Procoralan: new opportunities for vulnerable heart failure patients






Irina ELYUBAEVA,MD, PhD
Servier International
Division of Medical Information
Suresnes, FRANCE

Procoralan: new opportunities for vulnerable heart failure patients


by I. Elyubaeva, France



Once a relatively short-term, quickly fatal condition, systolic heart failure (HF) today is a chronic disease characterized by recurrent nonfatal events (hospital admissions). With the burden of hospitalizations for HF continuing to grow, prevention of rehospitalization has become the most urgent need in cardiology. Hospital discharge is an opportunity to identify modifiable prognostic factors and to optimize patient therapy. The clinical profile of HF patients is complex, mainly due to aging and the frequent presence of noncardiovascular and cardiovascular comorbidities. These conditions not only complicate management of HF patients, but also increase risk of in-hospital and postdischarge mortality and morbidity. The important role of Procoralan (ivabradine) in the management of patients with chronic HF is well established and supported by its benefits in prevention of morbidity and mortality. Efficacy and tolerability of ivabradine in patients with HF, including those with different clinical profiles (elderly; severe disease; low blood pressure; comorbidities, including renal dysfunction, diabetes, chronic obstructive pulmonary disease) make ivabradine particularly pertinent for achievement of all targets in the treatment of HF, including improvement of symptoms and well-being, as well as outcomes. This offers the promise of a better prognosis and improved quality of life for millions of patients with chronic HF.

Medicographia. 2015;37:185-192 (see French abstract on page 192)



Heart failure (HF) hospitalizations are a tremendous burden in terms of costs and patient outcomes. The huge burden of HF-related hospitalization makes its prevention the most urgent unmet need in cardiology.1 While patients hospitalized for worsening HF experience relatively low in-hospital mortality, they are at much higher risk for early postdischarge readmission and mortality.2 These early postdischarge mortality and readmission rates have remained largely unchanged and may even be worsening in all countries. Thus, clear predischarge planning is crucial to reduce preventable readmissions. Predischarge medications with proven prognostic benefits for long-term use is critical to reduce high early postdischarge risk and prevent readmission for HF.1




Elevated heart rate to predict the risk of readmission and mortality in patients with HF

The risk for postdischarge adverse events can be predicted with a high degree of fidelity by a small number of widely available clinical variables. In this regard, such a simple and standard clinical assessment as resting heart rate (HR) at discharge or early postdischarge provides important prognostic information. The recent analysis of a cohort of 9097 patients with HF discharged from hospital demonstrated that discharge HR was significantly associated with 30-day HF readmission— with adjusted hazard ratios of 1.26 (95% confidence interval, 1.04-1.54;P=0.021) in patients with the highest HRgroup (HR>90 beats per minute [bpm]) compared with the reference group with a HR of 61-70 bpm.3 There was a trend in patients with HR below 60 bpm toward the lowest risk with an adjusted hazard ratio of 0.87. The trend was consistent for 30-day cardiovascular (CV) readmission, mortality, and long-term outcomes. For example, the group with the highest HR—above 80 bpm—was associated with higher risk of 1-year HF mortality (1.26; P=0.023) compared with the reference group with a HR lower than 60 bpm. The recent analysis from the EVEREST trial (Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan)4 demonstrated that the survival curves of the patients, subdivided according to the HR measured 1 or 4 weeks after discharge, started to diverge relatively early, and continued to diverge during follow-up. These results are consistent with a long-lasting persistent effect of elevated HR on prognosis (Figure 1).5 This causal role is also consistent with the improvement in outcomes observed with pure HR reduction with ivabradine in patients with chronic HF on optimal medical treatment.


Figure 1
Figure 1. Mechanisms potentially involved in the untoward effects of elevated heart rate in heart failure.

Abbreviation: O2, oxygen.
After reference 5: Metra. JACC Heart Fail. 2013;1(6):497-499. © 2013, American College of Cardiology Foundation.
Published by Elsevier Inc. All rights reserved.


Pure HR reduction with procoralan (ivabradine): anti-ischemic effect and dual cardiac and vascular protection in coronary artery disease and HF

Procoralan (ivabradine) is a specific HR-lowering agent, and is the first agent of this type to be approved for therapeutic use.6 As opposed to other HR-lowering agents, ivabradine expresses unique action on pacemaker activity in the sinoatrial node of the heart, which results in important differences between ivabradine and nonselective HR-reducing agents such as β-blockers. Ivabradine inhibits If, an ionic current that modulates pacemaking activity, lowering HR without directly affecting cardiac conduction or contractility.7 Myocardial perfusion, particularly in the subendocardium, takes place almost entirely during diastole. Physiological changes in HR affect mainly the duration of diastole leading to prolongation in diastolic time at lower HR, both in absolute terms and as a fraction of the cardiac cycle, facilitating myocardial perfusion.8 Ivabradine, in common with physiological HR reduction, lowers HR essentially by prolonging diastole.9 By reducing HR, ivabradine decreases myocardial oxygen consumption and increases myocardial perfusion, both explaining the preserved cardiac energy metabolism, which is profoundly depleted during HF. Sustained HR reduction with ivabradine improves cardiac function by significantly decreasing left ventricular (LV) systolic diameter and increasing fractional shortening.10 Ivabradine preserves cardiac output due to increased stroke volume, reduced LV collagen density, and increased LV capillary density. Similar cardiac benefits have also been observed in rats when ivabradine was given immediately after myocardial infarction, highlighting both the preventive and curative benefits of ivabradine in HF.11

These experimental data show that long-term HR reduction with ivabradine optimizes energy consumption, reverses remodeling, and prevents disease progression in HF.12 Beneficial effects of ivabradine on LV volumes have been further documented by assessing its effects on the global cardiac remodeling process involved in HF. This adaptation following myocardial injury is defined as a series of biochemical and cellular modifications, such as fibrosis and local renin-angiotensin aldosterone system (RAAS) stimulation, and electrophysiological modifications, such as alteration of sarcoplasmic reticulum calcium cycling. Nonclinical data have shown that ivabradine has a marked beneficial effect on these remodeling parameters. At the cellular level, ivabradine reduces fibrosis and local RAAS stimulation (decrease in cardiac angiotensin II type 1 receptor).13 Ivabradine reduces triggered ventricular premature complexes in chronic HF (CHF) rats in addition to a decrease in ventricular fibrosis and sympathetic drive.14

These preclinical findings show that, in several models of HF, a pathological condition in which a series of phenotypic cardiac maladaptations is progressively induced, the long-term HR-reducing properties of ivabradine prevent progression of cardiac dysfunction and optimize energy consumption. In the short term, this is associated with increased diastolic time, improved myocardial perfusion, and reduced oxygen consumption. In the long term, ivabradine induces a global reversal of remodeling and prevents endothelial dysfunction. All these mechanisms contribute to the prognostic benefits of ivabradine in patients with HF.

Clinical benefits of pure HR reduction by ivabradine in patients with LV dysfunction and HF

The results of clinical trials are consistent with the importance of HR in the pathophysiology of HF, supporting the place of ivabradine as an important part of management of patients with LV systolic dysfunction (LVSD) and HF.

Improvement of symptoms and exercise capacity, and reduction in signs of decompensation in patients with HF
SHIFT (the Systolic Heart failure treatment with If inhibitor ivabradine Trial) found that ivabradine significantly improved the New York Heart Association (NYHA) class (29.0% vs 24.2% in the placebo group; P<0.0156) and patient-reported global assessment (65.9% vs 61.3% in placebo; P<0.0345) in the overall SHIFT population.15

In the randomized, open, blinded end point CARVIVA study (Effect of CARVedilol, IVAbradine or their combination on exercise capacity in patients with Heart Failure), after 3 months of therapy with ivabradine, the NYHA class was significantly more improved in patients receiving ivabradine and combination therapy compared with those allocated to carvedilol.16 Ivabradine alone or in combination was also more effective in improvement of exercise capacity comparedwith carvedilol alone.

The results of the recent INTENSIFY study (PractIcal daily effectiveNess and TolEraNce of Procoralan in chronic SystolIc heart Failure in GermanY) confirmed the clinical efficacy of ivabradine in daily practice over a 4-month period in 1956 patients with CHF.17 After 4 months, ivabradine reduced HR by 18.1±12.3 bpm to 67.1±8.9 bpm, accompanied by symptomatic improvement with a shift in NYHA classification of patients toward lower gradings (Figure 2)17 and a reduction in signs of decompensation from 23% to 5% of patients.


Figure 2
Figure 2. Proportion of patients in different NYHA classes over 4 months of therapy with ivabradine in patients with chronic heart failure participating in the INTENSIFY trial.

Abbreviations: INTENSIFY, PractIcal daily effective-Ness and TolEraNce of Procoralan in chronic SystolIc heart Failure in GermanY; n, number of patients; NYHA, New York Heart Association.
After reference 17: Zugck et al. Adv Ther.2014;31(9):961-974. © 2014, The Author(s).



Improvement of health-related quality of life in patients with HF
A substudy of the SHIFT trial in 1944 patients demonstrated that in parallel to a reduction in outcomes in the SHIFT trial, ivabradine improved health-related quality of life (HQOL) in patients with HF, assessed by the specific Kansas City Cardiomyopathy Questionnaire (KCCQ).18 Treatment with ivabradine significantly improved both scores measured with the KCCQ: the overall summary score (OSS) and the clinical summary score (CSS). The OSS, which includes the physical limitation, total symptom, QOL, and social limitation scores, was improved by ivabradine by 6.7 points vs 4.3 in the placebo group (P<0.001) by 12 months. The CSS, which includes the physical limitation and the total symptom domain scores, was improved by 5.0 points with ivabradine vs 3.3 in the placebo group (P=0.018) after 12 months. Qualitatively, similar benefits were found with ivabradine vs placebo at 4 months and were maintained throughout study follow-up.

The improvement of QOL was demonstrated in the randomized, open, blinded end point CARVIVA study.16 After 3 months of therapy, ivabradine improvedQOL comparedwith no change with carvedilol alone.

In the recent INTENSIFY study, scores from the European quality of life-5 dimensions (EQ-5D) index and the EQ-5D visual analog scale (EQ-5D-VAS) were improved from 0.64±0.28 to 0.79±0.21 and from 0.55±0.18 to 0.70±0.16, respectively, over 4 months of therapy with ivabradine.17

Reversing ventricular remodeling in patients with HF
Reversal of LV remodeling has important clinical implications as cardiac remodeling is a central feature of the progression of HF and is an established prognostic factor in patients with this condition. An echo substudy in 611 patients from SHIFT demonstrated that 8 months of therapy with ivabradine resulted in a 7 mL/m2 reduction in LV end-systolic volume index (LVESVI), as compared with 0.9 mL/m2 in the placebo group.19 The LV end-diastolic volume index (LVEDVI) was reduced by 7.9 mL/m2 as compared with 1.8 mL/m2 in the placebo group; LVEF was improved by 2.4%, whereas there was no change in the placebo group at all. Moreover, these results occurred despite treatment with β-blockers and RAAS inhibitors, each used in more than 90% of patients.

Further analysis from SHIFT demonstrated that HR reduction with ivabradine can directly affect the vascular system and that the reported reduction in afterload was mainly triggered by a decrease in vascular pulsatile load, whereas systemic resistance remained constant.20 Better arterial compliance appears to result in improved ventricular arterial coupling with a significant increase in LVEF and stroke volume, without changes in LV contractility and cardiac output (Figure 3).21 The beneficial impact of ivabradine on LV remodeling and function may contribute to the reduction in cardiac morbidity and mortality found in patients with HF.


Figure 3
Figure 3. Change in stroke volume and cardiac output over 8 months in patients with systolic chronic heart failure participating in the SHIFT trial.

Abbreviation: SHIFT, Systolic Heart failure treatment with the If inhibitor ivabradine Trial.
After reference 21: Ferrari. Cardiology. 2014;128(2):226-230. © 2014, S. Karger AG, Basel.



Prevention of hospital admissions and mortality in patients with HF
The effect of ivabradine to improve prognosis in HF has been successfully tested in the SHIFT trial—the randomized, placebo- controlled clinical trial in 6558 patients with moderate to severe chronic HF and LV systolic dysfunction (LVEF<35%; HR ≥70 bpm; with median follow-up of 22.9 months).15 The SHIFT trial clearly demonstrates that ivabradine offers major prognostic benefits for patients with HF on top of the best possible recommended therapy. The primary composite end point (CV death or hospital admission for worsening HF) was significantly reduced by 18% (P<0.0001). Ivabradine significantly reduced HF death (relative risk reduction [RRR], 26%; P=0.014) and hospitalization for HF (RRR, 26%; P<0.0001). Results were consistent across all subgroups, including patients with HF of ischemic and nonischemic origin (Figure 4).15 On the strength of the absolute RR of the primary end point, 26 patients would need to be treated for 1 year to prevent 1 CV death or HF-related hospital admission. CV death and all-cause death diminished by 9% and 10%, respectively,15 and achieved statistical significance in patients with a HR of at least 75 bpm, with 17% reduction in all-cause mortality (P=0.0109) and 17% reduction in CV mortality (P=0.0166).22


Figure 4
Figure 4. Reduction in cardiovascular death or hospitalization for
worsening heart failure (primary composite end point) in the prespecified
patients with systolic chronic heart failure of ischemic or
nonischemic etiology in the SHIFT trial.

Abbreviations: CI, confidence interval; HF, heart failure; SHIFT, Systolic Heart
failure treatment with the If inhibitor ivabradine Trial.
Based on data from reference 15: Swedberg et al. Lancet. 2010;376(9744):
875-885.



Prevention of HF readmission is identified today as the most urgent unmet need in cardiology. Such admissions are not only distressing for patients and their families, but are also implicated in disease progression and drive the huge economic burden of HF.23 The analysis from SHIFT showed that ivabradine substantially reduces the total number of HF hospitalizations by 25% (P=0.0002).24 Over 2 years of follow-up, ivabradine substantially reduced the risk of recurrent HF hospitalization: with a 34% (P<0.001) reduction in risk of second hospitalization and a 29% (P<0.012) reduction in risk of third hospitalization (Figure 5).24 Similar results for HF hospitalization were seen in the higher-risk subgroup of patients with a HR of at least 75 bpm (27% reduction; P=0.0006). Ivabradine also reduced hospitalizations for any cause (by 15%; P=0.001) and CV hospitalizations (by 16%; P=0.002).

Improvement of prognosis in patients with HF with different clinical profiles
Patients with HF are characterized by the presence of multiple comorbidities or conditions, including old age and low systolic blood pressure (SBP), which not only complicates treatment strategies, but also increases the risk of undesirable side effects and worsens prognosis. Therefore, it is imperative to analyze efficacy and tolerability of medications in patients with HF with different clinical profiles.

Patients with severe HF
Severe HF, ie, NYHA class IV, is associated with relatively poorer survival than patients with NYHA classes II and III. Moreover, patients with severe HF are the most difficult to treat. The analysis from the SHIFT trial explores the efficacy and safety of ivabradine in 712 patients with severe HF (NYHA class IV and/or LVEF ≤20%).25 The results indicated that the effect of ivabradine to reduce outcomes, including the primary outcome (CV mortality or hospitalization for HF), HF death, and hospitalization for worsening HF, is consistent in patients with severe and less-severe HF, with no significant statistical interaction between the results in the 2 groups. Treatment with ivabradine was also associated with improvement in NYHA functional status in patients with severe disease. Importantly, therapy with ivabradine was safe in these severe patients with no unexpected adverse events and no impact on blood pressure (BP).

The recently published study in patients with severe systolic HF who were hospitalized for worsening HF explored the use of ivabradine in the hospital setting. Ivabradine treatment was started within 6 days of admission on average.26 The mean dosage at discharge was 9.5±2.8 mg/day. The HR decreased by 10.7±7.2 bpm 24 hours after ivabradine administration. The maximum HR decrease was 16.3±8.2 bpm, at discharge. A HR under 70 bpm was achieved in 50% and 80% of patients 24 hours after administration and at discharge, respectively. Thus, the decrease in HR was rapid, but sustained. There was no significant variation in BP, which explains the hemodynamic stability. Moreover, HR had a significant association with N-terminal pro–B-type natriuretic peptide (NTproBNP) and NYHA class improvement.


Figure 5
Figure 5. Estimate of the effect of ivabradine on recurrence of hospitalizations for worsening heart failure.

Abbreviation: n, number of patients.
After reference 24: Borer et al. Eur Heart J. 2012;33(22):2813-2820. Published on behalf of the European Society of Cardiology. All rights reserved. ©2012, The Author.



Patients with renal dysfunction
Renal dysfunction, even transient, is common in HF patients and is a known predictor of CV outcomes and mortality in patients with cardiac disease. Worsening renal function has been associated with adverse outcomes in patients with HF, underuse of proven agents, and even discontinuation of beneficial medication.27 The analysis from SHIFT demonstrated that renal dysfunction defined as an estimated glomerular filtration rate (eGFR) under 60 mL/min was present in 24% of patients (n=1579).28 Ivabradine use was associated with a reduction in the primary composite end point of CV mortality or hospitalization for HF both in patients with (by 18% of RRR; P=0.023) or without renal dysfunction (by 19% of RRR; P<0.001) at baseline (P for interaction=0.89), and tolerability of ivabradine was comparable in the 2 groups.28 There were no differences in changes in renal function over time between ivabradine- and placebo-treated patients.

Patients with chronic pulmonary obstructive disease
Up to one-third of HF patients are affected with chronic obstructive pulmonary disease (COPD) and vice versa.29 Thus, it is important to know of the potential interference of COPD with any therapy in HF. Analysis from the SHIFT trial showed that COPD was present in 11% of HF patients (n=730).30 The primary end point (CV mortality or HF hospitalization) and its component, hospitalization for worsening HF, were more frequent in COPD patients (hazard ratios 1.22, P=0.006; and 1.34, P<0.001; respectively), but relative risk (RR) was reduced similarly by ivabradine in both COPD (14% and 17%) and non-COPD (18% and 27%) patients (P interaction=0.82 and 0.53, respectively). Ivabradine was similarly safe in chronic HF patients with or without COPD.

Patients with low BP
Of HF patients, 15% to 25% have low SBP (ie, <120 mm Hg), and are at greater risk of in-hospital and postdischarge mortality and morbidity.31 Moreover, the presence of low SBP complicates the management of HF, as many guideline-recommended HF medications also lower SBP, such as b-blockers and angiotensin-converting enzyme (ACE) inhibitors. The analysis from the SHIFT trial assessed the efficacy of ivabradine in patients with different baseline levels of SBP.32 The results of this analysis demonstrated that baseline SBP did not affect the impact of HR reduction with ivabradine on clinical outcomes in HF. There was a similar beneficial effect on both the primary composite end point of CV mortality or hospitalization for HF and on the selected secondary end points whatever the baseline SBP, including patients in the low-SBP group (<115 mm Hg). The safety profile of ivabradine was also similar in the 3 groups, and there was no difference compared with the global SHIFT population. The BP variation over 24 months was similar in ivabradine- and placebo-treated patients in the low-SBP group. ◆ Patients with diabetes mellitus
Recent analysis from the European Society of Cardiology (ESC) Heart Failure Pilot Survey demonstrated that 29% of patients with HF have diabetes mellitus (DM), which was independently associated with a higher risk of mortality and/or HF hospitalization.33 The preliminary data reported at the last European HF congress showed that 31% of patients with DM enrolled in SHIFT showed similar benefits from ivabradine in patients with or without DM.34 The RR of the primary composite end point of CV mortality or hospitalization for HF was decreased significantly by ivabradine in both groups: by 19% (P=0.012) in patients with DM and by 17% (P=0.002) in patients without. There was no significant difference in the impact of ivabradine in the 2 groups (P value for interaction= 0.864). The RR of HF hospitalization was reduced similarly by ivabradine in patients with (27%; P=0.001) or without DM (17%; P<0.001) (P for interaction=0.784).

Elderly patients
The analysis from the SHIFT trial demonstrated that age does not limit the benefits of ivabradine in patients with chronic HF and systolic dysfunction, with comparable safety and efficacy across all age groups.35 In a subgroup of 722 very elderly patients aged at least 75 years, end points also occurred less frequently with ivabradine than with placebo. The rate of CV deaths was lower (16% vs 22%; P=0.048), as was the rate of HF death (4% vs 8%; P=0.019).

Good tolerability profile and ease of use in practice

Ivabradine was well tolerated in patients with CHF. In the SHIFT trial, bradycardia led to study withdrawal in only 1% of the overall population, which is remarkable considering that 89% were receiving β-blockers.15 Based on the SHIFT trial, a starting dosage of 5 mg twice daily is recommended, and can be increased up to 7.5 mg twice daily according to tolerability and if resting HR is above 60 bpm. In patients aged 75 years or more, a lower starting dosage should be considered (2.5 mg twice daily with further uptitration if necessary). Ivabradine should not be used with moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors.

Due to its pharmacological properties and supported by clinical evidence, ivabradine is a particularly pertinent therapy to achieve all treatment targets in HF patients: the improvement of symptoms, well-being, and outcomes. Pharmacological therapy of HF patients is becoming increasingly complex as patients are older and increasingly develop noncardiac and CV comorbidities and disabilities. These conditions not only complicate the management of HF patients, but also increase the risk of in-hospital and postdischarge mortality and morbidity. The efficacy and tolerability of ivabradine in patients with HF and different clinical profiles (elderly, severe disease, low BP, presence of comorbidities including renal dysfunction, DM, COPD) make ivabradine an essential therapeutic modality for the management of patients with HF.

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Keywords: heart failure; heart rate reduction, hospitalization; If current; ivabradine; Procoralan