SHIFT: Adding HR-Slowing Agent Ivabradine to HF Meds Cuts Mortality, Hospitalization

August 29, 2010

Updated August 29, 2010 (Stockholm, Sweden) — Patients with chronic systolic heart failure who added ivabradine (Procoralan, Servier) to the medications they were already taking showed a significant 18% drop in the composite rate of cardiovascular death or heart-failure hospitalization, compared with a placebo control group, over about two years in a randomized trial presented here today at the European Society of Cardiology (ESC) Congress 2010.

The findings, from the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT), signal a new potential direction for the treatment of heart failure characterized by an elevated heart rate as a therapeutic target. Ivabradine is a selective inhibitor of a sodium-potassium channel highly expressed in the sinoatrial node, on which it has a mild dampening effect. The drug has few other, if any, known cardiac effects.

SHIFT was also simultaneously published online in the Lancet [1], with first author Dr Karl Swedberg (University of Gothenburg, Sweden), to coincide with its unveiling at the ESC sessions by Dr Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France).

Following Komajda's presentation, assigned discussant Dr Inder Anand (University of Minnesota, Minneapolis) was upbeat about the trial's implications and ivabradine's potential as an addition to the array of medications that can make a significant difference in heart failure.

"SHIFT confirms the importance of heart rate in the pathophysiology of heart failure and supports the concept that reduction of heart rate contributes significantly to beneficial outcomes in patients with heart failure. It appears therefore likely that heart rate is not only a risk factor but may well be a mediator of the progression of heart failure," he said.

"In patients with systolic heart failure who are in sinus rhythm, with heart rates over 70 bpm, receiving the usual clinical care, who are unable to tolerate higher doses of beta blockers," he said, "ivabradine is likely to improve their outcomes."

How Relevant to Contemporary Practice?

But others have expressed cautions about the trial and its message.

It appears ... likely that heart rate is not only a risk factor, but may well be a mediator of the progression of heart failure.

An editorial accompanying the SHIFT paper [2], which points out shortfalls in the background medical therapy of SHIFT participants, at least according to contemporary standards, questions how far the study's results can be generalized and says it's premature to list ivabradine among proven therapies for heart failure.

There are others who wonder how relevant the study might be to most patients with heart failure. According to Dr Clyde Yancy (Baylor University Medical Center, Dallas, TX), who isn't connected to SHIFT or the Lancet papers, "this is a very interesting study that tests a novel concept of heart-rate slowing as adjunctive therapy for heart failure, but sufficient questions remain regarding whom it is who would benefit most from this approach."

The study, he told heartwire , entered a somewhat atypical population: "younger than most patients with heart failure in the US, mostly white, sinus rhythm only, and status post–heart-failure hospitalization within the prior 12 months of enrollment."

Moreover, he noted, "the majority of the patients in this study were not only 'outside US' but also 'outside Western Europe.' We must begin to consider potential regional differences in the natural history of heart failure that may affect clinical-trial results and again create difficulty in extrapolating those results to a broader patient population."

What the Trial Showed

The SHIFT trial, conducted at 677 centers in 37 countries, randomized >6500 patients with NYHA class 2-4 heart failure, an LVEF <35%, a resting heart rate >70 bpm, and a heart-failure hospitalization within the previous year to receive either placebo or ivabradine at a starting dose of 5 mg twice daily, with adjustments to achieve a resting heart rate of 50 to 60 bpm. All patients were on standard heart-failure medications according to guidelines, including include ACE inhibitors or angiotensin-receptor blockers, beta blockers, aldosterone antagonists, and diuretics.

Over a mean follow-up of 23 months, patients taking ivabradine showed a highly significant 18% reduction in the hazard ratio for cardiovascular death or hospitalization for worsening heart failure, compared with the control group, driven by significant 26% reductions in hazard ratios for the individual secondary end points of death from heart failure and hospitalization for worsening heart failure.

SHIFT: Hazard Ratios for Primary and Individual Outcomes, Ivabradine vs Placebo Groups

Outcomes in SHIFT Ivabradine, n=3241 (%) Placebo, n=3264(%) HR (95% CI) p
CV death or HF hospitalization 24 29 0.82 (0.75–0.90) <0.0001
Death from heart failure 3 5 0.74 (0.58–0.94) 0.014
HF hospitalization 16 21 0.74 (0.66–0.83) <0.0001
CV death, HF hospitalization, or admission for nonfatal MI 25 30 0.82 (0.74-0.89) <0.0001

The benefit of ivabradine appeared to go up with increasing heart rate. The hazard ratio for the primary end point was 0.93 (95% CI 0.80–1.08) for patients starting out with a rate <77 bpm but was 0.75 (95% CI 0.67–0.85) among those with rates of >77 bpm; the difference between the subgroups was significant at p=0.029.

The authors describe ivabradine as being "well tolerated" despite a 10% rate of bradycardia, which prompted withdrawal from the study by 1% of patients receiving the drug.

That low rate, Komajda said to heartwire , is "reassuring." Bradycardia would be an obvious potential concern when adding a heart-rate-lowering agent to other drugs, notably beta blockers, that also lower heart rate.

He noted that only one patient in the trial needed implantation of a pacemaker, "which tells you about the safety of this drug in terms of bradycardia. One of the messages of SHIFT is that there is very good tolerance of ivabradine on top of beta blockers."

Was It a "Legitimate" Test of Ivabradine in Heart Failure?

Swedberg et al point out that about 90% of patients in both groups were on beta blockers at randomization, 91% were on either ACE inhibitors or angiotensin receptor blockers, and about 60% were on aldosterone antagonists. But they also note that only 49% of patients in the trial were at >50% of beta-blocker target dosage and only 26% were at target dosages.

"The average doses of the beta blockers were lower than doses used in clinical trials of beta blockers but are actually higher than doses reported in surveys and more closely mirror clinical practice than do doses used in trials testing these drugs," according to the authors.

But in his editorial accompanying the SHIFT paper, Dr John R Teerlink (University of California, San Francisco and San Francisco Veterans Affairs Medical Center) focuses on the trial's beta-blocker dosing as a major reason not to consider the trial a conclusive test of ivabradine in chronic heart failure. Conceivably, a significant reduction in the primary end point might not have emerged had beta blockers--which also reduce heart rate--been more consistently given "at or near target doses," he speculates.

Would these benefits have occurred if the dose of beta blocker had been more consistently closer to the recommended doses in the patients studied?

"SHIFT is a landmark trial of a novel approach to the treatment of patients with heart failure," he writes. Still, "although the beta-blocker doses and other background therapies used in SHIFT might reflect patterns in community practice, the standard for legitimate evaluation of these therapies should be the use of guideline-recommended agents and doses with proven efficacy. It is not clear that SHIFT successfully tested the hypothesis that ivabradine provided additional benefit to patients with heart failure treated with contemporary optimal heart-failure therapies."

Yancy raised similar issues. "Would these benefits have occurred if the dose of beta blocker had been more consistently closer to the recommended doses in the patients studied? Achieving recommended doses of evidence-based beta-blocker use in this study at only a 25% threshold despite urgings from well-recognized experts in heart failure highlights an opportunity to improve the quality of care of patients with heart failure."

But Anand contends that further beta blockade probably wouldn't have made much difference. In a meta-analysis of 23 beta-blocker heart-failure trials involving over 19 000 patients [3], he observed, "McAcalister and his colleagues found that the mortality benefit was related more to the magnitude of heart-rate reduction and not to the dose of beta blocker."

It is . . . unlikely that the use of higher doses of beta blocker in SHIFT would have caused further reduction in heart rate or altered outcomes much.

Moreover, according to Anand, "we know from clinical trials that higher doses of beta blockers have not been shown to reduce heart rate further." This was also the case in SHIFT, he said.

"It is therefore unlikely that the use of higher doses of beta blocker in SHIFT would have caused further reduction in heart rate or altered outcomes much. In the real world, physicians are unable to increase doses of beta blockers to target levels because of either actual or perceived side effects. SHIFT should be judged on the merits of its findings and in the population studied."

The effects of ivabradine in previous trials of patients with stable symptomatic coronary disease have been mixed, as previously reported by heartwire . In a >10 000-patient randomized, placebo-controlled trial called BEAUTIFUL, the drug was seen to lower heart rate by an average of 6 bpm over a median 19 months of follow-up but had no effect on the primary of cardiovascular death, hospital admission for MI, or new-onset or worsening heart failure.

In the much smaller ADD-IFI study, adding the drug to standard medical therapy in patients with stable angina significantly improved their exercise capacity.

Heart Rate: A Modifiable Risk Factor in Heart Failure?

A companion report [4] to the primary SHIFT results, with lead author Dr Michael Böhm (Universitätsklinikum des Saarlandes, Homburg/Saar, Germany), zeroes in on the relationship between heart rate and heart-failure outcomes in the trial. Its conclusion: the SHIFT results are consistent with increased heart rate not only as a risk marker but also as a modifiable risk factor with potential as a therapeutic target, in that lowering it should also reduce risk.

"Our finding [in SHIFT] that pretreatment heart rates [were] related to outcome in the placebo group confirms the relation between ambient heart rate and outcome suggested by many epidemiological studies in the general population and in several subpopulations with various forms of cardiovascular disease," the group writes. "However, before SHIFT, the benefit of isolated heart-rate reduction in reduction of outcome event rates had not been shown in a randomized prospective trial."

Risk for the trial's primary end point rose steeply with increasing baseline heart rate.

SHIFT: Hazard Ratio for Cardiovascular Death or Heart-Failure Hospitalization by Quintiles of Increasing Baseline Heart Rate, Relative to Lowest Quintile

Baseline heart rate quintiles, bpm HR (95% CI) p
70 to <72 1.00 -
72 to <75 1.15 (0.88–1.48) 0.308
75 to <80 1.33 (1.03–1.70) 0.027
80 to <87 1.80 (1.40–2.31) <0.0001
>87 2.34 (1.84–2.98) <0.0001

A similar pattern emerged by increasing heart-rate quintiles for the trial's secondary clinical end points. In a separate analysis, risk for the primary end point went up by 3% for every 1-bpm increase from the baseline heart rate; it went up 16% for every 5-bpm increase, according to the authors.

Among patients who received ivabradine, the risk of a primary end point went up with heart rate achieved after 28 days; adjustment of the trial's primary outcomes for change in heart rate at 28 days attenuated the drug's apparent treatment effect, making it nonsignificant (hazard ratio 0.95, 95% CI 0.85–1.06; p=0.352). The finding, according to Böhm et al, shows that heart-rate reduction accounts for much of ivabradine's treatment effect in the trial and supports heart rate as a potentially modifiable risk factor in heart failure.

"Both papers written by this group make a strong case that heart-rate slowing is potentially beneficial in patients with heart failure who have resting heart rates [in sinus rhythm] of about 80 bpm or greater," according to Yancy. "Importantly, the benefit was largely driven by a reduction in heart-failure hospitalizations, which is of considerable public-health importance in our country."

SHIFT was funded by Servier. Members of the trial's executive committee "received fees, research grants, or both from Servier, as well as fees for speaking or consulting from other major cardiovascular pharmaceutical companies," according to Komajda's presentation.

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