All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- All trial summaries are in chronological order, with the most recent one first and the oldest one last. I wrote the introduction at the beginning. IF YOU HAVE HEART FAILURE AND NEED TO TAKE A CALCIUM CHANNEL BLOCKER, AMLODIPINE SHOULD BE TRIED FIRST! Be very cautious about taking CCBs if you take beta-blockers. Some CCBs can interact in dangerous ways with beta-blockers and digoxin. --------------------------------------------------- CCBs = Calcium Channel Blockers, also called calcium antagonists. This is a class of drugs including: amlodipine [Lotrel, Norvasc] bepridil [Vascor] diltiazem [Cardia, Tiazac, Cardizem, Dilacor] gallopamil [Hydac, Munobal, Plendil] isradipine [DynaCirc, Lomir, Prescal, Vascal] nicardipine [Cardene, Nicardal, Nicodel, Nimicor] nifedipine [Procardia] nimodipine [Nimotop] verapamil [Calan, Covera, Isoptin, Verelan] CCBs are Class 4 anti-arrhythmic drugs also used to treat high blood pressure, angina, and pulmonary hypertension. Their use is controversial because they reduce the pumping strength of the heart and they may increase mortality for certain patients - including heart failure patients. ==================================================== Source: WebMD Title: Doctors Cautioned to Use Older Medications First Authors: McKeown L A, Flegel David. December 7, 2000 - A new study suggests doctors should be cautious about prescribing certain blood pressure drugs. An analysis of 9 different studies found that CCBs are less effective in preventing heart-related problems and may increase risk of heart attacks and heart failure. Doctors who did the analysis say the main lesson is that CCBs should never be given as a first- line treatment to people with high blood pressure. Dr. Marco Pahor - the study's author - compared results from 9 different blood pressure-lowering trials involving over 27,000 people. Patients in the trials took various drugs for high blood pressure, including CCBs, ACE inhibitors, diuretics and beta-blockers. Compared to people who took other drugs, people taking CCBs had a 26% higher risk of heart attack, 25% higher risk of CHF, and 10% higher risk of combined major heart disease. Another study in the same journal issue found that compared to ACE inhibitors, CCBs increase risk of heart disease by 19% and risk of heart failure by 18%. That study included over 26,000 people with high blood pressure. In an editorial, Dr. Jiang. He and Dr. Paul Whelton say the results agree with what a panel of experts said 3 years ago. They also say these newer studies "provide support for using ACE inhibitors as the first choice for lowering blood pressure. ACE inhibitors may be especially useful in patients who are at high risk for heart failure," they say. The new studies do not mean that CCBs are not useful drugs or that they are always harmful. Pahor's study found them to be just as effective as other drugs for lowering blood pressure. However, he says the other drugs may have benefits that CCBs do not have. Concerned patients taking CCBs should talk with their doctors BEFORE stopping the drug. "The risk of abruptly stopping a heart drug like a CCB is greater than continuing it until you can talk to your doctor about it," says Dr. Norman Feinsmith, FACC, a cardiologist at the University of Pennsylvania. ==================================================== Source: Circulation 2000 Feb 22;101(7):758-64. Title: Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial. Authors: Levine TB, Bernink PJ, Caspi A, Elkayam U, Geltman EM, Greenberg B, McKenna WJ, Ghali JK, Giles TD, Marmor A, Reisin LH, Ammon S, Lindberg E. PMID: 10683349. INTRODUCTION CCBs (Calcium Channel Blockers) have proved disappointing in long-term heart failure studies. Mibefradil is a new CCB that selectively blocks T-type calcium channels. It is effective for high blood pressure and angina. METHODS This randomized, double-blind study compared mibefradil to placebo, added to standard therapy in 2,590 heart failure patients. All patients were class 2 to class 4 with EF less than 35%. The starting 50 mg daily dose of mibefradil was raised to 100 mg after one month and continued up to 3 years. Patients were monitored at one week; one, 2, and 3 months; and every 3 months after that. All-cause mortality, heart-related mortality, and heart-related complications-plus-mortality were analyzed. Substudies included exercise tolerance, blood levels of hormone and cytokines, echo measurements, and quality of life. RESULTS Total mortality was 14% higher in mibefradil patients than in placebo patients in the first 3 months but was not much different beyond that point. Both groups had similar heart-related mortality and heart-related complications/mortality. Patients taking both mibefradil and class one or class 3 anti-arrhythmic drugs - including amiodarone - had a significantly increased risk of death. ================================================ Source: Prog Cardiovasc Dis 1998 Nov-Dec;41(3):191-206. Title: Calcium channel blockers in cardiac failure. Authors: Mahon N, McKenna WJ. PMID: 9872606. The role of CCBs in treating heart failure is unclear. The potential benefits of CCBs come from their vasodilator properties, but also from anti-ischemic effects, and benefits on endothelial function. Pitted against these potential benefits is the fact that they reduce the heart's pumping strength and can activate the very hormonal systems that cause damage in heart failure patients. Amlodipine causes no harm in heart failure patients. Mibefradil is of no benefit in managing heart failure. The potential role of calcium blockers in diastolic dysfunction and in combination with ACE inhibitors requires further study. ================================================ Source: J Am Geriatr Soc 1997 Oct;45(10):1252-7. Comment: J Am Geriatr Soc. 1998 Aug;46(8):1053-4. Title: Treatment of congestive heart failure in older persons. Author: Aronow WS. PMID: 9329490. Older persons with CHF associated with an abnormal EF should be treated with a low sodium diet and with diuretics plus ACE inhibitors. If CHF persists, digoxin should be added. If CHF still persists, isosorbide dinitrate plus hydralazine should be added. If CHF still persists, a beta-blocker should also be used. Calcium channel blockers should not be used. Older persons with CHF having a normal EF should be treated with a low sodium diet plus diuretics plus ACE inhibitors. If CHF persists, a beta-blocker or isosorbide dinitrate plus hydralazine or a calcium channel blocker should be added. ================================================== Source: Can J Cardiol 1997 Aug;13(8):757-66. Comment: Can J Cardiol. 1997 Nov;13(11):1015. Title: Calcium channel blockers: an evidence-based review. Author: Waters D. PMID: 9284842. The proper role of CCBs for treating heart disease is controversial. Although many important questions remain unanswered, trials have helped show when and how these drugs should be used. In general, the benefits of CCBs in controlling angina and high blood pressure are much more proven than their long-term effects mortality. A higher risk of death when using dihydropyridine CCBs has been clearly seen in several studies of patients with coronary artery disease. In heart failure patients, the risks of using nifedipine, diltiazem and verapamil outweigh any possible benefit. Long acting formulas and newer CCBs may be safer, but their long-term safety has not been proven. Understanding the limitations of CCBs, based on clinical trial evidence, may often lead a doctor to choose a drug from another class. ===================================================== Source: Am Heart J 1997 May;133(5):550-7. Title: Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction. Authors: Kostis JB, Lacy CR, Cosgrove NM, Wilson AC. The SOLVD trial studied the effect of enalapril in patients with systolic heart failure. We analyzed the link between CCBs (Calcium Channel Blockers) and fatal and nonfatal heart attacks in SOLVD patients. Hear attack occurred in 12% of 845 patients taking CCBs versus 8% of 2,551 patients not taking CCBs in the enalapril group. In the placebo group, heart attacks happened in 14% of 874 patients taking CCBs and in 9% of 2,527 patients not taking them. Adjusting for other factors, CCB use predicted heart attack. The higher risk of heart attack was greater in patients with a higher heart rate and lower blood pressure. In these patients with systolic heart failure, CCB use meant significantly higher risk of hear attack. ================================================= Source: J Hypertens Suppl 1997 Mar;15(2):S109-17. Title: Angiotensin converting enzyme inhibitor- calcium antagonist combination: an alliance for cardioprotection? Author: Ferrari R. PMID: 9218207. ACTION IN SMOOTH MUSCLE CCBs and ACE inhibitors seem to reinforce each other in reducing blood pressure. CCBs counter extra calcium entering through the electrically operated channels of smooth muscle inside our blood vessels. ACE inhibitors reduce substances that cause blood vessels to tighten up. By preventing that tightening up, pressure in our blood vessels is lowered, which eases the heart's work load. ACE inhibitors also have other beneficial effects on the lining of our blood vessels. So at the smooth muscle level, both CCBs and ACE inhibitors cause dilation, relaxing the arteries, which are largely controlled by the action of smooth muscle. At the molecular level, these 2 drugs may in some ways reinforce each other's actions in a way beneficial to the heart. Verapamil reduces mortality in heart attack patients as long as they do NOT have heart failure. ACE inhibitors may have other heart-protective properties that improve blood flow to the heart, prevent arrhythmia, reduce damage from oxygen free radicals, improve energy use by the heart, and prevent heart remodeling. ACE inhibitors also protect the heart from blood flow shortages by inhibiting bradykinin break down and by controlling central and peripheral nervous and hormonal systems. CONCLUSIONS Using both verapamil (CCB) with an ACE inhibitor is promising for treating high blood pressure and for ischemic heart disease. ================================================== Source: Am J Med 1996 Oct 8;101(4A):4A61S-69S; discussion 4A69S-70S. Title: Pharmacologic therapies after myocardial infarction. Authors: Rapaport E, Gheorghiade M. PMID: 8900339. Heart attack patients are at increased risk for a second heart event such as heart failure, sudden death, or another heart attack. The non-dihydropyridine CCBs diltiazem and verapamil can be considered for patients after heart attack only in those who cannot take beta-blockers and who have healthy systolic heart function and who do NOT have heart failure. In contrast, dihydropyridine CCBs like nifedipine have no role in heart patients after heart attack. Nitrates like nitroglycerin or isosorbide dinitrate are still useful when blood flow to the heart is not complete, with angina, heart failure, or persistent high blood pressure. Anti-arrhythmic drugs, except maybe amiodarone, are not usually a good idea in most patients after a heart attack. When drugs are prescribed to help prevent heart problems after a heart attack, they are usually prescribed in too-low dose to achieve full benefit. Target doses should be used. See: www.chfpatients.com/faq/target_dose.htm ================================================== Source: N Engl J Med 1996 Oct 10;335(15):1107-14. Comment: ACP J Club. 1996 Mar-Apr;126(2):30, N Engl J Med. 1997 Apr 3;336(14):1023-4. Title: Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group. (PRAISE) Authors: Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL. PMID: 8813041. INTRODUCTION Previous studies have shown that CCBs increase mortality and complications in heart failure patients. We studied the effect of a new calcium-channel blocker called amlodipine in patients with severe chronic heart failure. METHODS We randomly assigned 1,153 patients with EF less than 30% to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months. All patients continued taking their other CHF drugs. The primary end point was death from any cause and hospitalization for major heart-related events. RESULTS Primary end points were reached in 42% of the placebo group and 39% of the amlodipine group - a 9% relative reduction in risk of fatal and nonfatal events with amlodipine. 38% of placebo patients died versus 33% of the amlodipine group - a 16% relative reduction in risk of death with amlodipine. In patients with ischemic heart disease, there was no difference between taking amlodipine and placebo. However, in patients with non-ischemic CHF, amlodipine reduced the combined risk of fatal and nonfatal events by 31%, and reduced risk of death by 46%. CONCLUSIONS Amlodipine did no harm in patients with severe heart failure. ================================================= Source: Pharmacotherapy 1996 Mar-Apr;16(2 Pt 2):43S-49S. Title: Evolving role of calcium channel blockers in heart failure. Author: Pieper JA. PMID: 8668605. In theory, CCBs should help chronic systolic heart failure because they relax (dilate) arteries, fight ischemia, and relax the heart's main pumping chamber. Early CCBs like nifedipine, verapamil, and diltiazem reduce heart function, worsen heart failure, and may increase risk of cardiac events in CHFers who have had heart attacks. CCBs reduce the heart's beating strength short-term, and can activate neurohormonal systems due to the way they lower blood pressure - not good in CHFers. The more recent CCB felodipine doesn't activate the nervous system or hormonal systems, but it has no effect on exercise capacity or mortality. Amlodipine increases exercise time and reduces symptoms and neurohormones (a good thing). ============================================ Source: Pharmacotherapy 1996 Mar-Apr;16(2 Pt 2):43S-49S. Title: Evolving role of calcium channel blockers in heart failure. Author: Pieper JA. PMID: 8668605. CCBs are theoretically effective for treating systolic heart failure because they relax arteries, and help fight ischemia (reduced blood flow to the heart). However, older CCBS like nifedipine, verapamil, and diltiazem cause reduced heart function and worsening health in heart failure patients. These drugs also increase risk for another heart-related event in patients after a heart attack and in heart failure patients. These drugs reduce the heart's short-term pumping strength, and may activate neurohormonal systems, which is not good in CHF patients. A newer CCB called amlodipine does not activate these bodily systems, but it gives no benefit to heart failure patients in exercise capacity or mortality. It does lower blood pressure. =============================================== Source: Can J Cardiol 1995 Oct;11(9):823-6. Title: Calcium channel blockers for heart rate control in atrial fibrillation complicated by congestive heart failure. Author: Heywood JT. PMID: 7585281. We reviewed the safety and effectiveness of verapamil and diltiazem as they affect the heart's pumping in patients with a-fib and systolic heart failure. Articles up to 1993 were studied. There is not much data about the effects of verapamil and diltiazem on systolic heart function in CHF patients. In lab testing, diltiazem has fewer negative effects on the heart's pumping strength than verapamil. There are some reports of worsening health in patients with systolic heart failure taking verapamil. There is more information about diltiazem in CHF patients with a-fib. The drug does not appear to worsen heart failure symptoms. In chronic a-fib complicated by heart failure, there is concern that diltiazem may increase mortality. Options include digoxin, beta-blockers ablation. ================================================ Source: J Hypertens Suppl 1995 Aug;13(2):S57-63. Title: Update on the use of angiotensin converting enzyme inhibitors and calcium antagonists in post-infarction patients. Author: Persson S. PMID: 8576789. We reviewed recent studies on use of ACE inhibitors and CCBs in patients after a heart attack. ACE inhibitors reduce mortality and complications, and improve quality of life in a cost- effective way. CCBs (verapamil and possibly diltiazem) reduce mortality and complications, EXCEPT in patients with congestive heart failure without signs of reversible ischemia. Nifedipine may have negative effects in CHF patients. ===============================================