Chronic stable angina treatment calcium channel blockers

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [4]; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.;Aysha Anwar, M.B.B.S[5]

Overview

Calcium channel blockers (CCBs) consist of three sub-classes namely, dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil) and modified benzothiazepines (e.g., diltiazem). The beneficial anti-anginal effects of CCB include: reduction in the afterload consequent to systemic vasodilation as well as epicardial vessel vasodilation, enhancement of the coronary collateral flow with subsequent sub-endocardial perfusion due to the inhibition of calcium influx via L-type channels. Long-acting calcium channel blockers are an effective antianginal agent and are considered to be the first choice in post-MI patients with a contraindication to beta-blocker. Long-acting CCBs are also specifically used to control symptoms in patients with vasospastic angina. However short-acting CCBs, such as nifedipine, are avoided due to an increased risk of myocardial infarction and mortality.

Calcium Channel Blockers

Mechanisms of Benefit

• Calcium channel blockers reduce the trans-membrane flux of calcium via inhibition of slow calcium channels.

• Dihydropyridines (e.g., nifedipine) exert a greater inhibitory effect on vascular smooth muscle than on the myocardium. Thus, major therapeutic effect are expected to be peripheral and coronary vasodilation.

• Coronary vasodilation consequent to vasodilation of both, conductance and resistance coronary vessels as well as enhancement of the coronary collateral flow, subsequently results in sub-endocardial perfusion.
• Peripheral vasodilation results in afterload reduction and subsequently sequences the reflex adrenergic activation, tachycardia and stimulation of the rennin-angiotensin system. This has been implicated as the mechanism for the potentially adverse cardiovascular effects.

• Dihydropyridines also exert a negative inotropic effect and therefore can produce myocardial depression, which is less pronounced with amlodipine and nisoldipine.

• Calcium channel blockers, such as verapamil and diltiazem, may decrease heart rate and are associated with reduced myocardial oxygen consumption.

• Second generation vasoselective dihydropyridines, such as amlodipine and felodipine, are well tolerated by patients with left ventricular dysfunction and result in no increase in the risk of mortality. Furthermore, vasoselective long acting dihydropyridines, such as amlodipine, extended release nifedipine, slow release verapamil and diltiazem, have all been shown to reduce frequency and symptoms of angina.

• Calcium channel blockers have also been postulated to have anti atherosclerotic properties.

Indications

• In patients with a contra-indication to beta blockers, the second drug of choice is CCB.

• In patients with ejection fraction more than 35%, amlodipine can be combined with a beta blocker as it offers minimal negative inotropic effects.

• In patients with stable exertional angina, calcium channel blockers primarily decrease the myocardial oxygen consumption and hence improves exercise tolerance, reduces the time to onset of angina and ST segment depression during treadmill tests.

• In patients with vasospastic angina, CCBs along with nitrates effectively relieve and prevent epicardial coronary artery spasm. Some patients may also require a combination of two calcium channel blockers to achieve efficacy.

• In patients with mixed angina, walk through, postprandial, and late nocturnal angina, an increase in the coronary vascular tone appears to be the contributing factor for the pathogenesis of ischemia. The above mentioned types of angina benefit with the use of calcium channel blockers, particularly when nitrate therapy alone is inadequate.

• The new T-channel types of calcium blockers possess minimal negative inotropic effects, produce no edema or constipation and are effective in the management of hypertension and chronic angina.

• In a given patient, the hemodynamic profile should be considered while choosing a particular calcium channel blocker.

• Dihydropyridines are preferable in the presence of sinus bradycardia, sinus node dysfunction, or atrioventricular block, particularly when the blood pressure is not adequately controlled.
• Diltiazem or verapamil is preferable in patients with relative tachycardia.

Contraindications

• A combination of beta-blocker and diltiazem or dihydropyridine should be avoided in patients with EF less than 40%.

• Concomitant use of verapamil with a beta-blocker is considered unsafe as verapamil may cause conduction disturbances or worsen heart failure.

Drug Interactions

• Clopidogrel is activated by CYP3A4, which also metabolizes dihydropyridines, thus co-administration of dihydropyridines is associated with decreased platelet inhibition by clopidogrel.

• Concomitant use of beta blockers and non-dihydropyridines such as verapamil and diltiazem cause the sinus node to slow down, thereby increasing the potential effect of bradycardia.

Adverse Effects

• CCBs particularly dihydropyridines-induced peripheral vasodilation causes:

• Peripheral edema
• Headache
• Flushing
• Palpitation (due to reflex tachycardia)

• Verapamil may cause constipation.

• In post-MI patients with reduced left ventricular ejection fraction, diltiazem causes worsening congestive heart failure and is associated with the increase risk of mortality.

• Diltiazem and verapamil reduce myocardial contractility and therefore, can cause sinus bradycardia and different grades of atrioventricular blocks.

• Vaso-selective dihydropyridines such as nifedipine, amlodipine, and felodipine may elicit short term increase in heart rate, sympathetic counterregulation and renin release that subside over time. However, there is persistence of sympathetic activation signs even after months of treatment with a dihydropyridines.

Supportive Trial Data

• A meta-analysis on the safety of nifedipine in angina pectoris reviewed 60 randomized controlled trials to compare cardiovascular event rates in patients with stable angina receiving nifedipine as monotherapy or combination therapy and in active drug controls. Researchers reported that the primary endpoint from all major cardiovascular events such as death, non-fatal myocardial infarction, stroke and revascularization procedure plus increased angina between the two groups was 1.61 (95% CI, 0.91 to 2.87). Researchers concluded that nifedipine was safe in the management of chronic stable angina.

• A meta-analysis reviewed 72 randomized trials to compare the efficacy of treatment with calcium channel blockers, beta-blocker and long-acting nitrate therapy for patients with stable angina. The primary endpoint from all major cardiovascular events did not significantly differ between the beta-blocker and calcium channel blocker groups (OR 0.97; 95% CI, 0.67-1.38; P=0.79); however, differences between beta-blockers and calcium channel blockers were most striking with the nifedipine group (OR for adverse events with beta-blockers vs nifedipine 0.60; 95% CI, 0.47-0.77). Thus, the study concluded similar outcomes with both beta-blocker and calcium channel blocker classes; the main limitation being only 8-weeks of follow-up suggesting further extended study would be needed to more definitively conclude this relationship.

• In the CAPARES study, a prospective double-blind trial of 405 patients who were randomized to receive either, amlodipine or placebo, prior to angioplasty exercise tests and 48-hour ambulatory ECG tests, assessed the effects of amlodipine on post-PTCA ischemia. Researchers observed that amlodipine significantly reduced major cardiovascular end points such as death, MI, CABG, and repeat PCI.

• In the INTERCEPT trial, 874 patients with acute MI were randomized to either diltiazem or placebo. During a 6-month follow-up, reduction in the primary end point of all cause of mortality, refractory ischemia and a significant reduction in the need for revascularization was observed in the group treated with diltiazem.

• In the ACTION trial, 7665 patients with stable angina were randomized to either nifedipine or placebo. The primary end point (0.97 [0.88-1.07], p=0.54) of all causes of mortality such as death, MI, refractory angina, debilitating stroke and heart failure (0.89 [0.83-0.95], p=0.0012) during the 4.9 year follow-up did not significantly differ between the two groups. The study also reported that nifedipine therapy increased the need for peripheral revascularization (HR 1.25; P=0.073); however, the need for coronary bypass surgery was reduced in this group (HR 0.79; P=0.0021). Thus, the study concluded that nifedipine therapy had no effect on major cardiovascular event-free survival. Therefore, nifedipine therapy was concluded to be safe and reduced the need for coronary interventions.

• In the CAMELOT study, 1991 patients with angiographically documented coronary artery disease and diastolic blood pressure of more than 100 mm Hg were randomized to receive either amlodipine, enalapril, or placebo. During a 2-year follow-up, the study reported that amlodipine significantly reduced the primary end point (HR 0.81; 95% CI, 0.63-1.04; P=0.10) and cardiovascular event rate (HR 0.69; 95% CI, 0.54-0.88; P=0.003) in comparison to that of the enalapril group. The IVUS substudy showed evidence of slowing of atherosclerosis progression in amlodipine.

• DAVIT trial and its sub study- MDPIT trail reported the benefits of verapamil and diltiazem in improving the prognosis of post-MI patients.

• In the DAVIT trial, 897 post-MI patients were randomized to either verapamil or placebo. The 18-month mortality rates were 11.1 and 13.8% (p=0.11) and the major event rates 18.0 and 21.6% (p=0.03) between the verapamil and placebo groups respectively. The study concluded that long-term therapy with verapamil in post-MI was beneficial as verapamil was associated with significant reduction in major events, and patients without heart failure reported a positive effect.

• In the MDPIT study, 2466 patients with previous infarction were randomized to either diltiazem or placebo. The primary endpoint of all cause mortality or non-fatal MI during a mean follow-up of 2 years (range 1 to 4.3 years) reported a 11% fewer recurrent cardiac events in the diltiazem group than in the placebo group (202 vs. 226; Cox hazard ratio, 0.90; 95 percent confidence limits, 0.74 and 1.08). Thus, the study concluded that diltiazem exerted no overall effect on mortality or cardiac events in patients with previous infarction.

2012 ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina (DO NOT EDIT)

Calcium Channel Blockers (DO NOT EDIT)

Class I

"1. Calcium channel blockers or long-acting nitrates should be prescribed for relief of symptoms when beta blockers are contraindicated or cause unacceptable side effects in patients with SIHD. (Level of Evidence: B)"

"2. Calcium channel blockers or long-acting nitrates, in combination with beta blockers, should be prescribed for relief of symptoms when initial treatment with beta blockers is unsuccessful in patients with SIHD. (Level of Evidence: B)"

Class IIa

"1. Treatment with a long-acting nondihydropyridine calcium channel blocker (verapamil or diltiazem) instead of a beta blocker as initial therapy for relief of symptoms is reasonable in patients with SIHD (Level of Evidence: B)"

ESC Guidelines- Pharmacological Therapy to Improve Symptoms and/or Reduce Ischaemia in Patients with Stable Angina (DO NOT EDIT)

Calcium Channel Blockers (DO NOT EDIT)

Class I

"1. In case of beta-blocker intolerance or poor efficacy attempt monotherapy with a calcium channel blocker (CCB) (Level of Evidence: A), long-acting nitrate (Level of Evidence: C), or nicorandil. (Level of Evidence: C)"

"2. If the effects of beta-blocker monotherapy are insufficient, add a dihydropyridine CCB. (Level of Evidence: B)"

Class IIa

"1. If CCB monotherapy or combination therapy (CCB with beta-blocker) is unsuccessful, substitute the CCB with a long-acting nitrate or nicorandil. Be careful to avoid nitrate tolerance. (Level of Evidence: C)"