Hypertension: Therapy vs Calcium Channel Antagonists

Pharmacology Watch

Pharmacotherapy of hypertension has been much in the news in the last 2 months. Standard therapies such as atenolol have been challenged, while calcium channel antagonists may be making a comeback. Researchers from Sweden performed a meta-analysis of 9 randomized, controlled trials that looked at the effectiveness of atenolol on cardiovascular morbidity and mortality in patients with hypertension. Four of the studies compared atenolol with placebo or no treatment, and 5 studies compared atenolol with other antihypertensive drugs. Although atenolol was effective at lowering blood pressure, there were no outcome differences with regard to all cause mortality (RR 1.01; 95% CI, 0.89-1.15), cardiovascular mortality (RR 0.99; 95% CI, 0.83-1.18), or myocardial infarction (RR 0.99; 95% CI, 0.83-1.19), compared to placebo. The risk for stroke was lower with atenolol, compared to placebo (RR 0.85; 95% CI, 0.72-1.01). When compared with other antihypertensives, no difference in blood pressure lowering was noted between treatment groups, but the meta-analysis revealed a higher mortality with atenolol, compared with other treatments (RR 1.13; 95% CI, 1.02-1.25). This included a higher risk of cardiovascular mortality and stroke. The authors suggest that the results "cast doubts on atenolol as a suitable drug for hypertensive patients." They further postulate that atenolol's low lipophilic profile, which theoretically may reduce its ability to prevent cardiac arrhythmias, could be responsible for these findings (Lancet. 2004; 364: 1684-1689). Some have criticized the study because it did not include newer well-designed trials in which atenolol was used in combination with other drugs including diuretics. In these studies, including ALLHAT and SHEP, the addition of atenolol resulted in overwhelming benefit. In the meantime, use of atenolol as monotherapy needs to be reevaluated, however, addition of atenolol to an existing regimen will probably remain a part of most clinical guidelines.

GEMINI Trial

Speaking of beta-blockers, a new study suggests that carvedilol may be a better choice for diabetic patients than metoprolol. The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial was designed to compare the effects of beta-blockers with different pharmacological profiles on glycemic and metabolic control in diabetic patients who were already receiving renin-angiotensin system (RAS) blockade with either a ACEI or ARB. Over 1200 patients with diabetes and hypertension were randomized in GEMINI. The main outcome was change in baseline HbA1c after 5 months of therapy. A difference was noted in mean change of HbA1c for baseline between the drugs (0.13%;95%CI -0.22%-0.4%. P=.004) The mean HbA1c increased with metoprolol (0.15% [0.04%]; P < .001), but not for carvedilol (0.02% [0 .04%]; P = .65). Insulin sensitivity also improved with carvedilol but not with metoprolol, and progression to microalbuminuria was less frequent carvedilol than with metoprolol (6.4% vs 10.3%; P = .04). The drugs were used in equipotent doses to achieve similar blood pressure lowering effects. The authors conclude that the carvedilol, used in the presence of RAS blockade, does not effect glycemic control, and improves some components of metabolic syndrome relative to metoprolol in patients with diabetes and hypertension (JAMA. 2004;292:2227-2236). The study points out again that beta-blockers, with variable pharmacologic effects, may result in different clinical outcomes. Carvedilol is a nonselective beta antagonist, but has alpha 1 antagonist properties and mild vasodilatory properties.

CAMELOT Trial

The calcium channel antagonist amlodipine has beneficial cardiovascular effects in heart patients even if they have normal blood pressure according to new study. The Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study compared amlodipine 10 mg, enalapril 20 mg or placebo in patients with documented CAD and diatolic blood pressures < 100 mm Hg. The outcome measures were incidence of cardiovascular events and a second outcome was the use of intravascular ultrasound to measure atheroma volume. Nearly 2000 patients were followed over 24 months. New cardiovascular events (cardiovascular deaths, non-fatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina actors, hospitalization for congestive heart failure, fatal or non-fatal stroke or transient ischemic attack, or new diagnoses of peripheral vascular disease) occurred in 23.1% of placebo treated patients, 16.6% of amlodipine treated patients (HR 0.69; 95% CI, 0.54-0.88 [P = .003]) and 20.2% of enalapril treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]). Plaque volume by ultrasound showed a trend towards less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup of patients with higher systolic blood pressures (P = .02). Compared with baseline atheroma volume progression in the placebo group (P < .001), the study showed a trend towards progression in the enalapril group, and no progression in the amlodipine group. The authors conclude that amlodipine reduced cardiovascular events and slowed progression of atherosclerosis in patients with CAD and normal blood pressure (JAMA. 2004;292:2217-2225). An accompanying editorial reviews the data and suggests mechanisms for the findings. More than any other factor, the editorialists suggest that lowering blood pressure to a systolic in the 120 mm Hg range may be the most important factor of all in patients with CAD (JAMA. 2004;292:2271-2273).

INVEST Trial

The INVEST study suggests that verapamil is as effective as atenolol with regard to benefit and side effects in diabetic patients with hypertension (Hypertension 2004;44:614-615). The PEACE trial looked at patients with coronary disease and normal or slightly reduced left ventricular function to assess whether addition of an ACE inhibitor would convey benefit, and found no benefit for these patients (N Engl J Med. 2004; 351:2058-2068).

The Dangers of Vitamin E

And vitamin E? Don't expect it to prevent cardiovascular disease or cancer for that matter. As vitamin E doses increase, so does all cause mortality, according to a large meta-analysis. Nineteen trials, which included nearly 136,000 participants, were evaluated in the analysis, of which 11 tested high dose vitamin E (400 IU/d). The pooled all-cause mortality risk difference for the high-dosage vitamin E was 39 per 10,000 (95% CI, 3-74 per 10,000; P = .035). For doses less than 400 IU/d, the mortality risk difference was 16 per 10,000 (CI, -41 to 10 per 10,000; P > .2). A dose-response analysis revealed an increase in all cause mortality with vitamin E dosages > 150 IU/d. The authors suggest that an increased mortality with higher doses of vitamin E is biologically plausible. Low doses of vitamin E may have some antioxidant effects, but higher doses may be pro-oxidant, particularly to LDL cholesterol. High doses of vitamin E may also displace other fats soluble antioxidants, disrupting the natural balance of antioxidant systems. Vitamin E may also be a mild anticoagulant, which may explain the increased hemorrhagic stroke seen in some vitamin E trials. This study was felt important enough to warrant early release online, since many people worldwide take vitamin E supplements on a daily basis far in excess of 400 IU/d. The full study will be published in the January 2005 Annals of Internal Medicine.

FDA Actions

The FDA has approved a new form of biologic drug for the treatment of relapsing forms of multiple sclerosis. Natalizumab is a monoclonal antibody that is given intravenously once a month. It will be marketed by Biogen as "Tysabi."


This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: leslie.hamlin@thomson.com.