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Ticagrelor doesn’t beat clopidogrel in postfibrinolysis STEMI
NEW ORLEANS – In STEMI patients who aren’t able to undergo primary PCI, ticagrelor after fibrinolytic therapy offered no advantages over clopidogrel – a less potent and less costly antiplatelet agent – in rates of cardiovascular events or bleeding though 12 months of follow-up in the TREAT trial.
“In terms of efficacy, it is appropriate to interpret TREAT statistically as a neutral trial,” Otavio Berwanger, MD, PhD, advised at the annual meeting of the American College of Cardiology.
TREAT (Ticagrelor in patients with ST-elevation myocardial infarction treated with pharmacological thrombolysis) was a 10-country, 152-site, randomized, open-label clinical trial of 3,799 STEMI (ST-elevation MI) patients treated with fibrinolytic therapy followed an average of 11 hours later by a loading dose of either ticagrelor (Brilinta) or clopidogrel, then 12 months of standard-dose maintenance therapy of their designated potent antiplatelet drug. The adherence rate was 90% at 12 months. Participating countries included Russia, China, Brazil, Australia, and Canada, but not the United States.
The primary efficacy endpoint was the 12-month composite of death from a vascular cause, MI, stroke, severe recurrent ischemia, TIA, or another arterial thrombotic event. The rate was 8% in the ticagrelor group and 9.1% with clopidogrel, a 12% relative risk reduction in favor of ticagrelor that was not statistically significant. But then, TREAT was underpowered to show a difference in efficacy. However, the 12% relative risk reduction mirrors that seen in the earlier PLATO trial of 18,624 patients with acute coronary syndrome who were randomized to ticagrelor or clopidogrel in conjunction with primary PCI, a difference that was statistically significant because of PLATO’s much larger size (N Engl J Med. 2009 Sep 10;361[11]:1045-57).
TREAT was sufficiently powered to assess safety. There was no significant between-group difference in TIMI major bleeding, the primary safety endpoint. However, the rate of total bleeding events was significantly higher in the ticagrelor arm, by a margin of 10.25% versus 6.15%. Moreover, the rate of TIMI clinically significant bleeding requiring medical attention was also higher in the ticagrelor group – 5.2% versus 3.8% – and the TIMI minimal bleeding rate of 5.85% in the ticagrelor group was more than double that in the clopidogrel arm, reported Dr. Berwanger of the Heart Hospital Research Institute in São Paolo.
These 12-month outcomes echo those previously reported at the 30-day mark in TREAT (JAMA Cardiol. 2018 May 1;3[5]:391-9).
Discussant C. Michael Gibson, MD, put TREAT in perspective: “Here we’re looking to see if there are differences between two thienopyridine inhibitors. There’s nothing really that important on the efficacy side, although there was 1.5% missingness in the study. And there was a higher number of total bleeds with ticagrelor.
“Some of the junior members of the audience may not be all that familiar with fibrinolysis. In the era where it was more prominent, reocclusion occurred in 5%-8% of patients. When it did occur, it led to a tripling of mortality. It’s important to note that the first study of a thienopyridine inhibitor added to lytics was CLARITY, almost 15 years ago, showing a reduction in death, MI, or reocclusion down from about 15% to 7% [N Engl J Med 2005; 352:1179-89]. So it should be very clear to the audience that reocclusion is a problem and the addition of a thienopyridine inhibitor improves that,” explained Dr. Gibson, professor of medicine at Harvard Medical School, Boston.
The TREAT trial was funded by AstraZeneca. Dr. Berwanger reported receiving research grants from and serving as a consultant to that company and half a dozen others.
Simultaneously with the presentation, the TREAT study was published online (J Am Coll Cardiol. 2019 Mar 12. doi: 10.1016/j.jacc.2019.03.011).
NEW ORLEANS – In STEMI patients who aren’t able to undergo primary PCI, ticagrelor after fibrinolytic therapy offered no advantages over clopidogrel – a less potent and less costly antiplatelet agent – in rates of cardiovascular events or bleeding though 12 months of follow-up in the TREAT trial.
“In terms of efficacy, it is appropriate to interpret TREAT statistically as a neutral trial,” Otavio Berwanger, MD, PhD, advised at the annual meeting of the American College of Cardiology.
TREAT (Ticagrelor in patients with ST-elevation myocardial infarction treated with pharmacological thrombolysis) was a 10-country, 152-site, randomized, open-label clinical trial of 3,799 STEMI (ST-elevation MI) patients treated with fibrinolytic therapy followed an average of 11 hours later by a loading dose of either ticagrelor (Brilinta) or clopidogrel, then 12 months of standard-dose maintenance therapy of their designated potent antiplatelet drug. The adherence rate was 90% at 12 months. Participating countries included Russia, China, Brazil, Australia, and Canada, but not the United States.
The primary efficacy endpoint was the 12-month composite of death from a vascular cause, MI, stroke, severe recurrent ischemia, TIA, or another arterial thrombotic event. The rate was 8% in the ticagrelor group and 9.1% with clopidogrel, a 12% relative risk reduction in favor of ticagrelor that was not statistically significant. But then, TREAT was underpowered to show a difference in efficacy. However, the 12% relative risk reduction mirrors that seen in the earlier PLATO trial of 18,624 patients with acute coronary syndrome who were randomized to ticagrelor or clopidogrel in conjunction with primary PCI, a difference that was statistically significant because of PLATO’s much larger size (N Engl J Med. 2009 Sep 10;361[11]:1045-57).
TREAT was sufficiently powered to assess safety. There was no significant between-group difference in TIMI major bleeding, the primary safety endpoint. However, the rate of total bleeding events was significantly higher in the ticagrelor arm, by a margin of 10.25% versus 6.15%. Moreover, the rate of TIMI clinically significant bleeding requiring medical attention was also higher in the ticagrelor group – 5.2% versus 3.8% – and the TIMI minimal bleeding rate of 5.85% in the ticagrelor group was more than double that in the clopidogrel arm, reported Dr. Berwanger of the Heart Hospital Research Institute in São Paolo.
These 12-month outcomes echo those previously reported at the 30-day mark in TREAT (JAMA Cardiol. 2018 May 1;3[5]:391-9).
Discussant C. Michael Gibson, MD, put TREAT in perspective: “Here we’re looking to see if there are differences between two thienopyridine inhibitors. There’s nothing really that important on the efficacy side, although there was 1.5% missingness in the study. And there was a higher number of total bleeds with ticagrelor.
“Some of the junior members of the audience may not be all that familiar with fibrinolysis. In the era where it was more prominent, reocclusion occurred in 5%-8% of patients. When it did occur, it led to a tripling of mortality. It’s important to note that the first study of a thienopyridine inhibitor added to lytics was CLARITY, almost 15 years ago, showing a reduction in death, MI, or reocclusion down from about 15% to 7% [N Engl J Med 2005; 352:1179-89]. So it should be very clear to the audience that reocclusion is a problem and the addition of a thienopyridine inhibitor improves that,” explained Dr. Gibson, professor of medicine at Harvard Medical School, Boston.
The TREAT trial was funded by AstraZeneca. Dr. Berwanger reported receiving research grants from and serving as a consultant to that company and half a dozen others.
Simultaneously with the presentation, the TREAT study was published online (J Am Coll Cardiol. 2019 Mar 12. doi: 10.1016/j.jacc.2019.03.011).
NEW ORLEANS – In STEMI patients who aren’t able to undergo primary PCI, ticagrelor after fibrinolytic therapy offered no advantages over clopidogrel – a less potent and less costly antiplatelet agent – in rates of cardiovascular events or bleeding though 12 months of follow-up in the TREAT trial.
“In terms of efficacy, it is appropriate to interpret TREAT statistically as a neutral trial,” Otavio Berwanger, MD, PhD, advised at the annual meeting of the American College of Cardiology.
TREAT (Ticagrelor in patients with ST-elevation myocardial infarction treated with pharmacological thrombolysis) was a 10-country, 152-site, randomized, open-label clinical trial of 3,799 STEMI (ST-elevation MI) patients treated with fibrinolytic therapy followed an average of 11 hours later by a loading dose of either ticagrelor (Brilinta) or clopidogrel, then 12 months of standard-dose maintenance therapy of their designated potent antiplatelet drug. The adherence rate was 90% at 12 months. Participating countries included Russia, China, Brazil, Australia, and Canada, but not the United States.
The primary efficacy endpoint was the 12-month composite of death from a vascular cause, MI, stroke, severe recurrent ischemia, TIA, or another arterial thrombotic event. The rate was 8% in the ticagrelor group and 9.1% with clopidogrel, a 12% relative risk reduction in favor of ticagrelor that was not statistically significant. But then, TREAT was underpowered to show a difference in efficacy. However, the 12% relative risk reduction mirrors that seen in the earlier PLATO trial of 18,624 patients with acute coronary syndrome who were randomized to ticagrelor or clopidogrel in conjunction with primary PCI, a difference that was statistically significant because of PLATO’s much larger size (N Engl J Med. 2009 Sep 10;361[11]:1045-57).
TREAT was sufficiently powered to assess safety. There was no significant between-group difference in TIMI major bleeding, the primary safety endpoint. However, the rate of total bleeding events was significantly higher in the ticagrelor arm, by a margin of 10.25% versus 6.15%. Moreover, the rate of TIMI clinically significant bleeding requiring medical attention was also higher in the ticagrelor group – 5.2% versus 3.8% – and the TIMI minimal bleeding rate of 5.85% in the ticagrelor group was more than double that in the clopidogrel arm, reported Dr. Berwanger of the Heart Hospital Research Institute in São Paolo.
These 12-month outcomes echo those previously reported at the 30-day mark in TREAT (JAMA Cardiol. 2018 May 1;3[5]:391-9).
Discussant C. Michael Gibson, MD, put TREAT in perspective: “Here we’re looking to see if there are differences between two thienopyridine inhibitors. There’s nothing really that important on the efficacy side, although there was 1.5% missingness in the study. And there was a higher number of total bleeds with ticagrelor.
“Some of the junior members of the audience may not be all that familiar with fibrinolysis. In the era where it was more prominent, reocclusion occurred in 5%-8% of patients. When it did occur, it led to a tripling of mortality. It’s important to note that the first study of a thienopyridine inhibitor added to lytics was CLARITY, almost 15 years ago, showing a reduction in death, MI, or reocclusion down from about 15% to 7% [N Engl J Med 2005; 352:1179-89]. So it should be very clear to the audience that reocclusion is a problem and the addition of a thienopyridine inhibitor improves that,” explained Dr. Gibson, professor of medicine at Harvard Medical School, Boston.
The TREAT trial was funded by AstraZeneca. Dr. Berwanger reported receiving research grants from and serving as a consultant to that company and half a dozen others.
Simultaneously with the presentation, the TREAT study was published online (J Am Coll Cardiol. 2019 Mar 12. doi: 10.1016/j.jacc.2019.03.011).
REPORTING FROM ACC 19
PIONEER-HF Extension: Don’t stall starting sacubitril/valsartan
NEW ORLEANS – Waiting a few months after a patient has been hospitalized for acute decompensated heart failure before launching a switch from enalapril to sacubitril/valsartan imposes a steep price in terms of extra major cardiovascular events, compared with starting the angiotensin-neprilysin inhibitor during the initial hospitalization, according to the open-label extension of the PIONEER-HF trial.
“We think these data have important clinical implications: While sacubitril/valsartan decreases NT-proBNP compared with enalapril regardless of when it is initiated, the early improvement in postdischarge outcomes supports the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure,” Adam D. DeVore, MD, declared in presenting the PIONEER-HF Extension results at the annual meeting of the American College of Cardiology.
PIONEER-HF was a landmark, practice-changing, double-blind clinical trial in which 881 patients were randomized to initiation of sacubitril/valsartan (Entresto) or enalapril during hospitalization for acute decompensated heart failure. In the previously reported main outcome, 8 weeks after discharge the sacubitril/valsartan group had a 29% greater reduction in NT-proBNP (the N-terminal prohormone of brain natriuretic peptide) and a 42% lower rate of the composite clinical endpoint of cardiovascular death or heart failure rehospitalization than the enalapril group (N Engl J Med. 2019 Feb 7;380[6]:539-48).
The 4-week open-label extension of PIONEER-HF began at week 8, when participants initially randomized to enalapril during the double-blind phase were switched to sacubitril/valsartan, while those assigned to in-hospital initiation of the angiotensin-neprilysin inhibitor (ARNI) stayed the course.
At week 12, after 4 weeks of open-label treatment, patients on sacubitril/valsartan from the start experienced an additional 18.5% drop in NT-proBNP from their week-8 baseline of 1,218 pg/mL. Meanwhile, the NT-proBNP level in the switch group plunged by 35.8% from a week-8 baseline of 1,630 pg/mL. As a result, both groups ended up at the same much-improved biomarker level at week 12, observed Dr. DeVore, a cardiologist at Duke University in Durham, N.C.
Clinical event rates, however, were another story altogether. The clinical event gap between the two study arms documented at week 8 in the double-blind phase of the trial didn’t close significantly in the 4 weeks after the enalapril group crossed over to open-label sacubitril/valsartan. Indeed, the relative risk of the composite endpoint of cardiovascular death, heart failure rehospitalization, or left ventricular assist device implantation during the 4-week extension phase was 33% lower in the continuous sacubitril/valsartan group than in the switchers. The absolute risk reduction was 5.6%, with a favorable number needed to treat of 18.
This difference was driven mainly by less rehospitalization for heart failure. Few cardiovascular deaths or LVAD implantations occurred during the relatively brief 4-week extension phase of the trial.
“But this is an important thing as we think about what we’re trying to accomplish in heart failure: trying to find tools that improve rehospitalization rates after people leave the hospital is extremely important,” Dr. DeVore said. “We do know that the really vulnerable period for rehospitalization is early on, so my sus```picion – though I can’t prove it – is that’s the important part. That’s when we need to have patients on the best therapy.”
He was asked how practical it is to initiate sacubitril/valsartan during hospitalization for acute decompensated heart failure in real-world clinical practice, given that it can be done only after patients achieve hemodynamic stability.
“I think the definition of hemodynamic stability we used in the trial was a fairly straightforward one, very clinical, and one we can translate to the bedside,” Dr. DeVore replied. “Patients had to have a systolic blood pressure of 100 mm Hg or greater for 6 hours, which is easily documented in the hospital, no changes in IV diuretics or IV vasodilators for 6 hours, and no IV inotropes for the last 24 hours. That’s how we defined hemodynamic stability. I think we should be able to find these patients.”
Average length of stay in the index hospitalization in PIONEER-HF was just over 5 days, but the study protocol actually resulted in longer-than-needed hospitalization because it required that patients had to receive three double-blind doses of their study medication before discharge. In routine practice, it’s unlikely that in-hospital initiation of sacubitril/valsartan will result in a length of stay greater than the national average of about 4.5 days, according the cardiologist.
Current ACC/American Heart Association/Heart Failure Society of American guidelines on management of heart failure include a Class Ia recommendation to switch patients from an ACE inhibitor or angiotensin inhibitor to sacubitril/valsartan (Circulation. 2017 Aug 8;136[6]:e137-61).
However, heart failure specialists are concerned by national data showing that sacubitril/valsartan remains widely underprescribed.
Dr. DeVore reported serving as a consultant to Novartis and receiving research grants from a half dozen pharmaceutical companies as well as the American Heart Association, National Heart, Lung, and Blood Institute, and the Patient-Centered Outcomes Research Institute .
NEW ORLEANS – Waiting a few months after a patient has been hospitalized for acute decompensated heart failure before launching a switch from enalapril to sacubitril/valsartan imposes a steep price in terms of extra major cardiovascular events, compared with starting the angiotensin-neprilysin inhibitor during the initial hospitalization, according to the open-label extension of the PIONEER-HF trial.
“We think these data have important clinical implications: While sacubitril/valsartan decreases NT-proBNP compared with enalapril regardless of when it is initiated, the early improvement in postdischarge outcomes supports the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure,” Adam D. DeVore, MD, declared in presenting the PIONEER-HF Extension results at the annual meeting of the American College of Cardiology.
PIONEER-HF was a landmark, practice-changing, double-blind clinical trial in which 881 patients were randomized to initiation of sacubitril/valsartan (Entresto) or enalapril during hospitalization for acute decompensated heart failure. In the previously reported main outcome, 8 weeks after discharge the sacubitril/valsartan group had a 29% greater reduction in NT-proBNP (the N-terminal prohormone of brain natriuretic peptide) and a 42% lower rate of the composite clinical endpoint of cardiovascular death or heart failure rehospitalization than the enalapril group (N Engl J Med. 2019 Feb 7;380[6]:539-48).
The 4-week open-label extension of PIONEER-HF began at week 8, when participants initially randomized to enalapril during the double-blind phase were switched to sacubitril/valsartan, while those assigned to in-hospital initiation of the angiotensin-neprilysin inhibitor (ARNI) stayed the course.
At week 12, after 4 weeks of open-label treatment, patients on sacubitril/valsartan from the start experienced an additional 18.5% drop in NT-proBNP from their week-8 baseline of 1,218 pg/mL. Meanwhile, the NT-proBNP level in the switch group plunged by 35.8% from a week-8 baseline of 1,630 pg/mL. As a result, both groups ended up at the same much-improved biomarker level at week 12, observed Dr. DeVore, a cardiologist at Duke University in Durham, N.C.
Clinical event rates, however, were another story altogether. The clinical event gap between the two study arms documented at week 8 in the double-blind phase of the trial didn’t close significantly in the 4 weeks after the enalapril group crossed over to open-label sacubitril/valsartan. Indeed, the relative risk of the composite endpoint of cardiovascular death, heart failure rehospitalization, or left ventricular assist device implantation during the 4-week extension phase was 33% lower in the continuous sacubitril/valsartan group than in the switchers. The absolute risk reduction was 5.6%, with a favorable number needed to treat of 18.
This difference was driven mainly by less rehospitalization for heart failure. Few cardiovascular deaths or LVAD implantations occurred during the relatively brief 4-week extension phase of the trial.
“But this is an important thing as we think about what we’re trying to accomplish in heart failure: trying to find tools that improve rehospitalization rates after people leave the hospital is extremely important,” Dr. DeVore said. “We do know that the really vulnerable period for rehospitalization is early on, so my sus```picion – though I can’t prove it – is that’s the important part. That’s when we need to have patients on the best therapy.”
He was asked how practical it is to initiate sacubitril/valsartan during hospitalization for acute decompensated heart failure in real-world clinical practice, given that it can be done only after patients achieve hemodynamic stability.
“I think the definition of hemodynamic stability we used in the trial was a fairly straightforward one, very clinical, and one we can translate to the bedside,” Dr. DeVore replied. “Patients had to have a systolic blood pressure of 100 mm Hg or greater for 6 hours, which is easily documented in the hospital, no changes in IV diuretics or IV vasodilators for 6 hours, and no IV inotropes for the last 24 hours. That’s how we defined hemodynamic stability. I think we should be able to find these patients.”
Average length of stay in the index hospitalization in PIONEER-HF was just over 5 days, but the study protocol actually resulted in longer-than-needed hospitalization because it required that patients had to receive three double-blind doses of their study medication before discharge. In routine practice, it’s unlikely that in-hospital initiation of sacubitril/valsartan will result in a length of stay greater than the national average of about 4.5 days, according the cardiologist.
Current ACC/American Heart Association/Heart Failure Society of American guidelines on management of heart failure include a Class Ia recommendation to switch patients from an ACE inhibitor or angiotensin inhibitor to sacubitril/valsartan (Circulation. 2017 Aug 8;136[6]:e137-61).
However, heart failure specialists are concerned by national data showing that sacubitril/valsartan remains widely underprescribed.
Dr. DeVore reported serving as a consultant to Novartis and receiving research grants from a half dozen pharmaceutical companies as well as the American Heart Association, National Heart, Lung, and Blood Institute, and the Patient-Centered Outcomes Research Institute .
NEW ORLEANS – Waiting a few months after a patient has been hospitalized for acute decompensated heart failure before launching a switch from enalapril to sacubitril/valsartan imposes a steep price in terms of extra major cardiovascular events, compared with starting the angiotensin-neprilysin inhibitor during the initial hospitalization, according to the open-label extension of the PIONEER-HF trial.
“We think these data have important clinical implications: While sacubitril/valsartan decreases NT-proBNP compared with enalapril regardless of when it is initiated, the early improvement in postdischarge outcomes supports the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure,” Adam D. DeVore, MD, declared in presenting the PIONEER-HF Extension results at the annual meeting of the American College of Cardiology.
PIONEER-HF was a landmark, practice-changing, double-blind clinical trial in which 881 patients were randomized to initiation of sacubitril/valsartan (Entresto) or enalapril during hospitalization for acute decompensated heart failure. In the previously reported main outcome, 8 weeks after discharge the sacubitril/valsartan group had a 29% greater reduction in NT-proBNP (the N-terminal prohormone of brain natriuretic peptide) and a 42% lower rate of the composite clinical endpoint of cardiovascular death or heart failure rehospitalization than the enalapril group (N Engl J Med. 2019 Feb 7;380[6]:539-48).
The 4-week open-label extension of PIONEER-HF began at week 8, when participants initially randomized to enalapril during the double-blind phase were switched to sacubitril/valsartan, while those assigned to in-hospital initiation of the angiotensin-neprilysin inhibitor (ARNI) stayed the course.
At week 12, after 4 weeks of open-label treatment, patients on sacubitril/valsartan from the start experienced an additional 18.5% drop in NT-proBNP from their week-8 baseline of 1,218 pg/mL. Meanwhile, the NT-proBNP level in the switch group plunged by 35.8% from a week-8 baseline of 1,630 pg/mL. As a result, both groups ended up at the same much-improved biomarker level at week 12, observed Dr. DeVore, a cardiologist at Duke University in Durham, N.C.
Clinical event rates, however, were another story altogether. The clinical event gap between the two study arms documented at week 8 in the double-blind phase of the trial didn’t close significantly in the 4 weeks after the enalapril group crossed over to open-label sacubitril/valsartan. Indeed, the relative risk of the composite endpoint of cardiovascular death, heart failure rehospitalization, or left ventricular assist device implantation during the 4-week extension phase was 33% lower in the continuous sacubitril/valsartan group than in the switchers. The absolute risk reduction was 5.6%, with a favorable number needed to treat of 18.
This difference was driven mainly by less rehospitalization for heart failure. Few cardiovascular deaths or LVAD implantations occurred during the relatively brief 4-week extension phase of the trial.
“But this is an important thing as we think about what we’re trying to accomplish in heart failure: trying to find tools that improve rehospitalization rates after people leave the hospital is extremely important,” Dr. DeVore said. “We do know that the really vulnerable period for rehospitalization is early on, so my sus```picion – though I can’t prove it – is that’s the important part. That’s when we need to have patients on the best therapy.”
He was asked how practical it is to initiate sacubitril/valsartan during hospitalization for acute decompensated heart failure in real-world clinical practice, given that it can be done only after patients achieve hemodynamic stability.
“I think the definition of hemodynamic stability we used in the trial was a fairly straightforward one, very clinical, and one we can translate to the bedside,” Dr. DeVore replied. “Patients had to have a systolic blood pressure of 100 mm Hg or greater for 6 hours, which is easily documented in the hospital, no changes in IV diuretics or IV vasodilators for 6 hours, and no IV inotropes for the last 24 hours. That’s how we defined hemodynamic stability. I think we should be able to find these patients.”
Average length of stay in the index hospitalization in PIONEER-HF was just over 5 days, but the study protocol actually resulted in longer-than-needed hospitalization because it required that patients had to receive three double-blind doses of their study medication before discharge. In routine practice, it’s unlikely that in-hospital initiation of sacubitril/valsartan will result in a length of stay greater than the national average of about 4.5 days, according the cardiologist.
Current ACC/American Heart Association/Heart Failure Society of American guidelines on management of heart failure include a Class Ia recommendation to switch patients from an ACE inhibitor or angiotensin inhibitor to sacubitril/valsartan (Circulation. 2017 Aug 8;136[6]:e137-61).
However, heart failure specialists are concerned by national data showing that sacubitril/valsartan remains widely underprescribed.
Dr. DeVore reported serving as a consultant to Novartis and receiving research grants from a half dozen pharmaceutical companies as well as the American Heart Association, National Heart, Lung, and Blood Institute, and the Patient-Centered Outcomes Research Institute .
REPORTING FROM ACC 19
Key clinical point: over the next 12 weeks, compared with initiation of enalapril followed by a delayed switch to sacubitril/valsartan at 8 weeks.
Major finding: The number needed to treat with in-hospital initiation of sacubitril/valsartan instead of enalapril to avoid one cardiovascular death, heart failure rehospitalization, or implantation of a left ventricular assist device was 18.
Study details: The PIONEER-HF Extension study included 881 heart failure patients, all on open-label sacubitril/valsartan during the 4-week extension phase.
Disclosures: The study was sponsored by AstraZeneca. The presenter reported receiving research grants from and serving as a consultant to the company.
Clinicians, CMS confer over heart failure–readmission penalty
NEW ORLEANS – Mounting evidence shows that heart failure patient mortality increased as an unintended consequence of a Medicare program that penalizes hospitals with too many 30-day readmissions of heart failure patients. This has prompted discussions among cardiologists, Medicare officials, and other stakeholders in an attempt to modify the penalty program so it no longer considers just readmissions but instead bases penalties on broader and more nuanced measures of patient outcomes.
Staffers at the Centers for Medicare & Medicaid Services, the federal agency that manages Medicare, “said that they take this seriously and will look into it, and they are interested in next-generation measures that are more patient centered” than simply the 30-day readmission rate, Gregg C. Fonarow, MD, said in an interview at the annual meeting of the American College of Cardiology. “This is a case where there is credible evidence of increased mortality that is consistent, reproducible, and strongly associated with the penalty and cannot be otherwise explained,” said Dr. Fonarow, professor of medicine and cochief of cardiology at the University of California, Los Angeles.
He is among the most active researchers to document that, while CMS’s Hospital Readmissions Reduction Program (HRRP) led to significantly reduced readmission rates in patients with heart failure, this came at a cost of a significant increase in mortality among the same patients. For example, an article he published in 2018 that analyzed more than 115,000 Medicare beneficiaries during 2006-2014 showed that during the penalty phase, which began in 2012, readmissions fell after adjustment by a relative 8%, but adjusted mortality rose by a relative 10%, compared with how patients had fared prior to launching the HRRP (JAMA Cardiol. 2018 Jan;3[1]:44-53). Recent reports from other research groups have had similar findings, such as a study of more than 3 million Medicare beneficiaries with heart failure during 2005-2015 that also showed significantly increased mortality after the penalty phase for readmissions began (JAMA. 2018 Dec 25;320[24]:2542-52). In a commentary that accompanied this report, Dr. Fonarow cited the multiple analyses that show consistent findings and the need for CMS to “initiate an expeditious reconsideration and revision” of their current approach to penalizing hospitals for heart failure readmissions (JAMA. 2018 Dec 25;320[24]:2539-41).
The groups recently in discussion with CMS about this issue include the American College of Cardiology, the American Heart Association, the Heart Failure Society of America, the American College of Physicians, the American Hospital Association, and several other medical professional groups, said Biykem Bozkurt, MD, who has worked with Dr. Fonarow and representatives from these organizations in talks with CMS.
“We are trying to find a harmonized approach with patient-centric outcomes that reflect true improvements in quality of care,” she said in an interview. One possibility up for consideration is a combined measure of heart failure readmissions, mortality, and a patient-reported outcome. The measure would go to CMS directly from each patient’s electronic medical record, making data collection less burdensome to clinicians, said Dr. Bozkurt, professor of medicine at Baylor College of Medicine and cardiology section chief at the VA Medical Center in Houston. She expressed hope that a change in the CMS metric might happen later this year.
“CMS can’t simply stop the HRRP, so the discussion is on how to get a meaningful change. I’m increasingly optimistic, because the findings of harm [from current policies] are impossible to ignore,” Dr. Fonarow said. “There will be increasing pressure on CMS to develop a pathway to make modifications. It’s egregious to continue a policy that’s been associated with harm” to heart failure patients.
Dr. Fonarow and Dr. Bozkurt had no relevant commercial disclosures.
NEW ORLEANS – Mounting evidence shows that heart failure patient mortality increased as an unintended consequence of a Medicare program that penalizes hospitals with too many 30-day readmissions of heart failure patients. This has prompted discussions among cardiologists, Medicare officials, and other stakeholders in an attempt to modify the penalty program so it no longer considers just readmissions but instead bases penalties on broader and more nuanced measures of patient outcomes.
Staffers at the Centers for Medicare & Medicaid Services, the federal agency that manages Medicare, “said that they take this seriously and will look into it, and they are interested in next-generation measures that are more patient centered” than simply the 30-day readmission rate, Gregg C. Fonarow, MD, said in an interview at the annual meeting of the American College of Cardiology. “This is a case where there is credible evidence of increased mortality that is consistent, reproducible, and strongly associated with the penalty and cannot be otherwise explained,” said Dr. Fonarow, professor of medicine and cochief of cardiology at the University of California, Los Angeles.
He is among the most active researchers to document that, while CMS’s Hospital Readmissions Reduction Program (HRRP) led to significantly reduced readmission rates in patients with heart failure, this came at a cost of a significant increase in mortality among the same patients. For example, an article he published in 2018 that analyzed more than 115,000 Medicare beneficiaries during 2006-2014 showed that during the penalty phase, which began in 2012, readmissions fell after adjustment by a relative 8%, but adjusted mortality rose by a relative 10%, compared with how patients had fared prior to launching the HRRP (JAMA Cardiol. 2018 Jan;3[1]:44-53). Recent reports from other research groups have had similar findings, such as a study of more than 3 million Medicare beneficiaries with heart failure during 2005-2015 that also showed significantly increased mortality after the penalty phase for readmissions began (JAMA. 2018 Dec 25;320[24]:2542-52). In a commentary that accompanied this report, Dr. Fonarow cited the multiple analyses that show consistent findings and the need for CMS to “initiate an expeditious reconsideration and revision” of their current approach to penalizing hospitals for heart failure readmissions (JAMA. 2018 Dec 25;320[24]:2539-41).
The groups recently in discussion with CMS about this issue include the American College of Cardiology, the American Heart Association, the Heart Failure Society of America, the American College of Physicians, the American Hospital Association, and several other medical professional groups, said Biykem Bozkurt, MD, who has worked with Dr. Fonarow and representatives from these organizations in talks with CMS.
“We are trying to find a harmonized approach with patient-centric outcomes that reflect true improvements in quality of care,” she said in an interview. One possibility up for consideration is a combined measure of heart failure readmissions, mortality, and a patient-reported outcome. The measure would go to CMS directly from each patient’s electronic medical record, making data collection less burdensome to clinicians, said Dr. Bozkurt, professor of medicine at Baylor College of Medicine and cardiology section chief at the VA Medical Center in Houston. She expressed hope that a change in the CMS metric might happen later this year.
“CMS can’t simply stop the HRRP, so the discussion is on how to get a meaningful change. I’m increasingly optimistic, because the findings of harm [from current policies] are impossible to ignore,” Dr. Fonarow said. “There will be increasing pressure on CMS to develop a pathway to make modifications. It’s egregious to continue a policy that’s been associated with harm” to heart failure patients.
Dr. Fonarow and Dr. Bozkurt had no relevant commercial disclosures.
NEW ORLEANS – Mounting evidence shows that heart failure patient mortality increased as an unintended consequence of a Medicare program that penalizes hospitals with too many 30-day readmissions of heart failure patients. This has prompted discussions among cardiologists, Medicare officials, and other stakeholders in an attempt to modify the penalty program so it no longer considers just readmissions but instead bases penalties on broader and more nuanced measures of patient outcomes.
Staffers at the Centers for Medicare & Medicaid Services, the federal agency that manages Medicare, “said that they take this seriously and will look into it, and they are interested in next-generation measures that are more patient centered” than simply the 30-day readmission rate, Gregg C. Fonarow, MD, said in an interview at the annual meeting of the American College of Cardiology. “This is a case where there is credible evidence of increased mortality that is consistent, reproducible, and strongly associated with the penalty and cannot be otherwise explained,” said Dr. Fonarow, professor of medicine and cochief of cardiology at the University of California, Los Angeles.
He is among the most active researchers to document that, while CMS’s Hospital Readmissions Reduction Program (HRRP) led to significantly reduced readmission rates in patients with heart failure, this came at a cost of a significant increase in mortality among the same patients. For example, an article he published in 2018 that analyzed more than 115,000 Medicare beneficiaries during 2006-2014 showed that during the penalty phase, which began in 2012, readmissions fell after adjustment by a relative 8%, but adjusted mortality rose by a relative 10%, compared with how patients had fared prior to launching the HRRP (JAMA Cardiol. 2018 Jan;3[1]:44-53). Recent reports from other research groups have had similar findings, such as a study of more than 3 million Medicare beneficiaries with heart failure during 2005-2015 that also showed significantly increased mortality after the penalty phase for readmissions began (JAMA. 2018 Dec 25;320[24]:2542-52). In a commentary that accompanied this report, Dr. Fonarow cited the multiple analyses that show consistent findings and the need for CMS to “initiate an expeditious reconsideration and revision” of their current approach to penalizing hospitals for heart failure readmissions (JAMA. 2018 Dec 25;320[24]:2539-41).
The groups recently in discussion with CMS about this issue include the American College of Cardiology, the American Heart Association, the Heart Failure Society of America, the American College of Physicians, the American Hospital Association, and several other medical professional groups, said Biykem Bozkurt, MD, who has worked with Dr. Fonarow and representatives from these organizations in talks with CMS.
“We are trying to find a harmonized approach with patient-centric outcomes that reflect true improvements in quality of care,” she said in an interview. One possibility up for consideration is a combined measure of heart failure readmissions, mortality, and a patient-reported outcome. The measure would go to CMS directly from each patient’s electronic medical record, making data collection less burdensome to clinicians, said Dr. Bozkurt, professor of medicine at Baylor College of Medicine and cardiology section chief at the VA Medical Center in Houston. She expressed hope that a change in the CMS metric might happen later this year.
“CMS can’t simply stop the HRRP, so the discussion is on how to get a meaningful change. I’m increasingly optimistic, because the findings of harm [from current policies] are impossible to ignore,” Dr. Fonarow said. “There will be increasing pressure on CMS to develop a pathway to make modifications. It’s egregious to continue a policy that’s been associated with harm” to heart failure patients.
Dr. Fonarow and Dr. Bozkurt had no relevant commercial disclosures.
REPORTING FROM ACC 19
Dapagliflozin’s cardiovascular benefits bloom in T2D with prior MI
NEW ORLEANS – Dapagliflozin markedly reduces the risks of both major adverse cardiovascular events and heart failure hospitalization in the subset of patients with type 2 diabetes (T2D) and prior MI, according to a new subanalysis of the landmark DECLARE-TIMI 58 trial.
The effectiveness of dapagliflozin (Farxiga), an oral sodium glucose transporter-2 inhibitor (SGLT-2i), was particularly striking with regard to prevention of recurrent MI, Remo H.M. Furtado, MD, reported at the annual meeting of the American College of Cardiology.
“The 22% relative risk reduction in recurrent MI with dapagliflozin is comparable to other established therapies used in secondary prevention after MI, like DAPT [dual-antiplatelet therapy] and intensive lipid lowering,” observed Dr. Furtado of Brigham and Women’s Hospital, Boston.
Not bad for a drug developed as a glucose-lowering agent.
The new DECLARE-TIMI 58 subanalysis provides information that’s relevant to ACC guidelines issued in late 2018. The guidelines, in the form of an “expert consensus decision pathway,” emphatically recommend that all patients with T2D and known atherosclerotic cardiovascular disease (ASCVD) should have metformin as their first-line glucose-lowering agent, while at the same time giving serious consideration to the addition of either an oral SGLT-2i or a subcutaneously injected glucagonlike peptide–1 receptor agonist (GLP-1RA) with demonstrated cardiovascular benefit as a second glucose-lowering agent (J Am Coll Cardiol. 2018 Dec 18;72[24]:3200-23). The DECLARE-TIMI 58 subanalysis bolsters that guidance and shows, more specifically, that the cardioprotective benefits of dapagliflozin are significantly greater in T2D with prior MI than in those with known ASCVD but no history of MI, the cardiologist explained.
The main results of DECLARE-TIMI 58 have been published. The trial included 17,160 patients with T2D, 6,974 of whom had established ASCVD, while the remainder had multiple ASCVD risk factors. Participants were randomized to oral dapagliflozin at 10 mg/day or placebo on top of background guideline-directed medical therapy and followed for a median of 4.2 years. The dapagliflozin group had a 27% reduction in heart failure hospitalizations, compared with controls, but there were no significant between-group differences in the composite MACE (major adverse cardiovascular events) endpoint of cardiovascular death, MI, or ischemic stroke (N Engl J Med. 2019 Jan 24;380[4]:347-57).
Dr. Furtado presented a prespecified subgroup analysis focused on the 3,584 study participants with prior MI. Their rate of the composite endpoint of cardiovascular death, MI, or ischemic stroke was 15.2%, compared with 17.8% in controls, for a statistically significant and clinically meaningful 16% relative risk reduction and an absolute 2.6% risk reduction. Of note, the risk of recurrent MI was reduced by 22%. In contrast, there was no difference in MACE risk between the dapagliflozin and placebo groups in patients with no prior MI, even if they had established ASCVD.
A noteworthy finding was that the benefit in MACE reduction in patients with prior MI was greater in those who were closer in time to their most recent MI at enrollment in the study. Those who started on dapagliflozin within 12 months of their last MI had a 34% relative risk reduction in MACE, compared with placebo, while those who enrolled 12-24 months after their last MI enjoyed an even more robust 58% relative risk reduction on dapagliflozin. In contrast, patients who enrolled 24-36 months post MI had only a 17% relative risk reduction, and the 2,400 patients who enrolled more than 36 months after their last MI had a subsequent MACE rate no different from controls.
Session cochair Nadia R. Sutton, MD, a cardiologist at the University of Michigan, Ann Arbor, commented that she found this time-dependent benefit fascinating.
“Do you think this has anything to do with the escalation of other therapies, such as Plavix [clopidogrel]?” she asked.
Dr. Furtado replied, “This is a finding that we should interpret with a little bit of caution.” For one thing, patients in the acute phase of an MI were excluded from participation in the trial, so nothing is known about how they would fare on dapagliflozin. For another, only 844 of the 3,584 patients with T2D and prior MI had their most recent MI within 24 months of enrollment, so even though the differences were statistically significant, the confidence intervals are fairly wide.
That being said, the finding does underscore a truism about cardiovascular prevention: The higher the risk, the greater the benefit of effective therapy – and, of course, the initial months following an MI are a particularly high-risk period.
“Also, this finding is a caution to the clinicians to avoid clinical inertia in prescribing an SGLT-2i, because maybe you can get an early benefit if you prescribe the drug closer to the acute phase and not wait until some months after the patient has tried diet and exercise and so on,” he added.
With regard to the second coprimary endpoint comprising cardiovascular death or heart failure hospitalization in T2D patients with prior MI, the rate in the dapagliflozin group was 8.6%, a 19% relative risk reduction and absolute risk reduction of 1.9%, compared with the 10.5% rate with placebo.
Dr. Furtado noted that the main results of DECLARE TIMI-58 are consistent with a recent systematic review and meta-analysis of three randomized cardiovascular outcome trials of SGLT-2is for primary and secondary prevention of cardiovascular and renal outcomes in T2D. The meta-analysis included more than 34,000 patients, roughly half drawn from DECLARE-TIMI 58. SGLT-2i therapy reduced MACE by 14% in patients with established ASCVD but not significantly in those without. And the agents reduced the risk of cardiovascular death/heart failure hospitalization by 23%, regardless of whether or not patients had known ASCVD or a history of heart failure (Lancet. 2019 Jan 5;393[10166]:31-9).
Dr. Furtado reported serving as a consultant to AstraZeneca, which funded DECLARE-TIMI 58, as well as receiving direct institutional research grants from half a dozen other pharmaceutical companies.
Simultaneous with his presentation at ACC 2019 in New Orleans, the subanalysis results were published online (Circulation. 2019 Mar 18. doi: 10.1161/CIRCULATIONAHA.119.039996. [Epub ahead of print]).
NEW ORLEANS – Dapagliflozin markedly reduces the risks of both major adverse cardiovascular events and heart failure hospitalization in the subset of patients with type 2 diabetes (T2D) and prior MI, according to a new subanalysis of the landmark DECLARE-TIMI 58 trial.
The effectiveness of dapagliflozin (Farxiga), an oral sodium glucose transporter-2 inhibitor (SGLT-2i), was particularly striking with regard to prevention of recurrent MI, Remo H.M. Furtado, MD, reported at the annual meeting of the American College of Cardiology.
“The 22% relative risk reduction in recurrent MI with dapagliflozin is comparable to other established therapies used in secondary prevention after MI, like DAPT [dual-antiplatelet therapy] and intensive lipid lowering,” observed Dr. Furtado of Brigham and Women’s Hospital, Boston.
Not bad for a drug developed as a glucose-lowering agent.
The new DECLARE-TIMI 58 subanalysis provides information that’s relevant to ACC guidelines issued in late 2018. The guidelines, in the form of an “expert consensus decision pathway,” emphatically recommend that all patients with T2D and known atherosclerotic cardiovascular disease (ASCVD) should have metformin as their first-line glucose-lowering agent, while at the same time giving serious consideration to the addition of either an oral SGLT-2i or a subcutaneously injected glucagonlike peptide–1 receptor agonist (GLP-1RA) with demonstrated cardiovascular benefit as a second glucose-lowering agent (J Am Coll Cardiol. 2018 Dec 18;72[24]:3200-23). The DECLARE-TIMI 58 subanalysis bolsters that guidance and shows, more specifically, that the cardioprotective benefits of dapagliflozin are significantly greater in T2D with prior MI than in those with known ASCVD but no history of MI, the cardiologist explained.
The main results of DECLARE-TIMI 58 have been published. The trial included 17,160 patients with T2D, 6,974 of whom had established ASCVD, while the remainder had multiple ASCVD risk factors. Participants were randomized to oral dapagliflozin at 10 mg/day or placebo on top of background guideline-directed medical therapy and followed for a median of 4.2 years. The dapagliflozin group had a 27% reduction in heart failure hospitalizations, compared with controls, but there were no significant between-group differences in the composite MACE (major adverse cardiovascular events) endpoint of cardiovascular death, MI, or ischemic stroke (N Engl J Med. 2019 Jan 24;380[4]:347-57).
Dr. Furtado presented a prespecified subgroup analysis focused on the 3,584 study participants with prior MI. Their rate of the composite endpoint of cardiovascular death, MI, or ischemic stroke was 15.2%, compared with 17.8% in controls, for a statistically significant and clinically meaningful 16% relative risk reduction and an absolute 2.6% risk reduction. Of note, the risk of recurrent MI was reduced by 22%. In contrast, there was no difference in MACE risk between the dapagliflozin and placebo groups in patients with no prior MI, even if they had established ASCVD.
A noteworthy finding was that the benefit in MACE reduction in patients with prior MI was greater in those who were closer in time to their most recent MI at enrollment in the study. Those who started on dapagliflozin within 12 months of their last MI had a 34% relative risk reduction in MACE, compared with placebo, while those who enrolled 12-24 months after their last MI enjoyed an even more robust 58% relative risk reduction on dapagliflozin. In contrast, patients who enrolled 24-36 months post MI had only a 17% relative risk reduction, and the 2,400 patients who enrolled more than 36 months after their last MI had a subsequent MACE rate no different from controls.
Session cochair Nadia R. Sutton, MD, a cardiologist at the University of Michigan, Ann Arbor, commented that she found this time-dependent benefit fascinating.
“Do you think this has anything to do with the escalation of other therapies, such as Plavix [clopidogrel]?” she asked.
Dr. Furtado replied, “This is a finding that we should interpret with a little bit of caution.” For one thing, patients in the acute phase of an MI were excluded from participation in the trial, so nothing is known about how they would fare on dapagliflozin. For another, only 844 of the 3,584 patients with T2D and prior MI had their most recent MI within 24 months of enrollment, so even though the differences were statistically significant, the confidence intervals are fairly wide.
That being said, the finding does underscore a truism about cardiovascular prevention: The higher the risk, the greater the benefit of effective therapy – and, of course, the initial months following an MI are a particularly high-risk period.
“Also, this finding is a caution to the clinicians to avoid clinical inertia in prescribing an SGLT-2i, because maybe you can get an early benefit if you prescribe the drug closer to the acute phase and not wait until some months after the patient has tried diet and exercise and so on,” he added.
With regard to the second coprimary endpoint comprising cardiovascular death or heart failure hospitalization in T2D patients with prior MI, the rate in the dapagliflozin group was 8.6%, a 19% relative risk reduction and absolute risk reduction of 1.9%, compared with the 10.5% rate with placebo.
Dr. Furtado noted that the main results of DECLARE TIMI-58 are consistent with a recent systematic review and meta-analysis of three randomized cardiovascular outcome trials of SGLT-2is for primary and secondary prevention of cardiovascular and renal outcomes in T2D. The meta-analysis included more than 34,000 patients, roughly half drawn from DECLARE-TIMI 58. SGLT-2i therapy reduced MACE by 14% in patients with established ASCVD but not significantly in those without. And the agents reduced the risk of cardiovascular death/heart failure hospitalization by 23%, regardless of whether or not patients had known ASCVD or a history of heart failure (Lancet. 2019 Jan 5;393[10166]:31-9).
Dr. Furtado reported serving as a consultant to AstraZeneca, which funded DECLARE-TIMI 58, as well as receiving direct institutional research grants from half a dozen other pharmaceutical companies.
Simultaneous with his presentation at ACC 2019 in New Orleans, the subanalysis results were published online (Circulation. 2019 Mar 18. doi: 10.1161/CIRCULATIONAHA.119.039996. [Epub ahead of print]).
NEW ORLEANS – Dapagliflozin markedly reduces the risks of both major adverse cardiovascular events and heart failure hospitalization in the subset of patients with type 2 diabetes (T2D) and prior MI, according to a new subanalysis of the landmark DECLARE-TIMI 58 trial.
The effectiveness of dapagliflozin (Farxiga), an oral sodium glucose transporter-2 inhibitor (SGLT-2i), was particularly striking with regard to prevention of recurrent MI, Remo H.M. Furtado, MD, reported at the annual meeting of the American College of Cardiology.
“The 22% relative risk reduction in recurrent MI with dapagliflozin is comparable to other established therapies used in secondary prevention after MI, like DAPT [dual-antiplatelet therapy] and intensive lipid lowering,” observed Dr. Furtado of Brigham and Women’s Hospital, Boston.
Not bad for a drug developed as a glucose-lowering agent.
The new DECLARE-TIMI 58 subanalysis provides information that’s relevant to ACC guidelines issued in late 2018. The guidelines, in the form of an “expert consensus decision pathway,” emphatically recommend that all patients with T2D and known atherosclerotic cardiovascular disease (ASCVD) should have metformin as their first-line glucose-lowering agent, while at the same time giving serious consideration to the addition of either an oral SGLT-2i or a subcutaneously injected glucagonlike peptide–1 receptor agonist (GLP-1RA) with demonstrated cardiovascular benefit as a second glucose-lowering agent (J Am Coll Cardiol. 2018 Dec 18;72[24]:3200-23). The DECLARE-TIMI 58 subanalysis bolsters that guidance and shows, more specifically, that the cardioprotective benefits of dapagliflozin are significantly greater in T2D with prior MI than in those with known ASCVD but no history of MI, the cardiologist explained.
The main results of DECLARE-TIMI 58 have been published. The trial included 17,160 patients with T2D, 6,974 of whom had established ASCVD, while the remainder had multiple ASCVD risk factors. Participants were randomized to oral dapagliflozin at 10 mg/day or placebo on top of background guideline-directed medical therapy and followed for a median of 4.2 years. The dapagliflozin group had a 27% reduction in heart failure hospitalizations, compared with controls, but there were no significant between-group differences in the composite MACE (major adverse cardiovascular events) endpoint of cardiovascular death, MI, or ischemic stroke (N Engl J Med. 2019 Jan 24;380[4]:347-57).
Dr. Furtado presented a prespecified subgroup analysis focused on the 3,584 study participants with prior MI. Their rate of the composite endpoint of cardiovascular death, MI, or ischemic stroke was 15.2%, compared with 17.8% in controls, for a statistically significant and clinically meaningful 16% relative risk reduction and an absolute 2.6% risk reduction. Of note, the risk of recurrent MI was reduced by 22%. In contrast, there was no difference in MACE risk between the dapagliflozin and placebo groups in patients with no prior MI, even if they had established ASCVD.
A noteworthy finding was that the benefit in MACE reduction in patients with prior MI was greater in those who were closer in time to their most recent MI at enrollment in the study. Those who started on dapagliflozin within 12 months of their last MI had a 34% relative risk reduction in MACE, compared with placebo, while those who enrolled 12-24 months after their last MI enjoyed an even more robust 58% relative risk reduction on dapagliflozin. In contrast, patients who enrolled 24-36 months post MI had only a 17% relative risk reduction, and the 2,400 patients who enrolled more than 36 months after their last MI had a subsequent MACE rate no different from controls.
Session cochair Nadia R. Sutton, MD, a cardiologist at the University of Michigan, Ann Arbor, commented that she found this time-dependent benefit fascinating.
“Do you think this has anything to do with the escalation of other therapies, such as Plavix [clopidogrel]?” she asked.
Dr. Furtado replied, “This is a finding that we should interpret with a little bit of caution.” For one thing, patients in the acute phase of an MI were excluded from participation in the trial, so nothing is known about how they would fare on dapagliflozin. For another, only 844 of the 3,584 patients with T2D and prior MI had their most recent MI within 24 months of enrollment, so even though the differences were statistically significant, the confidence intervals are fairly wide.
That being said, the finding does underscore a truism about cardiovascular prevention: The higher the risk, the greater the benefit of effective therapy – and, of course, the initial months following an MI are a particularly high-risk period.
“Also, this finding is a caution to the clinicians to avoid clinical inertia in prescribing an SGLT-2i, because maybe you can get an early benefit if you prescribe the drug closer to the acute phase and not wait until some months after the patient has tried diet and exercise and so on,” he added.
With regard to the second coprimary endpoint comprising cardiovascular death or heart failure hospitalization in T2D patients with prior MI, the rate in the dapagliflozin group was 8.6%, a 19% relative risk reduction and absolute risk reduction of 1.9%, compared with the 10.5% rate with placebo.
Dr. Furtado noted that the main results of DECLARE TIMI-58 are consistent with a recent systematic review and meta-analysis of three randomized cardiovascular outcome trials of SGLT-2is for primary and secondary prevention of cardiovascular and renal outcomes in T2D. The meta-analysis included more than 34,000 patients, roughly half drawn from DECLARE-TIMI 58. SGLT-2i therapy reduced MACE by 14% in patients with established ASCVD but not significantly in those without. And the agents reduced the risk of cardiovascular death/heart failure hospitalization by 23%, regardless of whether or not patients had known ASCVD or a history of heart failure (Lancet. 2019 Jan 5;393[10166]:31-9).
Dr. Furtado reported serving as a consultant to AstraZeneca, which funded DECLARE-TIMI 58, as well as receiving direct institutional research grants from half a dozen other pharmaceutical companies.
Simultaneous with his presentation at ACC 2019 in New Orleans, the subanalysis results were published online (Circulation. 2019 Mar 18. doi: 10.1161/CIRCULATIONAHA.119.039996. [Epub ahead of print]).
REPORTING FROM ACC 19
Alirocumab reduces both type 1 and 2 MIs
NEW ORLEANS – Lowering LDL cholesterol with alirocumab to levels below what’s achievable with intensive statin therapy appears to be an important strategy for prevention of type 1 MI – and perhaps even more impressively, type 2 MI – following acute coronary syndrome, Harvey D. White, MD, reported at the annual meeting of the American College of Cardiology.
What’s so important about the 23% reduction in risk of type 2 MI achieved with alirocumab (Praluent) relative to placebo documented in a prespecified secondary analysis from the ODYSSEY Outcomes trial?
“For type 2 MI, this is the first data indicating that a lipid-lowering therapy can attenuate risk,” according to Dr. White, a cardiologist at Auckland (N.Z.) City Hospital.
The ODYSSEY Outcomes trial compared the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab to placebo in 18,924 patients with a recent acute coronary syndrome and an LDL cholesterol level of at least 70 mg/dL despite intensive statin therapy. At 4 months, the PCSK9 inhibitor plus statin therapy reduced participants’ mean LDL by 54%, from 93 to 48 mg/dL, while the LDL level actually drifted upward in the control group on placebo plus statin therapy. In the previously reported primary results of this landmark randomized clinical trial, alirocumab on top of background intensive statin therapy reduced the primary composite endpoint of death attributable to coronary heart disease, ischemic stroke, MI, or unstable angina requiring hospitalization by 15%, compared with controls (N Engl J Med. 2018 Nov 29;379[22]:2097-107).
During a median 2.8 years of prospective follow-up, there were 1,860 new MIs in study participants. A blinded clinical events committee evaluated the myocardial infarctions according to the Third Universal Definition and determined 66% were type 1 MIs, 21% were type 2, and 13% were type 4, with lesser numbers of types 3 and 5 MI.
Alirocumab reduced the risk of any MI by 15%, with a 6.8% incidence during follow-up, compared with 7.9% on placebo. The risk of type 1 MI, typically attributable to plaque rupture, was reduced by 13%, with an incidence of 4.9% with alirocumab and 5.6% with placebo. The risk reduction conferred by the PCSK9 inhibitor was even more robust for type 2 MI, the type caused by an oxygen supply/demand imbalance most commonly attributable to coronary artery spasm, coronary embolism, arrhythmias, anemia, hypertension, or hypotension: a 23% relative risk reduction as reflected in a 1.3% incidence in the alirocumab group, compared with a 1.7% rate in controls.
In contrast, alirocumab had no impact on the incidence of type 4 MI, a category that includes peri–percutaneous coronary intervention MIs as well as those attributable to stent thrombosis or restenosis.
The beneficial effect of alirocumab on MI risk mostly involved a reduction in larger MIs – those with a biomarker peak greater than three times the upper limit of normal.
An emphatic difference was found in the risk of death following type 1 as opposed to type 2 MI. Patients who experienced a type 1 MI during the study had an 11.9% mortality rate during an average of 1.6 years of post-MI follow-up, as compared with a 25.4% rate during 1.3 years of follow-up after a type 2 MI.
Alirocumab significantly reduced the risk of mortality following a type 1 MI, with a 10.2% rate as compared to 13.4% with placebo; that’s a 31% relative risk reduction. Yet the PCSK9 inhibitor had no impact on the risk of death after a type 2 MI: 24.8% in the alirocumab group and 25.9% in controls.
Asked for his thoughts as to possible explanatory mechanistic pathways for the benefit of alirocumab in preventing type 2 MI, Dr. White noted that in a Scottish study of the PCSK9 inhibitor evolocumab (Repatha), over the course of 72 months the drug appeared to reduce atherosclerotic progression and induce plaque stabilization and perhaps even regression.
“I think that’s the probable mechanism. And we also know that statins improve endothelial function,” he said.
He reported receiving research grant support and consultant fees from Sanofi and Regeneron, funders of the ODYSSEY Outcomes trial.
NEW ORLEANS – Lowering LDL cholesterol with alirocumab to levels below what’s achievable with intensive statin therapy appears to be an important strategy for prevention of type 1 MI – and perhaps even more impressively, type 2 MI – following acute coronary syndrome, Harvey D. White, MD, reported at the annual meeting of the American College of Cardiology.
What’s so important about the 23% reduction in risk of type 2 MI achieved with alirocumab (Praluent) relative to placebo documented in a prespecified secondary analysis from the ODYSSEY Outcomes trial?
“For type 2 MI, this is the first data indicating that a lipid-lowering therapy can attenuate risk,” according to Dr. White, a cardiologist at Auckland (N.Z.) City Hospital.
The ODYSSEY Outcomes trial compared the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab to placebo in 18,924 patients with a recent acute coronary syndrome and an LDL cholesterol level of at least 70 mg/dL despite intensive statin therapy. At 4 months, the PCSK9 inhibitor plus statin therapy reduced participants’ mean LDL by 54%, from 93 to 48 mg/dL, while the LDL level actually drifted upward in the control group on placebo plus statin therapy. In the previously reported primary results of this landmark randomized clinical trial, alirocumab on top of background intensive statin therapy reduced the primary composite endpoint of death attributable to coronary heart disease, ischemic stroke, MI, or unstable angina requiring hospitalization by 15%, compared with controls (N Engl J Med. 2018 Nov 29;379[22]:2097-107).
During a median 2.8 years of prospective follow-up, there were 1,860 new MIs in study participants. A blinded clinical events committee evaluated the myocardial infarctions according to the Third Universal Definition and determined 66% were type 1 MIs, 21% were type 2, and 13% were type 4, with lesser numbers of types 3 and 5 MI.
Alirocumab reduced the risk of any MI by 15%, with a 6.8% incidence during follow-up, compared with 7.9% on placebo. The risk of type 1 MI, typically attributable to plaque rupture, was reduced by 13%, with an incidence of 4.9% with alirocumab and 5.6% with placebo. The risk reduction conferred by the PCSK9 inhibitor was even more robust for type 2 MI, the type caused by an oxygen supply/demand imbalance most commonly attributable to coronary artery spasm, coronary embolism, arrhythmias, anemia, hypertension, or hypotension: a 23% relative risk reduction as reflected in a 1.3% incidence in the alirocumab group, compared with a 1.7% rate in controls.
In contrast, alirocumab had no impact on the incidence of type 4 MI, a category that includes peri–percutaneous coronary intervention MIs as well as those attributable to stent thrombosis or restenosis.
The beneficial effect of alirocumab on MI risk mostly involved a reduction in larger MIs – those with a biomarker peak greater than three times the upper limit of normal.
An emphatic difference was found in the risk of death following type 1 as opposed to type 2 MI. Patients who experienced a type 1 MI during the study had an 11.9% mortality rate during an average of 1.6 years of post-MI follow-up, as compared with a 25.4% rate during 1.3 years of follow-up after a type 2 MI.
Alirocumab significantly reduced the risk of mortality following a type 1 MI, with a 10.2% rate as compared to 13.4% with placebo; that’s a 31% relative risk reduction. Yet the PCSK9 inhibitor had no impact on the risk of death after a type 2 MI: 24.8% in the alirocumab group and 25.9% in controls.
Asked for his thoughts as to possible explanatory mechanistic pathways for the benefit of alirocumab in preventing type 2 MI, Dr. White noted that in a Scottish study of the PCSK9 inhibitor evolocumab (Repatha), over the course of 72 months the drug appeared to reduce atherosclerotic progression and induce plaque stabilization and perhaps even regression.
“I think that’s the probable mechanism. And we also know that statins improve endothelial function,” he said.
He reported receiving research grant support and consultant fees from Sanofi and Regeneron, funders of the ODYSSEY Outcomes trial.
NEW ORLEANS – Lowering LDL cholesterol with alirocumab to levels below what’s achievable with intensive statin therapy appears to be an important strategy for prevention of type 1 MI – and perhaps even more impressively, type 2 MI – following acute coronary syndrome, Harvey D. White, MD, reported at the annual meeting of the American College of Cardiology.
What’s so important about the 23% reduction in risk of type 2 MI achieved with alirocumab (Praluent) relative to placebo documented in a prespecified secondary analysis from the ODYSSEY Outcomes trial?
“For type 2 MI, this is the first data indicating that a lipid-lowering therapy can attenuate risk,” according to Dr. White, a cardiologist at Auckland (N.Z.) City Hospital.
The ODYSSEY Outcomes trial compared the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab to placebo in 18,924 patients with a recent acute coronary syndrome and an LDL cholesterol level of at least 70 mg/dL despite intensive statin therapy. At 4 months, the PCSK9 inhibitor plus statin therapy reduced participants’ mean LDL by 54%, from 93 to 48 mg/dL, while the LDL level actually drifted upward in the control group on placebo plus statin therapy. In the previously reported primary results of this landmark randomized clinical trial, alirocumab on top of background intensive statin therapy reduced the primary composite endpoint of death attributable to coronary heart disease, ischemic stroke, MI, or unstable angina requiring hospitalization by 15%, compared with controls (N Engl J Med. 2018 Nov 29;379[22]:2097-107).
During a median 2.8 years of prospective follow-up, there were 1,860 new MIs in study participants. A blinded clinical events committee evaluated the myocardial infarctions according to the Third Universal Definition and determined 66% were type 1 MIs, 21% were type 2, and 13% were type 4, with lesser numbers of types 3 and 5 MI.
Alirocumab reduced the risk of any MI by 15%, with a 6.8% incidence during follow-up, compared with 7.9% on placebo. The risk of type 1 MI, typically attributable to plaque rupture, was reduced by 13%, with an incidence of 4.9% with alirocumab and 5.6% with placebo. The risk reduction conferred by the PCSK9 inhibitor was even more robust for type 2 MI, the type caused by an oxygen supply/demand imbalance most commonly attributable to coronary artery spasm, coronary embolism, arrhythmias, anemia, hypertension, or hypotension: a 23% relative risk reduction as reflected in a 1.3% incidence in the alirocumab group, compared with a 1.7% rate in controls.
In contrast, alirocumab had no impact on the incidence of type 4 MI, a category that includes peri–percutaneous coronary intervention MIs as well as those attributable to stent thrombosis or restenosis.
The beneficial effect of alirocumab on MI risk mostly involved a reduction in larger MIs – those with a biomarker peak greater than three times the upper limit of normal.
An emphatic difference was found in the risk of death following type 1 as opposed to type 2 MI. Patients who experienced a type 1 MI during the study had an 11.9% mortality rate during an average of 1.6 years of post-MI follow-up, as compared with a 25.4% rate during 1.3 years of follow-up after a type 2 MI.
Alirocumab significantly reduced the risk of mortality following a type 1 MI, with a 10.2% rate as compared to 13.4% with placebo; that’s a 31% relative risk reduction. Yet the PCSK9 inhibitor had no impact on the risk of death after a type 2 MI: 24.8% in the alirocumab group and 25.9% in controls.
Asked for his thoughts as to possible explanatory mechanistic pathways for the benefit of alirocumab in preventing type 2 MI, Dr. White noted that in a Scottish study of the PCSK9 inhibitor evolocumab (Repatha), over the course of 72 months the drug appeared to reduce atherosclerotic progression and induce plaque stabilization and perhaps even regression.
“I think that’s the probable mechanism. And we also know that statins improve endothelial function,” he said.
He reported receiving research grant support and consultant fees from Sanofi and Regeneron, funders of the ODYSSEY Outcomes trial.
REPORTING FROM ACC 19
Has radial access PCI been overhyped?
NEW ORLEANS – , Michel R. Le May, MD, reported at the annual meeting of the American College of Cardiology.
Our findings suggest that adequately trained operators should be able to achieve similar results using either radial or femoral access for primary PCI,” declared Dr. Le May, professor of medicine at the University of Ottawa Heart Institute.
This is a controversial issue. European cardiologists have led a strong push for preferential use of radial access, citing reduced bleeding risk and an associated reduction in 30-day mortality. And this movement has spread to North America. But the evidence doesn’t convincingly support this position, the cardiologist said. He noted that of nine prior RCTs of radial versus the more traditional femoral access for primary PCI in STEMI, seven showed no difference in mortality. Nor did SAFARI-STEMI, which at 2,292 randomized STEMI patients was the second-largest trial to date.
SAFARI-STEMI was conducted at five high-volume Canadian PCI centers. Participating interventional cardiologists averaged 250 PCIs per year and were proficient in both access approaches. The study plan was to enroll 5,000 STEMI patients, but the trial was stopped after results were in for the first 2,292 because outcomes in the two study arms were so similar that the trial’s data safety monitoring board deemed it futile to continue.
The primary outcome was 30-day mortality. The rate was 1.5% in the radial access group and 1.3% in the femoral access group, with no differences among various subgroups.
Nor were there any between-group significant difference in the secondary endpoints of reinfarction (1.8% with radial, 1.6% with femoral), stroke (1.0% versus 0.4%), or the composite of death, reinfarction, or stroke, which occurred in 4.0% of the radial access group and 3.4% of the femoral group. Rates of non-CABG TIMI major or minor bleeding at 30 days were closely similar, as was need for transfusion. Definite or probable stent thrombosis occurred in 1.5% of the radial and 1.1% of the femoral groups.
Time from arrival at the PCI center to first balloon inflation was 47 minutes in the radial access group and significantly shorter at 44 minutes with femoral access, a noteworthy finding in the setting of STEMI, where time is myocardium. Fluoroscopy time was 1.2 minutes shorter in the femoral access group as well.
The reaction
Discussant Jacqueline E. Tamis-Holland, MD, said that, although she recently switched over to a radial access-first approach, her take away from SAFARI-STEMI is “It’s okay to do femoral.
“I think it’s comforting to the femoralists who are struggling to say, ‘I do a good femoral job and I don’t necessarily want to transition my STEMI patients to radial,’ ” said Dr. Tamis-Holland, associate director for the Mount Sinai St. Luke’s cardiac cath labs in New York.
Session cochair Martin B. Leon, MD, embraced the SAFARI-STEMI results with gusto.
“I’ve been tortured over the past 5 years by my junior interventional colleagues saying that, unless you’re doing transradial for STEMIs, that you’re not only out of step with the modern era of PCI, but you’re really moving against the evidence. And this study brings it back to a center position, where if you do a very-high-quality transfemoral approach, it is no different from transradial, not just from the standpoint of mortality but also bleeding complications. So I think we should aspire to be better transfemoral interventionalists, and if we do then there probably isn’t that much of a difference,” said Dr. Leon, professor of medicine at Columbia University in New York.
But discussant Sunil V. Rao, MD, who has championed radial access in the United States, was skeptical. “I think the results you achieved with femoral access in this trial are quite remarkable. We know from the registry data that those results are difficult to achieve in clinical practice.
“I would caution that the trial was stopped early, so I think it’s very challenging to try to apply this so as to influence our practice definitively,” said Dr. Rao of Duke University, Durham, N.C.
He asked Dr. Le May what advice he could give to femoralists in community practice to up their game and achieve results comparable to those in SAFARI-STEMI.
“We have to pay attention to their puncture,” Dr. Le May replied. “We use fluoroscopic guidance, and there are others who use ultrasound. We pay attention to the anticoagulation and antiplatelet therapy we use for these patients. We use GP IIb/IIIa inhibitors less today, and smaller sheaths. More than 90% of patients got ticagrelor before going to the cath lab. We’ve borrowed some of the techniques that the radial access people use.”
At a postpresentation ACC press conference, he indicated that it was difficult to recruit patients for the trial in the current strongly pro–radial access climate.
“I think there are people who think that, seriously, the horse is out of the barn, and it’s game over for the femoral. There is a mindset out there where people think that it’s just wrong to do a femoral approach,” said Dr. Le May. “We had comments that it’s not even ethical to randomize such patients.”
In fact, the issue is “very debatable,” he asserted, noting that radial artery occlusion is emerging as an important complication. And he suspects that cardiologists who strive to do 80%-90% of their percutaneous coronary interventions via the transradial route may become deskilled at using the femoral approach. That becomes a real concern when there is a problem in accessing the radial artery or need arises for a device that requires femoral access.
“I am of the school of thought that, given the results of our trial, we should teach people that you’re not a femoralist or a radialist. You should be an interventionalist that can do either and flip from one side to the other and be comfortable in doing that,” Dr. Le May concluded.
He reported having no conflicts regarding the study, funded by the Canadian Institutes of Health Research.
NEW ORLEANS – , Michel R. Le May, MD, reported at the annual meeting of the American College of Cardiology.
Our findings suggest that adequately trained operators should be able to achieve similar results using either radial or femoral access for primary PCI,” declared Dr. Le May, professor of medicine at the University of Ottawa Heart Institute.
This is a controversial issue. European cardiologists have led a strong push for preferential use of radial access, citing reduced bleeding risk and an associated reduction in 30-day mortality. And this movement has spread to North America. But the evidence doesn’t convincingly support this position, the cardiologist said. He noted that of nine prior RCTs of radial versus the more traditional femoral access for primary PCI in STEMI, seven showed no difference in mortality. Nor did SAFARI-STEMI, which at 2,292 randomized STEMI patients was the second-largest trial to date.
SAFARI-STEMI was conducted at five high-volume Canadian PCI centers. Participating interventional cardiologists averaged 250 PCIs per year and were proficient in both access approaches. The study plan was to enroll 5,000 STEMI patients, but the trial was stopped after results were in for the first 2,292 because outcomes in the two study arms were so similar that the trial’s data safety monitoring board deemed it futile to continue.
The primary outcome was 30-day mortality. The rate was 1.5% in the radial access group and 1.3% in the femoral access group, with no differences among various subgroups.
Nor were there any between-group significant difference in the secondary endpoints of reinfarction (1.8% with radial, 1.6% with femoral), stroke (1.0% versus 0.4%), or the composite of death, reinfarction, or stroke, which occurred in 4.0% of the radial access group and 3.4% of the femoral group. Rates of non-CABG TIMI major or minor bleeding at 30 days were closely similar, as was need for transfusion. Definite or probable stent thrombosis occurred in 1.5% of the radial and 1.1% of the femoral groups.
Time from arrival at the PCI center to first balloon inflation was 47 minutes in the radial access group and significantly shorter at 44 minutes with femoral access, a noteworthy finding in the setting of STEMI, where time is myocardium. Fluoroscopy time was 1.2 minutes shorter in the femoral access group as well.
The reaction
Discussant Jacqueline E. Tamis-Holland, MD, said that, although she recently switched over to a radial access-first approach, her take away from SAFARI-STEMI is “It’s okay to do femoral.
“I think it’s comforting to the femoralists who are struggling to say, ‘I do a good femoral job and I don’t necessarily want to transition my STEMI patients to radial,’ ” said Dr. Tamis-Holland, associate director for the Mount Sinai St. Luke’s cardiac cath labs in New York.
Session cochair Martin B. Leon, MD, embraced the SAFARI-STEMI results with gusto.
“I’ve been tortured over the past 5 years by my junior interventional colleagues saying that, unless you’re doing transradial for STEMIs, that you’re not only out of step with the modern era of PCI, but you’re really moving against the evidence. And this study brings it back to a center position, where if you do a very-high-quality transfemoral approach, it is no different from transradial, not just from the standpoint of mortality but also bleeding complications. So I think we should aspire to be better transfemoral interventionalists, and if we do then there probably isn’t that much of a difference,” said Dr. Leon, professor of medicine at Columbia University in New York.
But discussant Sunil V. Rao, MD, who has championed radial access in the United States, was skeptical. “I think the results you achieved with femoral access in this trial are quite remarkable. We know from the registry data that those results are difficult to achieve in clinical practice.
“I would caution that the trial was stopped early, so I think it’s very challenging to try to apply this so as to influence our practice definitively,” said Dr. Rao of Duke University, Durham, N.C.
He asked Dr. Le May what advice he could give to femoralists in community practice to up their game and achieve results comparable to those in SAFARI-STEMI.
“We have to pay attention to their puncture,” Dr. Le May replied. “We use fluoroscopic guidance, and there are others who use ultrasound. We pay attention to the anticoagulation and antiplatelet therapy we use for these patients. We use GP IIb/IIIa inhibitors less today, and smaller sheaths. More than 90% of patients got ticagrelor before going to the cath lab. We’ve borrowed some of the techniques that the radial access people use.”
At a postpresentation ACC press conference, he indicated that it was difficult to recruit patients for the trial in the current strongly pro–radial access climate.
“I think there are people who think that, seriously, the horse is out of the barn, and it’s game over for the femoral. There is a mindset out there where people think that it’s just wrong to do a femoral approach,” said Dr. Le May. “We had comments that it’s not even ethical to randomize such patients.”
In fact, the issue is “very debatable,” he asserted, noting that radial artery occlusion is emerging as an important complication. And he suspects that cardiologists who strive to do 80%-90% of their percutaneous coronary interventions via the transradial route may become deskilled at using the femoral approach. That becomes a real concern when there is a problem in accessing the radial artery or need arises for a device that requires femoral access.
“I am of the school of thought that, given the results of our trial, we should teach people that you’re not a femoralist or a radialist. You should be an interventionalist that can do either and flip from one side to the other and be comfortable in doing that,” Dr. Le May concluded.
He reported having no conflicts regarding the study, funded by the Canadian Institutes of Health Research.
NEW ORLEANS – , Michel R. Le May, MD, reported at the annual meeting of the American College of Cardiology.
Our findings suggest that adequately trained operators should be able to achieve similar results using either radial or femoral access for primary PCI,” declared Dr. Le May, professor of medicine at the University of Ottawa Heart Institute.
This is a controversial issue. European cardiologists have led a strong push for preferential use of radial access, citing reduced bleeding risk and an associated reduction in 30-day mortality. And this movement has spread to North America. But the evidence doesn’t convincingly support this position, the cardiologist said. He noted that of nine prior RCTs of radial versus the more traditional femoral access for primary PCI in STEMI, seven showed no difference in mortality. Nor did SAFARI-STEMI, which at 2,292 randomized STEMI patients was the second-largest trial to date.
SAFARI-STEMI was conducted at five high-volume Canadian PCI centers. Participating interventional cardiologists averaged 250 PCIs per year and were proficient in both access approaches. The study plan was to enroll 5,000 STEMI patients, but the trial was stopped after results were in for the first 2,292 because outcomes in the two study arms were so similar that the trial’s data safety monitoring board deemed it futile to continue.
The primary outcome was 30-day mortality. The rate was 1.5% in the radial access group and 1.3% in the femoral access group, with no differences among various subgroups.
Nor were there any between-group significant difference in the secondary endpoints of reinfarction (1.8% with radial, 1.6% with femoral), stroke (1.0% versus 0.4%), or the composite of death, reinfarction, or stroke, which occurred in 4.0% of the radial access group and 3.4% of the femoral group. Rates of non-CABG TIMI major or minor bleeding at 30 days were closely similar, as was need for transfusion. Definite or probable stent thrombosis occurred in 1.5% of the radial and 1.1% of the femoral groups.
Time from arrival at the PCI center to first balloon inflation was 47 minutes in the radial access group and significantly shorter at 44 minutes with femoral access, a noteworthy finding in the setting of STEMI, where time is myocardium. Fluoroscopy time was 1.2 minutes shorter in the femoral access group as well.
The reaction
Discussant Jacqueline E. Tamis-Holland, MD, said that, although she recently switched over to a radial access-first approach, her take away from SAFARI-STEMI is “It’s okay to do femoral.
“I think it’s comforting to the femoralists who are struggling to say, ‘I do a good femoral job and I don’t necessarily want to transition my STEMI patients to radial,’ ” said Dr. Tamis-Holland, associate director for the Mount Sinai St. Luke’s cardiac cath labs in New York.
Session cochair Martin B. Leon, MD, embraced the SAFARI-STEMI results with gusto.
“I’ve been tortured over the past 5 years by my junior interventional colleagues saying that, unless you’re doing transradial for STEMIs, that you’re not only out of step with the modern era of PCI, but you’re really moving against the evidence. And this study brings it back to a center position, where if you do a very-high-quality transfemoral approach, it is no different from transradial, not just from the standpoint of mortality but also bleeding complications. So I think we should aspire to be better transfemoral interventionalists, and if we do then there probably isn’t that much of a difference,” said Dr. Leon, professor of medicine at Columbia University in New York.
But discussant Sunil V. Rao, MD, who has championed radial access in the United States, was skeptical. “I think the results you achieved with femoral access in this trial are quite remarkable. We know from the registry data that those results are difficult to achieve in clinical practice.
“I would caution that the trial was stopped early, so I think it’s very challenging to try to apply this so as to influence our practice definitively,” said Dr. Rao of Duke University, Durham, N.C.
He asked Dr. Le May what advice he could give to femoralists in community practice to up their game and achieve results comparable to those in SAFARI-STEMI.
“We have to pay attention to their puncture,” Dr. Le May replied. “We use fluoroscopic guidance, and there are others who use ultrasound. We pay attention to the anticoagulation and antiplatelet therapy we use for these patients. We use GP IIb/IIIa inhibitors less today, and smaller sheaths. More than 90% of patients got ticagrelor before going to the cath lab. We’ve borrowed some of the techniques that the radial access people use.”
At a postpresentation ACC press conference, he indicated that it was difficult to recruit patients for the trial in the current strongly pro–radial access climate.
“I think there are people who think that, seriously, the horse is out of the barn, and it’s game over for the femoral. There is a mindset out there where people think that it’s just wrong to do a femoral approach,” said Dr. Le May. “We had comments that it’s not even ethical to randomize such patients.”
In fact, the issue is “very debatable,” he asserted, noting that radial artery occlusion is emerging as an important complication. And he suspects that cardiologists who strive to do 80%-90% of their percutaneous coronary interventions via the transradial route may become deskilled at using the femoral approach. That becomes a real concern when there is a problem in accessing the radial artery or need arises for a device that requires femoral access.
“I am of the school of thought that, given the results of our trial, we should teach people that you’re not a femoralist or a radialist. You should be an interventionalist that can do either and flip from one side to the other and be comfortable in doing that,” Dr. Le May concluded.
He reported having no conflicts regarding the study, funded by the Canadian Institutes of Health Research.
REPORTING FROM ACC 19
Ticagrelor reversal agent looks promising
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
NEW ORLEANS – A novel targeted ticagrelor reversal agent demonstrated rapid and sustained reversal of the potent antiplatelet agent in a phase 1 proof-of-concept study, Deepak L. Bhatt, MD, reported at the annual meeting of the American College of Cardiology.
“Hopefully the FDA will view this as something that really is a breakthrough,” commented Dr. Bhatt, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard University, both in Boston.
Why a breakthrough? Because despite recent major advances in the ability to reverse the action of the direct-acting oral anticoagulants and thereby greatly improve their safety margin, there have been no parallel developments with regard to the potent antiplatelet agents ticagrelor (Brilinta), prasugrel (Effient), and clopidogrel. The effects of these antiplatelet drugs take 3-5 days to dissipate after they’ve been stopped, which is highly problematic when they’ve induced catastrophic bleeding or a patient requires emergent or urgent surgery, the cardiologist explained.
“The ability to reverse tigracelor’s antiplatelet effects rapidly could distinguish it from other antiplatelet agents such as prasugrel or even generic clopidogrel and, for that matter, even aspirin,” Dr. Bhatt said.
The ticagrelor reversal agent, known for now as PB2452, is an intravenously administered recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment. It binds specifically and with high affinity to ticagrelor and its active metabolite. In the phase 1, placebo-controlled, double-blind study conducted in 64 healthy volunteers pretreated with ticagrelor for 48 hours, it reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
The only adverse events observed in blinded assessment were minor injection site issues.
PB2452 is specific to ticagrelor and will not reverse the activity of other potent antiplatelet agents. Indeed, because of their chemical structure, neither prasugrel nor clopidogrel is reversible, according to Dr. Bhatt.
He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
REPORTING FROM ACC 19
Key clinical point: Oral ticagrelor’s antiplatelet effect was reversed within 5 minutes by a novel targeted monoclonal antibody.
Major finding: A novel targeted monoclonal antibody reversed oral ticagrelor’s antiplatelet effects within 5 minutes and, with prolonged infusion, showed sustained effect for at least 20 hours.
Study details: This phase 1 study included 64 healthy subjects pretreated with 48 hours of ticagrelor before receiving various doses of the reversal agent or placebo.
Disclosures: The study was funded by PhaseBio Pharmaceuticals, which provided a research grant directly to Brigham and Women’s Hospital.
Occurrence of pulmonary embolisms in hospitalized patients nearly doubled during 2004-2015
NEW ORLEANS –
During 2004-2015 the incidence of all diagnosed pulmonary embolism (PE), based on discharge diagnoses, rose from 5.4 cases/1,000 hospitalized patients in 2004 to 9.7 cases/1,000 hospitalized patients in 2015, an 80% increase, Joshua B. Goldberg, MD said at the annual meeting of the American College of Cardiology. The incidence of major PE – defined as a patient who needed vasopressor treatment, mechanical ventilation, or had nonseptic shock – rose from 7.9% of all hospitalized PE diagnoses in 2004 to 9.7% in 2015, a 23% relative increase.
The data also documented a shifting pattern of treatment for all hospitalized patients with PE, and especially among patients with major PE. During the study period, treatment with systemic thrombolysis for all PE rose nearly threefold, and catheter-directed therapy began to show a steady rise in use from 0.2% of all patients in 2011 (and before) to 1% of all patients by 2015. Surgical intervention remained lightly used throughout, with about 0.2% of all PE patients undergoing surgery annually.
Most of these intervention options focused on patients with major PE. Among patients in this subgroup with more severe disease, use of one of these three types of interventions rose from 6% in 2004 to 12% in 2015, mostly driven by a rise in systemic thrombolysis, which jumped from 3% of major PE in 2004 to 9% in 2015. However, the efficacy of systemic thrombolysis in patients with major PE remains suspect. In 2004, 39% of patients with major PE treated with systemic thrombolysis died in hospital; in 2015 the number was 47%. “The data don’t support using systemic thrombolysis to treat major PE; the mortality is high,” noted Dr. Goldberg, a cardiothoracic surgeon at Westchester Medical Center in Valhalla, N.Y.
Although catheter-directed therapy began to be much more widely used in U.S. practice starting in about 2015, during the period studied its use for major PE held fairly steady at roughly 2%-3%, but this approach also showed substantial shortcomings for the major PE population. These sicker patients treated with catheter-directed therapy had 37% mortality in 2004 and a 31% mortality in 2015, a difference that was not statistically significant. In general, PE patients enrolled in the catheter-directed therapy trials were not as sick as the major PE patients who get treated with surgery in routine practice, Dr. Goldberg said in an interview.
The data showed much better performance using surgery, although only 1,237 patients of the entire group of 713,083 PE patients studied in the database underwent surgical embolectomy. Overall, in-hospital mortality in these patients was 22%, but in a time trend analysis, mortality among all PE patients treated with surgery fell from 32% in 2004 to 14% in 2015; among patients with major PE treated with surgery, mortality fell from 52% in 2004 to 21% in 2015.
Dr. Goldberg attributed the success of surgery in severe PE patients to the definitive nature of embolectomy and the concurrent use of extracorporeal membrane oxygenation that helps stabilize acutely ill PE patients. He also cited refinements that surgery underwent during the 2004-2015 period based on the experience managing chronic thromboembolic pulmonary hypertension, including routine use of cardiopulmonary bypass during surgery. “Very high risk [PE] patients should go straight to surgery, unless the patient is at high risk for surgery because of conditions like prior sternotomy or very advanced age, in which case catheter-directed therapy may be a safer option, he said. He cited a recent 5% death rate after surgery at his center among patients with major PE who did not require cardiopulmonary resuscitation.
The database Dr. Goldberg and his collaborator reviewed included 12,735 patients treated by systemic thrombolysis, and 2,595 treated by catheter-directed therapy. Patients averaged 63 years old. The most common indicator of major PE was mechanical ventilation, used on 8% of all PE patients in the study. Non-septic shock occurred in 2%, and just under 1% needed vasopressor treatment.
Published guidelines on PE management from several medical groups are “vague and have numerous caveats,” Dr. Goldberg said. He is participating in an update to the 2011 PE management statement from the American College of Cardiology and American Heart Association (Circulation. 2011 April 26;123[16]:1788-1830).
The study received no commercial funding. Dr. Goldberg had no disclosures.
SOURCE: Haider A et al. J Amer Coll Cardiol. 2019 March;73:9[suppl 1]: doi: 10.1016/S0735-1097(19)32507-0
At my center, Allegheny General Hospital, we often rely on catheter-directed therapy to treat major pulmonary embolism. We now perform more catheter-directed interventions than surgical embolectomies. Generally, when treating patients with major pulmonary embolism it comes down to a choice between those two options. We rarely use systemic thrombolysis for major pulmonary embolism any more.
Raymond L. Benza, MD , is professor of medicine at Temple University College of Medicine and program director for advanced heart failure at the Allegheny Health Network in Pittsburgh. He has been a consultant to Actelion, Gilead, and United Therapeutics, and he has received research funding from Bayer. He made these comments in an interview.
At my center, Allegheny General Hospital, we often rely on catheter-directed therapy to treat major pulmonary embolism. We now perform more catheter-directed interventions than surgical embolectomies. Generally, when treating patients with major pulmonary embolism it comes down to a choice between those two options. We rarely use systemic thrombolysis for major pulmonary embolism any more.
Raymond L. Benza, MD , is professor of medicine at Temple University College of Medicine and program director for advanced heart failure at the Allegheny Health Network in Pittsburgh. He has been a consultant to Actelion, Gilead, and United Therapeutics, and he has received research funding from Bayer. He made these comments in an interview.
At my center, Allegheny General Hospital, we often rely on catheter-directed therapy to treat major pulmonary embolism. We now perform more catheter-directed interventions than surgical embolectomies. Generally, when treating patients with major pulmonary embolism it comes down to a choice between those two options. We rarely use systemic thrombolysis for major pulmonary embolism any more.
Raymond L. Benza, MD , is professor of medicine at Temple University College of Medicine and program director for advanced heart failure at the Allegheny Health Network in Pittsburgh. He has been a consultant to Actelion, Gilead, and United Therapeutics, and he has received research funding from Bayer. He made these comments in an interview.
NEW ORLEANS –
During 2004-2015 the incidence of all diagnosed pulmonary embolism (PE), based on discharge diagnoses, rose from 5.4 cases/1,000 hospitalized patients in 2004 to 9.7 cases/1,000 hospitalized patients in 2015, an 80% increase, Joshua B. Goldberg, MD said at the annual meeting of the American College of Cardiology. The incidence of major PE – defined as a patient who needed vasopressor treatment, mechanical ventilation, or had nonseptic shock – rose from 7.9% of all hospitalized PE diagnoses in 2004 to 9.7% in 2015, a 23% relative increase.
The data also documented a shifting pattern of treatment for all hospitalized patients with PE, and especially among patients with major PE. During the study period, treatment with systemic thrombolysis for all PE rose nearly threefold, and catheter-directed therapy began to show a steady rise in use from 0.2% of all patients in 2011 (and before) to 1% of all patients by 2015. Surgical intervention remained lightly used throughout, with about 0.2% of all PE patients undergoing surgery annually.
Most of these intervention options focused on patients with major PE. Among patients in this subgroup with more severe disease, use of one of these three types of interventions rose from 6% in 2004 to 12% in 2015, mostly driven by a rise in systemic thrombolysis, which jumped from 3% of major PE in 2004 to 9% in 2015. However, the efficacy of systemic thrombolysis in patients with major PE remains suspect. In 2004, 39% of patients with major PE treated with systemic thrombolysis died in hospital; in 2015 the number was 47%. “The data don’t support using systemic thrombolysis to treat major PE; the mortality is high,” noted Dr. Goldberg, a cardiothoracic surgeon at Westchester Medical Center in Valhalla, N.Y.
Although catheter-directed therapy began to be much more widely used in U.S. practice starting in about 2015, during the period studied its use for major PE held fairly steady at roughly 2%-3%, but this approach also showed substantial shortcomings for the major PE population. These sicker patients treated with catheter-directed therapy had 37% mortality in 2004 and a 31% mortality in 2015, a difference that was not statistically significant. In general, PE patients enrolled in the catheter-directed therapy trials were not as sick as the major PE patients who get treated with surgery in routine practice, Dr. Goldberg said in an interview.
The data showed much better performance using surgery, although only 1,237 patients of the entire group of 713,083 PE patients studied in the database underwent surgical embolectomy. Overall, in-hospital mortality in these patients was 22%, but in a time trend analysis, mortality among all PE patients treated with surgery fell from 32% in 2004 to 14% in 2015; among patients with major PE treated with surgery, mortality fell from 52% in 2004 to 21% in 2015.
Dr. Goldberg attributed the success of surgery in severe PE patients to the definitive nature of embolectomy and the concurrent use of extracorporeal membrane oxygenation that helps stabilize acutely ill PE patients. He also cited refinements that surgery underwent during the 2004-2015 period based on the experience managing chronic thromboembolic pulmonary hypertension, including routine use of cardiopulmonary bypass during surgery. “Very high risk [PE] patients should go straight to surgery, unless the patient is at high risk for surgery because of conditions like prior sternotomy or very advanced age, in which case catheter-directed therapy may be a safer option, he said. He cited a recent 5% death rate after surgery at his center among patients with major PE who did not require cardiopulmonary resuscitation.
The database Dr. Goldberg and his collaborator reviewed included 12,735 patients treated by systemic thrombolysis, and 2,595 treated by catheter-directed therapy. Patients averaged 63 years old. The most common indicator of major PE was mechanical ventilation, used on 8% of all PE patients in the study. Non-septic shock occurred in 2%, and just under 1% needed vasopressor treatment.
Published guidelines on PE management from several medical groups are “vague and have numerous caveats,” Dr. Goldberg said. He is participating in an update to the 2011 PE management statement from the American College of Cardiology and American Heart Association (Circulation. 2011 April 26;123[16]:1788-1830).
The study received no commercial funding. Dr. Goldberg had no disclosures.
SOURCE: Haider A et al. J Amer Coll Cardiol. 2019 March;73:9[suppl 1]: doi: 10.1016/S0735-1097(19)32507-0
NEW ORLEANS –
During 2004-2015 the incidence of all diagnosed pulmonary embolism (PE), based on discharge diagnoses, rose from 5.4 cases/1,000 hospitalized patients in 2004 to 9.7 cases/1,000 hospitalized patients in 2015, an 80% increase, Joshua B. Goldberg, MD said at the annual meeting of the American College of Cardiology. The incidence of major PE – defined as a patient who needed vasopressor treatment, mechanical ventilation, or had nonseptic shock – rose from 7.9% of all hospitalized PE diagnoses in 2004 to 9.7% in 2015, a 23% relative increase.
The data also documented a shifting pattern of treatment for all hospitalized patients with PE, and especially among patients with major PE. During the study period, treatment with systemic thrombolysis for all PE rose nearly threefold, and catheter-directed therapy began to show a steady rise in use from 0.2% of all patients in 2011 (and before) to 1% of all patients by 2015. Surgical intervention remained lightly used throughout, with about 0.2% of all PE patients undergoing surgery annually.
Most of these intervention options focused on patients with major PE. Among patients in this subgroup with more severe disease, use of one of these three types of interventions rose from 6% in 2004 to 12% in 2015, mostly driven by a rise in systemic thrombolysis, which jumped from 3% of major PE in 2004 to 9% in 2015. However, the efficacy of systemic thrombolysis in patients with major PE remains suspect. In 2004, 39% of patients with major PE treated with systemic thrombolysis died in hospital; in 2015 the number was 47%. “The data don’t support using systemic thrombolysis to treat major PE; the mortality is high,” noted Dr. Goldberg, a cardiothoracic surgeon at Westchester Medical Center in Valhalla, N.Y.
Although catheter-directed therapy began to be much more widely used in U.S. practice starting in about 2015, during the period studied its use for major PE held fairly steady at roughly 2%-3%, but this approach also showed substantial shortcomings for the major PE population. These sicker patients treated with catheter-directed therapy had 37% mortality in 2004 and a 31% mortality in 2015, a difference that was not statistically significant. In general, PE patients enrolled in the catheter-directed therapy trials were not as sick as the major PE patients who get treated with surgery in routine practice, Dr. Goldberg said in an interview.
The data showed much better performance using surgery, although only 1,237 patients of the entire group of 713,083 PE patients studied in the database underwent surgical embolectomy. Overall, in-hospital mortality in these patients was 22%, but in a time trend analysis, mortality among all PE patients treated with surgery fell from 32% in 2004 to 14% in 2015; among patients with major PE treated with surgery, mortality fell from 52% in 2004 to 21% in 2015.
Dr. Goldberg attributed the success of surgery in severe PE patients to the definitive nature of embolectomy and the concurrent use of extracorporeal membrane oxygenation that helps stabilize acutely ill PE patients. He also cited refinements that surgery underwent during the 2004-2015 period based on the experience managing chronic thromboembolic pulmonary hypertension, including routine use of cardiopulmonary bypass during surgery. “Very high risk [PE] patients should go straight to surgery, unless the patient is at high risk for surgery because of conditions like prior sternotomy or very advanced age, in which case catheter-directed therapy may be a safer option, he said. He cited a recent 5% death rate after surgery at his center among patients with major PE who did not require cardiopulmonary resuscitation.
The database Dr. Goldberg and his collaborator reviewed included 12,735 patients treated by systemic thrombolysis, and 2,595 treated by catheter-directed therapy. Patients averaged 63 years old. The most common indicator of major PE was mechanical ventilation, used on 8% of all PE patients in the study. Non-septic shock occurred in 2%, and just under 1% needed vasopressor treatment.
Published guidelines on PE management from several medical groups are “vague and have numerous caveats,” Dr. Goldberg said. He is participating in an update to the 2011 PE management statement from the American College of Cardiology and American Heart Association (Circulation. 2011 April 26;123[16]:1788-1830).
The study received no commercial funding. Dr. Goldberg had no disclosures.
SOURCE: Haider A et al. J Amer Coll Cardiol. 2019 March;73:9[suppl 1]: doi: 10.1016/S0735-1097(19)32507-0
REPORTING FROM ACC 2019
BP control slowed brain damage in elderly hypertensives
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
REPORTING FROM ACC 19
Abstinence by moderate drinkers improves their AFib
NEW ORLEANS – Abstinence from alcohol on the part of moderate drinkers with atrial fibrillation resulted in clinically meaningful improvement in their arrhythmia in the randomized controlled Alcohol-AF trial, Aleksandr Voskoboinik, MBBS, reported at the annual meeting of the American College of Cardiology.
The benefits of abstinence included significant reductions in the AFib recurrence rate, total AFib burden, and symptom severity. And the payoff extended beyond the arrhythmia: The abstinent group also averaged a 12–mm Hg drop in systolic blood pressure and dropped 3 kg of body weight over the course of the 6-month trial, added Dr. Voskoboinik, a cardiologist at the Baker Heart & Diabetes Institute at the University of Melbourne.
“We would conclude that significant reduction in alcohol intake should be considered as part of the lifestyle intervention in moderate drinkers with AFib,” he said.
Some physicians already advise alcohol abstinence for moderate drinkers with AFib, but until now such recommendations were not evidence based. Instead, the guidance was based on extrapolation from the well-established harmful effects of heavy drinking and binge drinking on AFib as well as epidemiologic studies.
“We wanted to provide some evidence base for physicians to say, ‘If I have motivated patients, here’s what’s potentially achievable,’” he explained.
The key word here is “motivated.” Conducting the Alcohol-AF trial made clear that many moderate drinkers with AFib enjoy their beverages more than they hate having their arrhythmia. Indeed, out of 697 moderate-drinking patients with paroxysmal or persistent AFib who were deemed good candidates and were approached about study participation, more than 500 were excluded because they were flat out unwilling to consider abstinence. After Dr. Voskoboinik and his coinvestigators shortened the planned trial duration from 12 months to 6 because so many recruits were unwilling to abstain for a full year, 140 of the initial 697 patients were randomized to abstinence or continuation of their usual consumption. Thirty percent of them had previously undergone AFib ablation.
The Alcohol-AF study was a multicenter, prospective, open-label study conducted at six Australian hospitals. All subjects underwent comprehensive rhythm monitoring via an implantable loop recorder or an existing pacemaker. Twice daily they triggered the AliveCor mobile phone app together with Holter monitoring. Patients assigned to abstinence were counseled to abstain completely, got written and verbal advice to help with compliance, and had contact with the investigators on a monthly basis. They also underwent urine testing to monitor compliance. All study participants kept a weekly alcohol intake diary, reviewed monthly by investigators.
Participants averaged 17 standard drinks per week at enrollment. Two-thirds were primarily wine drinkers. At the 6-month mark, patients in the abstinence arm averaged two drinks per week, for an 88% reduction from baseline, and 43 of the 70, or 61%, had remained completely abstinent. The control arm averaged a 20% reduction in weekly consumption.
One of the two co-primary endpoints was recurrent AFib episodes lasting for at least 30 seconds. The rate was 53% in the abstinence group and 73% in controls. The time to first recurrence averaged 118 days in the abstinence group, compared to 86 days in controls, for a 37% prolongation through abstinence.
The other primary endpoint was total AFib burden. During the 6-month study, the abstinence group spent a mean of 5.6% of their time in AFib, compared to 8.2% in controls. The median times were 0.5% and 1.2%.
In a multivariate analysis, neither AFib type, duration, history of AFib ablation, age, nor gender predicted AFib recurrence. In fact, the only significant predictor was alcohol abstinence, which conferred a 48% reduction in risk.
Symptom severity, a secondary endpoint, showed an impressive between-group difference at follow-up. Ten percent of patients in the abstinence group had moderate or severe symptoms at follow-up as assessed via the European Heart Rhythm Association score of atrial fibrillation, compared to 32% of controls, for an absolute 22% difference. And 90% of the abstinence group had no or mild symptoms, as did 68% of controls. Nine percent of the abstinence group had an AFib-related hospitalization, as did 20% of controls.
Cardiac MRI, performed in all subjects, showed that the abstinence group experienced a significant reduction in left atrial area, from 29.5 cm2 at baseline to 27.1 cm2 at follow-up. They also experienced significant improvement in left atrial mechanical function, with their left atrial emptying fraction climbing from 42% to 50%.
The 3-kg weight loss from a baseline of 90 kg in the abstinent group represented a 0.7 kg/m2 reduction in body mass index.
In terms of the likely mechanism of benefit of alcohol abstinence in moderate drinkers, Dr. Voskoboinik noted that he and his colleagues recently demonstrated that regular moderate alcohol consumption, but not mild intake, is associated with potentially explanatory atrial electrical and structural changes, including conduction slowing, lower global bipolar atrial voltage, and an increase in complex atrial potentials (Heart Rhythm. 2019 Feb;16[2]:251-9).
Alcohol has been shown to be linked with AFib through multiple mechanisms. Alcohol has adverse effects on the atrial substrate, including promotion of left atrial remodeling, dilation, and fibrosis via oxidative stress, and alcohol has a contributory role in hypertension and obstructive sleep apnea. Alcohol can act as an acute trigger of AFib through binge drinking – the holiday heart syndrome – which causes autonomic changes, electrolyte abnormalities, and electrophysiologic effects, he continued.
Epidemiologic evidence in support of the notion that moderate drinking increases the risk of AFib includes a Swedish meta-analysis of seven prospective studies comprising 12,554 patients with AFib. The researchers concluded that the relative risk of AFib rose by about 8% with each drink per day, compared with the risk of a reference group composed of current drinkers at a rate of less than one drink per week (J Am Coll Cardiol. 2014 Jul 22;64[3]:281-9).
Although discussants were wowed by the 61% complete abstinence rate in the trial, Dr. Voskoboinik cautioned that the study participants were a highly motivated subset of the universe of moderate drinkers with AFib. And even so, “It was an incredibly challenging study to run,” he said.
“I think lifestyle change is a challenge, and with alcohol particularly so, because alcohol is so ubiquitous in our society. I think the important key message for us as physicians is to take an alcohol history and have a discussion with the patient. And we now have some data to show them. But at the end of the day, it’s up to the patient in conjunction with the physician,” he observed.
Discussant Annabelle S. Volgman, MD, noted that 85% of study participants were men, and because of important differences in AFib between men and women, she doesn’t consider the findings applicable to women.
“You need to redo the study in women,” advised Dr. Volgman, professor of medicine at Rush University, Chicago, and director of the Rush Heart Center for Women.
She suggested that an interventional trial such as this one is a great opportunity to utilize wearable device technology, such as the Apple Watch, which can detect irregular pulse rhythms as demonstrated in the Apple Heart Study. This technology is especially popular with younger individuals.
“A lot of young men and women drink a lot of alcohol,” Dr. Volgman noted.
“That’s a great idea. It gets around a problem with AliveCor, which can miss episodes while you’re sleeping,” Dr. Voskoboinik replied.
He reported having no financial conflicts regarding the investigator-initiated and -funded Alcohol-AF trial.
SOURCE: Voskoboinik A. ACC 19, Session 413-08.
NEW ORLEANS – Abstinence from alcohol on the part of moderate drinkers with atrial fibrillation resulted in clinically meaningful improvement in their arrhythmia in the randomized controlled Alcohol-AF trial, Aleksandr Voskoboinik, MBBS, reported at the annual meeting of the American College of Cardiology.
The benefits of abstinence included significant reductions in the AFib recurrence rate, total AFib burden, and symptom severity. And the payoff extended beyond the arrhythmia: The abstinent group also averaged a 12–mm Hg drop in systolic blood pressure and dropped 3 kg of body weight over the course of the 6-month trial, added Dr. Voskoboinik, a cardiologist at the Baker Heart & Diabetes Institute at the University of Melbourne.
“We would conclude that significant reduction in alcohol intake should be considered as part of the lifestyle intervention in moderate drinkers with AFib,” he said.
Some physicians already advise alcohol abstinence for moderate drinkers with AFib, but until now such recommendations were not evidence based. Instead, the guidance was based on extrapolation from the well-established harmful effects of heavy drinking and binge drinking on AFib as well as epidemiologic studies.
“We wanted to provide some evidence base for physicians to say, ‘If I have motivated patients, here’s what’s potentially achievable,’” he explained.
The key word here is “motivated.” Conducting the Alcohol-AF trial made clear that many moderate drinkers with AFib enjoy their beverages more than they hate having their arrhythmia. Indeed, out of 697 moderate-drinking patients with paroxysmal or persistent AFib who were deemed good candidates and were approached about study participation, more than 500 were excluded because they were flat out unwilling to consider abstinence. After Dr. Voskoboinik and his coinvestigators shortened the planned trial duration from 12 months to 6 because so many recruits were unwilling to abstain for a full year, 140 of the initial 697 patients were randomized to abstinence or continuation of their usual consumption. Thirty percent of them had previously undergone AFib ablation.
The Alcohol-AF study was a multicenter, prospective, open-label study conducted at six Australian hospitals. All subjects underwent comprehensive rhythm monitoring via an implantable loop recorder or an existing pacemaker. Twice daily they triggered the AliveCor mobile phone app together with Holter monitoring. Patients assigned to abstinence were counseled to abstain completely, got written and verbal advice to help with compliance, and had contact with the investigators on a monthly basis. They also underwent urine testing to monitor compliance. All study participants kept a weekly alcohol intake diary, reviewed monthly by investigators.
Participants averaged 17 standard drinks per week at enrollment. Two-thirds were primarily wine drinkers. At the 6-month mark, patients in the abstinence arm averaged two drinks per week, for an 88% reduction from baseline, and 43 of the 70, or 61%, had remained completely abstinent. The control arm averaged a 20% reduction in weekly consumption.
One of the two co-primary endpoints was recurrent AFib episodes lasting for at least 30 seconds. The rate was 53% in the abstinence group and 73% in controls. The time to first recurrence averaged 118 days in the abstinence group, compared to 86 days in controls, for a 37% prolongation through abstinence.
The other primary endpoint was total AFib burden. During the 6-month study, the abstinence group spent a mean of 5.6% of their time in AFib, compared to 8.2% in controls. The median times were 0.5% and 1.2%.
In a multivariate analysis, neither AFib type, duration, history of AFib ablation, age, nor gender predicted AFib recurrence. In fact, the only significant predictor was alcohol abstinence, which conferred a 48% reduction in risk.
Symptom severity, a secondary endpoint, showed an impressive between-group difference at follow-up. Ten percent of patients in the abstinence group had moderate or severe symptoms at follow-up as assessed via the European Heart Rhythm Association score of atrial fibrillation, compared to 32% of controls, for an absolute 22% difference. And 90% of the abstinence group had no or mild symptoms, as did 68% of controls. Nine percent of the abstinence group had an AFib-related hospitalization, as did 20% of controls.
Cardiac MRI, performed in all subjects, showed that the abstinence group experienced a significant reduction in left atrial area, from 29.5 cm2 at baseline to 27.1 cm2 at follow-up. They also experienced significant improvement in left atrial mechanical function, with their left atrial emptying fraction climbing from 42% to 50%.
The 3-kg weight loss from a baseline of 90 kg in the abstinent group represented a 0.7 kg/m2 reduction in body mass index.
In terms of the likely mechanism of benefit of alcohol abstinence in moderate drinkers, Dr. Voskoboinik noted that he and his colleagues recently demonstrated that regular moderate alcohol consumption, but not mild intake, is associated with potentially explanatory atrial electrical and structural changes, including conduction slowing, lower global bipolar atrial voltage, and an increase in complex atrial potentials (Heart Rhythm. 2019 Feb;16[2]:251-9).
Alcohol has been shown to be linked with AFib through multiple mechanisms. Alcohol has adverse effects on the atrial substrate, including promotion of left atrial remodeling, dilation, and fibrosis via oxidative stress, and alcohol has a contributory role in hypertension and obstructive sleep apnea. Alcohol can act as an acute trigger of AFib through binge drinking – the holiday heart syndrome – which causes autonomic changes, electrolyte abnormalities, and electrophysiologic effects, he continued.
Epidemiologic evidence in support of the notion that moderate drinking increases the risk of AFib includes a Swedish meta-analysis of seven prospective studies comprising 12,554 patients with AFib. The researchers concluded that the relative risk of AFib rose by about 8% with each drink per day, compared with the risk of a reference group composed of current drinkers at a rate of less than one drink per week (J Am Coll Cardiol. 2014 Jul 22;64[3]:281-9).
Although discussants were wowed by the 61% complete abstinence rate in the trial, Dr. Voskoboinik cautioned that the study participants were a highly motivated subset of the universe of moderate drinkers with AFib. And even so, “It was an incredibly challenging study to run,” he said.
“I think lifestyle change is a challenge, and with alcohol particularly so, because alcohol is so ubiquitous in our society. I think the important key message for us as physicians is to take an alcohol history and have a discussion with the patient. And we now have some data to show them. But at the end of the day, it’s up to the patient in conjunction with the physician,” he observed.
Discussant Annabelle S. Volgman, MD, noted that 85% of study participants were men, and because of important differences in AFib between men and women, she doesn’t consider the findings applicable to women.
“You need to redo the study in women,” advised Dr. Volgman, professor of medicine at Rush University, Chicago, and director of the Rush Heart Center for Women.
She suggested that an interventional trial such as this one is a great opportunity to utilize wearable device technology, such as the Apple Watch, which can detect irregular pulse rhythms as demonstrated in the Apple Heart Study. This technology is especially popular with younger individuals.
“A lot of young men and women drink a lot of alcohol,” Dr. Volgman noted.
“That’s a great idea. It gets around a problem with AliveCor, which can miss episodes while you’re sleeping,” Dr. Voskoboinik replied.
He reported having no financial conflicts regarding the investigator-initiated and -funded Alcohol-AF trial.
SOURCE: Voskoboinik A. ACC 19, Session 413-08.
NEW ORLEANS – Abstinence from alcohol on the part of moderate drinkers with atrial fibrillation resulted in clinically meaningful improvement in their arrhythmia in the randomized controlled Alcohol-AF trial, Aleksandr Voskoboinik, MBBS, reported at the annual meeting of the American College of Cardiology.
The benefits of abstinence included significant reductions in the AFib recurrence rate, total AFib burden, and symptom severity. And the payoff extended beyond the arrhythmia: The abstinent group also averaged a 12–mm Hg drop in systolic blood pressure and dropped 3 kg of body weight over the course of the 6-month trial, added Dr. Voskoboinik, a cardiologist at the Baker Heart & Diabetes Institute at the University of Melbourne.
“We would conclude that significant reduction in alcohol intake should be considered as part of the lifestyle intervention in moderate drinkers with AFib,” he said.
Some physicians already advise alcohol abstinence for moderate drinkers with AFib, but until now such recommendations were not evidence based. Instead, the guidance was based on extrapolation from the well-established harmful effects of heavy drinking and binge drinking on AFib as well as epidemiologic studies.
“We wanted to provide some evidence base for physicians to say, ‘If I have motivated patients, here’s what’s potentially achievable,’” he explained.
The key word here is “motivated.” Conducting the Alcohol-AF trial made clear that many moderate drinkers with AFib enjoy their beverages more than they hate having their arrhythmia. Indeed, out of 697 moderate-drinking patients with paroxysmal or persistent AFib who were deemed good candidates and were approached about study participation, more than 500 were excluded because they were flat out unwilling to consider abstinence. After Dr. Voskoboinik and his coinvestigators shortened the planned trial duration from 12 months to 6 because so many recruits were unwilling to abstain for a full year, 140 of the initial 697 patients were randomized to abstinence or continuation of their usual consumption. Thirty percent of them had previously undergone AFib ablation.
The Alcohol-AF study was a multicenter, prospective, open-label study conducted at six Australian hospitals. All subjects underwent comprehensive rhythm monitoring via an implantable loop recorder or an existing pacemaker. Twice daily they triggered the AliveCor mobile phone app together with Holter monitoring. Patients assigned to abstinence were counseled to abstain completely, got written and verbal advice to help with compliance, and had contact with the investigators on a monthly basis. They also underwent urine testing to monitor compliance. All study participants kept a weekly alcohol intake diary, reviewed monthly by investigators.
Participants averaged 17 standard drinks per week at enrollment. Two-thirds were primarily wine drinkers. At the 6-month mark, patients in the abstinence arm averaged two drinks per week, for an 88% reduction from baseline, and 43 of the 70, or 61%, had remained completely abstinent. The control arm averaged a 20% reduction in weekly consumption.
One of the two co-primary endpoints was recurrent AFib episodes lasting for at least 30 seconds. The rate was 53% in the abstinence group and 73% in controls. The time to first recurrence averaged 118 days in the abstinence group, compared to 86 days in controls, for a 37% prolongation through abstinence.
The other primary endpoint was total AFib burden. During the 6-month study, the abstinence group spent a mean of 5.6% of their time in AFib, compared to 8.2% in controls. The median times were 0.5% and 1.2%.
In a multivariate analysis, neither AFib type, duration, history of AFib ablation, age, nor gender predicted AFib recurrence. In fact, the only significant predictor was alcohol abstinence, which conferred a 48% reduction in risk.
Symptom severity, a secondary endpoint, showed an impressive between-group difference at follow-up. Ten percent of patients in the abstinence group had moderate or severe symptoms at follow-up as assessed via the European Heart Rhythm Association score of atrial fibrillation, compared to 32% of controls, for an absolute 22% difference. And 90% of the abstinence group had no or mild symptoms, as did 68% of controls. Nine percent of the abstinence group had an AFib-related hospitalization, as did 20% of controls.
Cardiac MRI, performed in all subjects, showed that the abstinence group experienced a significant reduction in left atrial area, from 29.5 cm2 at baseline to 27.1 cm2 at follow-up. They also experienced significant improvement in left atrial mechanical function, with their left atrial emptying fraction climbing from 42% to 50%.
The 3-kg weight loss from a baseline of 90 kg in the abstinent group represented a 0.7 kg/m2 reduction in body mass index.
In terms of the likely mechanism of benefit of alcohol abstinence in moderate drinkers, Dr. Voskoboinik noted that he and his colleagues recently demonstrated that regular moderate alcohol consumption, but not mild intake, is associated with potentially explanatory atrial electrical and structural changes, including conduction slowing, lower global bipolar atrial voltage, and an increase in complex atrial potentials (Heart Rhythm. 2019 Feb;16[2]:251-9).
Alcohol has been shown to be linked with AFib through multiple mechanisms. Alcohol has adverse effects on the atrial substrate, including promotion of left atrial remodeling, dilation, and fibrosis via oxidative stress, and alcohol has a contributory role in hypertension and obstructive sleep apnea. Alcohol can act as an acute trigger of AFib through binge drinking – the holiday heart syndrome – which causes autonomic changes, electrolyte abnormalities, and electrophysiologic effects, he continued.
Epidemiologic evidence in support of the notion that moderate drinking increases the risk of AFib includes a Swedish meta-analysis of seven prospective studies comprising 12,554 patients with AFib. The researchers concluded that the relative risk of AFib rose by about 8% with each drink per day, compared with the risk of a reference group composed of current drinkers at a rate of less than one drink per week (J Am Coll Cardiol. 2014 Jul 22;64[3]:281-9).
Although discussants were wowed by the 61% complete abstinence rate in the trial, Dr. Voskoboinik cautioned that the study participants were a highly motivated subset of the universe of moderate drinkers with AFib. And even so, “It was an incredibly challenging study to run,” he said.
“I think lifestyle change is a challenge, and with alcohol particularly so, because alcohol is so ubiquitous in our society. I think the important key message for us as physicians is to take an alcohol history and have a discussion with the patient. And we now have some data to show them. But at the end of the day, it’s up to the patient in conjunction with the physician,” he observed.
Discussant Annabelle S. Volgman, MD, noted that 85% of study participants were men, and because of important differences in AFib between men and women, she doesn’t consider the findings applicable to women.
“You need to redo the study in women,” advised Dr. Volgman, professor of medicine at Rush University, Chicago, and director of the Rush Heart Center for Women.
She suggested that an interventional trial such as this one is a great opportunity to utilize wearable device technology, such as the Apple Watch, which can detect irregular pulse rhythms as demonstrated in the Apple Heart Study. This technology is especially popular with younger individuals.
“A lot of young men and women drink a lot of alcohol,” Dr. Volgman noted.
“That’s a great idea. It gets around a problem with AliveCor, which can miss episodes while you’re sleeping,” Dr. Voskoboinik replied.
He reported having no financial conflicts regarding the investigator-initiated and -funded Alcohol-AF trial.
SOURCE: Voskoboinik A. ACC 19, Session 413-08.
REPORTING FROM ACC 19