Chapter 6 / Calcium Antagonist Controversies 81
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From: Contemporary Cardiology: Cardiac Drug Therapy, Seventh Edition M. Gabriel Khan © Humana Press Inc., Totowa, NJ
6 Calcium Antagonist Controversies
CALCIUM ANTAGONISTS AND HEART FAILURE
Calcium Antagonists Cause an Increased Incidence of Acute MI or HF:
True or False?
Calcium antagonists without doubt cause an increased incidence of heart failure (HF) as observed in several well-run randomized controlled trials (RCTs):
• Amlodipine in Antihypertensive and Lipid-Lowering Treatment (ALLHAT): HF 38% ver- sus diuretic (1).
• Nifedipine in Intervention as a Goal in Hypertension Treatment (INSIGHT): HF 46% ver- sus diuretic (2).
• Verapamil in Controlled Onset Verapamil Investigation of Cardiovascular End Points (CON- VINCE): HF 30% (3).
• Amlodipine in Prospective Randomized Amlodipine Survival Evaluation (PRAISE) caused significant increased pulmonary edema in patients with left ventricular (LV) dysfunction (4).
• Diltiazem caused a significant increase in HF in a non-Q-wave infarction study (5).
The short-acting preparations of nifedipine and other dihydropyridines have been shown in RCTs to cause an increased incidence of myocardial infarction (MI), and controversies raged during the 1990s. These formulations are no longer used.
• Although the sustained-release formulations have been shown to be much safer than the rapid-acting older preparations, these agents are contraindicated in patients with unstable angina or acute MI. Verapamil is also contraindicated in patients with acute ST-elevation MI (STEMI) and non-STEMI.
• Diltiazem is contraindicated in patients with LV dysfunction but may be used in patients with unstable angina if beta-blockers are contraindicated.
Newer Calcium Antagonists Are Better Than Older Agents:
True or False?
Lercanidipine was introduced into the United Kingdom a few years ago and is not avail- able in the United States and Canada. It appeared to have major advantages over amlo- dipine and older dihydropyridines. Because the drug dilates both afferent and efferent arterioles, the high incidence of peripheral edema caused by older calcium antagonists was reportedly reduced more than 50%. The balanced effect of lercanidipine and manid- ipine on efferent and afferent arterioles was believed to be important in renoprotection;
older calcium antagonists dilate only afferent arterioles.
Lercanidipine is only indicated for hypertension and is contraindicated in patients with
LV dysfunction; sick sinus syndrome (if pacemaker not fitted); hepatic impairment; aortic
stenosis; unstable angina; uncontrolled HF; within 1 mo of MI; and renal impairment.
82 Cardiac Drug Therapy
Adverse effects include: flushing, peripheral edema, palpitations, tachycardia, head- ache, dizziness, and asthenia; also gastrointestinal disturbances, hypotension, drowsiness, myalgia, polyuria, and rash. Thus, such agents are not more effective and do not possess more safety than older agents. Most important, the combination of lercanidipine and digoxin is potentially hazardous.
ARE CALCIUM ANTAGONISTS
USEFUL FOR HYPERTENSIVES WITH CAD?
Calcium antagonists have been used in patients to treat coronary artery disease (CAD) events, particularly stable angina, since about 1981. Their role in patients with unstable angina is limited, and caution is required for acute MI. Post-MI prophylaxis with verapa- mil has been advocated by few in the field and remains controversial. The author does not recommend verapamil post-MI.
Their use in hypertensive patients with unsuspected or stable CAD has been widespread for more than two decades because they cause more effective and consistent lowering of blood pressure than angiotensin-converting enzyme (ACE) inhibitors/ARBs, beta-blockers, and diuretics.
Their salutary effects on adverse cardiovascular disease (CVD) outcomes appear sim- ilar to the other three classes in patients without CAD. The large RCT International Verap- amil-Trandolapril (INVEST) trial (6) studied hypertensive patients with CAD.
• 22,576 hypertensive CAD patients aged 50 yr or older were randomly assigned to either CAS (verapamil sustained release) or NCAS (atenolol). However, at 24 mo, in the CAS group, 6391 patients (81.5%) were taking verapamil sustained release, 4934 (62.9%) were taking trandolapril, and 3430 (43.7%) were taking hydrochlorothiazide.
• In the NCAS group, 6083 patients (77.5%) were taking atenolol, 4733 (60.3%) were taking hydrochlorothiazide, and 4113 (52.4%) were taking trandolapril.
• Primary outcomes: First occurrence of death (all cause), nonfatal MI, or nonfatal stroke;
others: cardiovascular death, angina, adverse experiences, hospitalizations, and blood pres- sure control at 24 mo.
• Results: 2269 patients had a primary outcome event with no statistically significant dif- ference between treatment strategies (9.93% in CAS and 10.17% in NCAS; relative risk (RR), 0.98; 95% confidence interval (CI), 0.90–1.06). It is impossible to draw conclu- sions about the contribution of any single agent in this complex, open-label study that used blunderbuss drug combinations.
• The exception was patients with prior HF: those assigned to the NCAS strategy appeared to have fewer events ( p = 0.03 for interaction). Most important, verapamil, as expected, increased the incidence of HF even when combined with an angiotensin-converting enzyme (ACE) inhibitor and diuretic.
Thus, calcium antagonists are not the drugs of choice to treat hypertensive patients who have significant CAD, particularly those with LV dysfunction.
Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial (3) were as follows:
• Aim: To determine whether initial therapy with controlled-onset extended-release (COER)
verapamil is equivalent to a physician’s choice of atenolol or hydrochlorothiazide in pre-
venting cardiovascular disease.
Chapter 6 / Calcium Antagonist Controversies 83
• An RCT of 16,602 hypertensive patients who had one or more additional risk factors for CVD was conducted. After a mean of 3 yr of follow-up, the sponsor closed the study before unblinding the results.
• Initially, 8241 participants received 180 mg of COER verapamil, and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (e.g., a diuretic, beta- blocker, or ACE inhibitor) could be added in specified sequence if needed.
• Primary outcomes: First occurrence of stroke, MI, or cardiovascular disease (CVD)-related death.
• Results:
• 364 primary CVD-related events occurred in the COER verapamil group versus 365 in the atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% CI, 0.88–1.18;
p = 0.77).
• Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54; 95% CI, 1.16–2.04; p = 0.003).
• Most important, verapamil caused a 30% increase in HF.
• Importantly, more CVD-related events occurred between 6
AMand noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups.
I must emphasize that atenolol often has a less than 22-h duration of action, and studies have shown that it fails to quell early morning catecholamine surge, which is suppressed by other beta-blockers including metoprolol, timolol, bisoprolol, and carvedilol. Because most MIs occur during the hours of 6
AMand 11
AM, caution should be used with adminis- tration of poorly cardioprotective verapamil and atenolol.
• Clinicians should recognize that both verapamil and atenolol are not suitable anti- hypertensive agents, particularly in patients with CAD; verapamil is potentially harm- ful in the elderly who are at high risk for HF, and atenolol has only mild cardiovas- cular protective effects.
See the discussion of atenolol’s poor effectiveness in Chapters 2 and 9, Hypertension Controversies.
REFERENCES
1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major out- comes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997.
2. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment. Lancet 2000;356:366–372.
3. CONVINCE: Black HR, Elliott WJ, Grandits G, et al. for the CONVINCE Research Group. JAMA 2003;
289:2073–2082.
4. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure: For the Prospective Randomised Amlodipine Survival Evaluation Study Group.
N Engl J Med 1996;335:1107.
5. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and rein- farction after myocardial infarction. N Engl J Med 1989;319:385.
6. INVEST: Pepine CJ, Handberg EM, Rhonda M, et al. for the INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290:
2805–2816.
