Clinical benefits of Procoralan in angina: efficacy in a wide range of clinical situations

by I. Elyubaeva, France

Medical Affairs
Servier International
Suresnes, FRANCE

The success of revascularization and recent clinical trial findings may result in underestimation of the importance of angina. Yet angina has not gone away. Indeed, it remains the most common initial symptom of coronary artery disease and its severity is closely associated with every aspect of perceived health status. The aggressive treatment of angina is a cornerstone of patient management. Experimental and clinical data show that Procoralan (ivabradine) improves coronary flow reserve, coronary collateral circulation, and endothelial function in patients with angina. When added to β-blockers, Procoralan further improves exercise capacity and quality of life in angina patients. Analysis of pooled data from the Procoralan angina development program and from observational studies in daily practice provides clinical evidence that Procoralan diminishes angina in all types of patients, regardless of age, sex, angina severity, revascularization status, history of myocardial infarction, peripheral vascular disease, or diabetes. These clinical benefits show that Procoralan is an important agent for symptomatic treatment of patients with angina pectoris.

The success of revascularization and recent clinical trial data may suggest that the importance of angina has declined, but angina has not gone away. Indeed, it remains the most common initial symptom of coronary artery disease (CAD).1 Misconceptions about the importance of angina are driven largely by the success of revascularization in producing short-term symptom relief, although this is not associated with survival benefit.2 Furthermore, randomized clinical trials and meta-analyses have consistently shown that about 30% of stable CAD patients who undergo vascularization continue to experience angina symptoms.3 The severity of angina is closely associated with every aspect of perceived health status, more frequent hospitalizations, and increased health care spending.4,5 Optimal medical therapy, in line with guidelines, is the cornerstone of angina management6 and is known to relieve symptoms and improve quality of life. However, recent studies suggest that management of angina remains suboptimal and that physicians often underestimate the extent to which angina continues to limit patients’ lives.7 In the recent APPEAR trial (Angina Prevalence and Provider Evaluation of Angina Relief), 42% of more than 1000 outpatients reported a frequency of angina above that estimated by cardiologists.7 Under-recognition of angina by physicians is associated with less aggressive treatment escalation and may lead to poorer angina control. In addition, stable angina patients, particularly the elderly, often suffer from concomitant chronic diseases that frequently and unavoidably limit the choice of therapy. These findings indicate a clear need for improved medical management of stable angina. Procoralan is an antianginal agent with specific heart rate− lowering properties that selectively modulates pacemaker activity in the sinoatrial node of the heart, resulting in improved coronary perfusion and pump efficiency.8,9 Procoralan improves exercise capacity and quality of life when used as a single agent and also in combination with β-blockers. Large development programs in angina and data on antianginal efficacy from observational studies show that Procoralan diminishes angina in all types of patients, irrespective of age, sex, angina severity, revascularization status, history of myocardial infarction (MI), peripheral vascular disease, or diabetes.10,11

Improvement of coronary blood flow with Procoralan

Although the main antianginal mechanisms of Procoralan are reduction of myocardial oxygen consumption and improvement of coronary blood flow due to prolongation of diastolic perfusion time, more recent clinical investigations have demonstrated that Procoralan may reduce myocardial ischemia and its consequences through other beneficial effects that help improve coronary blood flow (Figure 1).8

Effect on diastolic perfusion time and coronary blood flow
As coronary blood flow occurs mostly during diastole, diastolic time is of major importance in ensuring an adequate blood supply to the myocardium. β-Blockers reduce heart rate, thereby decreasing myocardial oxygen demand, and also increase diastolic time. The effects of both Procoralan and the β-blocker atenolol on diastolic time, and the resulting coronary blood flow changes, were compared in dogs.12 Procoralan increased diastolic time at rest and during exercise to a greater extent than atenolol, with a larger increase in coronary blood flow, despite a similar reduction in heart rate with both agents.12

Figure 1. Mechanisms of improvement of coronary flow by Procoralan.

In a recent randomized, double-blind, crossover study, Dillinger et al13 reported an increase in diastolic time with Procoralan in stable coronary patients receiving β-blockers. Treatment with Procoralan over 3 weeks resulted in a 41% increase in diastolic time and a 39% increase in the subendocardial viability ratio, an index of myocardial oxygen supply and demand. This shows that Procoralan improves perfusion and has a positive impact on myocardial ischemia.14 These results are of major importance when the oxygen supply to the myocardium reaches the ischemic threshold in patients with angina pectoris.

Preservation of coronary vasodilatation
β-Blockers unmask α-adrenergic vasoconstriction, as is apparent to physicians when patients complain about Raynaud’s syndrome or cold fingertips after β-blockade. β-Blockade also unmasks α-adrenergic vasoconstriction in coronary arteries, as demonstrated in experimental dog models15 and in humans.16 In contrast, Procoralan does not unmask α-adrenergic vasoconstriction.17 Experimental data show that β-blockade results in constriction of coronary arteries during exercise, while Procoralan preserves coronary vasodilation during exercise, despite producing a similar reduction in heart rate.17 Importantly, α-adrenergic vasoconstriction is enhanced in the presence of endothelial dysfunction. Therefore, the ability of Procoralan to preserve coronary dilation during exercise is of major therapeutic importance in patients with CAD.

Improvement in endothelial function
Experimental data indicate that Procoralan may prevent deterioration of endothelial function in dyslipidemic mice,18 and recent clinical data suggest that Procoralan improves endothelial function in stable angina patients. Jedlickova et al used an Endo-PAT 2000 device to assess endothelial function in 30 stable angina patients treated with Procoralan for 3 months.19 They observed a significant improvement in mean reactive hyperemia index, which suggests improved endothelial function. Another recently published study—the RIVENDEL study (heart Rate reduction by IVabradine for improvement of ENDothELial function in patients with coronary artery disease)— evaluated the effect of Procoralan on endothelial function in 70 patients with CAD after complete revascularization by percutaneous coronary angioplasty. Patients were randomized to Procoralan 5 mg twice daily, subsequently uptitrated to 7.5 mg twice daily, or to continued standard medical therapy (control group).20 Procoralan significantly reduced heart rate and improved brachial artery reactivity, as witnessed by increases in flow-mediated dilation (12.2%±6.2% after 4 weeks, 15.0%±7.7% after next 4 weeks; P<0.001) and nitroglycerin mediated dilation (16.6%±10.4% after 4 weeks, 17.7%±10.8% after next 4 weeks; P<0.001). No significant changes were observed in the control group.

Improvement of coronary flow reserve
Coronary flow reserve (CFR) reflects the functional capacity of the coronary circulation to adapt to increased blood demand during cardiac work. Abnormal CFR can be due to narrowing of the epicardial coronary arteries or, in the absence of angiographically demonstrable obstructive CAD, may reflect dysfunction of the coronary microcirculation. The latter can be caused by structural or functional changes, which may involve endothelial dysfunction. Skalidis et al studied the effect of treatment with Procoralan on CFR in the “non-culprit vessel” in 21 patients with angina.21 Procoralan increased hyperemic coronary flow velocity in response to intracoronary adenosine and CFR (3.51±0.81 versus 2.78±0.61 at baseline, P<0.001). CFR at a pacing heart rate similar to baseline heart rate remained significantly improved compared with baseline. Therefore, improvement of CFR even after heart rate correction may suggest that Procoralan improves the microcirculation. In a more recent randomized, controlled study, Tagliamonte et al compared the effects of bisoprolol and Procoralan on CFR in 59 patients with stable CAD.22 After one month of treatment, CFR was increased in both groups, but significantly more in the Procoralan group than the bisoprolol group (3.52±0.64 versus 3.35±0.70, respectively; P<0.01), despite a similar reduction in heart rate.

Improvement in coronary collateral circulation
he development of collateral circulation is a natural mechanism that compensates for decreasing coronary flow as coronary artery stenosis progresses and protects the myocardium from ischemia. Procoralan promotes the development of coronary collaterals both in experimental models and in clinical trials. In an apolipoprotein E–deficient mouse model with hind limb ligation, Schirmer et al reported that Procoralan-induced heart rate reduction stimulated collateral artery growth.23 In a study in post-infarct remodeled hearts, reduction of heart rate with Procoralan promoted growth of coronary vessels in the surviving portion of the left ventricular myocardium.24 These experimental data are in line with clinical findings. In a recent proof-of-concept study, Gloekler et al examined the effect of heart rate reduction by Procoralan on coronary collateral function.25 In this randomized placebo-controlled study in 46 patients with stable CAD, coronary collateral function was assessed by invasive measurement of a collateral flow index (CFI) during balloon occlusion by means of a pressure guide wire distal to the balloon-occluded artery. CFI did not differ in the placebo group, but increased from 0.107±0.077 at baseline to 0.152±0.090 in the Procoralan group (P=0.0461). This improvement of CFI was accompanied by reduced ECG signs of ischemia.

Antianginal efficacy of Procoralan in combination with β-blockers in patients with angina

Throughout its development program, Procoralan effectively reduced angina attacks and improved exercise capacity in angina patients. Procoralan substantially reduced the frequency of angina attacks and the consumption of short-acting nitrates compared with placebo,26 standard antianginal therapies such as β-blockers or calcium channel blockers27,28 in the short term (2 to 3 months), and maintained antianginal efficacy in long-term (1 year) therapy, without development of pharmacological tolerance.29 Procoralan also showed significant anti-ischemic efficacy and improved exercise capacity, effects that are clinically important in angina. Procoralan improved time to 1-mm ST-segment depression, time to angina onset, and time to limiting angina in monotherapy,25,26 and in patients receiving β-blocker therapy.30 In addition, the clinical benefit of Procoralan is also confirmed in day-to-day practice when added to β-blockers, with significant reductions in angina attacks and short-acting nitrate consumption.31

The ASSOCIATE trial (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.30 In this double-blind trial, 889 patients on 50 mg atenolol daily were randomly assigned to additional treatment with either Procoralan up to 7.5 mg twice daily or a placebo for 4 months. This study clearly demonstrates that, in patients with stable angina receiving the β-blocker atenolol, Procoralan further improved significantly all parameters of the exercise test, at 2 and 4 months. 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 Procoralan with β-blockers the best evidence-based combination therapy for angina patients. In addition, treatment was well tolerated: less than 1% of patients stopped drug therapy because of side effects (generally bradycardia), and minor reversible visual effects were reported by 2% of the Procoralan-treated patients and 0.9% of the placebotreated patients.

Procoralan also showed substantial antianginal efficacy in day-to-day practice in the large open-label, multicenter ADDITIONS study (PrActical Daily efficacy anD safety of Procoralan® In combinaTION with betablockerS) conducted in a broad range of patients with stable angina. Procoralan added to β-blockers in 2330 patients with stable angina resulted in a significant reduction in angina attacks and short-acting nitrate consumption (from 1.7 to 0.3 and from 2.3 to 0.4 units per week, respectively).31 In addition to reducing angina attacks, Procoralan improved quality of life—assessed using the EQ-5D questionnaire (both the EQ-5D index and the EQ-5D visual analog scale)—throughout 4 months of treatment.

Figure 2. Increase in exercise capacity by Procoralan plus b-blocker
vs uptitration of b-blocker in patients with stable angina.
Based on data from reference 32: Amosova E et al. Cardiovasc Drugs Ther.
2011;25(6):531-537. © 2011, Springer Science+Business Media, LLC.

Two studies have addressed an important practical question: Is combining Procoralan and β-blocker therapy a more effective strategy for angina control than uptitration of β-blockers? Amosova et al compared the efficacy of a combination of Procoralan 7.5 mg twice daily with 5 mg od bisoprolol versus a full dose of bisoprolol (10 mg once daily) in patients with stable angina.32 Two months of treatment with Procoralan substantially reduced the mean weekly number of angina attacks compared with bisoprolol alone (from 3.3 to 1.7 vs from 3.2 to 2.5, respectively; P between groups, 0.041). As a result, there were more patients with CCS class I angina in the group with Procoralan than in the group with bisoprolol alone (82% vs 67%, respectively; P=0.037). Addition of Procoralan also improved exercise capacity, as shown by the results of the 6-minute walking and exercise tolerance tests, whereas in the bisoprolol group neither parameter was significantly affected (Figure 2). These results suggest that combining Procoralan with low-dose bisoprolol provides better antianginal and anti-ischemic efficacy than uptitration of bisoprolol in stable angina patients.

The above results were once again confirmed in a 16-week, multicenter, open-label comparative study (the CONTROL 2 study), which assessed the efficacy of combinations of Procoralan and β-blockers compared with uptitration of β-blockers in 1104 patients with stable angina.33 Addition of Procoralan to β-blockers resulted in a significantly lower heart rate than β-blocker uptitration at the end of the study (61±6 vs 63±8 bpm, P=0.001). At the end of the study more patients were free from angina (50.6% vs 34.2%, P<0.001) in the Procoralan combination group. The number of angina attacks for the last 8 treatment weeks was also significantly lower in the Procoralan group (4 [2;10] vs 6 [2;15], P=0.015). This resulted in significantly better quality of life assessed using a visual analog scale in the Procoralan group (P<0.001). Uptitration of β-blockers resulted in a twofold higher rate of adverse reactions compared with addition of Procoralan (18.4% vs 9.4%, P<0.001). Dyspnea (1.3% vs 0, P=0.009), hypotension (5.7% vs 0.9%, P<0.001), and fatigue (1.3% vs 0.1%, P=0.03) were significantly more common in the uptitration group than in the Procoralan group. The percentage of bradycardia— defined as heart rate <50 bpm—was equal in the Procoralan and β-blocker uptitration groups (0.7% vs 0.4%, P=1.0). This study demonstrated that combination therapy with Procoralan and β-blockers significantly improved angina symptoms and quality of life, with better tolerability than for β-blocker uptitration.

Clinical benefits of Procoralan across a wide range of angina patients

The antianginal efficacy of Procoralan in different subgroups of patients with stable angina was analyzed using pooled data from randomized clinical trials in the angina development program. 10 Data on the frequency of angina attacks, short-acting nitrate consumption, and heart rate were pooled from 5 randomized trials in patients with stable angina pectoris treated with Procoralan for 3 or 4 months. A recent pooled analysis of data from observational studies provides complementary data on the effectiveness and safety of Procoralan in real-life clinical situations.11 For this analysis, data were pooled from three German observational studies in stable angina patients receiving Procoralan for 4 months. Data from these two pooled analyses show that Procoralan diminishes angina in all types of patients, regardless of age, sex, angina severity, revascularization status, history of MI, peripheral vascular disease, or diabetes (Figure 3). Such clinical benefits show that Procoralan is valuable for symptomatic treatment of patients with angina pectoris.

Patients with a history of coronary revascularization
As CAD is a diffuse disease process, frequently involving the entire coronary vasculature, systemic treatments such as medical therapy are essential in controlling ischemia and angina. In the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation), only 4 of 10 patients treated with percutaneous coronary intervention (PCI) on top of medical therapy did not have angina 1 month after PCI and up to 40%-50% of patients were symptomatic 6 to 36 months after PCI.2 A recent meta-analysis confirmed that recurrent angina in the first year after PCI is seen in one-third of patients.3

The data from the two pooled analyses cited above10,11 show that Procoralan reduces angina attacks and the use of short acting nitrates in patients with a history of revascularization. Clinical data show that, even 3 to 6 months after PCI, endothelium- dependent vasodilation was impaired not only at the site of previous maximal stenosis, but also in segments directly injured by balloon inflation.34 In the recent RIVENDEL study, Procoralan improved endothelial function in CAD patients after PCI.20 Procoralan may, therefore, help maintain coronary dilation, and thus prevent microvascular dysfunction and recurrence of angina after coronary intervention.

Patients with a history of myocardial infarction
Rates of coronary heart disease death have fallen since the late 1970s. Data from the MONICA study (MONItoring trends and determinants in CArdiovascular disease)35 show that this trend has in part been due to a fall in the rate of occurrence of new major coronary events. However, falling incidences of MI in many countries have been largely offset by an increase in the incidence of angina.36 One-fifth of patients report angina symptoms 1 year after acute MI.37 Furthermore, these patients have a high risk of developing left ventricular systolic dysfunction (LVSD) and heart failure (HF), which occur in approximately 40% of acute MI patients.38 A large proportion of patients (up to 50%) in the two pooled analyses cited above10,11 had a history of MI. Procoralan significantly reduced angina attacks (by 86%) and short-acting nitrate consumption (by 87%) in these patients.11

Patients with left ventricular systolic dysfunction or heart failure
CAD is the major cause of chronic LVSD and HF, because of irreversible myocyte loss with scar formation and/or hibernating myocardium, ie, chronically dysfunctional but viable tissue, which improves function after revascularization.39 Furthermore, repeated episodes of myocardial ischemia followed by chronic stunning could be a potential mechanism of hibernation. A recent study demonstrated that Procoralan can limit episodes of stunning in patients with angina,40 and this cardioprotective effect, together with the anti-ischemic properties of Procoralan, could play a significant role in limiting progression to myocardial hibernation and LVSD. This mechanism could explain, at least in part, the reduction in coronary events in patients with CAD and LVSD seen in the population of the BEAUTIFUL study (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) with a resting heart rate ≥70 bpm.41 In patients with angina and heart rate ≥70 bpm, Procoralan reduced the risk of hospitalization for MI by 73%, with a 59% reduction in coronary revascularization. Procoralan was safe and well tolerated.42 These data suggest that Procoralan may reduce major coronary events in patients with stable CAD and LVSD who present with limiting angina.

Figure 3. Antianginal effectiveness after 4 months of treatment with Procoralan in different subpopulations.
Bars are relative changes from baseline (mean ± standard deviation). The values shown in the bars are absolute changes from baseline (mean ± standard deviation).
P<0.0001 for all changes.
From reference 11: Werdan K et al. Cardiology. 2016;135(3):141-150. © 2016 The Author(s). Published by S. Karger AG, Basel.

Procoralan improves prognosis in patients with chronic HF, as demonstrated by SHIFT (Heart failure treatment with If inhibitor Procoralan Trial), a randomized, placebo-controlled, clinical trial in 6558 patients with chronic HF and LVSD.43 The primary composite end point (cardiovascular death or hospital admission for worsening HF) was significantly reduced by 18% (P0.0001). Results were consistent across all 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 one cardiovascular death or HF-related hospital admission. Procoralan significantly reduced HF death by 26% (P=0.014) and hospitalization for HF by 26% (P<0.0001). Cardiovascular death and all-cause death diminished by 9% and 10%, respectively (both not significant). In patients with a heart rate of 75 bpm or higher, there were statistically significant reductions of 17% in all-cause death (P=0.0109) and 17% in cardiovascular death (P=0.0166).44 Of 6505 patients in SHIFT, 2220 (34%) reported angina at randomization. A recently published analysis suggests that the outcome benefits of Procoralan among such patients are maintained and are similar to those seen in individuals without angina and all patients with chronic HF.45

The recent ESC Guidelines on HF acknowledge the advantages of Procoralan in this population and recommend it as the antianginal of choice together with β-blockers, ahead of other antianginal agents such as nitrates, amlodipine, nicorandil, or ranolazine.46

Patients with concomitant diabetes
In two studies, nearly 19% of angina patients in a pooled population from randomized controlled trials and 46% of angina patients from daily clinical practice had diabetes.10,11 Recent trial data indicate that 82% of patients with CAD and type 2 diabetes may have angina symptoms despite the use of recommended therapies.47 The need for therapies that effectively reduce symptoms is thus essential. In addition, diabetic patients often develop cardiac autonomic neuropathy, leading to elevated sympathetic tone and resting tachycardia.48 As a result, a large proportion of angina patients who have diabetes may be eligible for Procoralan treatment. In this population, Procoralan was associated with significant reductions of 60% and 86% in angina attacks and of 61% and 85% in the use of short-acting nitrates in the pooled population from randomized controlled trials and the pooled population from observational studies, respectively.10,11 These data are consistent with the improved exercise tolerance and reduced angina symptoms observed in randomized controlled trials with Procoralan in subgroups of patients with angina and diabetes.48 Another important point to consider is that Procoralan does not alter glycosylated hemoglobin (HbA1c) and fasting glucose, whereas atenolol and amlodipine increase both.49

Elderly patients with angina
Elderly patients with stable angina represent a growing population with specific characteristics. They are hard to treat because of a higher prevalence of comorbidities and more frequent side effects or intolerance to drugs.50 Procoralan significantly reduced angina attacks and consumption of shortacting nitrates in a subgroup of 91 elderly patients with stable angina in a pooled analysis of randomized controlled trials.10 Pooled analysis of observational studies confirmed the antianginal effectiveness of Procoralan in more than 1600 patients aged ≥75 years seen in real clinical practice.11 In addition to the reduction in angina attacks (by 84%) and in use of short-acting nitrates (by 82%), Procoralan significantly improved quality of life in this elderly population with impaired health status scores at baseline.11 Importantly, all these beneficial effects were accompanied by a good safety profile, as the rate of adverse events was similar to that in younger patients.11

Patients undergoing cardiac rehabilitation
Cardiac rehabilitation is an integral part of the contemporary treatment of patients with multiple presentations of CAD and HF, because such measures cost-effectively reduce future morbidity and mortality, ameliorate symptoms, and increase exercise capacity. Cardiac rehabilitation is an effective and safe management strategy after MI and coronary revascularization, and in HF patients. In patients with angina who cannot be operated on or revascularized percutaneously, cardiac rehabilitation together with optimal medical therapy can increase the anginal threshold. A recent study demonstrated that the addition of Procoralan to low-dose bisoprolol (1.25 mg once daily) in patients who underwent cardiac rehabilitation after recent coronary artery bypass grafting (CABG) yielded further benefits compared with standard medical therapy including bisoprolol uptitration (2.5 to 3.75 mg once daily).51

Treatment with the Procoralan/bisoprolol regimen shortly after CABG was associated with improved functional status, increased LV ejection fraction, and improved exercise capacity. β-Blockers have well-documented direct effects on cardiovascular and pulmonary function, causing symptoms such as fatigue and dizziness, which limit exercise capacity. Procoralan could play a crucial role in cardiac rehabilitation, as it is devoid of inotropic, lusitropic, or vasoactive effects.52 The different mechanisms of action of Procoralan and β-blockers make their combination a valuable option in patients undergoing cardiac rehabilitation.

Patients treated with β-blockers
In a recent pooled analysis, a combination of Procoralan and metoprolol reduced heart rate, angina attacks, and nitrate use, and improved quality of life in 1376 stable angina patients.11 The investigators considered that this combination therapy was well tolerated, as there was a low rate of reported adverse events, with 1 patient reporting phosphenes and 1 experiencing symptomatic bradycardia with palpitations, although 30.3% of previously uncontrolled patients had a heart rate of 55-60 bpm.

The efficacy and tolerability of Procoralan in combination with metoprolol provide a rationale for a fixed-dose combination of these 2 drugs, which is now available as Implicor. Another combination, that of ivabradine and carvedilol (Carivalan), will be useful for symptomatic treatment of chronic stable angina pectoris for chronic stable angina pectoris or congestive heart failure with left ventricular systolic dysfunction. The use of fixed-dose combination treatments is well known to be associated with a significant reduction in the risk of nonadherence when compared with free combinations. Patel et al demonstrated that, after a year of taking a fixed-dose combination, adherence was significantly higher when compared with patients taking each treatment separately.53

Good tolerability and ease of use

Procoralan is well tolerated in patients with angina. Bradycardia was reported in 2.2% of angina patients treated with Procoralan 7.5 mg twice daily compared with 4.4% with atenolol 100 mg once daily.27 This low percentage is explained by the direct rate-related dynamics of the heart rate–lowering effect, ensuring the greatest heart rate reduction in patients with the highest pretreatment heart rate and limiting the risk of excessive bradycardia. Importantly, abrupt discontinuation of Procoralan does not result in a rebound phenomenon.54

The absence of rebound tachycardia with Procoralan not only simplifies the management of antianginal treatment, but also reduces the risk of adverse effects following missed doses or unscheduled gaps in medication administration. These characteristics of the heart rate–lowering action of Procoralan make it suitable and simple to use in most symptomatic patients with CAD. Procoralan improves exercise capacity and quality of life in patients with angina. Pooled data from the Procoralan angina development program and from observational studies provide clinical evidence that Procoralan diminishes angina in all types of patients, regardless of age, sex, angina severity, revascularization status, history of MI, peripheral vascular disease, or diabetes. ■

1. Hemingway H, McCallum A, Shipley M, et al. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA. 2006;295: 1404-1411.
2. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-1516.
3. Gaglia MA Jr, Torguson R, Lipinski MJ, et al. Frequency of angina pectoris after percutaneous coronary intervention and the effect of metallic stent type. Am J Cardiol. 2016;117:526-531.
4. Bengtsson I, Hagman M, Wedel H. Age and angina as predictors of quality of life after myocardial infarction: a prospective comparative study. Scand Cardiovasc J. 2001;35:252-258.
5. Arnold SV, Morrow DA, Lei Y, et al. Economic impact of angina after an acute coronary syndrome: insights from the MERLIN-TIMI 36 trial. Circ Cardiovasc Qual Outcomes. 2009;2:344-353.
6. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949-3003.
7. Qintar M, Spertus JA, Gosch KL, et al. Effect of angina under-recognition on treatment in outpatients with stable ischemic heart disease. Eur Heart J Qual Care Clin Outcomes. 2016;2:208-214.
8. Camici PG, Gloekler S, Levy BI, et al. Ivabradine in chronic stable angina: Effects by and beyond heart rate reduction. Int J Cardiol. 2016;215:1-6.
9. Pereira-Barretto AC. Addressing major unmet needs in patients with systolic heart failure: the role of ivabradine. Am J Cardiovasc Drugs. 2016;16:93-101.
10. Tendera M, Borer JS, Tardif JC. Efficacy of I(f) inhibition with ivabradine in different subpopulations with stable angina pectoris. Cardiology. 2009;114:116-125.
11. Werdan K, Perings S, Köster R, et al. Effectiveness of ivabradine treatment in different subpopulations with stable angina in clinical practice: a pooled analysis of observational studies. Cardiology. 2016;135(3):141-150.
12. 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:H676-H682.
13. Dillinger JG, Maher V, Vitale C, et al. Impact of ivabradine on central aortic blood pressure and myocardial perfusion in patients with stable coronary artery disease. Hypertension. 2015;66:1138-1144.
14. Heusch G, Skyschally A, Gres P, Van Caster P, Schilawa D, Schulz R. Improvement of regional myocardial blood flow and function and reduction of infarct size with Procoralan: protection beyond heart rate reduction. Eur Heart J. 2008;29: 2265-2275.
15. Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross Jr J. Intracoronary alpha 2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res. 1988;62:436-442.
16. Baumgart D, Haude M, Gorge G, et al. Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999;99:2090-2097.
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;275:659-666.
18. 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;154:749-757.
19. Jedlickova L, Merkovska L, Jackova L, et al. Effect of ivabradine on endothelial function in patients with stable angina pectoris: assessment with the Endo- PAT 2000 device. Adv Ther. 2015;32:962-970.
20. Mangiacapra F, Colaiori I, Ricottini E, et al. Heart Rate reduction by IVabradine for improvement of ENDothELial function in patients with coronary artery disease: the RIVENDEL study. Clin Res Cardiol. 2017;106:69-75.
21. Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis. 2011;215:160-165.
22. Tagliamonte E, Cirillo T, Rigo F, et al. Ivabradine and bisoprolol on doppler-derived coronary flow velocity reserve in patients with stable coronary artery disease: beyond the heart rate. Adv Ther. 2015;32:757-767.
23. Schirmer SH, Degen A, Baumhakel M, et al. Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis. Eur Heart J. 2012;33:1223-1231.
24. Dedkov EI, Zheng W, Christensen LP, Weiss RM, Mahlberg-Gaudin F, Tomanek RJ. Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen. Am J Physiol Heart Circ Physiol. 2007;293:H590-H598.
25. Gloekler S, Traupe T, Stoller M, et al. The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease. Heart. 2014;100:160-166.
26. Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.
27. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INITIATIVE Investigators. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
28. 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;67:393-405.
29. López-Bescós L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108:387-936.
30. Tardif JC, Ponikowski P, Kahan T; ASSOCIATE Study Investigators. Efficacy of the I(f) 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.
31. Werdan K, Ebelt H, Nuding S, Höpfner F, Hack G, Müller-Werdan U. Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. Clin Res Cardiol. 2012;101:365-373.
32. Amosova E, Andrejev E, Zaderey I, Rudenko U, Ceconi C, Ferrari R. Efficacy of ivabradine in combination with beta-blocker versus uptitration of beta-blocker in patients with stable angina. Cardiovasc Drugs Ther. 2011;25:531-537.
33. Karpov YA, Glezer MG, Vasyuk YA, Saygitov RT. Ivabradine in combination with beta-blocker is more effective than up-titration of beta-blockers in patients with stable angina. Eur Heart J. 2012;13(suppl 1):777.
34. Vassanelli C, Menegatti G, Zanolla L, Molinari J, Zanotto G, Zardini P. Coronary vasoconstriction in response to acetylcholine after balloon angioplasty: possible role of endothelial dysfunction. Coron Artery Dis. 1994;5(12):979-986.
35. Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolonen H, Ruokokoski E, Amouyel P; WHO MONICA (monitoring trends and determinants in cardiovascular disease) project. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA Project populations. Lancet. 1999;353:1547-1557.
36. Lampe FC, Morris RW, Walker M, Shaper AG, Whincup PH. Trends in rates of different forms of diagnosed coronary heart disease, 1978 to 2000: prospective, population based study of British men. BMJ. 2005;330:1046.
37. Maddox TM, Reid KJ, Spertus JA, et al. Angina at 1 year after myocardial infarction: prevalence and associated findings. Arch Intern Med. 2008;168:1310-1316.
38. Hellermann JP, Goraya TY, Jacobsen SJ, et al. Incidence of heart failure after myocardial infarction: is it changing over time? Am J Epidemiology. 2003;157: 1101-1107.
39. Wijns W, Vatner SF, Camici PG. Hibernating myocardium. N Engl J Med. 1998; 339:173-181.
40. Maranta F, Tondi L, Agricola E, Margonato A, Rimoldi O, Camici PG. Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia. Basic Res Cardiol. 2015;110:55.
41. 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;372:807-816.
42. 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;30:2337-2345.
43. 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;376:875-885.
44. Böhm M, Borer J, Ford I, et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol. 2013;102:11-22.
45. Borer JS, Swedberg K, Komajda M, et al. Efficacy profile of ivabradine in patients with heart failure plus angina pectoris. Cardiology. 2016;136:138-144.
46. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur J Heart Fail. 2016;18:891-975.
47. Dagenais GR, Lu J, Faxon DP, et al. Prognostic impact of the presence and absence of angina on mortality and cardiovascular outcomes in patients with type 2 diabetes and stable coronary artery disease: results from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. J Am Coll Cardiol. 2013;61:702-711.
48. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care. 2010;33:434-441.
49. Borer JS, Tardif JC: Efficacy of ivabradine, a selective I(f) inhibitor, in patients with chronic stable angina pectoris and diabetes mellitus. Am J Cardiol. 2010;105: 29-35.
50. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med. 1989;321:303-309.
51. Marazia S, Urso L, Contini M, et al. The role of ivabradine in cardiac rehabilitation in patients with recent coronary artery bypass graft. J Cardiovasc Pharmacol Ther. 2015;20:547-553.
52. DiFrancesco D, Camm AJ. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757-1765.
53. Patel BV, Leslie RS, Thiebaud P, et al. Adherence with single-pill amlodipine/ atorvastatin vs. a two-pill regimen. Vasc Health Risk Manag. 2008;4:673-681.
54. Borer JS, Le Heuzey JY. Characterization of the heart rate-lowering action of ivabradine, a selective I(f) current inhibitor. Am J Ther. 2008;15:461-473.

Keywords: angina, heart rate reduction; If current; Implicor; ivabradine; Procoralan; quality of life