Am Fam Physician. 2007 Feb 1;75(3):311-312.
to the editor: The STEPS department on amlodipine/atorvastatin (Caduet) in the March 15, 2006, issue of American Family Physician,1 contains several misleading statements that contradict available evidence.
First, the article states: “Amlodipine…has not been shown to reduce the risks of myocardial infarction, stroke, or death.”1 In ALLHAT, amlodipine was as efficacious as chlorthalidone (Hygroton) in reducing the risk of myocardial infarction, stroke, and death. Amlodipine was more efficacious in reducing strokes than was lisinopril (Zestril).
Secondly, the article states: “Amlodipine also has been associated with worse cardiovascular outcome than [angiotensin-converting enzyme] ACE inhibitors despite similar effects on blood-pressure lowering.”1 In the CAMELOT study, blood pressure was lowered similarly by enalapril (Vasotec) and amlodipine (Norvasc) in patients with coronary artery disease.2 The composite end point was significantly reduced by amlodipine, whereas enalapril was not different from placebo.2
Thirdly, the article states: “Atorvastatin has not been shown to decrease all-cause mortality in patients with or without coronary heart disease.”1 The double-blind, 10,000-patient, lipid-lowering arm of the ASCOT study was stopped prematurely because atorvastatin significantly reduced total mortality when compared with placebo.3
Another statement in the article was: “Calcium channel blockers, including amlodipine, are not the drugs of choice for treating hypertension; they are for patients who cannot tolerate or who do not experience adequate control with diuretics, beta blockers or ACE inhibitors.”1 The article does not mention the extensive literature attesting to the inefficacy of beta blockers as first-line antihypertensive drugs.4–6 In fact, beta blockers were recently removed from the list of first-line antihypertensive drugs by the Guidelines of the British Hypertension Society.
By selectively reviewing the literature and omitting findings from large perspective randomized trials, the authors make it difficult for readers to objectively assess the risk/benefit ratio of amlodipine and atorvastatin.
REFERENCESshow all references
1. Wilson SA, Sanford A. Amlodipine/atorvastatin (Caduet) for preventing heart disease [STEPS]. Am Fam Physician. 2006;73:1067–8....
2. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al., for the CAMELOT investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292:2217–25.
3. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M. et al., for the ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–58.
4. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA. 1998;279:1903–7.
5. Messerli FH, Beevers DG, Franklin SS, Pickering TG. Beta-blockers in hypertension—the emperor has no clothes: an open letter to present and prospective drafters of new guidelines for the treatment of hypertension. Am J Hypertens. 2003;16:870–3.
6. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366:1545–53.
in reply:We appreciate Dr. Messerli's comments, which offer an opportunity for clarification, correction, and discussion. However, they do not change our conclusion that there is no compelling reason to favor combination therapy with amlodipine/atorvastatin (Caduet) for the prevention of heart disease. We reviewed the highest quality articles about amlodipine (Norvasc) or atorvastatin (Lipitor) that addressed patient-oriented outcomes, especially all-cause mortality. When all variables were equal, cost was also considered.
Amlodipine has been shown not to decrease the following: (1) all-cause mortality, compared with chlorthalidone (Hygroton) and lisinopril (Zestril) based on findings in the ALLHAT study1; (2) the incidence of cardiovascular events compared with enalapril (Vasotec) based on findings in the CAMELOT study, as referenced by Dr. Messerli; or, (3) the all-cause mortality compared with other first-line antihypertensives based on the findings of two meta-analyses.2,3 Amlodipine increases the risk of nonfatal myocardial infarction2 and is less effective than ramipril (Altace) or metoprolol (Toprol XL) at preventing the composite of end-stage renal disease and death,4,5 especially in black patients.4
Current practice is to use statin therapy only in patients who are dyslipidemic or diabetic. The ASCOT-LLA study assessed the role of atorvastatin in hypertensive patients with normal lipid levels. Although there was a decrease in stroke and some cardiac end points, there was no significant decrease in all-cause and cardiovascular mortality compared with placebo.
Dr. Messerli correctly raises questions about the efficacy of beta blockers to treat hypertension in the general population. Regardless, beta blockers are proven, effective front-line therapy for patients who are hypertensive and who have or had congestive heart failure, obstructive cardiomyopathy, angina, or myocardial infarction. The statement in our article could have more clearly stated this. The meta-analyses that Dr. Messerli references provide the fodder for the discussion and debate about beta blockers as general first-line therapy for hypertension because they concluded that beta blockers did not decrease all-cause mortality. Many of the studies included in these meta-analyses involved atenolol. This may have negatively affected the findings because atenolol does not reduce all-cause mortality when compared with placebo.6 Hence, further study or re-analysis excluding atenolol studies may be required to assess drug class versus atenolol effect.
REFERENCESshow all references
1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes 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) [Published corrections appear in JAMA 2003;289:178 and JAMA 2004;291:2196]. JAMA. 2002;288:2981–97....
2. Opie LH, Schall R. Evidence-based evaluation of calcium channel blockers for hypertension: equality of mortality and cardiovascular risk relative to conventional therapy. J Am Coll Cardiol. 200239:315–22.
3. Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Cavazzini C, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet. 2000;356:1949–54.
4. Wright JT, Bakris G, Greene L, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421–31.
5. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001;285:2719–28.
6. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004;364:16849.
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