Heart Rate Cut With Ivabradine, Trims Heart Failure Deaths in Phase III Study

STOCKHOLM – Patients with moderate to severe systolic heart failure and an elevated heart rate had a marked drop in their rate of heart failure death and hospitalization when they were treated with the heart-rate–lowering drug ivabradine in a phase III, randomized trial with more than 6,500 patients.

In addition to making ivabradine an important new agent for treating many heart failure patients, the findings proved that heart rate is an effective intervention target for this disease. Patients who received the drug on top of a standard heart failure regimen had a 5% absolute and 18% relative drop in their incidence of cardiovascular mortality and heart failure hospitalization, the study’s primary end point, during a median treatment duration of 23 months, Dr. Michel Komajda said on Aug. 29 at the European Society of Cardiology Congress 2010.

Heart failure mortality fell by 2%, a 26% relative drop that was statistically significant, reported Dr. Komajda, head of the cardiovascular department at Piti?-Salpetri?re Hospital in Paris. Also well tolerated, ivabradine had a serious adverse event rate of 45%, significantly better than the 48% rate in the placebo arm. “We are very happy to see one positive trial in chronic heart failure after several years of disappointments,” he said.

This safety finding and the significant impact of the investigational drug both on the combined primary end point of the study and on heart failure mortality should give ivabradine a clear path toward Food and Drug Administration approval, followed by widespread adoption in practice, predicted U.S. heart failure experts.

“Once you have the mortality benefit, it’s very hard to go back” and do a second placebo-controlled trial, commented Dr. Bertram Pitt, a cardiologist at the University of Michigan in Ann Arbor. “These are compelling data. I would use this” on my patients, he said in an interview.

Analysis of results from SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) also showed the critical role that heart rate played in the rate of the primary end point, both patients’ heart rate at entry into the study, and their achieved heart rate after 4 weeks on ivabradine. When the primary end point analysis dichotomized the enrolled patients by their median baseline heart rate of 77 bpm, those with an entry rate of 76 bpm or lower showed no significant benefit from ivabradine treatment, whereas those at 77 bpm or greater had a significant benefit, leading Dr. Komajda to call patients with a rate of at least 77 bpm the target population for the drug.

In addition, patients with a baseline heart rate of 80-86 bpm had a significant, 80% relative increased rate of the primary end point, compared with patients who entered the study with the lowest heart rates allowed by the enrollment criteria (70-72 bpm). Patients who entered with a rate of 87 bpm or higher had a greater-than-twofold increased risk for the primary end point.

Once treatment started and ran for 28 days, patients who achieved a heart rate lower than 60 bpm had a 17% rate of the primary end point during complete follow-up, whereas those with a heart rate of 75 bpm or greater after 28 days had an eventual 32% rate of cardiovascular death or heart failure hospitalization, also a statistically significant difference. The average achieved heart rate after 28 days was 64 bpm on ivabradine, compared with 75 bpm in placebo patients. At 1 year, the rates averaged 67 bpm and 75 bpm, respectively.

“SHIFT confirms the importance of heart rate in the pathophysiology of heart failure,” commented Dr. Inder Anand, professor of medicine at the University of Minnesota in Minneapolis.

Based on this finding, a physician who treats heart failure patients with ivabradine should titrate the dosage to a target heart rate of 60 bpm, assuming the patient remains tolerant, said Dr. Karl Swedberg, professor of medicine at the G?teborg (Sweden) University, who led the study along with Dr. Komajda.

Simultaneously with the meeting report, the SHIFT results appeared online in two Lancet articles (2010 Aug. 29 [doi:10.1016/S0140-6736(10)61198-1]; 2010 Aug. 29 [doi:10.1016/S0140-6736(10)61259-1]).

SHIFT randomized 6,558 patients with systolic heart failure at 677 centers in 37 countries. (No U.S. center participated.) Patients could have New York Heart Association class II-IV heart failure, with a left ventricular ejection fraction of 35% or less and a heart rate of at least 70 bpm. Their average age was 60 years and their median heart rate was 77 bpm; roughly half had class II heart failure and the other half class III disease.

Given that ivabradine works exclusively by lowering heart rate, specifically targeting the heart-rate controlling “funny” (If) current of the sinus node, the use of beta-blockers by study patients received extra scrutiny, with 89% of enrolled patients receiving a beta-blocker, and with 56% receiving at least half of their target beta-blocker dosage and 26% getting the complete, recommended dosage. In addition, more than 90% of patients received an ACE inhibitor or an angiotensin receptor blocker.

Patients in the study received the highest background dose of a beta-blocker in a heart failure trial outside of a beta-blocker study,” said Dr. Swedberg. “We think they had the best treatment available. This is the best we can achieve today with a beta-blocker.” All patients in SHIFT began a beta-blocker, and only those who were completely intolerant of the drug came off it. The added heart-rate reduction that ivabradine provided on top of the beta-blocker “saved energy in a compromised myocardium,” he explained.

“We encouraged up-titration [of beta-blockers] as much as possible,” Dr. Komajda said.

“It’s unlikely that use of higher beta-blocker doses in SHIFT would have caused a further reduced heart rate. In the real world, clinicians are unable to increase doses of beta-blockers to target levels because of actual or perceived side effects,” Dr. Anand said.

“There are adverse effects from beta-blockers. Sometimes you can’t push high doses,” said Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia. Ivabradine “supplements the titration of a beta-blocker when you run out of room because of side effects,” he said in an interview. Dr. Bove said that the 50% prevalence of a heart rate of 77 bpm or greater in the SHIFT patients reasonably reflected the rate in average heart failure patients of the type enrolled, and was a rate indicating inadequately controlled heart failure. Among similar patients who were managed in a more intensive, closely monitored program, perhaps 25% would have such an elevated heart rate and would be good candidates for ivabradine treatment, he said in an interview.

Dr. Anand recommended excluding heart failure patients with atrial fibrillation from ivabradine treatment, but despite that, he estimated that roughly 40% of all heart failure patients with left ventricular systolic dysfunction who were on current, standard-of-care therapy might benefit from the addition of ivabradine to their regimen.

SHIFT was sponsored by Servier Laboratories, which markets ivabradine in Europe under the name Procoralan for the treatment of patients with chronic stable angina. Ivabradine does not have an approved indication from the U.S. Food and Drug Administration. Dr. Komajda and Dr. Swedberg have received fees and research grants from Servier, and two of their coauthors on the study are employees of Servier. Dr. Pitt has received honoraria from and has been a consultant to Merck & Co., Novartis, and Pfizer Inc. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems. Dr. Anand has served on an advisory board for and received research grants from Corventis Inc.

STOCKHOLM – Patients with moderate to severe systolic heart failure and an elevated heart rate had a marked drop in their rate of heart failure death and hospitalization when they were treated with the heart-rate–lowering drug ivabradine in a phase III, randomized trial with more than 6,500 patients.

In addition to making ivabradine an important new agent for treating many heart failure patients, the findings proved that heart rate is an effective intervention target for this disease. Patients who received the drug on top of a standard heart failure regimen had a 5% absolute and 18% relative drop in their incidence of cardiovascular mortality and heart failure hospitalization, the study’s primary end point, during a median treatment duration of 23 months, Dr. Michel Komajda said on Aug. 29 at the European Society of Cardiology Congress 2010.

Heart failure mortality fell by 2%, a 26% relative drop that was statistically significant, reported Dr. Komajda, head of the cardiovascular department at Piti?-Salpetri?re Hospital in Paris. Also well tolerated, ivabradine had a serious adverse event rate of 45%, significantly better than the 48% rate in the placebo arm. “We are very happy to see one positive trial in chronic heart failure after several years of disappointments,” he said.

This safety finding and the significant impact of the investigational drug both on the combined primary end point of the study and on heart failure mortality should give ivabradine a clear path toward Food and Drug Administration approval, followed by widespread adoption in practice, predicted U.S. heart failure experts.

“Once you have the mortality benefit, it’s very hard to go back” and do a second placebo-controlled trial, commented Dr. Bertram Pitt, a cardiologist at the University of Michigan in Ann Arbor. “These are compelling data. I would use this” on my patients, he said in an interview.

Analysis of results from SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) also showed the critical role that heart rate played in the rate of the primary end point, both patients’ heart rate at entry into the study, and their achieved heart rate after 4 weeks on ivabradine. When the primary end point analysis dichotomized the enrolled patients by their median baseline heart rate of 77 bpm, those with an entry rate of 76 bpm or lower showed no significant benefit from ivabradine treatment, whereas those at 77 bpm or greater had a significant benefit, leading Dr. Komajda to call patients with a rate of at least 77 bpm the target population for the drug.

In addition, patients with a baseline heart rate of 80-86 bpm had a significant, 80% relative increased rate of the primary end point, compared with patients who entered the study with the lowest heart rates allowed by the enrollment criteria (70-72 bpm). Patients who entered with a rate of 87 bpm or higher had a greater-than-twofold increased risk for the primary end point.

Once treatment started and ran for 28 days, patients who achieved a heart rate lower than 60 bpm had a 17% rate of the primary end point during complete follow-up, whereas those with a heart rate of 75 bpm or greater after 28 days had an eventual 32% rate of cardiovascular death or heart failure hospitalization, also a statistically significant difference. The average achieved heart rate after 28 days was 64 bpm on ivabradine, compared with 75 bpm in placebo patients. At 1 year, the rates averaged 67 bpm and 75 bpm, respectively.

“SHIFT confirms the importance of heart rate in the pathophysiology of heart failure,” commented Dr. Inder Anand, professor of medicine at the University of Minnesota in Minneapolis.

Based on this finding, a physician who treats heart failure patients with ivabradine should titrate the dosage to a target heart rate of 60 bpm, assuming the patient remains tolerant, said Dr. Karl Swedberg, professor of medicine at the G?teborg (Sweden) University, who led the study along with Dr. Komajda.

Simultaneously with the meeting report, the SHIFT results appeared online in two Lancet articles (2010 Aug. 29 [doi:10.1016/S0140-6736(10)61198-1]; 2010 Aug. 29 [doi:10.1016/S0140-6736(10)61259-1]).

SHIFT randomized 6,558 patients with systolic heart failure at 677 centers in 37 countries. (No U.S. center participated.) Patients could have New York Heart Association class II-IV heart failure, with a left ventricular ejection fraction of 35% or less and a heart rate of at least 70 bpm. Their average age was 60 years and their median heart rate was 77 bpm; roughly half had class II heart failure and the other half class III disease.

Given that ivabradine works exclusively by lowering heart rate, specifically targeting the heart-rate controlling “funny” (If) current of the sinus node, the use of beta-blockers by study patients received extra scrutiny, with 89% of enrolled patients receiving a beta-blocker, and with 56% receiving at least half of their target beta-blocker dosage and 26% getting the complete, recommended dosage. In addition, more than 90% of patients received an ACE inhibitor or an angiotensin receptor blocker.

Patients in the study received the highest background dose of a beta-blocker in a heart failure trial outside of a beta-blocker study,” said Dr. Swedberg. “We think they had the best treatment available. This is the best we can achieve today with a beta-blocker.” All patients in SHIFT began a beta-blocker, and only those who were completely intolerant of the drug came off it. The added heart-rate reduction that ivabradine provided on top of the beta-blocker “saved energy in a compromised myocardium,” he explained.

“We encouraged up-titration [of beta-blockers] as much as possible,” Dr. Komajda said.

“It’s unlikely that use of higher beta-blocker doses in SHIFT would have caused a further reduced heart rate. In the real world, clinicians are unable to increase doses of beta-blockers to target levels because of actual or perceived side effects,” Dr. Anand said.

“There are adverse effects from beta-blockers. Sometimes you can’t push high doses,” said Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia. Ivabradine “supplements the titration of a beta-blocker when you run out of room because of side effects,” he said in an interview. Dr. Bove said that the 50% prevalence of a heart rate of 77 bpm or greater in the SHIFT patients reasonably reflected the rate in average heart failure patients of the type enrolled, and was a rate indicating inadequately controlled heart failure. Among similar patients who were managed in a more intensive, closely monitored program, perhaps 25% would have such an elevated heart rate and would be good candidates for ivabradine treatment, he said in an interview.

Dr. Anand recommended excluding heart failure patients with atrial fibrillation from ivabradine treatment, but despite that, he estimated that roughly 40% of all heart failure patients with left ventricular systolic dysfunction who were on current, standard-of-care therapy might benefit from the addition of ivabradine to their regimen.

SHIFT was sponsored by Servier Laboratories, which markets ivabradine in Europe under the name Procoralan for the treatment of patients with chronic stable angina. Ivabradine does not have an approved indication from the U.S. Food and Drug Administration. Dr. Komajda and Dr. Swedberg have received fees and research grants from Servier, and two of their coauthors on the study are employees of Servier. Dr. Pitt has received honoraria from and has been a consultant to Merck & Co., Novartis, and Pfizer Inc. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems. Dr. Anand has served on an advisory board for and received research grants from Corventis Inc.

STOCKHOLM – Patients with moderate to severe systolic heart failure and an elevated heart rate had a marked drop in their rate of heart failure death and hospitalization when they were treated with the heart-rate–lowering drug ivabradine in a phase III, randomized trial with more than 6,500 patients.

In addition to making ivabradine an important new agent for treating many heart failure patients, the findings proved that heart rate is an effective intervention target for this disease. Patients who received the drug on top of a standard heart failure regimen had a 5% absolute and 18% relative drop in their incidence of cardiovascular mortality and heart failure hospitalization, the study’s primary end point, during a median treatment duration of 23 months, Dr. Michel Komajda said on Aug. 29 at the European Society of Cardiology Congress 2010.

Heart failure mortality fell by 2%, a 26% relative drop that was statistically significant, reported Dr. Komajda, head of the cardiovascular department at Piti?-Salpetri?re Hospital in Paris. Also well tolerated, ivabradine had a serious adverse event rate of 45%, significantly better than the 48% rate in the placebo arm. “We are very happy to see one positive trial in chronic heart failure after several years of disappointments,” he said.

This safety finding and the significant impact of the investigational drug both on the combined primary end point of the study and on heart failure mortality should give ivabradine a clear path toward Food and Drug Administration approval, followed by widespread adoption in practice, predicted U.S. heart failure experts.

“Once you have the mortality benefit, it’s very hard to go back” and do a second placebo-controlled trial, commented Dr. Bertram Pitt, a cardiologist at the University of Michigan in Ann Arbor. “These are compelling data. I would use this” on my patients, he said in an interview.

Analysis of results from SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) also showed the critical role that heart rate played in the rate of the primary end point, both patients’ heart rate at entry into the study, and their achieved heart rate after 4 weeks on ivabradine. When the primary end point analysis dichotomized the enrolled patients by their median baseline heart rate of 77 bpm, those with an entry rate of 76 bpm or lower showed no significant benefit from ivabradine treatment, whereas those at 77 bpm or greater had a significant benefit, leading Dr. Komajda to call patients with a rate of at least 77 bpm the target population for the drug.

In addition, patients with a baseline heart rate of 80-86 bpm had a significant, 80% relative increased rate of the primary end point, compared with patients who entered the study with the lowest heart rates allowed by the enrollment criteria (70-72 bpm). Patients who entered with a rate of 87 bpm or higher had a greater-than-twofold increased risk for the primary end point.

Once treatment started and ran for 28 days, patients who achieved a heart rate lower than 60 bpm had a 17% rate of the primary end point during complete follow-up, whereas those with a heart rate of 75 bpm or greater after 28 days had an eventual 32% rate of cardiovascular death or heart failure hospitalization, also a statistically significant difference. The average achieved heart rate after 28 days was 64 bpm on ivabradine, compared with 75 bpm in placebo patients. At 1 year, the rates averaged 67 bpm and 75 bpm, respectively.

“SHIFT confirms the importance of heart rate in the pathophysiology of heart failure,” commented Dr. Inder Anand, professor of medicine at the University of Minnesota in Minneapolis.

Based on this finding, a physician who treats heart failure patients with ivabradine should titrate the dosage to a target heart rate of 60 bpm, assuming the patient remains tolerant, said Dr. Karl Swedberg, professor of medicine at the G?teborg (Sweden) University, who led the study along with Dr. Komajda.

Simultaneously with the meeting report, the SHIFT results appeared online in two Lancet articles (2010 Aug. 29 [doi:10.1016/S0140-6736(10)61198-1]; 2010 Aug. 29 [doi:10.1016/S0140-6736(10)61259-1]).

SHIFT randomized 6,558 patients with systolic heart failure at 677 centers in 37 countries. (No U.S. center participated.) Patients could have New York Heart Association class II-IV heart failure, with a left ventricular ejection fraction of 35% or less and a heart rate of at least 70 bpm. Their average age was 60 years and their median heart rate was 77 bpm; roughly half had class II heart failure and the other half class III disease.

Given that ivabradine works exclusively by lowering heart rate, specifically targeting the heart-rate controlling “funny” (If) current of the sinus node, the use of beta-blockers by study patients received extra scrutiny, with 89% of enrolled patients receiving a beta-blocker, and with 56% receiving at least half of their target beta-blocker dosage and 26% getting the complete, recommended dosage. In addition, more than 90% of patients received an ACE inhibitor or an angiotensin receptor blocker.

Patients in the study received the highest background dose of a beta-blocker in a heart failure trial outside of a beta-blocker study,” said Dr. Swedberg. “We think they had the best treatment available. This is the best we can achieve today with a beta-blocker.” All patients in SHIFT began a beta-blocker, and only those who were completely intolerant of the drug came off it. The added heart-rate reduction that ivabradine provided on top of the beta-blocker “saved energy in a compromised myocardium,” he explained.

“We encouraged up-titration [of beta-blockers] as much as possible,” Dr. Komajda said.

“It’s unlikely that use of higher beta-blocker doses in SHIFT would have caused a further reduced heart rate. In the real world, clinicians are unable to increase doses of beta-blockers to target levels because of actual or perceived side effects,” Dr. Anand said.

“There are adverse effects from beta-blockers. Sometimes you can’t push high doses,” said Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia. Ivabradine “supplements the titration of a beta-blocker when you run out of room because of side effects,” he said in an interview. Dr. Bove said that the 50% prevalence of a heart rate of 77 bpm or greater in the SHIFT patients reasonably reflected the rate in average heart failure patients of the type enrolled, and was a rate indicating inadequately controlled heart failure. Among similar patients who were managed in a more intensive, closely monitored program, perhaps 25% would have such an elevated heart rate and would be good candidates for ivabradine treatment, he said in an interview.

Dr. Anand recommended excluding heart failure patients with atrial fibrillation from ivabradine treatment, but despite that, he estimated that roughly 40% of all heart failure patients with left ventricular systolic dysfunction who were on current, standard-of-care therapy might benefit from the addition of ivabradine to their regimen.

SHIFT was sponsored by Servier Laboratories, which markets ivabradine in Europe under the name Procoralan for the treatment of patients with chronic stable angina. Ivabradine does not have an approved indication from the U.S. Food and Drug Administration. Dr. Komajda and Dr. Swedberg have received fees and research grants from Servier, and two of their coauthors on the study are employees of Servier. Dr. Pitt has received honoraria from and has been a consultant to Merck & Co., Novartis, and Pfizer Inc. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems. Dr. Anand has served on an advisory board for and received research grants from Corventis Inc.