful to get some skills in using buprenorphine in the inpatient setting. You don’t need an X waiver, but I encourage everyone to do the X-waiver training because it’s a terrific educational session. It’s 8 hours for physicians and well worth it,” Dr. Vettese noted.
By federal law the inpatient physician also can prescribe 3 days of buprenorphine at discharge to get the patient to an outpatient provider.
Misconceptions also abound about NSAIDs as a nonopioid component of acute pain management in hospitalized patients. They actually are extremely effective for the treatment of musculoskeletal, orthopedic, procedural, migraine, and some types of cancer pain. The number needed to treat (NNT) for postoperative pain relief for ibuprofen or celecoxib is 2.5, and when used in conjunction with acetaminophen at 325 mg every 4 hours, that NNT drops to 1.5, similar to the NNT of 1.7 for oxycodone at 15 mg. It should be noted, however, that the bar defining effective pain relief in randomized studies is set rather low: A 50% greater reduction in pain than achieved with placebo.
Many hospitalists would like to use NSAIDs more often, but they’re leery of the associated risks of GI bleeding, ischemic cardiovascular events, and worsening kidney function. Dr. Vettese offered several risk-mitigation strategies to increase the use of NSAIDs as opioid-sparing agents for acute pain management.
She has changed her own clinical practice with regard to using NSAIDs in patients with chronic kidney disease in response to a 2019 systematic review by investigators at the University of Ottawa.
“This was a game changer for me because in this review, low-dose NSAIDs were safe in that they didn’t significantly increase the risk of worsening kidney failure even in patients with stage 3 chronic kidney disease. So this has expanded my use of NSAIDs in this population through stage 3 CKD. With a creatinine clearance below 30, however, kidney failure worsened rapidly, so I don’t do it in patients with CKD stage 4,” Dr. Vettese said.
Gastroenterologists categorize patients as being at high risk of GI bleeding related to NSAID use if they have a history of a complicated ulcer or they have at least three of the following risk factors: Age above 65 years, history of an uncomplicated ulcer, being on high-dose NSAID therapy, or concurrent use of aspirin, glucocorticoids, or anticoagulants. Patients are considered at moderate risk if they have one or two of the risk factors, and low risk if they have none. Dr. Vettese said that, while NSAIDs clearly should be avoided in the high-risk group, moderate-risk patients are a different matter.
“Many avoid the use of NSAIDs with moderate risk, but I think we can expand their use if we use the right NSAID and we use protective strategies,” Dr. Vettese said.
Celecoxib is the safest drug in terms of upper GI bleeding risk, but ibuprofen is close. They are associated with a 2.2-fold increased risk of bleeding when compared with risk in patients not on an NSAID. Naproxen or indeomethacin use carries a fourfold to fivefold increased risk.
“Celecoxib with a proton pump inhibitor is safest, followed by celecoxib alone, followed by ibuprofen with a proton pump inhibitor. So I advocate using NSAIDs more frequently in people who are at moderate risk by using them with a PPI,” she said.
There is persuasive evidence of increased cardiovascular risk in association with even short-duration NSAIDs, as the drugs are utilized in the treatment of acute pain in hospitalized patients. That being said, Dr. Vettese believes hospitalists can use these drugs safely in more patients by following a thoughtful cardiovascular risk-mitigation strategy developed by Italian investigators.
Communicating about pain management
“Communication is always the key to effective pain management in every situation,” Dr. Vettese emphasized.
“I talk to the patient about the goals of effective pain management. I’ll discourage the use of the 1-10 pain scale, and instead, I’ll be honest about expectations, saying, ‘You have a problem that will cause acute pain, and it’s unlikely that I will be able to completely relieve your pain. The goal is to improve your function so that you can get up and go the bathroom by yourself, and so that you can sleep for a few hours. That’s how we’re going to measure the efficacy of our pain-management program.’ ”
She explains to the patient that she’ll be using nonopioid medications and nondrug therapies along with oral opioid pain medications, which are less risky than IV opioids. She offers reassurance that this treatment strategy won’t cause an OUD relapse. She lets the patient know up-front that the opioids will be tapered as the acute pain improves.
For the patient who comes into the hospital on buprenorphine for OUD, she immediately checks with the state prescription drug monitoring program to make sure everything is above board and there’s no indication of doctor shopping for prescriptions. For in-hospital acute pain, it’s safe and effective to continue the outpatient dose. On an outpatient basis, however, the drug is given once daily. On that dosing schedule both the euphoric effect as well as the analgesic effect are lost, so for acute pain management in the hospital it’s recommended to split the dose into twice- or thrice-daily doses to achieve an analgesic effect.
Oral NSAIDs are part of the treatment strategy whenever possible. For severe acute pain, Dr. Vettese will prescribe an immediate-release opioid having a high affinity to the mu opioid receptor, such as oral hydromorphone, on an as-needed basis. The drug has onset of effect in 30 minutes, peak effect in 1 hour, and a duration of effect of 4-6 hours, although she recommends going with 4 hours to provide adequate analgesia.
“These patients will require much higher doses than the patients who are opioid naive,” she advised.
For the patient with acute pain who is admitted while on methadone for OUD, it’s important to call the outpatient treatment program to verify the dosage.
“You can split the dose of methadone to try to get better analgesia, although I can tell you that patients who are treated with methadone for OUD frequently don’t want to do that. And if they don’t want to, then I don’t,” the hospitalist said.
As with the patient on buprenorphine for OUD, she’ll use additional oral immediate-release opioids as needed for acute severe pain in a patient on methadone for medication-assisted OUD treatment.
Dr. Vettese reported having no financial conflicts regarding her presentation.
FROM HM20 VIRTUAL