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Am J Cardiovasc Drugs 2012; 12 (6): 357-359 1175-3277/12/0006-0357/$49.95/0 COMMENTARY Adis ª 2012 Springer International Publishing AG. All rights reserved. Ivabradine in Heart Failure Hope or Hype? Prakash C. Deedwania University of California, San Francisco School of Medicine, Fresno, CA, USA During the past two decades considerable progress has been made in understanding the pathophysiology of heart failure (HF) and subsequent development of several therapeutic agents primarily based on the neurohormonal blockade with reninangiotensin-aldosterone system (RAAS) blocking agents (e.g., angiotension-converting enzyme inhibitors [ACEIs], angiotensin II receptor blockers [ARBs], and aldosterone receptor blockers) and b-blockers.[1] Although these drugs are highly effective in reducing the morbidity and mortality in HF, there is considerable residual risk that remains despite appropriate use of these agents. Ivabradine, which is a specific heart rate (HR)-lowering agent that acts by inhibiting funny channels (If), a key ‘pacemaker’ current in the sino-atrial node, has recently been shown to be effective in the treatment of patients already receiving guideline-based therapy with RAAS blocking agents and bblockers bringing new hope of further reducing the residual risk of recurrent hospitalization and death due to HF. In this issue of the American Journal of Cardiovascular Drugs, the Drug Profile on ivabradine[2] provides an excellent overview regarding the pharmacology of this drug and its role in the treatment of HF based on the results of SHIFT (Systolic Heart failure treatment with If inhibitor ivabradine Trial).[3] Despite the obvious and highly significant benefit observed during treatment with ivabradine in the SHIFT study, there has been some discussion and debate in the academic community regarding the precise role of ivabradine in patients with HF in the clinic.[4,5] A careful examination of the SHIFT study shows that treatment with ivabradine was indeed associated with significant reduction in the primary composite endpoint consisting of cardiovascular death and hospitalization for worsening HF.[3] There was a 26% reduction in hospitalizations due to worsening HF and also a 26% reduction in deaths related to HF. These effects were seen primarily in the patients who had baseline HR ‡75 beats/min.[6] The fact that ivabradine was primarily effective in those with higher HR should not be surprising given the fact that it works primarily by slowing the HR by blocking the If channels. Although there are some data in experimental settings demonstrating various other actions, these require further confirmation and evaluation in humans. 1. Heart Rate (HR) in Heart Failure (HF) and Effects of Ivabradine The role of HR in various cardiovascular disorders and specifically in HF has been extensively evaluated and most studies show a strong association of higher HR with worse outcome.[7,8] The evidence is now overwhelming that elevated HR is a powerful predictor of mortality and morbidity in a range of chronic cardiovascular disorders including HF, independent of other risk factors and clinical variables.[7,8] In the placebo arm of the SHIFT study, patients with the highest HR (‡87 beats/min) had more than twice the risk of primary endpoint compared with those with a lower HR (70 to <72 beats/min). It was also shown that with every 1 beat/min increase from baseline during the follow-up the risk of primary endpoint increased by 3%. These data clearly establish the adverse effects of increased HR in HF. Although the precise mechanism responsible for adverse outcome associated with higher rate in HF is not established, it might be related to increased energy expenditure as well as perpetuating myocardial ischemia in those with ischemic cardiomyopathy. Whatever the underlying mechanism for the adverse consequences of increased HR might be, the beneficial effects of ivabradine, a pure HR-slowing agent devoid of effect on other hemodynamic parameters, or on myocardial function, as seen in SHIFT, clearly establishes the importance of slowing the HR in the setting of HF. The beneficial effects of b-blockers are also thought to be related, at least in part, to their HRlowering effect. However, b-blockers do have other hemodynamic actions as well as effects on cellular transcription factors that might also contribute to their effects on cardiac remodeling, a critical process in HF. Deedwania 358 2. Is Reduction in Hospitalization for Worsening HF a Valid and Important Endpoint? The significant reduction in hospitalization for worsening HF in SHIFT was one of the main components responsible for the positive results of the study as there was no reduction in cardiovascular deaths, the other component of the composite primary endpoint. Although this has been a topic of some discussion, it is important to emphasize that hospitalization for HF is not only a major contributor to the high morbidity but also relates to the escalating cost of health-care expenditure in HF. Admission for HF is the main reason for hospitalization in people >65 years of age in the USA, and accounts for more than 1 million admissions per year. It is also known that once hospitalized the rate of recurrent hospitalizations over the subsequent year is quite high (25–40%) in patients with HF. The recent sub-analysis from SHIFT showing a significant decrease in the rate of recurrent hospitalizations for worsening HF in patients treated with ivabradine is a further testament of its efficacy in reducing this important sequela of HF.[9] 3. b-Blocker Therapy versus Ivabradine in HF Based on the results of several large randomized controlled trials (RCTs), b-blocker use has been well established as an integral part of standard guideline-based therapy for all patients with HF. One of the criticisms of the SHIFT results has been focused on the fact that some of the patients in the study were not receiving a b-blocker at all and others were not getting recommended and adequate doses of b-blockers.[4] However, it is important to note that 89% of patients in SHIFT were receiving b-blockers and the majority were receiving an adequately tolerated dose of a b-blocker. It was prespecified in the investigator brochure that unless contraindicated or not tolerated all patients were to receive the recommended dose of b-blockers. A recent sub-analysis of SHIFT evaluated the effects of ivabradine in combination with b-blocker therapy and demonstrated that it was the magnitude of HR reduction with ivabridine rather than the dose of b-blocker patients were receiving that determined the subsequent effects on clinical outcome.[10] These findings clearly emphasize two main points: first, whenever possible an adequate dose of b-blocker must be given to obtain optimal control of HR, and second, ivabradine provides additional benefit in patients with HF who have a faster HR (>75 beats/min) despite the use of a b-blocker as well as in those who cannot tolerate b-blocker therapy. It is well recognized that despite the compelling evidence of the benefit of b-blockers in HF they are under-prescribed, both Adis ª 2012 Springer International Publishing AG. All rights reserved. in terms of the proportion of patients who receive them and the doses achieved. Much of this under-prescription is linked to their range of actions additional to HR lowering, which may result in an absolute or relative contraindication and a reluctance among physicians to prescribe. The prescribing of bblockers in HF has increased in recent years. However, the doses received remain low and evidence from registry studies indicates that HR control remains poor. In the IMPROVE HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study, although 84.1% of HF patients without devices received b-blockers, only 15.3% took them at recommended target doses and the median resting HR was 72.2 beats/min.[11] In the OPTIMIZE-HF (Organized Program To Initiate life-saving treatMent In hospitaliZEd patients with Heart Failure) registry, only 17.5% and 7.9% of hospitalized patients with chronic systolic HF treated in cardiology practices were receiving recommended target doses of carvedilol and metoprolol succinate, respectively, at the 60- to 90-day post-discharge follow-up.[12] Similarly, in the ESC-HF (European Society of Cardiology Heart Failure) pilot study, 86.7% of patients received b-blockers, but target doses of carvedilol, bisoprolol, and metoprolol were reached in only 37.3, 20.7, and 21.4% of patients, respectively, and the mean HR was 72 beats/min.[13] Older patients and those with more severe HF symptoms are more likely not to receive b-blocker therapy or to receive only low doses,[14] a phenomenon that has been termed the ‘risktreatment mismatch’ in the pharmacotherapy of HF.[15] It seems clear that the way b-blockers are used in current clinical practice does not produce HR control in the optimal 50–60 beats/min range in most patients. Because ivabradine is devoid of some of the major side effects associated with b-blockers (e.g., fatigue, erectile dysfunction, glycemic perturbations, etc.) it is likely to be better tolerated by patients with HF. Furthermore, many patients with bronchospastic lung disease, peripheral vascular disease, diabetes mellitus, and atrioventricular blocks who have contraindications to the use of b-blockers can now be given ivabradine to provide them with additional therapeutic benefit. 4. Summary Based on careful examination of the available evidence it is clear that ivabradine does provide hope for many patients with HF, especially those who continue to be symptomatic and are at risk of recurrent hospitalization for worsening HF. Specifically, this should include patients with HF who continue to have a faster HR despite currently recommended therapy as well as Am J Cardiovasc Drugs 2012; 12 (6) Ivabradine in Heart Failure those who cannot tolerate treatment with an adequate dosage of b-blockers and those in whom b-blocker use is contraindicated. Acknowledgments Dr Deedwania serves as a consultant and advisor for Forrest Pharmaceuticals, Servier laboratories and Takeda Pharmaceuticals. References 1. Deedwania P, Carbajal E. Evidence based therapy in heart failure. Med Clin North Am 2012; 96: 2813-20 2. Perry CM. Ivabradine in adults with chronic heart failure with reduced left ventricular ejection fraction. Am J Cardiovasc Drugs 2012; 12 (6): 415-26 3. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure: a randomised placebo-controlled study. Lancet 2010; 376: 875-85 4. Teerlink JR. Ivabradine in heart failure: no paradigm SHIFTyyet. Lancet 2010; 376: 847-9 5. Cullington D, Goode KM, Cleland JGF, et al. Limited role of ivabradine in the treatment of chronic heart failure. Heart 2011; 97: 1961-6 6. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 2010; 376: 886-94 7. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007; 50: 823-30 8. Castagno D, Skali H, Takeuchi M, et al. Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) Program. J Am Coll Cardiol 2012; 59: 1785-95 Adis ª 2012 Springer International Publishing AG. All rights reserved. 359 9. Borer JS, Bohm M, Ford I, et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT study. Eur Heart J 2012; 33: 2813-20 10. Swedberg K, Komajda M, Bohm M, et al. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose? Findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol 2012; 59: 1938-45 11. Heywood JT, Fonarow GC, Yancy CW, et al. Comparison of medical therapy dosing in outpatients cared for in cardiology practices with heart failure and reduced ejection fraction with and without device therapy: report from IMPROVE HF. Circ Heart Fail 2010; 3: 596-605 12. Fonarow GC, Abraham WT, Albert NM, et al. Dosing of beta-blocker therapy before, during, and after hospitalization for heart failure (from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure). Am J Cardiol 2008; 102: 1524-9 13. Maggioni AP, Dahlström U, Filippatos G, et al. EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2010; 12: 1076-84 14. Yancy CW, Fonarow GC, Albert NM, et al. Influence of patient age and sex on delivery of guideline-recommended heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF. Am Heart J 2009; 157: 754-62 15. Lee DS, Tu JV, Juurlink DN, et al. Risk-treatment mismatch in the pharmacotherapy of heart failure. JAMA 2005; 294: 1240-7 Correspondence: Dr Prakash Deedwania MD, FACC, FAHA, Chief Cardiology Division, VACCHCS/UCSF, Fresno, CA, Professor of Medicine, UCSF School of Medicine, San Francisco, 2615 E. Clinton Ave, Fresno, CA 93703, USA. E-mail: [email protected] Am J Cardiovasc Drugs 2012; 12 (6)