AUTHORS' CHRONICLES

Real world indications to ivabradine treatment in chronic systolic heart failure

Indicaciones en la práctica diaria para el tratamiento con ivabradina en la insuficiencia cardíaca sistólica crónica

 

Gabriele Fragasso¹

¹ IRRCS San Raffaele, Milán, Italia

 

Gabriele Fragasso describes for SIIC his article published in Journal of Cardiovascular Medicine 19(7):351-356, Jul 2018.

 

 

Milán, Italia (special for SIIC)

Ivabradine, a relatively recently developed drug, acts by reducing the heart rate (HR) via specific inhibition of the funny current, a mechanism different from that of beta-blockers (BB). Its use in patients with ischemic heart disease or heart failure (HF) has been endorsed by the results of the BEAUTIFUL and SHIFT studies. In HF patients ivabradine is at present recommended by the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America in symptomatic patients (NYHA II-IV), with left ventricular ejection fractions (LVEF) of 35% or less, who are in sinus rhythm and either do not tolerate BB, or have a resting HR at least 70 beats/min despite the maximally tolerated BB dose.

We have recently analysed and reported the real-life proportion of HF patients eligible for ivabradine treatment, according to ESC guidelines.

From a total cohort of 1070 patients attending our HF clinic in a 68 month period of observation, we identified 308 patients with systolic HF, NYHA class at least 2 at first visit, who were previously seen in the clinic at least two times, to ensure that there was enough time to optimize treatment. Patients with heart failure with preserved ejection fraction (HFpEF) and those who were visited only once during this observation period were excluded from our analysis. This choice is justified by the fact that at least two visits are needed, at variable time intervals, to optimize and up-titrate guideline-directed medical therapy (GDMT), including the attainment of the maximally tolerated BB dose, which is regularly attained within 6 months.

In our analysis we started from patients who were being treated with BB at the maximum tolerated dose and we identified how many of these patients met all three criteria (EF ≤ 35%, HR ≥ 70 beats/min and NYHA class ≥ 2) considered as necessary for ivabradine eligibility. Some of these patients had already introduced ivabradine in their therapy and were added to the count. Out of 308 reviewed patients, 251 patients were on optimized BB therapy according to present recommendations, up-titrated to maximally tolerated dose: only 31 of these needed to introduce ivabradine or had already introduced it.

Therefore, out of the 308 patients reviewed, 57 were not on beta-blocker therapy due to either intolerance or major contraindications. Among them, 13 were on ivabradine alone. The final 44 patients were neither on BB nor on ivabradine treatment. Out of these 44 patients without negative chronotropic treatment, only 8 patients resulted to be eligible for ivabradine, according to NYHA class and EF parameters.

Overall ivabradine was indicated in 52 patients (16.8%) out of 308 enrolled.

Indications to ivabradine treatment in HF patients are based on the results of the SHIFT study. In the SHIFT study, however, despite investigators had to attain the up-titration of BB therapy, only 75% of patients were taking an evidence-based BB for HFrEF, and only 26% were at target dose. Additionally, no statistically significant differences were found in the subgroup of patients who took at least half the maximum BB dose between the ivabradine and placebo arms in terms of the primary outcome or overall mortality.

The beneficial effects of BB in all grades of HF have been demonstrated in several studies, determining an indication of class 1A according to the European and American professional guidelines. Apart from HR reduction, beneficial effects on myocardial energetics could provide a potential ancillary mechanism for decreased myocardial oxygen consumption and improved energy efficiency induced by BB in heart failure. In patients with HF, the magnitude of HR reduction could, therefore, be just a marker of a better functional response following beta-blocker administration, a consequent effect rather than a mechanism. On the other hand, pure negative chronotropism is the sole mechanism by which ivabradine exerts its effect.

In recent years, implementation of BB in HF has been steadily increasing. The proportion of patients in BB therapy can reach rates above 90% if patients are treated according to European and International guidelines and in HF clinics where the up-titration protocol is routinely attained. Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry shows that 92.7% of patients are on BB therapy. Our analysis confirms the high percentage of appropriately managed HF patients on properly up-titrated BB therapy; additionally, it shows that around 17% of them necessitate the introduction of ivabradine in order to optimize HR control.

In our study, the attained doses of BB were similar to those previously reported, confirming that the individual response to BB is very variable and that, probably, their effectiveness in reducing HR is often obtained with doses lower than those evinced from randomized clinical trials.

In conclusion, overall these results confirm the limited percentage of HFrEF patients needing to ivabradine to reach target HR. However, considering the sizeable proportion of HFrEF patients intolerant to BB or with persistent HR ≥ 70 beats/min despite adequate BB implementation, the possibility to prescribe ivabradine in order to tailor therapy appears as an important additional therapeutic tool, especially in view of the increasing prevalence and related economic costs of HF.