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European Society of Cardiology (ESC): Annual Congress
ACC/AHA risk calculator compares well with European SCORE
BARCELONA— Risk calculators are usually confined to certain populations, but the recently updated ACC/AHA calculator might be effective beyond the United States borders in a Southern European population.
Researchers from Portugal compared the ACC/AHA risk calculator to the European Systematic COronary Risk Evaluation (SCORE) in a patient population that was treated with lipid-lowering drugs. They found that the ACC/AHA calculator’s cut-off point at 7.5% was "extremely effective in discriminating high-risk subject," said Dr. Manuel Oliveira-Santos of Coimbra (Portugal) University, who presented the findings at the annual congress of the European Society of Cardiology.
They also found that that the two scoring systems were strongly correlated and well calibrated. Both calculators overestimated the cardiovascular (CV) risk, "which confirms the previous findings and shows that the calculator works, since many patients in the study were treated with statins," said Dr. Kim A. Williams Sr., president-elect of the American College of Cardiology, who was not involved in the study.
One of the main differences between the two calculators is that the ACC/AHA risk calculator predicts atherosclerotic cardiovascular disease (ASCVD) events, while SCORE estimates the individual risk of fatal noncoronary atherosclerotic and coronary heart disease only, said Dr. Oliveira-Santos.
The study's primary endpoint was acute myocardial infarction, stroke and CV death at 10 years, and the aim was to find out if the ASCVD could be a meaningful tool for this particular patient population in Portugal, said Dr. Oliveira-Santos.
The team retrospectively calculated the two scores for 446 CV-naive patients who were treated at a lipidology clinic between 1994 and 2007. Patients were divided to four groups according to the ASCVD (cut points at 5%, 7.5%, and 10%) and the SCORE system (cut points at 1%, 5%, and 10%).
The mean age of the population was 49 years; more than half were men; 21% were smokers, 25% had type 2 diabetes. More than half were on antihypertensive drug therapy and 72% were receiving statin treatment.
Researchers were able to follow up 85% of the patients at 10 years. Of those, 3.4% had an acute MI, 2.4% had a stroke, and 1.5% died of a cardiovascular event.
The median calculated CV death risk based on SCORE was 0.95%, and the median CV risk calculated by ASCVD was 8.5%. The observed event rate based on the SCORE definition was 1%, compared to 6% based on the ASCVD definition.
When ASCVD was applied to the study cohort, the majority of the patients fell at the very low (less than 5%) or very high (10% or higher) risk categories. About 20% of the patients were at medium risk categories.
Patients who fell in the low and very low risk categories – in other words, they had a CV risk of less than 7.5% – had – no actual cardiovascular events. In the 10% or higher risk group, the predicted event rate was nearly twice the observed rate.
The overestimation, especially in the low risk category (5% to 7.5%) could lead to unnecessary statin therapy and may raise some safety concerns, but the overestimation in the high-risk category is not problematic, Dr. Oliveira-Santos said.
Meanwhile, the group at medium-high risk (from 7.5% to less than 10%) had a slightly higher rate of actual CV events than that estimated using the calculator. "We don’t see that as a cause for concern since those are high risk patients in whom statin therapy is indicated. The statin-treated patients in our study are the majority," he said.
When the SCORE calculator was applied to the cohort, the CV death risk was overestimated in all groups. The majority of the patients fell in the very-low- or low-risk categories, and there were no CV deaths in the very-low-risk category, which included 51% of the patient population.
Researchers conducted further analysis and found that the SCORE and ASCVD systems were positively correlated and they both had "good and similar discriminative power," in addition to good calibration, Dr. Oliveira-Santos reported.
Dr. Williams said that the correlation of the two systems is good news. "There’s always going to be interest in how well an American score will predict the risk in a European population. And the fact that there’s good correlation is reassuring.
"And the most important thing is whether or not an individual practitioner in another country should feel comfortable using this calculator, and that’s why we need more of this kind of study — to find out if they need to build another application or whether they can use what we’ve already created," said Dr. Williams, professor and chief of cardiology at Rush University in Chicago.
Dr. Oliveira-Santos and Dr. Williams had no relevant financial disclosures.
Twitter: @naseemmiller
BARCELONA— Risk calculators are usually confined to certain populations, but the recently updated ACC/AHA calculator might be effective beyond the United States borders in a Southern European population.
Researchers from Portugal compared the ACC/AHA risk calculator to the European Systematic COronary Risk Evaluation (SCORE) in a patient population that was treated with lipid-lowering drugs. They found that the ACC/AHA calculator’s cut-off point at 7.5% was "extremely effective in discriminating high-risk subject," said Dr. Manuel Oliveira-Santos of Coimbra (Portugal) University, who presented the findings at the annual congress of the European Society of Cardiology.
They also found that that the two scoring systems were strongly correlated and well calibrated. Both calculators overestimated the cardiovascular (CV) risk, "which confirms the previous findings and shows that the calculator works, since many patients in the study were treated with statins," said Dr. Kim A. Williams Sr., president-elect of the American College of Cardiology, who was not involved in the study.
One of the main differences between the two calculators is that the ACC/AHA risk calculator predicts atherosclerotic cardiovascular disease (ASCVD) events, while SCORE estimates the individual risk of fatal noncoronary atherosclerotic and coronary heart disease only, said Dr. Oliveira-Santos.
The study's primary endpoint was acute myocardial infarction, stroke and CV death at 10 years, and the aim was to find out if the ASCVD could be a meaningful tool for this particular patient population in Portugal, said Dr. Oliveira-Santos.
The team retrospectively calculated the two scores for 446 CV-naive patients who were treated at a lipidology clinic between 1994 and 2007. Patients were divided to four groups according to the ASCVD (cut points at 5%, 7.5%, and 10%) and the SCORE system (cut points at 1%, 5%, and 10%).
The mean age of the population was 49 years; more than half were men; 21% were smokers, 25% had type 2 diabetes. More than half were on antihypertensive drug therapy and 72% were receiving statin treatment.
Researchers were able to follow up 85% of the patients at 10 years. Of those, 3.4% had an acute MI, 2.4% had a stroke, and 1.5% died of a cardiovascular event.
The median calculated CV death risk based on SCORE was 0.95%, and the median CV risk calculated by ASCVD was 8.5%. The observed event rate based on the SCORE definition was 1%, compared to 6% based on the ASCVD definition.
When ASCVD was applied to the study cohort, the majority of the patients fell at the very low (less than 5%) or very high (10% or higher) risk categories. About 20% of the patients were at medium risk categories.
Patients who fell in the low and very low risk categories – in other words, they had a CV risk of less than 7.5% – had – no actual cardiovascular events. In the 10% or higher risk group, the predicted event rate was nearly twice the observed rate.
The overestimation, especially in the low risk category (5% to 7.5%) could lead to unnecessary statin therapy and may raise some safety concerns, but the overestimation in the high-risk category is not problematic, Dr. Oliveira-Santos said.
Meanwhile, the group at medium-high risk (from 7.5% to less than 10%) had a slightly higher rate of actual CV events than that estimated using the calculator. "We don’t see that as a cause for concern since those are high risk patients in whom statin therapy is indicated. The statin-treated patients in our study are the majority," he said.
When the SCORE calculator was applied to the cohort, the CV death risk was overestimated in all groups. The majority of the patients fell in the very-low- or low-risk categories, and there were no CV deaths in the very-low-risk category, which included 51% of the patient population.
Researchers conducted further analysis and found that the SCORE and ASCVD systems were positively correlated and they both had "good and similar discriminative power," in addition to good calibration, Dr. Oliveira-Santos reported.
Dr. Williams said that the correlation of the two systems is good news. "There’s always going to be interest in how well an American score will predict the risk in a European population. And the fact that there’s good correlation is reassuring.
"And the most important thing is whether or not an individual practitioner in another country should feel comfortable using this calculator, and that’s why we need more of this kind of study — to find out if they need to build another application or whether they can use what we’ve already created," said Dr. Williams, professor and chief of cardiology at Rush University in Chicago.
Dr. Oliveira-Santos and Dr. Williams had no relevant financial disclosures.
Twitter: @naseemmiller
BARCELONA— Risk calculators are usually confined to certain populations, but the recently updated ACC/AHA calculator might be effective beyond the United States borders in a Southern European population.
Researchers from Portugal compared the ACC/AHA risk calculator to the European Systematic COronary Risk Evaluation (SCORE) in a patient population that was treated with lipid-lowering drugs. They found that the ACC/AHA calculator’s cut-off point at 7.5% was "extremely effective in discriminating high-risk subject," said Dr. Manuel Oliveira-Santos of Coimbra (Portugal) University, who presented the findings at the annual congress of the European Society of Cardiology.
They also found that that the two scoring systems were strongly correlated and well calibrated. Both calculators overestimated the cardiovascular (CV) risk, "which confirms the previous findings and shows that the calculator works, since many patients in the study were treated with statins," said Dr. Kim A. Williams Sr., president-elect of the American College of Cardiology, who was not involved in the study.
One of the main differences between the two calculators is that the ACC/AHA risk calculator predicts atherosclerotic cardiovascular disease (ASCVD) events, while SCORE estimates the individual risk of fatal noncoronary atherosclerotic and coronary heart disease only, said Dr. Oliveira-Santos.
The study's primary endpoint was acute myocardial infarction, stroke and CV death at 10 years, and the aim was to find out if the ASCVD could be a meaningful tool for this particular patient population in Portugal, said Dr. Oliveira-Santos.
The team retrospectively calculated the two scores for 446 CV-naive patients who were treated at a lipidology clinic between 1994 and 2007. Patients were divided to four groups according to the ASCVD (cut points at 5%, 7.5%, and 10%) and the SCORE system (cut points at 1%, 5%, and 10%).
The mean age of the population was 49 years; more than half were men; 21% were smokers, 25% had type 2 diabetes. More than half were on antihypertensive drug therapy and 72% were receiving statin treatment.
Researchers were able to follow up 85% of the patients at 10 years. Of those, 3.4% had an acute MI, 2.4% had a stroke, and 1.5% died of a cardiovascular event.
The median calculated CV death risk based on SCORE was 0.95%, and the median CV risk calculated by ASCVD was 8.5%. The observed event rate based on the SCORE definition was 1%, compared to 6% based on the ASCVD definition.
When ASCVD was applied to the study cohort, the majority of the patients fell at the very low (less than 5%) or very high (10% or higher) risk categories. About 20% of the patients were at medium risk categories.
Patients who fell in the low and very low risk categories – in other words, they had a CV risk of less than 7.5% – had – no actual cardiovascular events. In the 10% or higher risk group, the predicted event rate was nearly twice the observed rate.
The overestimation, especially in the low risk category (5% to 7.5%) could lead to unnecessary statin therapy and may raise some safety concerns, but the overestimation in the high-risk category is not problematic, Dr. Oliveira-Santos said.
Meanwhile, the group at medium-high risk (from 7.5% to less than 10%) had a slightly higher rate of actual CV events than that estimated using the calculator. "We don’t see that as a cause for concern since those are high risk patients in whom statin therapy is indicated. The statin-treated patients in our study are the majority," he said.
When the SCORE calculator was applied to the cohort, the CV death risk was overestimated in all groups. The majority of the patients fell in the very-low- or low-risk categories, and there were no CV deaths in the very-low-risk category, which included 51% of the patient population.
Researchers conducted further analysis and found that the SCORE and ASCVD systems were positively correlated and they both had "good and similar discriminative power," in addition to good calibration, Dr. Oliveira-Santos reported.
Dr. Williams said that the correlation of the two systems is good news. "There’s always going to be interest in how well an American score will predict the risk in a European population. And the fact that there’s good correlation is reassuring.
"And the most important thing is whether or not an individual practitioner in another country should feel comfortable using this calculator, and that’s why we need more of this kind of study — to find out if they need to build another application or whether they can use what we’ve already created," said Dr. Williams, professor and chief of cardiology at Rush University in Chicago.
Dr. Oliveira-Santos and Dr. Williams had no relevant financial disclosures.
Twitter: @naseemmiller
AT THE ESC CONGRESS 2014
Key clinical finding: The ACC/AHA risk calculator effectively identified high-risk patients in Portugal who were on statin therapy.
Major Finding: The median calculated CV death risk based on SCORE was 0.95%, and the median CV risk calculated by ASCVD was 8.5%.
Data Source: Analysis of 10-year follow-up data from 446 patients treated at a lipidology clinic in Portugal.
Disclosures: Dr. Oliveira-Santos and Dr. Williams had no relevant financial disclosures.
SIGNIFY: Ivabradine no help in stable CAD
Adding ivabradine to standard background therapy did not improve outcomes in a large, randomized, placebo-controlled trial of more than 19,000 patients who had stable coronary artery disease without clinical heart failure.
At 3 months, the mean heart rate was 60.7 beats per minute in 9,550 patients in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) who were assigned to receive ivabradine, compared with 70.6 beats per minute in 9,552 patients who received placebo. At a median of 27.8 months, the percentage of patients reaching a composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction was 6.8% and 6.4% in the groups, respectively (hazard ratio,1.08), Dr. Kim Fox of Royal Brompton Hospital, London and colleagues reported at the 2014 European Society of Cardiology Congress.
The differences between the ivabradine and placebo groups were not statistically significant, but ivabradine was associated with a nonsignificant increase in the incidence of the primary end point in patients with Canadian Cardiovascular Society class II angina or higher (7.6% vs. 6.5%, hazard ratio, 1.18), the investigators said.
The findings were simultaneously published online Aug. 31 in the New England Journal of Medicine (N. Engl. J. Med 2014 Aug. 30[doi:10.1056/NEJMoa1406430].
Study participants, who were recruited from 1,139 centers in 51 countries between October 12, 2009 and April 30, 2012, were at least 55 years of age with documented and treated stable coronary artery disease, but no evidence of clinical heart failure. They also had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive readings, and have at least one major or two minor adverse prognostic factors.
All patients completed a 2- to 4-week placebo run-in phase then were randomized to ivabradine at a dose of 7.5 mg twice daily (or 5 mg twice daily for those over age 74 years) or placebo in addition to stable background therapy prescribed according to contemporary guidelines. Dosing was adjusted as needed to 5, 7.5, or 10 mg twice daily based on heart rate and bradycardia. The target heart rate was 55-60 beats per minute, and the mean study-drug dose throughout the trial was 8.2 mg twice daily in the ivabradine group, and 9.5 mg twice daily in the placebo group.
Adverse events occurred in significantly more patients in the ivabradine group (73.3% vs. 66.9%). Bradycardia, in particular, was increased in the ivabradine group (7.9% vs. 1.2% for symptomatic bradycardia, and 11.0% vs. 1.3% for asymptomatic bradycardia. Atrial fibrillation and phosphenes were also increased in the ivabradine group (5.3 vs. 3.8% and 5.4% vs. 0.5%, respectively).
Serious adverse events were also significantly more common in the ivabradine group, with 37.6% and 35.4% of patients in the groups, respectively, experiencing a serious adverse event. These events were classified as cardiac disorders in 19.0% and 16.7% of patients in the groups, respectively.
The SIGNIFY findings contrast with those from previous post hoc analyses that suggested ivabradine improves outcomes in patients with stable coronary artery disease.
"In addition, in patients with heart failure, the reduction in heart rate with ivabradine has been shown to improve clinical outcomes, beyond the improvements observed with beta-blockers," the investigators said.
In fact, on the basis of findings from the phase III Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), the U.S. Food and Drug Administration recently granted priority review designation for ivabradine for the treatment of chronic heart failure.
Ivabradine lowers heart rate without affecting blood pressure or left ventricular systolic function, by inhibiting the If, or pacemaker, current in the sinoatrial node. It is approved in numerous countries outside the United States and is used for reducing angina symptoms and for chronic heart failure.
A number of hypotheses may explain the SIGNIFY findings.
"It is possible that ivabradine decreased the heart rate too much or that there may be a J-shaped curve for the relationship between heart rate and outcome," the investigators said, explaining that "ivabradine may have unintended effects (e.g., adjustment of the doses of other heart-rate lowering agents) that may have affected the potential benefits of the lowering of heart rate with ivabradine."
Further, heart rate-reducing antianginal agents may have no effect on outcomes in patients with stable coronary artery disease, they said.
The findings may also reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in those with heart failure and those with stable coronary artery disease, they noted.
"Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes- in patients who have stable coronary artery disease without clinical heart failure," they concluded.
This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.
The increased incidence of the primary endpoint among patients with Canadian Cardiovascular Society Class II or higher levels of angina in the SIGNIFY trial was surprising and warrants further study to ascertain whether this angina subgroup is one in which caution should be exercised.
In the meantime, caution should indeed be exercised with respect to the use of ivabradine (by physicians who have access to the drug) in those with more severe forms of angina, and adjustment of beta-blocker doses to effective levels should be considered before initiating ivabradine.
The experience from the trial of ivabradine in heart failure suggests that nearly 60% of patients were receiving inadequate doses of beta-blockers and that the majority of benefit with ivabradine was among patients who could not take beta-blockers or who were taking a lower dose. Whether this holds true for patients with angina is unknown, but a cautious approach may be reasonable pending better understanding of the matter.
More therapies are needed for patients with chronic angina – particularly in the United States, both to improve symptoms and to improve quality of life.
What we may need to consider is the level at which an individual patient might be willing to trade some potential risk of major nonfatal cardiovascular events for less angina and a better quality of life.
Dr. E. Magnus Ohman and Dr. Karen P. Alexander of Duke University, Durham, N.C., made these remarks in an accompanying editorial (N. Engl. J. Med. 2014, Aug. 31[doi: 10.1056/NEJMe1409369]). Dr. Ohman reported receiving grant support and/or consulting fees from Abiomed, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Janssen, Pozen, Sanofi Aventis, The Medicines Company, and WebMD. Dr. Alexander reported receiving grant support from Gilead.
The increased incidence of the primary endpoint among patients with Canadian Cardiovascular Society Class II or higher levels of angina in the SIGNIFY trial was surprising and warrants further study to ascertain whether this angina subgroup is one in which caution should be exercised.
In the meantime, caution should indeed be exercised with respect to the use of ivabradine (by physicians who have access to the drug) in those with more severe forms of angina, and adjustment of beta-blocker doses to effective levels should be considered before initiating ivabradine.
The experience from the trial of ivabradine in heart failure suggests that nearly 60% of patients were receiving inadequate doses of beta-blockers and that the majority of benefit with ivabradine was among patients who could not take beta-blockers or who were taking a lower dose. Whether this holds true for patients with angina is unknown, but a cautious approach may be reasonable pending better understanding of the matter.
More therapies are needed for patients with chronic angina – particularly in the United States, both to improve symptoms and to improve quality of life.
What we may need to consider is the level at which an individual patient might be willing to trade some potential risk of major nonfatal cardiovascular events for less angina and a better quality of life.
Dr. E. Magnus Ohman and Dr. Karen P. Alexander of Duke University, Durham, N.C., made these remarks in an accompanying editorial (N. Engl. J. Med. 2014, Aug. 31[doi: 10.1056/NEJMe1409369]). Dr. Ohman reported receiving grant support and/or consulting fees from Abiomed, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Janssen, Pozen, Sanofi Aventis, The Medicines Company, and WebMD. Dr. Alexander reported receiving grant support from Gilead.
The increased incidence of the primary endpoint among patients with Canadian Cardiovascular Society Class II or higher levels of angina in the SIGNIFY trial was surprising and warrants further study to ascertain whether this angina subgroup is one in which caution should be exercised.
In the meantime, caution should indeed be exercised with respect to the use of ivabradine (by physicians who have access to the drug) in those with more severe forms of angina, and adjustment of beta-blocker doses to effective levels should be considered before initiating ivabradine.
The experience from the trial of ivabradine in heart failure suggests that nearly 60% of patients were receiving inadequate doses of beta-blockers and that the majority of benefit with ivabradine was among patients who could not take beta-blockers or who were taking a lower dose. Whether this holds true for patients with angina is unknown, but a cautious approach may be reasonable pending better understanding of the matter.
More therapies are needed for patients with chronic angina – particularly in the United States, both to improve symptoms and to improve quality of life.
What we may need to consider is the level at which an individual patient might be willing to trade some potential risk of major nonfatal cardiovascular events for less angina and a better quality of life.
Dr. E. Magnus Ohman and Dr. Karen P. Alexander of Duke University, Durham, N.C., made these remarks in an accompanying editorial (N. Engl. J. Med. 2014, Aug. 31[doi: 10.1056/NEJMe1409369]). Dr. Ohman reported receiving grant support and/or consulting fees from Abiomed, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Janssen, Pozen, Sanofi Aventis, The Medicines Company, and WebMD. Dr. Alexander reported receiving grant support from Gilead.
Adding ivabradine to standard background therapy did not improve outcomes in a large, randomized, placebo-controlled trial of more than 19,000 patients who had stable coronary artery disease without clinical heart failure.
At 3 months, the mean heart rate was 60.7 beats per minute in 9,550 patients in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) who were assigned to receive ivabradine, compared with 70.6 beats per minute in 9,552 patients who received placebo. At a median of 27.8 months, the percentage of patients reaching a composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction was 6.8% and 6.4% in the groups, respectively (hazard ratio,1.08), Dr. Kim Fox of Royal Brompton Hospital, London and colleagues reported at the 2014 European Society of Cardiology Congress.
The differences between the ivabradine and placebo groups were not statistically significant, but ivabradine was associated with a nonsignificant increase in the incidence of the primary end point in patients with Canadian Cardiovascular Society class II angina or higher (7.6% vs. 6.5%, hazard ratio, 1.18), the investigators said.
The findings were simultaneously published online Aug. 31 in the New England Journal of Medicine (N. Engl. J. Med 2014 Aug. 30[doi:10.1056/NEJMoa1406430].
Study participants, who were recruited from 1,139 centers in 51 countries between October 12, 2009 and April 30, 2012, were at least 55 years of age with documented and treated stable coronary artery disease, but no evidence of clinical heart failure. They also had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive readings, and have at least one major or two minor adverse prognostic factors.
All patients completed a 2- to 4-week placebo run-in phase then were randomized to ivabradine at a dose of 7.5 mg twice daily (or 5 mg twice daily for those over age 74 years) or placebo in addition to stable background therapy prescribed according to contemporary guidelines. Dosing was adjusted as needed to 5, 7.5, or 10 mg twice daily based on heart rate and bradycardia. The target heart rate was 55-60 beats per minute, and the mean study-drug dose throughout the trial was 8.2 mg twice daily in the ivabradine group, and 9.5 mg twice daily in the placebo group.
Adverse events occurred in significantly more patients in the ivabradine group (73.3% vs. 66.9%). Bradycardia, in particular, was increased in the ivabradine group (7.9% vs. 1.2% for symptomatic bradycardia, and 11.0% vs. 1.3% for asymptomatic bradycardia. Atrial fibrillation and phosphenes were also increased in the ivabradine group (5.3 vs. 3.8% and 5.4% vs. 0.5%, respectively).
Serious adverse events were also significantly more common in the ivabradine group, with 37.6% and 35.4% of patients in the groups, respectively, experiencing a serious adverse event. These events were classified as cardiac disorders in 19.0% and 16.7% of patients in the groups, respectively.
The SIGNIFY findings contrast with those from previous post hoc analyses that suggested ivabradine improves outcomes in patients with stable coronary artery disease.
"In addition, in patients with heart failure, the reduction in heart rate with ivabradine has been shown to improve clinical outcomes, beyond the improvements observed with beta-blockers," the investigators said.
In fact, on the basis of findings from the phase III Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), the U.S. Food and Drug Administration recently granted priority review designation for ivabradine for the treatment of chronic heart failure.
Ivabradine lowers heart rate without affecting blood pressure or left ventricular systolic function, by inhibiting the If, or pacemaker, current in the sinoatrial node. It is approved in numerous countries outside the United States and is used for reducing angina symptoms and for chronic heart failure.
A number of hypotheses may explain the SIGNIFY findings.
"It is possible that ivabradine decreased the heart rate too much or that there may be a J-shaped curve for the relationship between heart rate and outcome," the investigators said, explaining that "ivabradine may have unintended effects (e.g., adjustment of the doses of other heart-rate lowering agents) that may have affected the potential benefits of the lowering of heart rate with ivabradine."
Further, heart rate-reducing antianginal agents may have no effect on outcomes in patients with stable coronary artery disease, they said.
The findings may also reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in those with heart failure and those with stable coronary artery disease, they noted.
"Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes- in patients who have stable coronary artery disease without clinical heart failure," they concluded.
This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.
Adding ivabradine to standard background therapy did not improve outcomes in a large, randomized, placebo-controlled trial of more than 19,000 patients who had stable coronary artery disease without clinical heart failure.
At 3 months, the mean heart rate was 60.7 beats per minute in 9,550 patients in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) who were assigned to receive ivabradine, compared with 70.6 beats per minute in 9,552 patients who received placebo. At a median of 27.8 months, the percentage of patients reaching a composite endpoint of death from cardiovascular causes or nonfatal myocardial infarction was 6.8% and 6.4% in the groups, respectively (hazard ratio,1.08), Dr. Kim Fox of Royal Brompton Hospital, London and colleagues reported at the 2014 European Society of Cardiology Congress.
The differences between the ivabradine and placebo groups were not statistically significant, but ivabradine was associated with a nonsignificant increase in the incidence of the primary end point in patients with Canadian Cardiovascular Society class II angina or higher (7.6% vs. 6.5%, hazard ratio, 1.18), the investigators said.
The findings were simultaneously published online Aug. 31 in the New England Journal of Medicine (N. Engl. J. Med 2014 Aug. 30[doi:10.1056/NEJMoa1406430].
Study participants, who were recruited from 1,139 centers in 51 countries between October 12, 2009 and April 30, 2012, were at least 55 years of age with documented and treated stable coronary artery disease, but no evidence of clinical heart failure. They also had to be in sinus rhythm, have a resting heart rate of 70 beats per minute or more on two consecutive readings, and have at least one major or two minor adverse prognostic factors.
All patients completed a 2- to 4-week placebo run-in phase then were randomized to ivabradine at a dose of 7.5 mg twice daily (or 5 mg twice daily for those over age 74 years) or placebo in addition to stable background therapy prescribed according to contemporary guidelines. Dosing was adjusted as needed to 5, 7.5, or 10 mg twice daily based on heart rate and bradycardia. The target heart rate was 55-60 beats per minute, and the mean study-drug dose throughout the trial was 8.2 mg twice daily in the ivabradine group, and 9.5 mg twice daily in the placebo group.
Adverse events occurred in significantly more patients in the ivabradine group (73.3% vs. 66.9%). Bradycardia, in particular, was increased in the ivabradine group (7.9% vs. 1.2% for symptomatic bradycardia, and 11.0% vs. 1.3% for asymptomatic bradycardia. Atrial fibrillation and phosphenes were also increased in the ivabradine group (5.3 vs. 3.8% and 5.4% vs. 0.5%, respectively).
Serious adverse events were also significantly more common in the ivabradine group, with 37.6% and 35.4% of patients in the groups, respectively, experiencing a serious adverse event. These events were classified as cardiac disorders in 19.0% and 16.7% of patients in the groups, respectively.
The SIGNIFY findings contrast with those from previous post hoc analyses that suggested ivabradine improves outcomes in patients with stable coronary artery disease.
"In addition, in patients with heart failure, the reduction in heart rate with ivabradine has been shown to improve clinical outcomes, beyond the improvements observed with beta-blockers," the investigators said.
In fact, on the basis of findings from the phase III Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), the U.S. Food and Drug Administration recently granted priority review designation for ivabradine for the treatment of chronic heart failure.
Ivabradine lowers heart rate without affecting blood pressure or left ventricular systolic function, by inhibiting the If, or pacemaker, current in the sinoatrial node. It is approved in numerous countries outside the United States and is used for reducing angina symptoms and for chronic heart failure.
A number of hypotheses may explain the SIGNIFY findings.
"It is possible that ivabradine decreased the heart rate too much or that there may be a J-shaped curve for the relationship between heart rate and outcome," the investigators said, explaining that "ivabradine may have unintended effects (e.g., adjustment of the doses of other heart-rate lowering agents) that may have affected the potential benefits of the lowering of heart rate with ivabradine."
Further, heart rate-reducing antianginal agents may have no effect on outcomes in patients with stable coronary artery disease, they said.
The findings may also reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in those with heart failure and those with stable coronary artery disease, they noted.
"Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, these results suggest that an elevated heart rate is only a marker of risk – but not a modifiable determinant of outcomes- in patients who have stable coronary artery disease without clinical heart failure," they concluded.
This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.
FROM THE ESC CONGRESS 2014
Key clinical point: The investigational drug ivabradine did not improve outcomes in stable CAD patients with no heart failure.
Major finding: No significant difference was seen between ivabradine and placebo; HR for composite endpoint of death from cardiovascular causes or nonfatal MI, 1.08.
Data source: SIGNIFY, a randomized, double blind, placebo-controlled trial in 19.102 patients.
Disclosures: This study was funded by Servier. Dr. Fox reported receiving personal fees and/or nonfinancial support from Servier, AstraZeneca, TaurX, Armgo, Broadview Ventures, and CellAegis. She also is director of Heart Research Lt. and Vesalius Trials Ltd. Detailed disclosures for all study authors are available at NEJM.org.
Diabetes increases risk of atrial fibrillation
BARCELONA – Adults with diabetes mellitus are at increased risk of subsequent new-onset atrial fibrillation – and the younger the age at diabetes onset, the greater the likelihood of developing the arrhythmia.
That’s the key finding from a Danish national registry study in which all 5,168,416 Danish adults without atrial fibrillation in 1996 were followed through 2012 for development of atrial fibrillation (AF). The study population included 75,197 Danes with diabetes at baseline and another 235,327 who developed the disease during follow-up, Dr. Jannik L. Pallisgaard explained at the annual congress of the European Society of Cardiology.
During follow-up, 5.6% of those with diabetes and 3.3% of those without diabetes developed AF. The mean time from diabetes onset to AF onset was 5 years, reported Dr. Pallisgaard of the University of Copenhagen.
"What was particularly interesting, I think, is that we found the youngest patients were the group at highest risk" of developing AF, he said. "We suggest that starting at the onset of diabetes, routine pulse palpation, ECGs, and focused patient interviews asking about any signs of atrial fibrillation could prove beneficial in detecting the arrhythmia."
The incidence rate ratio for developing AF per 1,000 person-years of follow-up was roughly 2.5-fold greater in 18- to 39-year-olds with diabetes than in their nondiabetic peers. From this peak rate in young adults, the magnitude of relative risk dropped in stepwise fashion with age: The variability in risk was lower in 40- to 60-year-old diabetics than in the 18- to 39-year olds and lower still in 65- to 74-year olds. Variability in the incidence rate ratio finally bottomed out at a still statistically significant 1.3-fold increased risk of developing AF in diabetic individuals ages 75 and older compared to their nondiabetic peers.
Dr. Pallisgaard noted that while the relative risk of developing AF was greatest in the 18- to 39-year-olds, the absolute number of new cases of AF was far greater in older patients because there were so many more of them with diabetes. He cautioned that as the obesity epidemic leads to more and more patients developing type 2 diabetes at younger ages, more cases of AF can be expected in young adults.
Dr. Pallisgaard cited two likely mechanisms underlying the observed increased risk of AF in diabetic patients: left ventricular hypertrophy and vascular inflammation, which are both often present in the diabetic population.
He reported having no financial conflicts regarding this study, conducted with Danish institutional research funds.
BARCELONA – Adults with diabetes mellitus are at increased risk of subsequent new-onset atrial fibrillation – and the younger the age at diabetes onset, the greater the likelihood of developing the arrhythmia.
That’s the key finding from a Danish national registry study in which all 5,168,416 Danish adults without atrial fibrillation in 1996 were followed through 2012 for development of atrial fibrillation (AF). The study population included 75,197 Danes with diabetes at baseline and another 235,327 who developed the disease during follow-up, Dr. Jannik L. Pallisgaard explained at the annual congress of the European Society of Cardiology.
During follow-up, 5.6% of those with diabetes and 3.3% of those without diabetes developed AF. The mean time from diabetes onset to AF onset was 5 years, reported Dr. Pallisgaard of the University of Copenhagen.
"What was particularly interesting, I think, is that we found the youngest patients were the group at highest risk" of developing AF, he said. "We suggest that starting at the onset of diabetes, routine pulse palpation, ECGs, and focused patient interviews asking about any signs of atrial fibrillation could prove beneficial in detecting the arrhythmia."
The incidence rate ratio for developing AF per 1,000 person-years of follow-up was roughly 2.5-fold greater in 18- to 39-year-olds with diabetes than in their nondiabetic peers. From this peak rate in young adults, the magnitude of relative risk dropped in stepwise fashion with age: The variability in risk was lower in 40- to 60-year-old diabetics than in the 18- to 39-year olds and lower still in 65- to 74-year olds. Variability in the incidence rate ratio finally bottomed out at a still statistically significant 1.3-fold increased risk of developing AF in diabetic individuals ages 75 and older compared to their nondiabetic peers.
Dr. Pallisgaard noted that while the relative risk of developing AF was greatest in the 18- to 39-year-olds, the absolute number of new cases of AF was far greater in older patients because there were so many more of them with diabetes. He cautioned that as the obesity epidemic leads to more and more patients developing type 2 diabetes at younger ages, more cases of AF can be expected in young adults.
Dr. Pallisgaard cited two likely mechanisms underlying the observed increased risk of AF in diabetic patients: left ventricular hypertrophy and vascular inflammation, which are both often present in the diabetic population.
He reported having no financial conflicts regarding this study, conducted with Danish institutional research funds.
BARCELONA – Adults with diabetes mellitus are at increased risk of subsequent new-onset atrial fibrillation – and the younger the age at diabetes onset, the greater the likelihood of developing the arrhythmia.
That’s the key finding from a Danish national registry study in which all 5,168,416 Danish adults without atrial fibrillation in 1996 were followed through 2012 for development of atrial fibrillation (AF). The study population included 75,197 Danes with diabetes at baseline and another 235,327 who developed the disease during follow-up, Dr. Jannik L. Pallisgaard explained at the annual congress of the European Society of Cardiology.
During follow-up, 5.6% of those with diabetes and 3.3% of those without diabetes developed AF. The mean time from diabetes onset to AF onset was 5 years, reported Dr. Pallisgaard of the University of Copenhagen.
"What was particularly interesting, I think, is that we found the youngest patients were the group at highest risk" of developing AF, he said. "We suggest that starting at the onset of diabetes, routine pulse palpation, ECGs, and focused patient interviews asking about any signs of atrial fibrillation could prove beneficial in detecting the arrhythmia."
The incidence rate ratio for developing AF per 1,000 person-years of follow-up was roughly 2.5-fold greater in 18- to 39-year-olds with diabetes than in their nondiabetic peers. From this peak rate in young adults, the magnitude of relative risk dropped in stepwise fashion with age: The variability in risk was lower in 40- to 60-year-old diabetics than in the 18- to 39-year olds and lower still in 65- to 74-year olds. Variability in the incidence rate ratio finally bottomed out at a still statistically significant 1.3-fold increased risk of developing AF in diabetic individuals ages 75 and older compared to their nondiabetic peers.
Dr. Pallisgaard noted that while the relative risk of developing AF was greatest in the 18- to 39-year-olds, the absolute number of new cases of AF was far greater in older patients because there were so many more of them with diabetes. He cautioned that as the obesity epidemic leads to more and more patients developing type 2 diabetes at younger ages, more cases of AF can be expected in young adults.
Dr. Pallisgaard cited two likely mechanisms underlying the observed increased risk of AF in diabetic patients: left ventricular hypertrophy and vascular inflammation, which are both often present in the diabetic population.
He reported having no financial conflicts regarding this study, conducted with Danish institutional research funds.
AT THE ESC CONGRESS 2014
Key clinical point: Starting at the onset of diabetes, routine pulse palpation, ECGs, and patient interviews focused on signs of atrial fibrillation might improve detection of the arrhythmia.
Major finding: During follow-up, 5.6% of those with diabetes and 3.3% of those without diabetes developed AF.
Data source: This was a national registry study including all of the nearly 5.2 million Danish adults without atrial fibrillation in 1996. Follow-up ran through 2012.
Disclosures: The presenter reported having no financial conflicts regarding this study, funded by Danish institutional research grants.
VIDEO: New dual heart-failure formulation scores several benefits
BARCELONA – It’s been a while since physicians had a new treatment for heart failure patients with reduced ejection fraction that makes them feel better, stay out of hospital, and live longer. But the investigational drug LCZ696 did just that in PARADIGM-HF, a controlled, pivotal trial with more than 8,000 patients, Dr. John McMurray said at the annual congress of the European Society of Cardiology.
In addition to robustly beating the comparator drug enalapril with reduced rates of both cardiovascular deaths and the combined endpoint of cardiovascular deaths and heart-failure hospitalizations, the new LCZ696 combination drug boosted patients’ quality of life in several clinically meaningful ways. The magnitude of the quality of life effect matched that seen in prior, successful, heart-failure treatment trials, Dr. McMurray, a professor of medical cardiology at the University of Glasgow, said in an interview.
He stressed that the combination of sacubitril, a new drug that inhibits neprilysin and thereby boosts levels of endogenous vasoactive peptides, and the well-established angiotensin-receptor blocker valsartan helped patients with milder, New York Heart Association class II heart failure, roughly 70% of enrolled patients. Activity in these less severely ill patients means that treatment with LCZ696 can "keep these patients stable, feeling well, functional, and out of the hospital as well as improve their survival," he said.
PARADIGM-HF was sponsored by Novartis, the company developing LCZ696. Dr. McMurray said that he has received travel support from Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Twitter: @mitchelzoler
BARCELONA – It’s been a while since physicians had a new treatment for heart failure patients with reduced ejection fraction that makes them feel better, stay out of hospital, and live longer. But the investigational drug LCZ696 did just that in PARADIGM-HF, a controlled, pivotal trial with more than 8,000 patients, Dr. John McMurray said at the annual congress of the European Society of Cardiology.
In addition to robustly beating the comparator drug enalapril with reduced rates of both cardiovascular deaths and the combined endpoint of cardiovascular deaths and heart-failure hospitalizations, the new LCZ696 combination drug boosted patients’ quality of life in several clinically meaningful ways. The magnitude of the quality of life effect matched that seen in prior, successful, heart-failure treatment trials, Dr. McMurray, a professor of medical cardiology at the University of Glasgow, said in an interview.
He stressed that the combination of sacubitril, a new drug that inhibits neprilysin and thereby boosts levels of endogenous vasoactive peptides, and the well-established angiotensin-receptor blocker valsartan helped patients with milder, New York Heart Association class II heart failure, roughly 70% of enrolled patients. Activity in these less severely ill patients means that treatment with LCZ696 can "keep these patients stable, feeling well, functional, and out of the hospital as well as improve their survival," he said.
PARADIGM-HF was sponsored by Novartis, the company developing LCZ696. Dr. McMurray said that he has received travel support from Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Twitter: @mitchelzoler
BARCELONA – It’s been a while since physicians had a new treatment for heart failure patients with reduced ejection fraction that makes them feel better, stay out of hospital, and live longer. But the investigational drug LCZ696 did just that in PARADIGM-HF, a controlled, pivotal trial with more than 8,000 patients, Dr. John McMurray said at the annual congress of the European Society of Cardiology.
In addition to robustly beating the comparator drug enalapril with reduced rates of both cardiovascular deaths and the combined endpoint of cardiovascular deaths and heart-failure hospitalizations, the new LCZ696 combination drug boosted patients’ quality of life in several clinically meaningful ways. The magnitude of the quality of life effect matched that seen in prior, successful, heart-failure treatment trials, Dr. McMurray, a professor of medical cardiology at the University of Glasgow, said in an interview.
He stressed that the combination of sacubitril, a new drug that inhibits neprilysin and thereby boosts levels of endogenous vasoactive peptides, and the well-established angiotensin-receptor blocker valsartan helped patients with milder, New York Heart Association class II heart failure, roughly 70% of enrolled patients. Activity in these less severely ill patients means that treatment with LCZ696 can "keep these patients stable, feeling well, functional, and out of the hospital as well as improve their survival," he said.
PARADIGM-HF was sponsored by Novartis, the company developing LCZ696. Dr. McMurray said that he has received travel support from Novartis.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Twitter: @mitchelzoler
AT ESC 2014
Darapladib flunks another phase III trial
A drug designed to stabilize atherosclerotic plaques failed to reduce the risk of major coronary events when given to patients hospitalized with an acute coronary syndrome.
After 2.5 years, there was no significant difference between darapladib and placebo in a composite endpoint of coronary heart disease, death, myocardial infarction, or urgent coronary revascularization (16.3% vs. 15.6%). Nor did the drug confer any significant benefit when each of these outcomes was separately examined, Dr. Michelle L. O’Donoghue and her colleagues reported at the annual congress of the European Society of Cardiology. The study was simultaneously published online in the Journal of the American Medical Association (JAMA 2014 [doi:10.1001/jama.2014.11061]).
Subgroup analyses of the SOLID-TIMI 52 study also failed to identify any patient group that experienced any significant benefit in the composite or individual endpoints, reported Dr. O’Donoghue of Brigham and Women’s Hospital, Boston, and her coauthors.
Darapladib is an investigational selective inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2); it has been shown to prevent the expansion of necrotic cores in atherosclerotic plaques.
The study randomized 13,026 patients to either darapladib 160 mg/day or placebo. They were a median of 64 years old; 75% were male. The initial acute coronary events were ST-elevation myocardial infarction (45%), non-ST-elevation MI (43%), and unstable angina (12%). Cardiac catheterization was common (86%), as was percutaneous coronary intervention (77%)
Nearly all patients were taking statins at baseline (95%). More than 85% were also taking other recommended therapies, including aspirin, beta-blockers, and antiplatelet agents.
By the end of the follow-up period, the primary combined endpoint had occurred in 903 patients in the active group and 910 in the placebo group (HR 1.00). The secondary endpoint (cardiovascular death, MI, or stroke) occurred in 824 taking darapladib and 838 taking placebo (15% each; HR 0.99).
Death occurred in 7% of each group (HR 0.94).
The authors conducted several subgroup analyses and failed to find a significant benefit regardless of age, geographical region, renal dysfunction or any other baseline comorbidities. Baseline low-density lipoprotein cholesterol had no interaction with outcomes.
Darapladib was considered safe; the incidence of any serious adverse events was similar to placebo (45% vs. 46%). Alamine aminotransferase elevations occurred in less than 1% of each group.
Adverse events leading to discontinuation occurred in 17% of the active group and 12% of the placebo group. This significant difference was mostly driven by body odor events in the darapladib group.
"Consistent with prior studies, patients treated with darapladib were more likely to report an odor-related concern than those in the placebo group," at 11% vs. 2%, the authors noted.
These included skin odors (4% vs. 0.4%), urine odors (5% vs. 1%), and feces odors (8% vs. 1%). Diarrhea was also significantly more common among those taking the study drug (11% vs. 6%).
SOLID-TIMI 52 is the drug’s second failed phase III trial. The STABILITY study, which followed almost 16,000 patients for more than 3 years, also found that darapladib conferred no significant benefit in major cardiovascular outcomes.
These findings, combined with the current study, suggest that Lp-PLA2 may not be a good therapeutic target for a population already sufficiently treated with plaque-stabilizing statins, Dr. O’Donoghue and her coauthors said. "In addition, although unlikely, the possibility that Lp-PLA remains an important target cannot be excluded, but variable plaque penetration of the drug or unidentified off-target effects of darapladib could be responsible for the absence of efficacy in the current study."
The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. Dr. O’Donoghue has received institutional research funding from the company, and has consulting fees from Aegerion. Her coauthors disclosed relationships with numerous pharmaceutical companies.
A drug designed to stabilize atherosclerotic plaques failed to reduce the risk of major coronary events when given to patients hospitalized with an acute coronary syndrome.
After 2.5 years, there was no significant difference between darapladib and placebo in a composite endpoint of coronary heart disease, death, myocardial infarction, or urgent coronary revascularization (16.3% vs. 15.6%). Nor did the drug confer any significant benefit when each of these outcomes was separately examined, Dr. Michelle L. O’Donoghue and her colleagues reported at the annual congress of the European Society of Cardiology. The study was simultaneously published online in the Journal of the American Medical Association (JAMA 2014 [doi:10.1001/jama.2014.11061]).
Subgroup analyses of the SOLID-TIMI 52 study also failed to identify any patient group that experienced any significant benefit in the composite or individual endpoints, reported Dr. O’Donoghue of Brigham and Women’s Hospital, Boston, and her coauthors.
Darapladib is an investigational selective inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2); it has been shown to prevent the expansion of necrotic cores in atherosclerotic plaques.
The study randomized 13,026 patients to either darapladib 160 mg/day or placebo. They were a median of 64 years old; 75% were male. The initial acute coronary events were ST-elevation myocardial infarction (45%), non-ST-elevation MI (43%), and unstable angina (12%). Cardiac catheterization was common (86%), as was percutaneous coronary intervention (77%)
Nearly all patients were taking statins at baseline (95%). More than 85% were also taking other recommended therapies, including aspirin, beta-blockers, and antiplatelet agents.
By the end of the follow-up period, the primary combined endpoint had occurred in 903 patients in the active group and 910 in the placebo group (HR 1.00). The secondary endpoint (cardiovascular death, MI, or stroke) occurred in 824 taking darapladib and 838 taking placebo (15% each; HR 0.99).
Death occurred in 7% of each group (HR 0.94).
The authors conducted several subgroup analyses and failed to find a significant benefit regardless of age, geographical region, renal dysfunction or any other baseline comorbidities. Baseline low-density lipoprotein cholesterol had no interaction with outcomes.
Darapladib was considered safe; the incidence of any serious adverse events was similar to placebo (45% vs. 46%). Alamine aminotransferase elevations occurred in less than 1% of each group.
Adverse events leading to discontinuation occurred in 17% of the active group and 12% of the placebo group. This significant difference was mostly driven by body odor events in the darapladib group.
"Consistent with prior studies, patients treated with darapladib were more likely to report an odor-related concern than those in the placebo group," at 11% vs. 2%, the authors noted.
These included skin odors (4% vs. 0.4%), urine odors (5% vs. 1%), and feces odors (8% vs. 1%). Diarrhea was also significantly more common among those taking the study drug (11% vs. 6%).
SOLID-TIMI 52 is the drug’s second failed phase III trial. The STABILITY study, which followed almost 16,000 patients for more than 3 years, also found that darapladib conferred no significant benefit in major cardiovascular outcomes.
These findings, combined with the current study, suggest that Lp-PLA2 may not be a good therapeutic target for a population already sufficiently treated with plaque-stabilizing statins, Dr. O’Donoghue and her coauthors said. "In addition, although unlikely, the possibility that Lp-PLA remains an important target cannot be excluded, but variable plaque penetration of the drug or unidentified off-target effects of darapladib could be responsible for the absence of efficacy in the current study."
The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. Dr. O’Donoghue has received institutional research funding from the company, and has consulting fees from Aegerion. Her coauthors disclosed relationships with numerous pharmaceutical companies.
A drug designed to stabilize atherosclerotic plaques failed to reduce the risk of major coronary events when given to patients hospitalized with an acute coronary syndrome.
After 2.5 years, there was no significant difference between darapladib and placebo in a composite endpoint of coronary heart disease, death, myocardial infarction, or urgent coronary revascularization (16.3% vs. 15.6%). Nor did the drug confer any significant benefit when each of these outcomes was separately examined, Dr. Michelle L. O’Donoghue and her colleagues reported at the annual congress of the European Society of Cardiology. The study was simultaneously published online in the Journal of the American Medical Association (JAMA 2014 [doi:10.1001/jama.2014.11061]).
Subgroup analyses of the SOLID-TIMI 52 study also failed to identify any patient group that experienced any significant benefit in the composite or individual endpoints, reported Dr. O’Donoghue of Brigham and Women’s Hospital, Boston, and her coauthors.
Darapladib is an investigational selective inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2); it has been shown to prevent the expansion of necrotic cores in atherosclerotic plaques.
The study randomized 13,026 patients to either darapladib 160 mg/day or placebo. They were a median of 64 years old; 75% were male. The initial acute coronary events were ST-elevation myocardial infarction (45%), non-ST-elevation MI (43%), and unstable angina (12%). Cardiac catheterization was common (86%), as was percutaneous coronary intervention (77%)
Nearly all patients were taking statins at baseline (95%). More than 85% were also taking other recommended therapies, including aspirin, beta-blockers, and antiplatelet agents.
By the end of the follow-up period, the primary combined endpoint had occurred in 903 patients in the active group and 910 in the placebo group (HR 1.00). The secondary endpoint (cardiovascular death, MI, or stroke) occurred in 824 taking darapladib and 838 taking placebo (15% each; HR 0.99).
Death occurred in 7% of each group (HR 0.94).
The authors conducted several subgroup analyses and failed to find a significant benefit regardless of age, geographical region, renal dysfunction or any other baseline comorbidities. Baseline low-density lipoprotein cholesterol had no interaction with outcomes.
Darapladib was considered safe; the incidence of any serious adverse events was similar to placebo (45% vs. 46%). Alamine aminotransferase elevations occurred in less than 1% of each group.
Adverse events leading to discontinuation occurred in 17% of the active group and 12% of the placebo group. This significant difference was mostly driven by body odor events in the darapladib group.
"Consistent with prior studies, patients treated with darapladib were more likely to report an odor-related concern than those in the placebo group," at 11% vs. 2%, the authors noted.
These included skin odors (4% vs. 0.4%), urine odors (5% vs. 1%), and feces odors (8% vs. 1%). Diarrhea was also significantly more common among those taking the study drug (11% vs. 6%).
SOLID-TIMI 52 is the drug’s second failed phase III trial. The STABILITY study, which followed almost 16,000 patients for more than 3 years, also found that darapladib conferred no significant benefit in major cardiovascular outcomes.
These findings, combined with the current study, suggest that Lp-PLA2 may not be a good therapeutic target for a population already sufficiently treated with plaque-stabilizing statins, Dr. O’Donoghue and her coauthors said. "In addition, although unlikely, the possibility that Lp-PLA remains an important target cannot be excluded, but variable plaque penetration of the drug or unidentified off-target effects of darapladib could be responsible for the absence of efficacy in the current study."
The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. Dr. O’Donoghue has received institutional research funding from the company, and has consulting fees from Aegerion. Her coauthors disclosed relationships with numerous pharmaceutical companies.
FROM THE ESC CONGRESS 2014
Key clinical point: Darapladib failed to improve cardiovascular outcomes after acute coronary events.
Major finding: After 2.5 years, there was no significant difference between darapladib and placebo in a composite endpoint of coronary heart disease, death, MI, or urgent coronary revascularization (16.3% vs. 15.6%).
Data source: The trial randomized 13,026 patients to either darapladib 160 mg/day or placebo.
Disclosures: The SOLID-TIMI 52 trial was funded by GlaxoSmithKline. Dr. O’Donoghue has received institutional research funding from the company, and has consulting fees from Aegerion. Her coauthors disclosed relationships with numerous pharmaceutical companies.
COPPS-2 curtails colchicine enthusiasm in cardiac surgery
Patients undergoing cardiac surgery who took colchicine had significantly less postpericardiotomy syndrome than did those on placebo, but this protective effect did not extend to postoperative atrial fibrillation and pericardial or pleural effusions in the double-blind COPPS-2 trial.
The failure of colchicine to prevent postoperative atrial fibrillation (AF) was probably due to more frequent adverse events (36 vs. 21 with placebo), especially gastrointestinal intolerance (26 vs. 12), and drug discontinuation (39 vs. 32), since a prespecified on-treatment analysis showed a significant reduction in AF in patients tolerating the drug, Dr. Massimo Imazio reported at the annual congress of the European Society of Cardiology.
"The high rate of adverse effects is a reason for concern and suggests that colchicine should be considered only in well-selected patients," Dr. Imazio and his associates wrote in an article on COPPS-2 simultaneously published online (JAMA 2014 [doi:10.1001/jama.2014.11026]).
Colchicine has been a promising strategy for postpericardiotomy syndrome prevention, besting methylprednisolone and aspirin in a large meta-analysis (Am. J. Cardiol. 2011;108:575-9).
In the largest trial, COPPS (Colchicine for the Prevention of the Postpericardiotomy Syndrome), Dr. Imazio reported that colchicine significantly reduced the incidence of postpericardiotomy syndrome (8.9% vs. 21.1%), postoperative pericardial effusions (relative risk reduction, 43.9%), and pleural effusions (RRR, 52.3%) at 12 months, compared with placebo (Am. Heart J. 2011;162:527-32 and Eur. Heart J. 2010;31:2749-54). Colchicine was given for 1 month, beginning on the third postoperative day with a 1-mg twice-daily loading dose.
In COPPS-2, the 360 consecutive candidates for cardiac surgery also were given colchicine or placebo for 1 month, but treatment was started 48-72 hours before surgery to pretreat patients and improve colchicine’s ability to prevent postoperative systemic inflammation and its complications.
Colchicine also was administered using weight-based dosing (0.5 mg twice daily in patients weighing at least 70 kg or 0.5 mg once daily in those under 70 kg), and they avoided the loading dose in an effort to improve adherence.
"However, we observed a 2-fold increase of adverse effects and study drug discontinuations compared with those reported in the COPPS trial, likely due to significant vulnerability of patients in the perioperative phase, when the use of antibiotics and proton pump inhibitors is common and also increases the risk of gastrointestinal effects (e.g., diarrhea)," explained Dr. Imazio of Maria Vittoria Hospital and the University of Torino (Italy).
Still, colchicine provided significant protection in the COPPS-2 primary outcome of postpericardiotomy syndrome, compared with placebo (19.4% vs. 29.4%; 95% confidence interval, 1.1%-18.7%). The number needed to treat was 10.
The outcome did not differ significantly among predetermined subgroups based on age, sex, and presence or absence of pericardial effusion, although colchicine was especially efficacious in the setting of systemic inflammation with elevated C-reactive protein, the authors noted.
The intention-to-treat analysis revealed no significant differences between the colchicine and placebo groups for postoperative AF (33.9% vs. 41.7%; 95% CI, –2.2%-17.6%) or postoperative pericardial/pleural effusion (57.2% vs. 58.9%; 95% CI, –8.5%-11.7%).
The prespecified on-treatment analysis, however, showed a 14.2% absolute difference in postoperative AF, favoring colchicine over placebo (27% vs. 41.2%; 95% CI, 3.3%-24.7%).
"While the efficacy of colchicine for postpericardiotomy syndrome prevention is confirmed, the extent of efficacy for postoperative AF needs to be further investigated in future trials," Dr. Imazio stated.
Ongoing studies also will better clarify the potential of colchicine using lower doses that may be better tolerated.
The 360 patients were evenly randomized from 11 centers in Italy between March 2012 and March 2014. Their mean age was 67.5 years, 69% were men, and 36% had planned valvular surgery. Key exclusion criteria were absence of sinus rhythm at enrollment, urgent cardiac surgery, cardiac transplantation, and contraindications to colchicine.
COPPS-2 was supported by the Italian National Health Service and FARGIM. Acarpia provided the study drug. Dr. Imazio reported no conflicts of interest. A coauthor reported consultancy for Servier, serving on an advisory board for Boehringer Ingelheim, and lecturer fees from Abbott, AstraZeneca, Merck, Serono, Richter Gedeon, and Teva.
Patients undergoing cardiac surgery who took colchicine had significantly less postpericardiotomy syndrome than did those on placebo, but this protective effect did not extend to postoperative atrial fibrillation and pericardial or pleural effusions in the double-blind COPPS-2 trial.
The failure of colchicine to prevent postoperative atrial fibrillation (AF) was probably due to more frequent adverse events (36 vs. 21 with placebo), especially gastrointestinal intolerance (26 vs. 12), and drug discontinuation (39 vs. 32), since a prespecified on-treatment analysis showed a significant reduction in AF in patients tolerating the drug, Dr. Massimo Imazio reported at the annual congress of the European Society of Cardiology.
"The high rate of adverse effects is a reason for concern and suggests that colchicine should be considered only in well-selected patients," Dr. Imazio and his associates wrote in an article on COPPS-2 simultaneously published online (JAMA 2014 [doi:10.1001/jama.2014.11026]).
Colchicine has been a promising strategy for postpericardiotomy syndrome prevention, besting methylprednisolone and aspirin in a large meta-analysis (Am. J. Cardiol. 2011;108:575-9).
In the largest trial, COPPS (Colchicine for the Prevention of the Postpericardiotomy Syndrome), Dr. Imazio reported that colchicine significantly reduced the incidence of postpericardiotomy syndrome (8.9% vs. 21.1%), postoperative pericardial effusions (relative risk reduction, 43.9%), and pleural effusions (RRR, 52.3%) at 12 months, compared with placebo (Am. Heart J. 2011;162:527-32 and Eur. Heart J. 2010;31:2749-54). Colchicine was given for 1 month, beginning on the third postoperative day with a 1-mg twice-daily loading dose.
In COPPS-2, the 360 consecutive candidates for cardiac surgery also were given colchicine or placebo for 1 month, but treatment was started 48-72 hours before surgery to pretreat patients and improve colchicine’s ability to prevent postoperative systemic inflammation and its complications.
Colchicine also was administered using weight-based dosing (0.5 mg twice daily in patients weighing at least 70 kg or 0.5 mg once daily in those under 70 kg), and they avoided the loading dose in an effort to improve adherence.
"However, we observed a 2-fold increase of adverse effects and study drug discontinuations compared with those reported in the COPPS trial, likely due to significant vulnerability of patients in the perioperative phase, when the use of antibiotics and proton pump inhibitors is common and also increases the risk of gastrointestinal effects (e.g., diarrhea)," explained Dr. Imazio of Maria Vittoria Hospital and the University of Torino (Italy).
Still, colchicine provided significant protection in the COPPS-2 primary outcome of postpericardiotomy syndrome, compared with placebo (19.4% vs. 29.4%; 95% confidence interval, 1.1%-18.7%). The number needed to treat was 10.
The outcome did not differ significantly among predetermined subgroups based on age, sex, and presence or absence of pericardial effusion, although colchicine was especially efficacious in the setting of systemic inflammation with elevated C-reactive protein, the authors noted.
The intention-to-treat analysis revealed no significant differences between the colchicine and placebo groups for postoperative AF (33.9% vs. 41.7%; 95% CI, –2.2%-17.6%) or postoperative pericardial/pleural effusion (57.2% vs. 58.9%; 95% CI, –8.5%-11.7%).
The prespecified on-treatment analysis, however, showed a 14.2% absolute difference in postoperative AF, favoring colchicine over placebo (27% vs. 41.2%; 95% CI, 3.3%-24.7%).
"While the efficacy of colchicine for postpericardiotomy syndrome prevention is confirmed, the extent of efficacy for postoperative AF needs to be further investigated in future trials," Dr. Imazio stated.
Ongoing studies also will better clarify the potential of colchicine using lower doses that may be better tolerated.
The 360 patients were evenly randomized from 11 centers in Italy between March 2012 and March 2014. Their mean age was 67.5 years, 69% were men, and 36% had planned valvular surgery. Key exclusion criteria were absence of sinus rhythm at enrollment, urgent cardiac surgery, cardiac transplantation, and contraindications to colchicine.
COPPS-2 was supported by the Italian National Health Service and FARGIM. Acarpia provided the study drug. Dr. Imazio reported no conflicts of interest. A coauthor reported consultancy for Servier, serving on an advisory board for Boehringer Ingelheim, and lecturer fees from Abbott, AstraZeneca, Merck, Serono, Richter Gedeon, and Teva.
Patients undergoing cardiac surgery who took colchicine had significantly less postpericardiotomy syndrome than did those on placebo, but this protective effect did not extend to postoperative atrial fibrillation and pericardial or pleural effusions in the double-blind COPPS-2 trial.
The failure of colchicine to prevent postoperative atrial fibrillation (AF) was probably due to more frequent adverse events (36 vs. 21 with placebo), especially gastrointestinal intolerance (26 vs. 12), and drug discontinuation (39 vs. 32), since a prespecified on-treatment analysis showed a significant reduction in AF in patients tolerating the drug, Dr. Massimo Imazio reported at the annual congress of the European Society of Cardiology.
"The high rate of adverse effects is a reason for concern and suggests that colchicine should be considered only in well-selected patients," Dr. Imazio and his associates wrote in an article on COPPS-2 simultaneously published online (JAMA 2014 [doi:10.1001/jama.2014.11026]).
Colchicine has been a promising strategy for postpericardiotomy syndrome prevention, besting methylprednisolone and aspirin in a large meta-analysis (Am. J. Cardiol. 2011;108:575-9).
In the largest trial, COPPS (Colchicine for the Prevention of the Postpericardiotomy Syndrome), Dr. Imazio reported that colchicine significantly reduced the incidence of postpericardiotomy syndrome (8.9% vs. 21.1%), postoperative pericardial effusions (relative risk reduction, 43.9%), and pleural effusions (RRR, 52.3%) at 12 months, compared with placebo (Am. Heart J. 2011;162:527-32 and Eur. Heart J. 2010;31:2749-54). Colchicine was given for 1 month, beginning on the third postoperative day with a 1-mg twice-daily loading dose.
In COPPS-2, the 360 consecutive candidates for cardiac surgery also were given colchicine or placebo for 1 month, but treatment was started 48-72 hours before surgery to pretreat patients and improve colchicine’s ability to prevent postoperative systemic inflammation and its complications.
Colchicine also was administered using weight-based dosing (0.5 mg twice daily in patients weighing at least 70 kg or 0.5 mg once daily in those under 70 kg), and they avoided the loading dose in an effort to improve adherence.
"However, we observed a 2-fold increase of adverse effects and study drug discontinuations compared with those reported in the COPPS trial, likely due to significant vulnerability of patients in the perioperative phase, when the use of antibiotics and proton pump inhibitors is common and also increases the risk of gastrointestinal effects (e.g., diarrhea)," explained Dr. Imazio of Maria Vittoria Hospital and the University of Torino (Italy).
Still, colchicine provided significant protection in the COPPS-2 primary outcome of postpericardiotomy syndrome, compared with placebo (19.4% vs. 29.4%; 95% confidence interval, 1.1%-18.7%). The number needed to treat was 10.
The outcome did not differ significantly among predetermined subgroups based on age, sex, and presence or absence of pericardial effusion, although colchicine was especially efficacious in the setting of systemic inflammation with elevated C-reactive protein, the authors noted.
The intention-to-treat analysis revealed no significant differences between the colchicine and placebo groups for postoperative AF (33.9% vs. 41.7%; 95% CI, –2.2%-17.6%) or postoperative pericardial/pleural effusion (57.2% vs. 58.9%; 95% CI, –8.5%-11.7%).
The prespecified on-treatment analysis, however, showed a 14.2% absolute difference in postoperative AF, favoring colchicine over placebo (27% vs. 41.2%; 95% CI, 3.3%-24.7%).
"While the efficacy of colchicine for postpericardiotomy syndrome prevention is confirmed, the extent of efficacy for postoperative AF needs to be further investigated in future trials," Dr. Imazio stated.
Ongoing studies also will better clarify the potential of colchicine using lower doses that may be better tolerated.
The 360 patients were evenly randomized from 11 centers in Italy between March 2012 and March 2014. Their mean age was 67.5 years, 69% were men, and 36% had planned valvular surgery. Key exclusion criteria were absence of sinus rhythm at enrollment, urgent cardiac surgery, cardiac transplantation, and contraindications to colchicine.
COPPS-2 was supported by the Italian National Health Service and FARGIM. Acarpia provided the study drug. Dr. Imazio reported no conflicts of interest. A coauthor reported consultancy for Servier, serving on an advisory board for Boehringer Ingelheim, and lecturer fees from Abbott, AstraZeneca, Merck, Serono, Richter Gedeon, and Teva.
FROM THE ESC CONGRESS 2014
Key clinical point: Perioperative use of colchicine should be considered only in well-selected patients.
Major finding: Perioperative colchicine use cut the incidence of postpericardiotomy syndrome, but not postoperative atrial fibrillation or pericardial/pleural effusion.
Data source: Double-blind, randomized clinical trial in 360 consecutive candidates for heart surgery.
Disclosures: COPPS-2 was supported by the Italian National Health Service and FARGIM. Acarpia provided the study drug. Dr. Imazio reported no conflicts of interest. A coauthor reported consultancy for Servier, serving on an advisory board for Boehringer Ingelheim, and lecturer fees from Abbott, AstraZeneca, Merck, Serono, Richter Gedeon, and Teva.
