Pharmacologic management of stable angina: role of ivabradine
Cardiology, Centre Hospitalier Bichat-Claude Bernard, 46 rue Henri Huchard. 75018 Paris, France
* Corresponding author. Tel: +33 1 40 25 86 68; fax: +33 1 40 25 88 65. E-mail address: gabriel.steg{at}bch.aphp.fr
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Abstract |
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 Top Abstract Control of risk factorsPrevention of cardiovascular...Control of anginal symptomsUnmet medical needsLimitations of treatment in...Ivabradine: new agent for...Clinical trials of ivabradineComparison with other anti...Current clinical role for...References |
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The current management of patients with stable angina involves control of symptoms, prevention of major cardiovascular events, and treatment of risk factors. Usually, this requires the prescription of multiple pharmacological agents. Recent registries have shown that, despite the use of polypharmacy, many patients have poor symptom control, poor compliance with therapy, suboptimal dosages of drugs, or side effects from medications. In addition, the choice of anti-anginals is often limited in patients with comorbidities, such as heart failure or asthma. Overall, persistent symptoms and/or side effects from treatments affect the quality of life of angina patients. Ivabradine is a specific inhibitor of the If current that lowers heart rate without impacting contractility, conduction, or repolarization. It is safe and its most frequent side effects are mild, dose-related, transient, and reversible visual symptoms. Its clinical efficacy has been established by a series of randomized trials, which have, in particular, outlined that ivabradine is non-inferior to atenolol or amlodipine, has prolonged efficacy over 1 year and is well tolerated. This promising agent has a role in the management of patients with stable angina, particularly when beta-blockers are contraindicated or poorly tolerated, and in addition to other anti-anginals when control of symptoms is insufficient.
Key Words: Beta-blockers • Heart rate • Ischaemia • Ivabradine • Stable angina
Current guidelines1–3 have outlined that the management of stable angina has several components: the control of anginal symptoms, the prevention of cardiovascular events, such as acute coronary syndromes, stroke, and cardiovascular death, and the control of risk factors for atherosclerosis, which contributes to preventing or slowing the progression of the disease.
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Control of risk factors |
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This involves a host of interventions to reduce major modifiable risk factors. Smoking cessation is possibly the most important and generally requires nicotine replacement therapy, associated with proper counselling. Additional pharmacological interventions with drugs such as bupropion may be required. Control of dyslipidaemia and diabetes is also essential and usually requires a combination of lifestyle (particularly dietary) and pharmacological interventions. In hypertensive patients, control of blood pressure to target levels of
140/90 mmHg (130/80 mmHg among diabetics) has been demonstrated to reduce drastically the risk of recurrent events. Finally, regular physical activity should be encouraged and stress management is recommended. |
Prevention of cardiovascular events |
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Three main pharmacological classes have been demonstrated to be associated with improvement in clinical outcomes in patients with coronary artery disease: anti-platelet agents, statins, and angiotensin-converting enzyme inhibitors.
Anti-platelet agents
They are of proven efficacy in preventing cardiac events and death in all forms of established coronary heart disease: unstable angina, acute myocardial infarction, but also stable angina. A collaborative analysis of trials of anti-platelet agents showed a 22 per thousand absolute reduction in the risk of adverse vascular events for 2 years of treatment in patients with stable angina.4 Thus, aspirin is widely recommended for patients with all forms of ischaemic heart disease, including patients with stable angina, in the absence of contraindication. In patients who are intolerant or allergic to aspirin, thienopyridines, and specifically clopidogrel may be an alternative therapy.3 When aspirin is absolutely necessary (e.g. for patients who do not have prolonged access to clopidogrel or when the patient has received a stent), desensitization to aspirin can be performed.5 Although there are no data available regarding the specific group of patients with stable angina, the Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial suggests that in a secondary prevention trial of cardiovascular disease,6 clopidogrel is at least as effective as aspirin. Combination therapy with aspirin and clopidogrel has been tested in stable high-risk cardiovascular patients, including patients with stable angina, in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management, and Avoidance (CHARISMA) trial, but failed to demonstrate overall benefit, although further studies are warranted to explore a potential benefit in patients with established prior cardiovascular events.7
Statins
There is a solid evidence for the reduction in cardiovascular events with statin therapy in patients with elevated cholesterol. The Heart Protection Study demonstrated that treatment with 40 mg of simvastatin was associated with the reduction in all-cause mortality in patients at high risk of cardiovascular events, including patients with ‘normal’ lipid levels and with the substantial (odds ratio 0.76) reduction in the risk of any vascular event in patients with all forms of coronary heart disease. More recently, the Treating to New Targets randomized trial8 demonstrated that intensive lipid-lowering therapy with a high dose of atorvastatin, to lower low-density lipoprotein (LDL) cholesterol levels below 1 g/L (mean 0.77 g/L) in patients with stable angina was associated with significant clinical benefit, compared with a group treated with a lower dose (10 mg of atorvastatin), which reached the ‘conventional’ target of 1 g/L LDL.8 Therefore, aggressive lipid-lowering treatment should be initiated in patients with established coronary artery disease such as stable angina and probably target LDL cholesterol levels below 0.70 g/L.9
Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme inhibitors are of proven efficacy for treating hypertension and heart failure and also for patients with left ventricular dysfunction following myocardial infarction. The Heart Outcomes Prevention Evaluation (HOPE) trial10 established the benefit of a 10 mg dose of ramipril in 9297 patients at high risk of cardiovascular events, defined as age >55, with evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low-ejection fraction or heart failure. In that trial, total mortality was reduced by 16% (P=0.006), and the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke was reduced from 17.7 to 14.1% (P<0.001). The randomized EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA)11 established the ability of perindopril to reduce cardiovascular death, myocardial infarction, and cardiac arrest in patients with stable coronary artery disease and without heart failure or hypertension. After 4.2 years of follow-up, patients assigned to perindopril had a lower rate of cardiovascular death, myocardial infarction, or cardiac arrest than patients randomized to placebo (8.0 vs. 9.9%, P=0.0003). This was associated with a consistent benefit on secondary endpoints, notably the combined endpoint of total mortality, myocardial infarction, unstable angina, and cardiac arrest (14.8 vs. 17.1%, P=0.0009), which had been the original primary endpoint of the study. With respect to the primary endpoint of the trial, approximately 50 patients must be treated for 4 years to prevent one major cardiovascular event. EUROPA confirms and extends the results seen in the HOPE trial. In aggregate, these two trials strongly suggest that all patients with coronary artery disease should receive perindopril 8 mg or ramipril 10 mg daily. More recently, the Prevention of Events with Angiotensin-Converting Enzyme inhibition (PEACE) trial did not find benefit of 4 mg of trandolapril.12 A meta-analysis of all clinical trials of angiotensin-converting enzyme inhibitors in patients with coronary artery disease but without left ventricular dysfunction, heart failure, or hypertension found a clinical benefit with a 12% relative reduction in all-cause mortality, a 17% reduction in cardiovascular deaths, a 17% reduction in myocardial infarction, and a 23% reduction in the incidence of stroke.13
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Control of anginal symptoms |
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This includes curative and preventive treatment of anginal symptoms with anti-anginal drugs, and revascularization using either coronary artery bypass grafting or percutaneous coronary intervention (PCI).
There are various classes of agents available to control or prevent myocardial ischaemia and anginal symptoms in patients with coronary artery disease, including beta-blockers, calcium channel blockers, nitrates and nitrate-like agents (e.g. molsidomine), metabolic agents (e.g. trimetazidine or ranolazine), and potassium channel blockers (e.g. nicorandil). It is generally estimated that these agents have a similar efficacy against angina (judged from the number of angina attacks or the use of rapid-acting nitrates) or against ischaemia (judged from the duration of exercise on a stress test). Yet, most of these agents have not been proved to reduce morbidity/mortality in patients with angina, largely because of the small number of trials performed and because of the low-background rate of events in patients with stable coronary artery disease.
Beta-blockers
Beta-blockers represent the cornerstone of anti-ischaemic therapy for stable effort angina (in patients with pure rest angina related to coronary spasm with angiographically normal coronary arteries, beta-blockers are ineffective and may in fact exacerbate symptoms by resulting in unopposed alpha-receptor activation).
The benefit of beta-blockers may well extend beyond their ability to control anginal symptoms. The survival benefit of beta-blockers in secondary prevention after myocardial infarction14 suggests that they might be effective in preventing recurrent episodes of instability and myocardial infarction. In addition, considering the role of the sympathetic nervous system in triggering ventricular tachyarrythmias, beta-blockers may also be beneficial to patients with stable angina by preventing ventricular arrhythmias or sudden death. However, no trial has unequivocally established this in patients without previous infarction. In addition, because of the side effects of beta-blockers (related to their action on left ventricular function, conduction or blood pressure or to extracardiac effects such as exacerbation of chronic obstructive pulmonary disease or erectile dysfunction), many patients cannot tolerate long-term therapy with these agents.
Calcium-blockers
As a class, calcium antagonists appear very similar to beta-blockers in relieving anginal symptoms in chronic stable angina.3 These agents have been shown to be very effective in reducing angina in patients with vasospastic angina. Yet, their impact on patient's outcomes has been the subject of intense debate: some,15 but not all, analyses of retrospective case–control studies in hypertensive patients have shown increased risks of myocardial infarction with calcium antagonists, mostly with immediate or short-acting dihydropyridines. The 2002 American College of Cardiology (ACC)/American Heart Association (AHA) updated guidelines for the management of chronic stable angina have indicated that relatively short-acting dihydropyridine calcium antagonists have the potential to enhance the risk of adverse cardiac events and should be avoided, whereas long-acting calcium antagonists, including slow release and long-acting dihydropyridines and non-dihydropyridines are effective in relieving symptoms and should be used in combination with beta-blockers if they are not sufficient or a substitute when they are contraindicated or have unacceptable side effects.3 Recently, A Coronary Disease Trial Investigating Outcome with Nifedipine GITS (ACTION) trial compared the long-acting gastrointestinal therapeutic system (GITS) formulation of nifedipine with placebo.16 This is in contrast to the previous studies that have used short-acting formulations of nifedipine. Just under 8000 patients were followed for a mean of 4.9 years. Mortality was 1.64 per 100 patient-years among patients allocated to nifedipine compared with 1.53 on placebo (P=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (P=0.54). Nifedipine had no effect on the rate of myocardial infarction. These data suggest that long-acting nifedipine is safe in the context of stable angina.
Nitrates
Nitrates are highly effective in relieving anginal symptoms, for which short-acting sublingual spray or tablet preparations are mostly used. In addition, transdermal or oral long-acting nitrates also prevent ischaemic episodes and anginal recurrences. Despite their unequivocal efficacy in curing or preventing anginal attacks, there have not been outcome studies performed to demonstrate the benefit of nitrates on clinical outcomes in stable angina. Thus, presently, this class of agents is mostly indicated for symptom relief and prevention, alone or in addition to beta-blockers or calcium-blockers.
Nicorandil
Nicorandil is a potassium channel activator that has haemodynamic effects similar to those of nitrates and appears effective in the treatment of stable angina. In addition to its anti-ischaemic properties, this agent may have cardioprotective effects related to mimicking the myocardial preconditioning effect. The Impact Of Nicorandil in Angina (IONA) trial17 has demonstrated that, in patients with stable angina, nicorandil was associated with a reduction in the combined endpoint of coronary heart disease death, non-fatal myocardial infarction or unplanned hospitalization for cardiac chest pain after a mean follow-up of 1.6 years (15.5 vs. 13.1% in the placebo and nicorandil groups, respectively, P=0.014). The trial did not demonstrate the reduction in mortality or combined mortality and non-fatal myocardial infarction.
Metabolic agents
Trimetazidine has been shown, in several double-blind randomized trials, to improve exercise capacity and anginal symptoms.18 These symptomatic benefits are equivalent to those of propranolol or nifedipine and additive with diltiazem or metoprolol.19 Another agent is ranolazine, which has been shown to be effective in improving symptoms in patients with chronic stable angina, notably in the recent Combination Assessment of Ranolazine In Stable Angina (CARISA) placebo-controlled randomized trial.20,21 However, for both of these agents, no benefit on clinical outcomes has been demonstrated yet.
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Unmet medical needs |
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TopAbstractControl of risk factorsPrevention of cardiovascular...Control of anginal symptomsUnmet medical needsLimitations of treatment in...Ivabradine: new agent for...Clinical trials of ivabradineComparison with other anti...Current clinical role for...References |
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Despite this host of therapies available for the management of stable angina, there remain important unmet medical needs, which have been highlighted by recent registries and polls regarding treatment of patients with coronary artery disease, particularly the EuroHeart Survey on angina.22–25
Poor symptom control
Even in the revascularization era, many stable angina patients suffer from persistent anginal symptoms and/or silent ischaemia. For example, after successful revascularization for stable angina, a condition theoretically at low risk of acute events, myocardial ischaemia often persists, and, in the majority of cases is silent.26 Data from the National Heart, Lung, and Blood Institute (NHLBI) Dynamic registry that enrolled 1755 consecutive PCI patients (including 26% with angina in the previous 6 weeks) show that 1 year later, event rates were high, and higher among patients with more severe angina prior to revascularization.27 The same study also showed that the combined prevalence of angina and events was superior to 18%. Finally, use of anti-anginal medications was needed in a substantial number of patients, even when they were symptom-free: >60% of the patients were on beta-blockers and roughly a third of the patients were taking at least one other anti-anginal. Even allowing for the indication of beta-blockers after acute myocardial infarction, these figures demonstrate the relatively frequent need for anti-anginal therapy in patients who undergo successful contemporary percutaneous revascularization. In another study using systematic myocardial perfusion assessment following PCI, 19% of patients complained of angina after PCI and 32% had evidence of ischaemia on perfusion imaging.26 Silent ischaemia impacted negatively on outcomes, but symptomatic ischaemia was associated with a very high rate (52%) of critical events at follow-up. In some patients, the problem of chronic refractory angina may be major,28 prompting the study of new, unorthodox therapies, such as spinal cord stimulation, external counterpulsation, laser therapy, etc.
Side effects of anti-anginal drugs
Current anti-anginal agents almost all have frequent and sometimes severe side effects, most of which are related to their haemodynamic impact. Even side effects that are considered as relatively mild (e.g. headaches with nitrates or leg oedema with calcium-blockers), although certainly not life-threatening, are common causes for treatment discontinuation. The problem of side effects is even bigger given the frequency of use of ‘combination therapy’ with several anti-ischaemic agents to prevent or control ischaemic symptoms. In that case, side effects such as hypotension, leg oedema, and negative inotropy become much more frequent. A frequent side effect of beta-blockers is erectile dysfunction, which affects quality of life and may result in poor compliance or even discontinuation of therapy. The net result of the combination of poor symptom control and of the side effects of anti-anginal drugs is that many patients with angina have persistent alterations in quality of life.
Poor compliance
As the treatment of stable angina implies use of pharmacological therapy to control ischaemic symptoms (anti-anginal agents) and of therapy to prevent cardiovascular events (e.g. statins, anti-platelet agents, and angiotensin-converting enzyme inhibitors), most patients need to take four or more medications long term. In addition, proper control of risk factors such as diabetes or hypertension, per se, may require additional long-term pharmacological therapy. In this context, it is not unusual to see patients who need to take seven or eight different agents every day. This is obviously associated with low long-term compliance.
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Limitations of treatment in patients with comorbidities |
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TopAbstractControl of risk factorsPrevention of cardiovascular...Control of anginal symptomsUnmet medical needsLimitations of treatment in...Ivabradine: new agent for...Clinical trials of ivabradineComparison with other anti...Current clinical role for...References |
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There are patient subsets that are difficult to treat, for example, patients with angina pectoris and congestive heart failure. While their prognosis is far more severe than patients with angina of the same age, treatment options are often limited in this group. In the context of acute heart failure, it is impossible to institute beta-blockers or other negative inotropic anti-anginal agents, and it is usually necessary to discontinue them if they were previously prescribed. Therefore, in that context, nitrates and nitrate-like agents are often the only anti-ischaemic therapy that can be used. In fact, despite the overall frank clinical benefit of beta-blockers in chronic heart failure, patients with angina and congestive heart failure remain undertreated with beta-blockers.29
Overall, these limitations of current therapies of stable angina are not cosmetic: they explain the well-documented and persistent lag between guidelines and practice22,23 and, given the relation between guideline-based care and outcomes,30–33 they explain the persistently poor prognosis of patients with stable angina.24,34 In the recent EuroHeart Survey of stable angina, the rates of death or myocardial infarction in the first year after enrolment were 2.3 per 100 patient-years and the rate was 3.9 per 100 patient-years in the group with angiographic confirmation of coronary disease.24 Similar rates have been observed in the ongoing global REduction of Atherothrombosis for Continued Health (REACH) registry.35
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Ivabradine: new agent for treatment of angina pectoris |
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TopAbstractControl of risk factorsPrevention of cardiovascular...Control of anginal symptomsUnmet medical needsLimitations of treatment in...Ivabradine: new agent for...Clinical trials of ivabradineComparison with other anti...Current clinical role for...References |
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Ivabradine (Procoralan®) is a selective and specific inhibitor of the sinus node f channel.36 Therefore, its administration produces inhibition of the If current and substantial heart rate lowering. Because direct If inhibition depends on the current driving force, ivabradine is most effective at higher heart rates.37 Pharmacological studies with ivabradine have shown that it is associated with pure heart rate lowering effects, without effect on contractility of the left ventricle, on cardiac conduction, corrected-QT interval,38 or on peripheral vasomotion. There is no rebound effect with drug cessation or tolerance with prolonged use. It also does not have some of the negative lusitropic effects seen with beta-blockade, related to depression of the exercise-induced acceleration of relaxation.39 Contrary to beta-blockers, If inhibition increases stroke volume and may improve left ventricular function and ventricular remodelling.40,41
The side effects of ivabradine are dose-related visual symptoms, the majority being phosphene-like events (luminous phenomena). These effects have been most frequent with high doses (10 mg twice daily), are transient and always reversible and are related to the action of the drug on retinal hyperpolarization-activated cyclic nucleotide gated (HCN1) channels, similar to those mediating If.
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Clinical trials of ivabradine |
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Ivabradine has been studied in several randomized clinical trials, either comparing it with placebo or with active anti-anginal medications.
Anti-ischaemic efficacy of ivabradine
The efficacy of ivabradine was studied in a randomized, placebo-controlled, dose-ranging study in 360 patients with stable angina and documented coronary artery disease,42 in which patients were randomly assigned to receive placebo or one of the three oral doses of ivabradine for 2 weeks (2.5, 5, or 10 mg bid). At the trough of drug activity, ivabradine produced dose-dependent reductions in the heart rate at rest and exercise (Figure 1), which were associated with anti-ischaemic and anti-anginal effects (increases in time to ST-segment depression and angina) during exercise treadmill testing. There were no rebound or tolerance phenomena. Visual symptoms were reported by approximately 15% of patients receiving the highest dose (10 mg bid) and <2% of patients receiving the 5 and 2.5 mg doses. All resolved spontaneously.
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The long-term efficacy and safety of ivabradine was studied in 386 patients with stable angina and documented coronary artery disease, who received either ivabradine 5 or 7.5 mg bid for 12 months, on top of standard medications. Both doses were effective in reducing heart rate and the number of angina attacks and the drug was safe and well tolerated. Mild transient phosphenes were the most frequently reported adverse events.43
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Comparison with other anti-anginals |
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TopAbstractControl of risk factorsPrevention of cardiovascular...Control of anginal symptomsUnmet medical needsLimitations of treatment in...Ivabradine: new agent for...Clinical trials of ivabradineComparison with other anti...Current clinical role for...References |
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Ivabradine was compared with atenolol in the randomized INternatIonal TrIAl on the Treatment of angina with IVabradinE vs. atenolol (INITIATIVE) study.44 In this study, 939 patients with stable angina received ivabradine 5 mg bid for 4 weeks and then either 7.5 or 10 mg bid for 12 weeks or atenolol 50 mg od for 4 weeks and then 100 mg od for 12 weeks. The efficacy was judged on repeated treadmill exercise tests at baseline, 4, and 16 weeks. Ivabradine was non-inferior to atenolol in terms of increases in total exercise duration at M1 and M4 with a non-significant trend for a dose-dependent superiority of ivabradine (Figure 2). Therefore, ivabradine was as effective as atenolol on exercise capacity in patients with stable angina.
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Ivabradine was compared with amlodipine as monotherapy for chronic stable angina45 in a double-blind, parallel-group non-inferiority trial in 1195 patients with documented coronary artery disease and a history of stable angina for at least 3 months. Patients received 7.5 or 10 mg bid of ivabradine or amlodipine 10 mg od for 3 months. Total exercise duration at trough, measured during bicycle exercise tolerance tests performed monthly, was similar in the three groups as were time to limiting angina, time to angina onset, and time to 1 mm ST-segment depression. Therefore, ivabradine was, in that study, as effective (and safe) as amlodipine.
Finally, a small pilot placebo-controlled randomized study in 65 patients with coronary artery disease and moderate left ventricular systolic dysfunction has suggested that ivabradine may be associated with improved left ventricular remodelling.46 The clinical utility of ivabradine in that patient population is currently being explored in the morBidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIfUL), a large-scale international randomized trial.
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Current clinical role for ivabradine |
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TopAbstractControl of risk factorsPrevention of cardiovascular...Control of anginal symptomsUnmet medical needsLimitations of treatment in...Ivabradine: new agent for...Clinical trials of ivabradineComparison with other anti...Current clinical role for...References |
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Given the current data on its efficacy and safety, there appears to be an important role for ivabradine: it is an effective and safe anti-anginal agent, with anti-ischaemic efficacy that appears non-inferior to atenolol and amlodipine. Its efficacy appears maintained over the long term, and there is no risk of rebound after discontinuation or of tolerance during prolonged therapy. It is safe, with no cardiac side effects, and its main side effect is related to mild, transient and always reversible visual effects, which are dose-related. It does not interfere with cardiac, respiratory, or sexual function. Its efficacy does not appear lessened in specific patient populations in whom other anti-anginal agents may be either contraindicated or less well tolerated (e.g. diabetics, patients with asthma, the elderly). It is a logical addition to the treatment of stable angina patients who are intolerant or have contraindications to beta-blockers. It is also a logical addition to the treatment of such patients when symptoms are not controlled by previous anti-anginal medications. This role is outlined in the recent algorithm for the medical management of stable angina (Figure 3).
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Conflict of interest: P.G.S. has received honoraria for consulting or speaking from AstraZeneca, Bristol-Myers-Squibb, GSK, MSD, Novartis, Sanofi-Aventis, Servier, Takeda. D.T. has no conflict of interest to report.
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