Michel KOMAJDA, MD
Department of Cardiology
Pierre and Marie Curie University
Assistance-Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital
SHIFT: what are the major findings and the implications for clinical practice?
Heart failure with reduced ejection fraction (EF) is associated with poor outcomes, and heart rate is a risk factor for cardiovascular events in this condition. SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) enrolled 6505 chronic heart failure patients in sinus rhythm with a recent heart failure hospitalization, low EF ≤35%, and elevated heart rate ≥70 bpm to investigate the role of heart rate in heart failure. Patients were randomized to either the specific heart rate–reducing agent ivabradine, an If current inhibitor, or to placebo, on top of the best possible recommended heart failure therapy. The addition of ivabradine resulted in a highly significant 18% reduction in the occurrence of the primary composite end point, cardiovascular mortality or heart failure hospitalization. This beneficial effect was mainly driven by significant 26% reductions in heart failure deaths and heart failure hospitalizations. Overall, the safety of ivabradine was good; in particular, the number of bradycardic adverse effects was low. This good cardiac tolerability was recently confirmed in a 24-hour Holter monitoring substudy. Ivabradine also improved quality of life. In patients with reduced EF, elevated heart rate, and in sinus rhythm, the addition of ivabradine on top of recommended heart failure medications improves cardiovascular outcomes. Special attention should be paid to heart rate measured under standardized conditions, and efforts should be made to reduce elevated heart rate to <60 bpm.
Heart rate is recognized as a strong predictor of mortality and morbidity in the general population as well as in patients with a broad spectrum of cardiovascular disorders, including hypertension, myocardial infarction, coronary artery disease, and chronic heart failure (with reduced as well as preserved ejection fraction).1-6 The underlying mechanism of the deleterious effect of elevated heart rate remains partially unknown. Elevated heart rate creates an imbalance in oxygen supply/ expenditure to the myocardium, but it is also is associated in experimental models with vascular oxidative stress, endothelial dysfunction, acceleration of atherogenesis, and coronary plaque instability.7
In heart failure, β-blocker therapy is associated with a marked improvement in outcomes that seems proportional to the magnitude of heart rate reduction and might involve a reverse remodeling effect.8,9 However, since β-blockers have multiple mechanisms of action, it was not known until the recent publication of SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) whether specific heart rate reduction obtained by a heart rate–reducing agent devoid of any other significant pharmacological properties, the If channel inhibitor ivabradine, would be beneficial in this condition. This question is all the more important as recent surveys conducted in Europe suggest that more than 50% of patients with heart failure have an elevated heart rate, despite the wide dissemination of β-blockers, suggesting therefore that underdosage is common in real life.10,11
Figure 1. Kaplan-Meier cumulative event curves for different end points in SHIFT.
hospitalizations (Panel C) and heart failure deaths (Panel D) in the ivabradine and the placebo arms of SHIFT.
Abbreviations: CV, cardiovascular; HF, heart failure; SHIFT, Systolic Heart failure treatment with the If inhibitor ivabradine Trial.
Modified from reference 12: Swedberg et al; SHIFT Investigators. Lancet. 2010;376:875-885. © 2010, Elsevier Ltd.
Major findings from SHIFT
In a population of 6505 chronic heart failure patients with reduced ejection fraction, who had experienced a recent heart failure hospitalization, were in sinus rhythm, and with elevated heart rate ≥70 bpm, the addition of ivabradine 5 mg to 7.5 mg bid on top of the best possible recommended therapy provided additional benefit and significantly reduced the occurrence of the primary composite outcome, cardiovascular mortality or heart failure hospitalizations, by 18%. This effect is driven mainly by a significant reduction in heart failure hospitalizations (-26%) and heart failure deaths (–26%) (Figure 1).12
This beneficial effect was observed in a well-treated population: 93% of the patients were taking an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker, and 89% were receiving a β-blocker. Moreover, 56% of these patients were receiving at least 50% of the β-blocker target dose recommended by the European Society of Cardiology guidelines and 26% were at target dose.
The baseline characteristics of the population show that this was a relatively young, predominantly male (76%) population with a mean age of 60 years and with ischemic etiology (68%). The mean ejection fraction was markedly diminished (29%), and patients were almost evenly distributed in terms of heart failure severity, based on NYHA (New York Heart Association) class (49% in class II, 51% in class III/IV).
The beneficial effect on the outcomes detailed above occurred rapidly, and the survival curves show that the separation was rapid after randomization. This mirrored heart rate reduction, which occurred early on: heart rate decreased from 80 to 64 bpm 1 month after randomization in the ivabradine group, and the difference, corrected for placebo, was 11 bpm. The difference in heart rate between the two groups was 8 bpm at the end of the trial.
The reduction in the occurrence of the primary composite end point was consistent in all prespecified subgroups, including age, sex, etiology of heart failure, and use/nonuse of β-blockers, with one notable exception: the magnitude of benefit derived from ivabradine was significantly greater in the subgroup with baseline heart rate above the median value (77 bpm in the SHIFT population).
In the subgroup of patients receiving at least 50% of the target dose of β-blockers, the effects of ivabradine were consistent with those observed in the overall population, although less marked, probably due to a lower rate of cardiovascular events and therefore a limited power.
Table I. Adverse events leading to treatment discontinuation in
the ivabradine and in the placebo arms of SHIFT.
Modified from reference 12: Swedberg et al; SHIFT Investigators. Lancet.
2010;376:875-885. © 2010, Elsevier Ltd.
There was also a small but significant improvement in quality of life, assessed by change in NYHA class and patient and physician reported assessment at the last visit, in ivabradinetreated patients. This was recently confirmed by a subanalysis of health-related quality of life using the Kansas City cardiomyopathy questionnaire, a self-reported instrument that includes several dimensions, such as symptoms, quality of life, and social limitations.13
Overall, the tolerability of ivabradine was good and serious adverse effects were less frequent in the active arm than in the placebo arm (Table I).12 Symptomatic and asymptomatic bradycardia were reported in 5% and 6% of patients, respectively, in the ivabradine arm, but led to treatment discontinuation in only 1% of cases for each of these two adverse effects. Visual side effects were also uncommon and led to treatment discontinuation in only a few cases. Overall, approximately 70% of the patients in the ivabradine arm were at target dose (7.5 mg bid) and less than 10% had to be downtitrated to the lowest dosage (2.5 mg bid).
This excellent cardiac tolerability was recently confirmed by a 24-hour Holter substudy conducted in 602 patients: in the 501 patients suitable for analysis after 8 months of treatment, the number of pauses was similar in both groups; while in the ivabradine group the number of second or higher degree atrioventricular blocks was smaller (4 vs 9); there were no cases of third degree AV block; and only the number of heart rate episodes <40 bpm increased (54 vs 21).14
The first lesson from SHIFT is therefore that the addition of the selective heart rate–reducing agent ivabradine on top of the best possible recommended therapy, including βblockers in 90%of cases, significantly improves cardiovascular outcomes and particularly hospitalizations or deaths related to heart failure, with good tolerability.
The SHIFT study also demonstrates that heart rate is not only a risk marker, but also a risk factor in heart failure: the risk of cardiovascular outcomes increases with heart rate and every 5 bpm increase in baseline heart rate is associated with a 16% increase in the risk of primary outcome in the placebo arm. The beneficial effect of ivabradine is solely accounted for by heart rate reduction, since the adjustment for change in heart rate at 28 days in the active arm neutralizes the effect of the drug for subsequent outcomes.15 Another important finding is that in the active arm, minimal risk is observed in patients who reach a target heart rate <60 bpm at 28 days.
SHIFT suggests therefore that greater attention should be paid to a simple biomarker, resting heart rate, a powerful predictor of outcomes in chronic heart failure. Indeed, epidemiological studies suggest that despite the dissemination of β-blocker therapy, heart rate remains elevated >70 bpm in a substantial proportion of patients.10,11
This is at least partially the result of underdosage of this therapy as a result of poor tolerance, prescribers’ reluctance, or lack of awareness of recommended target doses in real life. In the Heart Failure pilot study, comprising 3226 patients with chronic heart failure enrolled in twelve European countries, only 21% to 37% of patients were at β-blocker target dose (of carvedilol, bisoprolol or metoprolol). In CIBIS-ELD (Cardiac Insufficiency BIsoprolol Study in Elderly), the primary objective of reaching and maintaining target dose of carvedilol or bisoprolol was observed in only 25% of patients.16
_ What should the optimal heart rate in chronic heart failure be?
Since the analysis of the relationship between heart rate reduction achieved at 28 days with ivabradine and subsequent outcomes suggests that patients with the lowest risk reached a heart rate <60 bpm, it is reasonable to recommend this target in daily practice when tolerated. There is no information available on the potential benefit/harm of lowering heart rate further, although it should be remembered that cardiac output is the product of heart rate and stroke volume, so that very low heart rates result in a significant decrease in cardiac output and therefore in reduced oxygen delivery to the body. Empirically, achieving a target heart rate at rest of 50-60 bpm therefore seems a reasonable objective.
_ Is uptitrating &btea;-blockers or combining ivabradine with low/medium doses of β-blockers the best strategy?
There is no clear answer yet to this important practical question from the SHIFT results, since more than 50% of the patients enrolled in this trial were taking at least half of the target recommended dose and 26% were at target dose. The investigators were repeatedly encouraged by the Executive Committee to provide the best possible therapy to their patients, including β-blockers at target dose. The SHIFT results should therefore be interpreted as heart rate reduction by ivabradine bringing an incremental benefit in patients with elevated heart rate who are unlikely to tolerate maximal doses of β-blockers, as frequently observed in daily practice.
_ Can ivabradine replace β-blocker therapy in chronic heart failure?
SHIFT provides no insights into this question, since the overwhelming majority of patients included in this trial were on β-blocker therapy (90%). It was not a trial designed to compare ivabradine face to face with β-blocker therapy, and the only scientifically valid conclusion that can be drawn from SHIFT is that in chronic heart failure patients treated with β-blockers whose heart rate remains elevated for any reason, ivabradine should be considered on top of their existing therapy in order to improve outcomes, particularly heart failure events, regardless of efforts to maximize β-blocker dose. This course of action has indeed been proposed in the recently published Australian and New Zealand Guidelines.17 However, the magnitude of the benefit provided by ivabradine was similar in the small subgroup who did not receive a β-blocker (10% of the population) to that observed in the rest of the population, suggesting that reducing heart rate with ivabradine in chronic heart failure patients intolerant to β-blockers provides a similar benefit to that observed in other patients and could be considered as an alternative.
_ Can the results be generalized to the overall heart failure population?
Patients in SHIFT were selected on the basis of several criteria: high resting heart rate >70 bpm, normal heart beat (sinus rhythm), and reduced ejection fraction (≤35%). In addition, the proportion of elderly patients was limited. Therefore, the effects of ivabradine cannot be generalized to apply in the overall heart failure population, nor in particular to patients with permanent atrial fibrillation (where there is no indication for ivabradine due to the mechanism of action of this drug) or to patients with heart failure and preserved ejection fraction.
SHIFT has brought new insights into the role of heart rate as a risk factor in chronic heart failure and on the importance of heart rate reduction—when elevated—in improving outcomes in heart failure in sinus rhythm and with reduced ejection fraction. The addition of a specific bradycardic agent, ivabradine, to the best possible recommended heart failure therapy provides a significant improvement in cardiovascular outcomes in this population and should be considered to further reduce the burden of chronic heart failure and the risks related to this disorder. The tolerability of the combination of this new heart rate–reducing agent with β-blockers was good, particularly with regards to cardiac safety. _
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Keywords: chronic heart failure, heart rate, clinical trial, heart rate reduction