Calcium channel blockers in the management of chronic coronary syndrome

INTRODUCTION — Calcium channel blockers are a heterogeneous group of compounds used in a variety of cardiovascular disorders such as stable angina pectoris, vasospastic angina, hypertension, hypertrophic cardiomyopathy, and supraventricular arrhythmias.

This topic review will present the major issues regarding the use of calcium channel blockers in the patient with stable angina and the evidence that these drugs are effective. Their role, compared with other drugs, in the overall management of chronic coronary syndrome is discussed separately. (See "Chronic coronary syndrome: Overview of care".)

MECHANISM OF ACTION — Calcium influx into the myocyte initiates a series of events essential for contractility. Calcium entry into the myocyte first triggers intracellular calcium release; the released calcium then binds the regulatory protein troponin, resulting in a calcium-troponin complex which allows actin and myosin to interact and contract. The sequence of events is the same in vascular smooth muscle cells, except that a calcium-calmodulin complex instead of calcium-troponin permits the interaction between actin and myosin. The net effect is vasodilatation; the ensuing fall in blood pressure decreases cardiac work and may contribute to the efficacy of these drugs in the patient with angina.

Calcium channel blockers work by blocking the initial calcium influx into myocytes and vascular smooth muscle cells, preventing the cascade of events detailed above. The available calcium channel blocking agents block receptors on the L-type calcium channel which gives rise to a slowly inactivating high threshold current in cardiac cells.

CARDIOVASCULAR AND ADVERSE SIDE EFFECTS — The currently available calcium channel blockers may be categorized into three groups based upon different chemical structures:

●The dihydropyridines (nifedipine, amlodipine, and others)

●Verapamil, which is structurally similar to papaverine

●Diltiazem, a benzothiazepine derivative

These classes have varying mechanisms of action, leading to different effects on cardiovascular function and different types of side effects.

Dihydropyridines — The dihydropyridines have the following actions:

●They block slow calcium channels in a dose-dependent fashion [1,2].

●They have a greater selectivity for vascular smooth muscle than for the myocardium, making them more potent vasodilators than either verapamil or diltiazem.

●They vasodilate coronary arteries, reduce coronary resistance, increase coronary blood flow, and may enhance the development of coronary collaterals [3,4]. The vasodilatation and increase in coronary artery blood flow result from the blockade of calcium influx as well as an increase the levels of nitric oxide and bradykinin; therefore, the increase in coronary artery blood flow is a result of bradykinin/nitric oxide-dependent and -independent mechanisms [5].

●They elicit a strong reflex beta-adrenergic response, making any potential negative inotropic or chronotropic effect clinically insignificant. This adrenergic response often includes a reflex tachycardia [6].

These actions determine the side effect profile of the dihydropyridines and the clinical settings in which they should or should not be used. Short-acting nifedipine has a relatively high incidence of adverse side effects, including peripheral edema (not related to heart failure), flushing, headaches, and lightheadedness, all caused by peripheral vasodilatation. (See "Major side effects and safety of calcium channel blockers".) These symptoms are less common with long-acting nifedipine or second generation dihydropyridines such as amlodipine and nicardipine.

There are several potential problems that must be considered when using a dihydropyridine in a patient with angina.

●Nifedipine may exacerbate ischemia in some patients by causing a reflex tachycardia, preventing its use in patients with unstable angina or myocardial infarction (MI).

●There is only a mild negative inotropic effect, but these agents should be used with caution in patients with severe myocardial depression.

Verapamil — Verapamil has different physiologic effects from the dihydropyridines because of a different interaction with the calcium channels. Verapamil is effective in angina because it decreases myocardial oxygen demand by acting as a negative inotrope and chronotrope and by lowering the systemic blood pressure. Changes in contractility are minimal in patients without heart disease; however, verapamil can exacerbate heart failure in patients with cardiac dysfunction due to its negative inotropic activity. This effect is more pronounced in patients who are also treated with a beta blocker, a combination that is not generally used. Verapamil also slows cardiac conduction, an effect that may be deleterious in patients with sinus node dysfunction or atrioventricular block.

Verapamil is much less potent vasodilator than the dihydropyridines. As a result, side effects such as headache, flushing, peripheral edema, and lightheadedness are less common. It should be avoided in patients with a left ventricular ejection fraction less than 40 percent.

Diltiazem — Diltiazem has actions that fall between the dihydropyridines and verapamil.

●Diltiazem is a potent coronary but a mild arterial vasodilator, producing improved blood flow through coronary epicardial vessels, collaterals, and normal and ischemic myocardium, as well as lowering mean arterial pressure [7,8].

●It may depress sinus node automaticity and AV nodal conduction time but this effect is less prominent than that seen with verapamil.

●Diltiazem is a negative inotrope.

The net effect is that diltiazem may be somewhat better tolerated than the other calcium channel blockers, since it is neither a potent vasodilator nor a myocardial depressant.

EFFECTIVENESS — All calcium channel blockers are effective in the treatment of stable angina pectoris [9]. However, short-acting nifedipine is limited by reflex tachycardia which may exacerbate ischemia, thereby preventing its use as monotherapy in this disorder. It should be avoided in patients with a left ventricular ejection fraction less than 40 percent.

Dihydropyridines — A number of studies have demonstrated the effectiveness of the dihydropyridines in stable angina [10-12]. In the International Multicenter Angina Exercise (IMAGE) trial, 280 patients with chronic stable angina were randomized to six weeks therapy with long-acting preparations of nifedipine (20 mg BID) or metoprolol (200 mg once daily) [10]. Nifedipine reduced the frequency of angina and increased the mean exercise time to 1-mm ST segment depression. However, the increase in exercise time was less than that seen with controlled-release metoprolol (43 versus 70 seconds, p<0.05).

In patients already treated with beta blockers and/or nitrates, long-acting nifedipine has no significant effect on survival. This was demonstrated in the ACTION trial, in which 7665 patients with angina were randomly assigned to long-acting nifedipine 60 mg daily or placebo [13]. At five years, mortality was similar for nifedipine and placebo (1.64 versus 1.53 deaths per 100 patients per year). Nifedipine did significantly reduce the subsequent rates of coronary angiography and bypass surgery. (See "Goal blood pressure in adults with hypertension".)

Second generation dihydropyridines (such as amlodipine and nicardipine) are also effective antianginal agents. Amlodipine increases exercise duration, decreases the number of anginal attacks, and reduces the consumption of nitroglycerin [12]. It is given once daily (at a dose of five or 10 mg) and is well tolerated. Common side effects of the dihydropyridines are less likely with amlodipine [12].

Nicardipine, a short-acting dihydropyridine with a side effect profile similar to nifedipine, has also been shown to be effective in angina. It is remarkably effective in vasospastic (variant) angina [14].

Reflex tachycardia may limit the effectiveness of nifedipine and, to a lesser degree, the other dihydropyridines in the treatment of stable angina. This can be overcome by the use of nifedipine in combination with a beta blocker. The effectiveness of nifedipine plus propranolol versus either drug alone was compared to placebo in a study of 16 patients with exertional angina [15]. Combination therapy decreased the number of ischemic episodes as determined by ST segment depression on 48 hour ambulatory monitoring when compared to monotherapy or placebo (see 'Combination therapy with beta blockers' below).

Dihydropyridines versus verapamil or diltiazem — Several studies have compared the efficacy of nifedipine to that of verapamil and diltiazem in patients with stable angina. These studies can be summarized as follows:

●One report of 32 patients found that exercise time improved from 5.7 minutes with placebo to eight minutes with nifedipine and up to 10 minutes with verapamil [16]. Side effects included a mild bradycardia with verapamil, a mild tachycardia with nifedipine, and angina in four patients taking nifedipine.

●Another report of 21 patients in a double blind crossover study showed that nifedipine and diltiazem appeared to be equally effective in improving exercise time, but fewer patients experienced adverse reactions with diltiazem [17,18].

●A large study of 551 patients compared amlodipine (10 mg daily) and amlodipine (10 mg daily) plus atenolol (50 mg daily) to extended-release verapamil (480 mg daily given at bedtime) [19]. Compared to placebo, all three strategies improved exercise capacity and there was no difference among them in regard to time to symptoms with exercise, time to ≥1 mm ST segment depression, or number of patients experiencing angina with exercise. However, verapamil and the combination of amlodipine plus atenolol were more effective than amlodipine alone for decreasing myocardial ischemia frequency and duration on ambulatory monitoring, especially in the morning between 6 am and noon.

Verapamil — Verapamil has been shown to increase exercise duration, reduce the number of anginal attacks, and decrease the consumption of nitroglycerin tablets in numerous double blind, placebo-controlled randomized trials of patients with chronic stable angina [9,20-22]. The usual effective dose is 360 to 480 mg/day.

Verapamil is a safe and effective alternative to beta blockers. Verapamil and propranolol are equally effective in preventing anginal attacks and in prolonging exercise duration [23-26]. The choice between the two, therefore, largely depends upon the clinical setting and the side effects of each drug. In recent years, sustained release preparations of verapamil have become available and are as effective as but more convenient than the regular formulation [27,28].

Diltiazem — Diltiazem has been shown to reduce anginal frequency, nitroglycerin consumption, and increase exercise performance in patients with chronic stable angina in several randomized placebo controlled trials [9,29-31]. The effective antianginal dose is 240 to 360 mg/day. Once and twice daily preparations (such as diltiazem CD) have been found to be as effective as the short-acting form [32-34].

Diltiazem is as effective as beta blockers in the treatment of chronic stable angina. As an example, one study of 33 patients found no difference in efficacy between diltiazem and metoprolol [35]. Diltiazem is also a safe alternative to beta blockers due to its low incidence of side effects.

Combination therapy with beta blockers — Combination therapy with a calcium channel blocker plus a beta blocker is more effective than therapy with either drug alone.

Verapamil — Verapamil plus a beta blocker may be the most effective combination but it is associated with the highest incidence of significant side effects due to the negative and additive inotropic and chronotropic actions of both drugs [36].

Nifedipine — The combination of nifedipine and a beta blocker is associated with fewer side effects than verapamil and beta blocker, but is also less efficacious than the combination of beta blockers and other calcium channel blockers [37]. As an example, the IMAGE study described above compared long-acting preparations of nifedipine and metoprolol, given alone or in combination [10]. Patients received monotherapy for six weeks and combination therapy for another four weeks; exercise testing was performed at both 6 and 10 weeks. The mean increase in exercise time to 1-mm ST segment depression increased with the addition of a second drug (107 versus 37 to 49 seconds with the addition of placebo). However, the anti-ischemic effect from the combination was primarily due to improvement in patients who had not responded to monotherapy rather than to an additive effect of the two drugs. A true additive effect was seen in a minority of patients (14 percent in whom nifedipine was added to metoprolol, and 24 percent in whom metoprolol was added to nifedipine).

Amlodipine — One study randomized 147 patients with angina and a positive exercise test despite optimal beta blockade to amlodipine or placebo [38]. After eight weeks of therapy, there was no difference in time to 1 mm ST segment depression, time to chest pain, or exercise duration, but the number of patients with chest pain during exercise testing was lower with amlodipine than placebo. In the subgroup of patients with early onset of angina (<6 minutes) amlodipine significantly increased the time to chest pain and reduced the amount of ST segment depression and the double product at comparable workloads. There was no difference in the frequency of side effects between the two groups.

A second study compared amlodipine to diltiazem in 97 patients with persistent angina despite atenolol therapy and found a significant and equivalent reduction in the frequency of anginal episodes with the two agents [39]. However, patients taking diltiazem reported twice as many adverse reactions than those on amlodipine.

Felodipine — The effect of felodipine along with or instead of a beta blocker was evaluated in 363 patients with angina despite therapy with metoprolol [40]. The addition of felodipine to metoprolol therapy increased the time to 1 mm ST segment depression and the time to angina during exercise testing and reduced the maximal ST segment depression. In contrast, the exercise test results after replacement of metoprolol with felodipine were not different from those observed during metoprolol therapy.

Given these data, the choice of a particular calcium channel blocker-beta blocker combination largely depends upon the clinical setting, the tolerance of side effects, and the severity of ischemic symptoms.

ARE CALCIUM CHANNEL BLOCKERS SAFE? — The preceding findings as well as other studies suggested an adverse effect on cardiovascular disease in patients treated with short-acting dihydropyridines and high doses of diltiazem and verapamil  (figure 1) [41-43]. In particular, the marked hemodynamic perturbations of large doses of short-acting nifedipine when given to such vulnerable patients appeared to increase mortality (figure 2).

These adverse hemodynamic effects are generally not seen when long-acting calcium channel blockers are given to patients with hypertension or stable angina (table 1). The safety of long acting calcium channel blockers, when used for either blood pressure control or relief of angina, was evaluated in a meta-analysis of 15 studies including over 47,000 patients with coronary artery disease [44]. There were no significant differences between the calcium channel blockers and other classes of agents (such as angiotensin converting enzyme inhibitors or beta blockers) or placebo in the rates of all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, or heart failure. A significant 21 percent relative reduction in the risk of stroke and, as expected, a significant reduction in the risk of angina were noted. No apparent difference was seen between dihydropyridine and nondihydropyridine drugs.

The FDA has given the long acting and heart rate lowering calcium channel blockers a "clean bill of health," while warning against short acting nifedipine [45]. (See "Major side effects and safety of calcium channel blockers", section on 'Proposed but unproven serious adverse effects'.)

RECOMMENDATIONS OF OTHERS — We agree with recommendations made by American College of Cardiology Foundation/American Heart Association/American College of Physicians/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for Cardiovascular Angiography and Interventions/Society of Thoracic Surgeons in their stable ischemic heart disease guideline [46-48].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic coronary syndrome".)

SUMMARY

●Introduction – Beta blockers or nitrates should be used for the initial treatment of chronic coronary syndrome. A calcium channel blocker should be considered if there are contraindications or adverse reactions to either beta blockers or nitrates or if symptoms are not well controlled with a combination of these agents.

●Effectiveness – All calcium channel blockers are effective in the treatment of chronic coronary syndrome. (See 'Effectiveness' above.)

●Cardiovascular and adverse side effects – The use of short-acting dihydropyridines, such as nifedipine, is limited by reflex tachycardia which may exacerbate ischemia, thereby preventing its use as monotherapy in this disorder. In addition some studies suggest an increase in mortality when these particular calcium channel blockers are used. (See 'Cardiovascular and adverse side effects' above.)

●Combination therapy – Therapy with a calcium channel blocker plus a beta blocker is more effective than therapy with either drug alone. We suggest choosing amlodipine or felodipine before other calcium channel blockers, given their better side effect profiles when used in combination with beta blockers. (See 'Combination therapy with beta blockers' above.)

●Vasospastic angina – In patients with chronic coronary syndrome, when a vasoactive component to angina is suspected, we suggest a trial of a calcium channel blocker in addition to a beta blocker. (See "Vasospastic angina", section on 'Management'.)

●Adverse side effects – Calcium channel blockers, particularly verapamil and diltiazem, should be used with caution in patients with left ventricular systolic dysfunction, such as those with an ejection fraction less than 40 percent, or heart failure due to their negative inotropic effect. (See 'Cardiovascular and adverse side effects' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Julian M. Aroesty for his contributions as an author to prior versions of this topic review.