Chronic stable angina treatment calcium channel blockers

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Phone:617-632-7753; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [3]; John Fani Srour, M.D.; Jinhui Wu, M.D.

Overview

• Calcium channel blockers consist of three subclasses, such as:

• Dihydropyridines (e.g., nifedipine),
• Phenylalkylamines (e.g., verapamil), and
• The modified benzothiazepines (e.g., diltiazem).

• Verapamil is a more effective antianginal agent than diltiazem or dihydropyridines (DHPs) and is considered a first choice, but the drug must be used with caution and must not be combined with a beta blocker.

Mechanisms of benefit

• Calcium channel blockers reduce the transmembrane flux of calcium via slow calcium channels.

• The dihydropyridines (for example nifedipine), exert a greater inhibitory effect on vascular smooth muscle than on the myocardium. Thus, the major therapeutic effect can be expected to be peripheral or coronary vasodilation.

• These agents, however, also exert a negative inotropic effect and therefore can produce myocardial depression, which is less pronounced with amlodipine and nisoldipine.
• The peripheral vasodilation caused by the dihydropyridines also can cause reflex adrenergic activation, tachycardia, and stimulation of the rennin-angiotensin system.
• These agents increase coronary blood flow owing to vasodilation of both conductance and resistance coronary vessels.
• Intermittent adrenergic activation with short-acting dihydropyridines has been implicated as the mechanism for the potentially adverse cardiovascular effects.

• The non-dihydropyridine calcium channel blockers such as verapamil and diltiazem cause slowing of the sinus node and hence may potentiate the bradycardia of beta blockers.

• However, they are less potent peripheral vasodilators than the dihydropyridines and less likely to cause hypotension, flushing, and dizziness.
• Calcium channel blockers such as verapamil and diltiazem, may decrease heart rate and is associated with a reduced myocardial oxygen requirement.

• Second generation vasoselective dihydropyridine derivative calcium channel blockers, such as amlodipine and felodipine, are well tolerated by patients with left ventricular dysfunction and even overt clinical heart failure, and no increase in the risk of mortality has been described. Furthermore, vasoselective long acting dihydropyridines (such as amlodipine) and extended release (nifedipine) and slow release (verapamil and diltiazem) have all been shown to reduce frequency and symptoms of angina.

• The new T channel types of calcium blockers are also effective in controlling hypertension and angina. They appear to possess little negative inotropic effect and produce little or no edema or constipation.

Indications

• These agents are used as second line therapy when beta blockers are genuinely contraindicated.

• Amlodipine has minimal negative inotropic effects and can be combined with a beta blocker in patients with EF more than 35%.

• In patients with stable exertional angina, calcium channel blockers improve exercise tolerance (longer time to the onset of angina and to ST segment depression) during treadmill exercise tests. The mechanism of these beneficial effects is primarily decreased myocardial oxygen consumption. Calcium channel blockers and beta blockers in combination can produce synergistic beneficial effects in patients with stable angina pectoris.

• Epicardial coronary artery spasm is effectively relieved and prevented by calcium channel blockers, so that these are the agents of choice (along with nitrates) for the treatment of vasospastic angina. Some patients with coronary spasm may require a combination of two calcium channel blockers to achieve efficacy.
• In patients with mixed angina, walk through, postprandial, and late nocturnal angina, in which increased coronary vascular tone appears to contribute to the pathogenesis of the ischemia, the use of calcium channel blockers may be of benefit, particularly when nitrate therapy alone is inadequate.

• The new T channel types of calcium blockers are also effective in controlling hypertension and angina.

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

Adverse effects

• General side effects of calcium channel blockers are:

• Constipation,
• Peripheral edema,
• Dizziness,
• Flushing and
• Occasionally headache.

• Controversy exists for the use of calcium channel blockers for the long term treatment of stable exertional angina, since the short acting, immediate release dihydropyridines, such as nifedipine, may increase the risk of myocardial infarction and mortality.

• Worsening congestive heart failure and increased mortality has also been observed with diltiazem in post infarction patients with depressed left ventricular ejection fraction.

• With dihydropyridines, a reflex tachycardia may produce palpitation.

• With diltiazem and verapamil, sinus bradycardia and different grades of atrioventricular blocks may occur. Verapamil may cause constipation.

• Although beta-blockers may be used in patients with EF <30%, the combination of a beta-blocker with diltiazem or dihydropyridine should be avoided in patients with EF <40%. Verapamil and, to a lesser extent, diltiazem, when added to a beta-blocker, may cause conduction disturbances or HF, and the verapamil combination is considered unsafe.

Supportive trial data

• Several trials have shown that verapamil is as effective as beta-blockers in the control of angina, but this agent does not prolong life.

• Calcium antagonists have also been postulated to have anti atherosclerotic properties. The Prospective Randomized Evaluation of the Vascular Effect of Norvasc Trial (PREVENT) did demonstrate slowing of atherosclerotic progression in carotid but not in the coronary vasculatures.

• Given to patients prior to undergoing PTCA, amlodipine was shown to reduce major cardiovascular end points (death, MI, CABG, repeat PCI) in the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES).

ACC/AHA Guidelines- Pharmacotherapy to Prevent MI and Death and Reduce Symptoms (DO NOT EDIT)

“

Class I 1. Calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as initial therapy for reduction of symptoms when beta-blockers are contraindicated. (Level of Evidence: B) 2. Calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates in combination with beta-blockers when initial treatment with beta-blockers is not successful. (Level of Evidence: B) 3. Calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) and/or long-acting nitrates as a substitute for beta-blockers if initial treatment with beta-blockers leads to unacceptable side effects. (Level of Evidence: C) Class IIa 1. Long-acting non-dihydropyridine calcium antagonists (short-acting dihydropyridine calcium antagonists should be avoided) instead of beta-blockers as initial therapy. (Level of Evidence: B)

”

ESC Guidelines- Pharmacological therapy to improve symptoms and/or reduce ischaemia in patients with stable angina (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)

”

Vote on and Suggest Revisions to the Current Guidelines

• The Chronic Stable Angina Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Sources

• The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina

• TheACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina

• The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina

• Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology

References

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