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AMSTERDAM – Patients with heart failure appeared to continue to benefit from full-dose beta-blocker therapy against a background of optimal, contemporary treatment, based on an analysis of data collected from an 1,800-patient trial of cardiac resynchronization therapy.
Dr. L. Brent Mitchell, who presented this finding at the annual congress of the European Society of Cardiology, acknowledged that assessing the efficacy of drugs in a study that did not randomize patients based on their use of those drugs had questionable validity and was vulnerable to unidentified confounding, but he also noted that data on the role of beta-blockers in contemporary heart failure management were unlikely to come from any other source.
"You need some tool to ask whether beta-blockers are still useful," said Dr. Mitchell, professor of cardiac sciences at the University of Calgary (Alta.). "The purpose of this analysis was to ask if beta-blockers at full dosages are still better than not using a full-dose beta-blocker despite all the other treatments" that patients received while in the study during 2003-2009. The analysis showed that those receiving full-dosage or nearly full-dosage beta-blocker regimens had a one-third cut in all-cause death or heart failure hospitalization, compared with patients receiving less than half the recommended dosage, after adjustment for many baseline differences between these two subgroups.
The analysis also showed that just half of the nearly 1,500 patients who received treatment with a beta-blocker in this cohort received an adequate dosage, defined as at least 50% of the level recommended by the European Society of Cardiology in heart failure treatment guidelines issued last year (Euro. Heart J. 2012;33:1787-847). Two-thirds of the patients on carvedilol received at least half of the recommended target dosage of 50 mg/day. In contrast, about a third of patients being treated with either bisoprolol or metoprolol received a dosage that was at least half the target dosage (10 mg/day for bisoprolol, 200 mg/day for metoprolol).
The analysis used data collected in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), which enrolled 1,798 patients primarily with New York Heart Association class II heart failure at 34 centers worldwide. When the primary endpoint of RAFT was evaluated, treatment with cardiac resynchronization therapy (CRT) with defibrillator capability was more effective at preventing death or heart failure hospitalization in the study population than was an implanted defibrillator alone against a background of optimal medical treatment (N. Engl. J. Med. 2010;363:2385-95).
Dr. Mitchell and his associates focused on 1,474 patients who all received beta-blocker treatment while in RAFT. Like the entire RAFT population, 97% of these patients also received treatment with an ACE inhibitor or angiotensin receptor blocker, and 42% received treatment with spironolactone, and their average left ventricular ejection fraction was 23%.
The patients in this group who were undertreated with beta-blockers were significantly older and had a significantly greater prevalence of New York Heart Association class III heart failure and heart failure with an ischemic etiology compared with those who received at least 50% of the target dosage.
In a regression model that adjusted for all measured baseline differences, patients treated with at least half of the recommended dosage had an incidence of mortality or heart failure hospitalization during an average 40 months of follow-up that was 33% below the rate among patients on lower beta-blocker dosages, a statistically significant difference. This 33% relative risk reduction with adequate beta-blocker treatment is "indistinguishable" from the risk reductions seen with placebo in the major beta-blocker efficacy trials in heart failure patients during the 1990s, Dr. Mitchell noted. "This suggests that beta-blocker treatment still has potency," he said.
Other significant, independent predictors of the primary outcome in this model were prior coronary artery bypass, which boosted the risk by 63%; a history of ischemic heart disease, which raised the risk by 39%; having peripheral vascular disease, which increased the risk by 36%; and receiving CRT, which cut the risk by 33%. In addition, adverse outcomes rose 10% for each reduction of 5 mL/min per 1.73 m2 in estimated glomerular filtration rate.
The impact of underdosing was roughly similar across all three beta-blockers, bisoprolol, carvedilol, and metoprolol. The adverse effect of underdosing was mitigated to some extent when patients also received CRT.
RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.
On Twitter @mitchelzoler
A post hoc analysis of the nonrandomized interventions that patients receive during randomized clinical trials is generally discouraged. Patients treated with lower dosages of hemodynamically active drugs like beta-blockers are often sicker and have a worse prognosis. This problem can be seen in the baseline characteristics of the two subgroups in this analysis, which revealed many significant differences between the two. Performing statistical compensations to counterbalance these differences is very uncertain.
In addition, a few years ago, my associates and I ran the Systolic Heart Failure Treatment With the If inhibitor Ivabradine Trial (SHIFT) (Lancet 2010;376:875-85) to assess the efficacy and safety of ivabradine to lower heart rate and improve outcomes in optimally treated heart failure patients. In SHIFT we saw a relationship similar to the one seen in RAFT by the current investigators: Patients on lower dosages of beta-blockers were sicker and at higher risk than patients on higher beta-blocker dosages. In our analyses, adjusting for differences in heart rate eliminated the link between beta-blocker dosage and outcomes. We found that the entire treatment effect could be explained by differences in patient heart rate.
Dr. Karl Swedberg is a professor of medicine at the University of Gothenburg (Sweden). He was lead investigator for the SHIFT trial, which was funded by Servier, the company that markets ivabradine (Procoralan). He made these comments as designated discussant for Dr. Mitchell’s report.
A post hoc analysis of the nonrandomized interventions that patients receive during randomized clinical trials is generally discouraged. Patients treated with lower dosages of hemodynamically active drugs like beta-blockers are often sicker and have a worse prognosis. This problem can be seen in the baseline characteristics of the two subgroups in this analysis, which revealed many significant differences between the two. Performing statistical compensations to counterbalance these differences is very uncertain.
In addition, a few years ago, my associates and I ran the Systolic Heart Failure Treatment With the If inhibitor Ivabradine Trial (SHIFT) (Lancet 2010;376:875-85) to assess the efficacy and safety of ivabradine to lower heart rate and improve outcomes in optimally treated heart failure patients. In SHIFT we saw a relationship similar to the one seen in RAFT by the current investigators: Patients on lower dosages of beta-blockers were sicker and at higher risk than patients on higher beta-blocker dosages. In our analyses, adjusting for differences in heart rate eliminated the link between beta-blocker dosage and outcomes. We found that the entire treatment effect could be explained by differences in patient heart rate.
Dr. Karl Swedberg is a professor of medicine at the University of Gothenburg (Sweden). He was lead investigator for the SHIFT trial, which was funded by Servier, the company that markets ivabradine (Procoralan). He made these comments as designated discussant for Dr. Mitchell’s report.
A post hoc analysis of the nonrandomized interventions that patients receive during randomized clinical trials is generally discouraged. Patients treated with lower dosages of hemodynamically active drugs like beta-blockers are often sicker and have a worse prognosis. This problem can be seen in the baseline characteristics of the two subgroups in this analysis, which revealed many significant differences between the two. Performing statistical compensations to counterbalance these differences is very uncertain.
In addition, a few years ago, my associates and I ran the Systolic Heart Failure Treatment With the If inhibitor Ivabradine Trial (SHIFT) (Lancet 2010;376:875-85) to assess the efficacy and safety of ivabradine to lower heart rate and improve outcomes in optimally treated heart failure patients. In SHIFT we saw a relationship similar to the one seen in RAFT by the current investigators: Patients on lower dosages of beta-blockers were sicker and at higher risk than patients on higher beta-blocker dosages. In our analyses, adjusting for differences in heart rate eliminated the link between beta-blocker dosage and outcomes. We found that the entire treatment effect could be explained by differences in patient heart rate.
Dr. Karl Swedberg is a professor of medicine at the University of Gothenburg (Sweden). He was lead investigator for the SHIFT trial, which was funded by Servier, the company that markets ivabradine (Procoralan). He made these comments as designated discussant for Dr. Mitchell’s report.
AMSTERDAM – Patients with heart failure appeared to continue to benefit from full-dose beta-blocker therapy against a background of optimal, contemporary treatment, based on an analysis of data collected from an 1,800-patient trial of cardiac resynchronization therapy.
Dr. L. Brent Mitchell, who presented this finding at the annual congress of the European Society of Cardiology, acknowledged that assessing the efficacy of drugs in a study that did not randomize patients based on their use of those drugs had questionable validity and was vulnerable to unidentified confounding, but he also noted that data on the role of beta-blockers in contemporary heart failure management were unlikely to come from any other source.
"You need some tool to ask whether beta-blockers are still useful," said Dr. Mitchell, professor of cardiac sciences at the University of Calgary (Alta.). "The purpose of this analysis was to ask if beta-blockers at full dosages are still better than not using a full-dose beta-blocker despite all the other treatments" that patients received while in the study during 2003-2009. The analysis showed that those receiving full-dosage or nearly full-dosage beta-blocker regimens had a one-third cut in all-cause death or heart failure hospitalization, compared with patients receiving less than half the recommended dosage, after adjustment for many baseline differences between these two subgroups.
The analysis also showed that just half of the nearly 1,500 patients who received treatment with a beta-blocker in this cohort received an adequate dosage, defined as at least 50% of the level recommended by the European Society of Cardiology in heart failure treatment guidelines issued last year (Euro. Heart J. 2012;33:1787-847). Two-thirds of the patients on carvedilol received at least half of the recommended target dosage of 50 mg/day. In contrast, about a third of patients being treated with either bisoprolol or metoprolol received a dosage that was at least half the target dosage (10 mg/day for bisoprolol, 200 mg/day for metoprolol).
The analysis used data collected in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), which enrolled 1,798 patients primarily with New York Heart Association class II heart failure at 34 centers worldwide. When the primary endpoint of RAFT was evaluated, treatment with cardiac resynchronization therapy (CRT) with defibrillator capability was more effective at preventing death or heart failure hospitalization in the study population than was an implanted defibrillator alone against a background of optimal medical treatment (N. Engl. J. Med. 2010;363:2385-95).
Dr. Mitchell and his associates focused on 1,474 patients who all received beta-blocker treatment while in RAFT. Like the entire RAFT population, 97% of these patients also received treatment with an ACE inhibitor or angiotensin receptor blocker, and 42% received treatment with spironolactone, and their average left ventricular ejection fraction was 23%.
The patients in this group who were undertreated with beta-blockers were significantly older and had a significantly greater prevalence of New York Heart Association class III heart failure and heart failure with an ischemic etiology compared with those who received at least 50% of the target dosage.
In a regression model that adjusted for all measured baseline differences, patients treated with at least half of the recommended dosage had an incidence of mortality or heart failure hospitalization during an average 40 months of follow-up that was 33% below the rate among patients on lower beta-blocker dosages, a statistically significant difference. This 33% relative risk reduction with adequate beta-blocker treatment is "indistinguishable" from the risk reductions seen with placebo in the major beta-blocker efficacy trials in heart failure patients during the 1990s, Dr. Mitchell noted. "This suggests that beta-blocker treatment still has potency," he said.
Other significant, independent predictors of the primary outcome in this model were prior coronary artery bypass, which boosted the risk by 63%; a history of ischemic heart disease, which raised the risk by 39%; having peripheral vascular disease, which increased the risk by 36%; and receiving CRT, which cut the risk by 33%. In addition, adverse outcomes rose 10% for each reduction of 5 mL/min per 1.73 m2 in estimated glomerular filtration rate.
The impact of underdosing was roughly similar across all three beta-blockers, bisoprolol, carvedilol, and metoprolol. The adverse effect of underdosing was mitigated to some extent when patients also received CRT.
RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.
On Twitter @mitchelzoler
AMSTERDAM – Patients with heart failure appeared to continue to benefit from full-dose beta-blocker therapy against a background of optimal, contemporary treatment, based on an analysis of data collected from an 1,800-patient trial of cardiac resynchronization therapy.
Dr. L. Brent Mitchell, who presented this finding at the annual congress of the European Society of Cardiology, acknowledged that assessing the efficacy of drugs in a study that did not randomize patients based on their use of those drugs had questionable validity and was vulnerable to unidentified confounding, but he also noted that data on the role of beta-blockers in contemporary heart failure management were unlikely to come from any other source.
"You need some tool to ask whether beta-blockers are still useful," said Dr. Mitchell, professor of cardiac sciences at the University of Calgary (Alta.). "The purpose of this analysis was to ask if beta-blockers at full dosages are still better than not using a full-dose beta-blocker despite all the other treatments" that patients received while in the study during 2003-2009. The analysis showed that those receiving full-dosage or nearly full-dosage beta-blocker regimens had a one-third cut in all-cause death or heart failure hospitalization, compared with patients receiving less than half the recommended dosage, after adjustment for many baseline differences between these two subgroups.
The analysis also showed that just half of the nearly 1,500 patients who received treatment with a beta-blocker in this cohort received an adequate dosage, defined as at least 50% of the level recommended by the European Society of Cardiology in heart failure treatment guidelines issued last year (Euro. Heart J. 2012;33:1787-847). Two-thirds of the patients on carvedilol received at least half of the recommended target dosage of 50 mg/day. In contrast, about a third of patients being treated with either bisoprolol or metoprolol received a dosage that was at least half the target dosage (10 mg/day for bisoprolol, 200 mg/day for metoprolol).
The analysis used data collected in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), which enrolled 1,798 patients primarily with New York Heart Association class II heart failure at 34 centers worldwide. When the primary endpoint of RAFT was evaluated, treatment with cardiac resynchronization therapy (CRT) with defibrillator capability was more effective at preventing death or heart failure hospitalization in the study population than was an implanted defibrillator alone against a background of optimal medical treatment (N. Engl. J. Med. 2010;363:2385-95).
Dr. Mitchell and his associates focused on 1,474 patients who all received beta-blocker treatment while in RAFT. Like the entire RAFT population, 97% of these patients also received treatment with an ACE inhibitor or angiotensin receptor blocker, and 42% received treatment with spironolactone, and their average left ventricular ejection fraction was 23%.
The patients in this group who were undertreated with beta-blockers were significantly older and had a significantly greater prevalence of New York Heart Association class III heart failure and heart failure with an ischemic etiology compared with those who received at least 50% of the target dosage.
In a regression model that adjusted for all measured baseline differences, patients treated with at least half of the recommended dosage had an incidence of mortality or heart failure hospitalization during an average 40 months of follow-up that was 33% below the rate among patients on lower beta-blocker dosages, a statistically significant difference. This 33% relative risk reduction with adequate beta-blocker treatment is "indistinguishable" from the risk reductions seen with placebo in the major beta-blocker efficacy trials in heart failure patients during the 1990s, Dr. Mitchell noted. "This suggests that beta-blocker treatment still has potency," he said.
Other significant, independent predictors of the primary outcome in this model were prior coronary artery bypass, which boosted the risk by 63%; a history of ischemic heart disease, which raised the risk by 39%; having peripheral vascular disease, which increased the risk by 36%; and receiving CRT, which cut the risk by 33%. In addition, adverse outcomes rose 10% for each reduction of 5 mL/min per 1.73 m2 in estimated glomerular filtration rate.
The impact of underdosing was roughly similar across all three beta-blockers, bisoprolol, carvedilol, and metoprolol. The adverse effect of underdosing was mitigated to some extent when patients also received CRT.
RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2013
Major finding: Heart failure patients on recommended beta-blocker dosages had 33% fewer deaths or hospitalizations than did patients on lower dosages.
Data source: A post hoc subgroup analysis of results from RAFT, with 1,798 patients with heart failure at 34 worldwide sites.
Disclosures: RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.