Clinical advantages of Procoralan in cardiovascular prevention




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

Clinical advantages of Procoralan in cardiovascular prevention


by I . Elyubaeva, France

Cardiovascular death is the major cause of premature death in most countries. Further to the well-established importance of conventional risk factors, the role of heart rate (HR) is now better understood as a main determinant ofmyocardial ischemia and cardiac work, and as an important therapeutic opportunity, since it can be easily modified in clinical practice. Recent large randomized clinical studies have confirmed earlier epidemiological and clinical data in showing that resting HR is an independent cardiovascular risk factor in patients with coronary artery disease or heart failure. HR reduction is being increasingly recognized today as a valuable therapeutic approach in patients with acute or chronic coronary disease or with congestive heart failure. Procoralan is a selective HR-lowering agent, and the first agent of this type to be approved for therapeutic use. As opposed to other HR-lowering agents, Procoralan has a unique action on pacemaker activity in the sinoatrial node. Procoralan reduces HR through its selective and specific inhibition of the pacemaker If current, while avoiding any deleterious cardiovascular effects. Randomized clinical trials have established the clinical benefits of Procoralan in preventing angina and minimizing underlying ischemia both in monotherapy and in combination with other treatments, including β-blockers. The BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) showed that, in addition to symptomatic improvement, Procoralan also improves clinical outcomes in symptomatic coronary patients or in those with a baseline heart rate ≥70 bpm. The recent results from SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) have significantly extended the range of clinical benefits of Procoralan by showing substantial reductions in main heart failure outcomes in patients with chronic heart failure. This evidence confirms Procoralan as having as an essential therapeutic role in improving the management of patients with coronary artery disease or heart failure.

Medicographia. 2011;33:432-439 (see French abstract on page 439)

Cardiovascular death is the main cause of premature death in most countries.1 Major advances have been made in appreciating the role of risk factors and the reduction in morbidity and mortality in patients with cardiovascular disease resulting from their modification. Heart rate (HR) reduction is being increasingly recognized today as a valuable therapeutic approach in patients with acute or chronic coronary disease or with congestive heart failure. However, data from epidemiological surveys or clinical registries have revealed that the majority of patients continue to have elevated HR in clinical practice.2-4 Insufficient attention is being given to HR control in routine practice, and β-blocker dosage is often suboptimal and seldom readjusted during long-term therapy. Very often the target dose of β-blocker is not reached because of intolerance or side effects such as fatigue, depression, bronchospasm, or erectile dysfunction. The inadequate control of HR in clinical practice means there is an important need for novel therapeutic modalities to remedy this missed opportunity and improve the management of patients with cardiovascular disease.

Procoralan is a selective HR-lowering agent, the first agent of this type to be approved for therapeutic use and the first of an entirely new therapeutic class. Its concept is based on the elucidation of the key role of the If current as the basic mechanism underlying the generation of spontaneous pacemaker activity.5,6 The If current, which is a mixed Na+-K+ current, determines HR by modifying the diastolic depolarization slope.7 It is also involved in the control of the spontaneous frequency of pacemaker cells, and thus HR, through the action of the sympathetic (accelerating) and vagal (slowing) systems.8 This makes the If current a natural target for pharmacological intervention aimed at HR control. As opposed to other HR-lowering agents, Procoralan has a unique action on pacemaker activity in the sinoatrial node of the heart.9 Through its selective and specific inhibition of the If pacemaker current, Procoralan reduces HR, providing all the benefits of HR reduction without any of the deleterious cardiovascular effects observed with other treatments.10

Clinical benefits of Procoralan in the management of stable CAD

The optimal management of coronary artery disease (CAD) is based on achieving a dual goal: reducing myocardial ischemia and preventing cardiovascular events. HR plays an important role in the pathophysiology of CAD as a well-established determinant of ischemia.11 Elevated HR is now increasingly acknowledged as a prognostic factor.12 Thus, HR reduction has a clear role as a key therapeutic goal in patients with CAD, leading to better prevention of ischemia in the short-term and better prevention of cardiovascular events in the long-term.

Experimental data clearly support the anti-ischemic effects of Procoralan, which result from its action on both determinants of the oxygen balance: Procoralan reduces myocardial oxygen demand and improves myocardial oxygen supply by increasing diastolic perfusion time.13 The specific nature of HR-lowering with Procoralan fully distinguishes it from other HR-reducing therapies and explains its unique beneficial properties. In contrast to β-blockers, Procoralan does not alter left ventricular (LV) function and preserves isovolumic LV relaxation, thereby achieving the benefits of prolonged diastolic time while preserving the physiological mechanisms allowing adaptation to the exercise to take place.14-16 Importantly, Procoralan preserves flow-mediated increase in large coronary artery diameter during exercise, whereas propranolol induces vasoconstriction by unmasking the α-adrenergic coronary vasoconstrictor tone.17

Figure 1
Figure 1. Effect of Procoralan on coronary flow velocity reserve
(CFR) in Skalidis et al study.

Box-plots of coronary CFR at baseline (Baseline) and after 1 week’s Procoralan
treatment, both at the intrinsic heart rate (Procoralan, [ivabradine]) and at a paced
rate identical to that at baseline (Ivabradine-pace).
After reference 18: Skalidis et al. Atherosclerosis. 2011;215(1):160-165. © 2010,
Elsevier Ireland Ltd.

The effect of Procoralan on coronary flow velocity and coronary flow reserve was evaluated in a recent study in 21 patients with stable CAD who underwent coronary flow velocity measurements in a nonculprit vessel, using a Doppler guidewire, at rest and after adenosine administration to achieve maximal hyperemia.18 A significant increase in coronary flow reserve after short-term treatment with Procoralan (1 week) was reported.

Although resting coronary blood flow velocity returned to pretreatment values after HR correction, the enhancement of hyperemic coronary blood flow velocity reserve persisted (Figure 1). This means that the improvement in hyperemic coronary blood flow is not totally HR-dependent, and that it depends on the integrity (functional or structural) of the microcirculation. This study confirmed previous experimental data on the improvement in coronary hemodynamics with Procoralan. Improvement in coronary flow reserve has profound clinical implications since it predicts long-term cardiovascular outcomes.19

The results of clinical trials are consistent with the role of HR in determining the frequency of angina and the severity of underlying ischemia as well as long-term ischemic outcomes. By reducing HR during exercise, Procoralan provides relief from symptoms of chronic stable angina. Benefits also accrue from the decrease in resting heart rate, which has been shown to reduce the risk of long-term cardiovascular events.

Data from randomized clinical trials and experience from daily practice provide strong proof of the clinical benefits of Procoralan and support its value in the management of patients with CAD.

_ Antianginal and anti-ischemic efficacy of Procoralan
Improvement in angina symptoms results in a significant improvement in quality of life, which is one of the essential goals of medical treatment. The substantial reduction in HR with Procoralan translates into antianginal and anti-ischemic benefits confirmed by the significant decrease in angina symptoms and short-acting nitrate consumption and improvement in exercise capacity observed both in monotherapy and in combination with other antianginal therapies such as the β-blockers.

_ Reduction in angina attacks
Procoralan substantially reduces the frequency of angina attacks and the consumption of short-acting nitrates compared with placebo: at the end of a 2- or 3-month open-label extension study, angina attacks decreased from 4.14±5.59 per week to 0.95±2.24 per week (P<0.001), while consumption of short-acting nitrates decreased from 2.28+3.74 units per week to 0.50+1.14 units per week (P<0.001). At the end of the open-label treatment phase, patients underwent double-blind random assignment to continue on ivabradine or withdraw to placebo for 1 week. Frequency of angina attacks and short-acting nitrate consumption were unchanged among those patients who continued treatment with Procoralan, but increased in patients withdrawn to placebo.20 The antianginal efficacy of Procoralan was confirmed in INITIATIVE (INternatIonal TrIAl on the Treatment of angina with IVabradinE vs atenolol): the number of angina attacks decreased at 4 months by –1.6±4.1 with Procoralan and –1.2± 3.4 with atenolol 100 mg od.21

In another double-blind, parallel-group, noninferiority trial in 1195 patients with chronic stable angina and documented CAD, Procoralan 7.5 mg bid was associated with substantial antianginal efficacy similar to that of amlodipine 10 mg od, reducing the number of angina attacks by about two thirds and short-acting nitrate consumption by about one half.22

The efficacy of Procoralan in reducing the frequency of angina symptoms was also assessed in a 1-year study.23 Treatment with Procoralan 5 and 7.5 mg bid showed significant reductions in angina attack frequency from 50% to 67% relative to baseline at 1 year of treatment, demonstrating maintenance of antianginal efficacy in long-term therapy, without development of pharmacological tolerance.

A pooled post-hoc analysis of these studies confirmed the antianginal efficacy of Procoralan across a wide range of populations with stable angina, including the elderly, female patients, and patients with asthma/chronic obstructive pulmonary disease. Data from 2425 stable angina patients treated with Procoralan (5, 7.5, or 10 mg bid) for 3 or 4 months demonstrated reduction in frequency of angina attacks by 59.4% and in short-acting nitrate consumption by 53.7, in all subpopulations considered.24 These data highlight the wide scope of therapeutic usefulness of Procoralan in the management of angina patients.

The antianginal efficacy and safety of Procoralan has also been confirmed in routine day-to-day practice in the large open-label, multicenter REDUCTION trial (not an acronym) conducted in a broad range of patients with stable angina.25 In this multicenter study, 4954 patients with stable angina pectoris received Procoralan for 4 months. Procoralan angina pectoris attacks decreased from 2.4±3.1 to 0.4±1.5 per week (P<0.0001). Consumption of short-acting nitrates decreased from 3.3±4.4 to 0.6±1.6 units per week (P<0.0001). In the 344 patients treated concomitantly with β-blockers, angina pectoris episodes decreased from 2.8±3.3 to 0.5±1.3 per week, (P<0.0001) and consumption of short-acting nitrates was reduced from 3.7±5.6 to 0.7±1.7 units per week (P>0.0001).26

_ Anti-ischemic efficacy
Procoralan showed significant anti-ischemic efficacy compared with placebo in the aforementioned randomized, double- blind study reported by Borer et al.20 Procoralan-mediated improvements in time to 1-mm ST segment depression in the double-blind phase were maintained in the open-label phase. Procoralan demonstrated improvements in time to angina onset and time to limiting angina compared with placebo.

This anti-ischemic efficacy of Procoralan was also confirmed in comparison with β-blockers and calcium antagonists, which are widely used in the treatment of angina. Thus, in the INI TIATIVE study, an increase in time to 1-mm ST-segment depression by approximately 1.5 min was observed with Procoralan.21 The Procoralan 7.5 mg bid group showed an increase in total exercise duration, at the trough of drug activity, of 86.8 s, compared with 78.8 s in the atenolol 100 mg od group, and noninferiority was found for all exercise tolerance test parameters (P<0.001) (Figure 2).

Figure 2
Figure 2. Anti-ischemic effect of Procoralan in
the INITIATIVE trial.

Effect of 4 months of treatment with Procoralan (ivabradine)
7.5 mg bid or atenolol 100 mg od on exercise tolerance
parameters at trough of drug activity, P values for
noninferiority. INITIATIVE (INternatIonal TrIAl on the Treatment
of angina with IVabradinE vs atenolol). Based on
data from reference 21.

The fact that in INITIATIVE there was a similar improvement in exercise capacity with Procoralan for a comparatively smaller reduction in HR suggested greater efficiency in increasing exercise capacity per heartbeat, compared with atenolol. Indeed, for a given reduction of HR (1 beat) Procoralan achieved a greater improvement in exercise capacity (10.1 s) than atenolol (5.6 s).27 This greater improvement in exercise capacity illustrates the clinical advantage of pure HR reduction, unburdened by effects on other cardiovascular characteristics that limit the heart-rate–reducing benefits.

A recent trial, ASSOCIATE (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr), examined the effects of Procoralan in patients with chronic stable angina pectoris receiving β-blocker therapy.28 In this double-blind trial in 889 patients, all on 50 mg of atenolol daily, were randomly assigned to additional treatment with either Procoralan up to 7.5 mg bid or a placebo. Patients were then subjected to an exercise treadmill test at trough of drug activity 2 and 4 months later. Findings showed that Procoralan, on top of β-blocker treatment with atenolol, provided further significant long-term improvement in all parameters of the exercise test, at 2 and 4 months (Figure 3). This improvement was consistent across all parameters of the exercise test, at through of drug activity, as evidenced by the rigorous standard Bruce protocol. This the most compelling evidence published to date of the benefit of any combination of antianginal drugs. Importantly, despite the fact that combination therapy is widely used in clinical practice to achieve adequate control of angina, clinical trials evaluating combination therapy have yielded inconsistent results. This makes the coadministration of Procoralan with β-blockers the best evidencebased combination therapy for angina patients. ASSOCIATE also showed that treatment was well tolerated, with less than 1% of patients stopping drug therapy because of bradycardia and minor reversible visual effects in 2% of Procoralantreated patients vs 0.9% of placebo-treated patients. These data establish Procoralan as an effective and well-tolerated anti-anginal agent, alone or in combination with other drugs, including β-blockers.

Figure 3
Figure 3. Procoralan and exercise tolerance criteria in the ASSOCIATE trial.

Changes in exercise tolerance test criteria between baseline and after 2 months of treatment with Procoralan
(ivabradine) (M2 visit) and between baseline and end of study (M4). ASSOCIATE trial (evaluation
of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a
beTa-blockEr).
After reference 28: Tardif et al. Eur Heart J. 2009;30:540-548. ESC/Oxford University Press © 2009,
The Author.

_ Improvement in long-term clinical outcomes in stable CAD patients
In addition to the beneficial effects of HR reduction on the prevention of angina, lower HR is also associated with a more favorable prognosis in patients with CAD. A large body of evidence shows that high resting HR is a strong predictor for cardiovascular mortality and morbidity in patients with cardiovascular diseases.

_ Procoralan prevents coronary events in CAD patients with elevated HR
The importance of HR as a risk factor and of its reduction for the improvement in prognosis was confirmed in the BEAUTIFUL trial (morbidity–mortality EvAlUaTion of the If inhibitor Procoralan in patients with coronary disease and left ventricULar dysfunction). This was a large international doubleblind randomized clinical trial of Procoralan vs placebo on top of optimal medical therapy in patients with stable CAD and left ventricular dysfunction (left ventricular ejection fraction [LVEF] of less than 40%). A prospective analysis of the data from the placebo arm of BEAUTIFUL evidenced the association of HR with clinical outcomes in this coronary disease population.29 Patients with a HR of 70 bpm or more had an increased risk of cardiovascular death (34%, P=0.0041), admission to hospital for heart failure (53%, P<0.0001), admission to hospital for myocardial infarction (46%, P=0.0066), and coronary revascularization (38%, P=0.037) after adjustment for other predictors of outcome. Consistent with these data on increased cardiovascular risk with HR of 70 bpm or more, Procoralan reduced CAD end points of admission to hospital for fatal or nonfatal myocardial infarction by 36% (P=0.001) and coronary revascularization by 30% (P=0.016) in these patients at high risk of cardiovascular events (Figure 4).30 Procoralan also resulted in a 22% reduction in hospitalization for fatal and nonfatal myocardial infarction or unstable angina despite the fact that this population was receiving optimal treatment. Furthermore, there was a 30% reduction in the need for elective revascularization in the whole population with Procoralan vs placebo, most likely because of the well-established effect of Procoralan on anginal pain in patients with stable angina (P<0.024).31

Figure 4
Figure 4. Effect of Procoralan on risk of hospitalization for myocardial
infarction (BEAUTIFUL trial). HR, hazard ratio.

Effect of Procoralan (ivabradine) in patients with baseline heart rate above 70 bpm
in the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the
If inhibitor ivabradine
in patients with coronary disease and left ventricULar dysfunction).
After reference 30: Fox et al. Lancet. 2008;372(9641):807-817. © 2008,
Elsevier Ltd.

Figure 5
Figure 5. Effect of Procoralan on cardiovascular outcomes in patients
with limiting angina in the BEAUTIFUL trial. HR, hazard ratio.

Effect of Procoralan (ivabradine) on the primary composite end point of the
BEAUTIFUL (morBidity-mortality EvAlUaTion of the
If inhibitor ivabradine in patients
with coronary disease and left ventricULar dysfunction) trial (cardiovascular
death, myocardial infarction, or heart failure requiring admission to hospital)
in patients with limiting angina at baseline.
After reference 32: Fox et al. Eur Heart J. 2009;30(19):2337-2345. ESC/Oxford
University Press © 2009, The Author.

_ Procoralan prevents outcomes in symptomatic CAD patients
A recent analysis in 1507 patients with symptoms of angina at baseline in the BEAUTIFUL trial has evaluated the prognostic benefit of Procoralan in this population.32 The reduction in the primary end point of the study (cardiovascular death, myocardial infarction, or hospitalization for heart failure) was 24% in the whole group of patients with limiting angina and 31% in the group with baseline heart rate ≥70 bpm (Figure 5). The primary end point appears to be driven by the coronary outcomes since there was a 42% reduction in the risk for hospitalization for fatal and nonfatal myocardial infarction in patients with limiting angina treated with Procoralan. There were consistent, smaller reductions in all other end points examined, with 13%, 12%, and 28% reductions in all-cause, cardiovascular, and cardiac death, respectively; a 16% reduction in new-onset or worsening heart failure; and a 30% reduction in the risk for coronary revascularization. The reduction in the risk of cardiovascular outcomes was even greater in patients with angina and heart rate ≥70 bpm, notably with a significant 73% Procoralan-related reduction in hospitalization for fatal and nonfatal myocardial infarction and a 59% reduction in coronary revascularization. These data confirm that angina places coronary patients at high risk of coronary events. The effect of Procoralan on coronary outcomes is quite remarkable as it extends the efficacy of this agent beyond the symptomatic improvement of anginal or ischemic symptoms.

The results of BEAUTIFUL have important implications, as they showed that elevated heart rate increases cardiovascular risk and should be used to guide optimal therapy in coronary patients. They also evidenced the benefits of Procoralan beyond the control of anginal symptoms. Procoralan is now established as a treatment able to modify the clinical course of CAD and called to play an important role in the management of patients with stable CAD. Another major trial is currently evaluating the efficacy of Procoralan in patients with preserved left ventricular function. This is SIGNIFY (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease), which will include stable CAD patients with LVEF >40%, and without clinical signs of heart failure. After a run-in period of 2 to 4 weeks, patients will be randomized to placebo bid or Procoralan, with a starting dose of 7.5 mg bid. The target heart rate is 55 to 60 bpm. The study is expected to include more than 16 000 patients from 50 countries.

Clinical benefits of Procoralan in the management of heart failure

The prognostic value of HR in patients with heart failure and the ability of Procoralan to decrease HR without impairing key cardiovascular or hemodynamic parameters such as myocardial contractility, ventricular relaxation, and cardiac conduction, have prompted its evaluation in heart failure. The prevalence of this very disabling condition is rising, due to the aging of the population and the improved survival from conditions such as CAD.33 Despite advances in the treatment of chronic heart failure (CHF) over the past decade, mortality and morbidity remain high.34 A number of factors support the benefit that may be derived from HR reduction in heart failure. Elevated HR is associated with impairment of LV filling, decrease in myocardial perfusion, increase in myocardial oxygen consumption, and worsening LV function, and leads to greater mechanical dyssynchrony in patients with CHF.35 Resting HR is thought to have an independent prognostic value in heart failure, across a large spectrum of severity of the disease.

This concept was successfully tested in the recent SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial).36 SHIFT was a randomized placebo-controlled clinical trial evaluating the effects of Procoralan, on top of guidelinerecommended therapies, on morbidity and mortality in 6558 patients with moderate-to-severe CHF, LV systolic dysfunction (LVEF ≤35%), and resting HR ≥70 bpm. Median followup was 22.9 months.37

Figure 6
Figure 6. Procoralan: findings from SHIFT. HR, hazard ratio.

Kaplan-Meier time-to-event curves from the SHIFT (Systolic Heart failure treatment
with the
If inhibitor ivabradine Trial) study in patients with heart failure (HF),
showing the effect of HR reduction with Procoralan (ivabradine) on hospitalization
for HF and death from HF.
After reference 37: Swedberg et al. Lancet. 2010;376(9744)875-885. © 2010,
Elsevier Ltd.

More than half of patients were receiving at least 50% of the target dose of β-blocker, with 26% at target dose. Hypotension (44%) and fatigue (32%) were the main reasons for not reaching target dose. After 28 days, Procoralan reduced heart rate by 15.4 bpm (10.9 bpm placebo-corrected). The primary composite end point (CV death or hospital admission for worsening HF) was significantly reduced by 18% (P<0.0001), largely due to significant reductions in death (RRR, 26%; P=0.014) and hospitalization for HF (RRR, 26%; P<0.0001) (Figure 6). Results were consistent across subgroups. On the strength of the absolute risk reduction of the primary end point, 26 patients would need to be treated for 1 year to prevent 1 cardiovascular death or HF-related hospital admission. CV death and all-cause death nominally diminished by 9% and 10%, respectively. Quality of life assessments by both patients and their physicians, as well as New York Heart Association [NYHA] classification, significantly improved with Procoralan. The results of SHIFT clearly demonstrate that Procoralan substantially and significantly reduced major outcomes associated with heart failure when added to guideline-based treatment.

In addition to the clinical standpoint, SHIFT has important implications regarding the pathophysiological standpoint, demonstrating for the first time that HR reduction with Procoralan reduces clinical events in heart failure and therefore that HR is clearly a risk factor in heart failure.

How does Procoralan prevent cardiovascular outcomes?

A growing body of evidence from experimental studies increasingly suggests that pure HR reduction with Procoralan has a significant potential as an intervention able to improve endothelial function and attenuate progression of atherosclerosis, thereby providing cardiovascular protection in addition to the symptomatic treatment of myocardial ischemia. Prevention of endothelial dysfunction, which is the first step in the formation of atherosclerosis, was demonstrated in a transgenic mouse model of dyslipidemia and endothelial dysfunction.38 Three months’ treatment with Procoralan preserved endothelium-mediated vasodilation in the renal and cerebral arteries of mice expressing human apoprotein B (apoB-100). Procoralan restored the endothelium-dependent vasodilation in cerebral vessels, whereas metoprolol failed to restore endothelial function to the same degree. This could be because of inhibitory effects of metoprolol on β-adrenoreceptor–mediated activation of endothelial nitric oxide synthase.

In addition to improvement in endothelial function, Procoralan also markedly reduced vascular oxidative stress, as reflected by the decrease in NADPH oxidase activity, superoxide production, lipid peroxidation, and monocyte chemotactic protein- 1 (MCP-1) expression.39 MCP-1 provides a link between endothelial dysfunction and atherosclerotic lesion formation by inducing leukocyte arrest and transendothelial migration. Recent experimental data suggest that Procoralan inhibits chemokine-induced migration of CD4-positive lymphocytes, which has a crucial role in early atherogenesis.40

All these effects of Procoralan could contribute clinically to the prevention of progression of atherosclerosis. Preclinical studies have shown that Procoralan reduces atherosclerotic plaque size in the aortic root and ascending aorta by 40% and 70%, respectively (P<0.05).39 All these effects of HR reduction with Procoralan, together with reduced O2 requirement and improved oxygen supply, could contribute to the clinical benefits of Procoralan reported in the clinical setting.

In a model of CHF, long-term HR reduction with Procoralan improved LV function and increased stroke volume, resulting in preserved cardiac output.41 This improvement in cardiac function was also associated with modifications of LV structure and/or myocyte properties, as indicated by reduction in LV collagen density and increase in LV capillary density.

In parallel with long-term HR reduction, Procoralan significantly reduced plasma norepinephrine levels.41 In a recently published study in hypercholesterolemic rabbits, Procoralan attenuated LV diastolic dysfunction and reduced atrial fibrosis, ventricular fibrosis, and LV collagen type I.42 Circulating angiotensin II and aldosterone levels were also reduced with Procoralan and correlated with HR. These beneficial effects on cardiac function and remodeling could also contribute to the beneficial effects of Procoralan in CHF.

These experimental data support the rationale for heart rate reduction with Procoralan as a disease-modifying intervention for improving clinical status and cardiovascular event prevention in patients with CAD or heart failure.

Conclusion

The clinical efficacy and safety of Procoralan in stable angina have been documented in both placebo-controlled and comparative studies, which yielded consistent evidence of the clinical benefits of Procoralan in preventing angina and minimizing underlying ischemia, in monotherapy as well in combination with other treatments, including &beta:-blockers. BEAUTIFUL has shown that, in addition to symptomatic improvement, treatment with Procoralan also improves clinical outcomes in symptomatic coronary patients or those with a baseline HR ≥70 bpm, when added to modern background therapy. The recent SHIFT results have significantly extended the range of clinical benefits of Procoralan by showing substantial reductions in the main heart failure outcomes in patients with CHF. All these findings support the important place of Procoralan as an essential therapeutic modality to improve the management of patients with CAD or heart failure. _

References
1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747-1757.
2. Daly CA, Clemens F, Sendon JL, et al; Euro Heart Survey Investigators. Inadequate control of heart rate in patients with stable angina: results from the European heart survey. Postgrad Med J. 2010;86(1014):212-217.
3. Herman M, Donovan J, Tran M, et al. Use of β-blockers and effects on heart rate and blood pressure post–acute coronary syndromes: are we on target? Am Heart J. 2009;158:378-385.
4. Maggioni AP, Dahlström U, Filippatos G, et al; Heart Failure Association of ESC (HFA). EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2010;12(10):1076-1084.
5. DiFrancesco D. The cardiac hyperpolarizing-activated current, If. Origins and developments. Prog Biophys Molec Biol. 1985;46:163-183.
6. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455-472.
7. DiFrancesco D, Ferroni A, Mazzanti M, Tromba C. Properties of the hyperpolarizingactivated current If in cells isolated from the rabbit sino-atrial node. J Physiol. 1986;377:61-88.
8. DiFrancesco D, Ducouret P, Robinson RB. Muscarinic modulation of cardiac rate at low acetylcholine concentrations. Science. 1989;243:669-671.
9. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol. 1996; 118 (4):1051-1057.
10. Ferrari R, Campo G, Gardini E, Pasanisi G, Ceconi C. Specific and selective If inhibition: expected clinical benefits from pure heart rate reduction in coronary patients. Eur Heart J. 2005;7(suppl H):H16-H21.
11. Collins P, Fox KM. Pathophysiology of angina. Lancet. 1990;1:94-96.
12. Tardif JC. Heart rate as a treatable cardiovascular risk factor. Br Med Bull. 2009; 90:71-84.
13. P. Colin, B. Ghaleh, X. Monnet, L. Hittinger, A. Berdeaux. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and dias tolic time in exercising dogs. J Pharmacol Exp Ther. 2004;308(1):236-240.
14. Colin P, Ghaleh B, Hittinger L, et al. Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during exercise. Am J Physiol Heart Circ Physiol. 2002;282(2):H672-H679.
15. Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284(2):H676-H682.
16. Monnet X, Colin P, Ghaleh B, Hittinger L, Giudicelli JF, Berdeaux A. Heart rate reduction during exercise-induced myocardial ischemia and stunning. Eur Heart J. 2004;25(7):579-586.
17. Simon L, Ghaleh B, Puybasset L, Giudicelli JF, Berdeaux A. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995;275(2):659-666.
18. Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis. 2011;215(1):160-165.
19. Britten MB, Zeiher AM, Schächinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron Artery Dis. 2004;15:259-264.
20. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107(6):817-823.
21. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26(23):2529-2536.
22. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67(3):393-405.
23. Lopez-Bescos L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108:387-396.
24. Tendera M, Borer JS, Tardif JC. Efficacy of If inhibition with ivabradine in different subpopulations with stable angina pectoris. Cardiology. 2009;114(2): 116-125.
25. Köster R, Kaehler J, Meinertz T; REDUCTION Study Group. Treatment of stable angina pectoris by ivabradine in every day practice: the REDUCTION study. Am Heart J. 2009;158(4):e51-e7.
26. Koester R, Kaehler J, Ebelt H, Soeffker G, Werdan K, Meinertz T. Ivabradine in combination with beta-blocker therapy for the treatment of stable angina pectoris in every day clinical practice. Clin Res Cardiol. 2010;99(10):665-672.
27. Tardif JC. Ivabradine: If inhibition in the management of stable angina pectoris and other cardiovascular diseases. Drugs Today. 2008;44(3):171-181.
28. Tardif JC, Ponikowski P, Kahan T. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.
29. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 372(9641):817-821, 2008.
30. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction BEAUTIFUL: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807-816.
31. Cook S, Hess O, Fox K. Senkung der Herzfrequenz zur Behandlung von Angina Pectoris. Cardiovasc. 2009;6:26-29.
32. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J. 2009;30(19):2337-2345.
>33. Bleumink GS, Knetsch AM, Sturkenboom MC, et al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure. The Rotterdam Study. Eur Heart J. 2004;25(18):1614-1619.
34. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005;26:1115-1140.
35. Reil JC, Böhm M. The role of heart rate in the development of cardiovascular disease. Clin Res Cardiol. 2007;96:585-592.
36. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail. 2010;12(1):75-81.
37. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-885.
38. Drouin A, Gendron ME, Thorin E, Gillis MA, Mahlberg-Gaudin F, Tardif JC. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol. 2008;154(4):749-757.
39. Custodis F, Baumhäkel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2008;117(18): 2377-2387.
40. Walcher T, Bernhardt P, Vasic D, Bach H, Durst R, Rottbauer W, Walcher D. Ivabradine reduces chemokine-induced CD4-positive lymphocyte migration. Mediators Inflamm. 2010; Volume 2010, Article ID 751313, 8 pages; doi: 10.1155/2010/751313. Epub 2010 Dec 5.
41. Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004;109(13):1674-1679.
42. Busseuil D, Shi Y, Mecteau M, et al. Heart rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis. Cardiology. 2010;117(3): 234-242.

Keywords: heart rate reduction; If current; heart failure; ivabradine; stable coronary artery disease