The present study in hypertensive men (40-64 years old) with untreated diastolic blood pressure above 100 mm Hg was aimed at investigating whether metoprolol (n = 1,609) given as initial treatment would lower the risk for coronary events (sudden death and myocardial infarction) more effectively than thiazide diuretics (n=1,625). A substantial part of this study was the metoprolol arm of the Heart Attack Primary Prevention in Hypertension (HAPPHY) study. The HAPPHY study was a pooling of the effect of different /J-blockers, mainly metoprolol and atenolol, in which no favorable effect in relative risk was observed for atenolol as compared with diuretics. In the present study, 255 patients suffered definite coronary events during follow-up; 25% of these events were fatal, 39% were acute myocardial infarctions, and 36% were silent myocardial infarctions. The risk for coronary events was significantly lower in patients on metoprolol than in patients on diuretics (111 versus 144 cases, p=0.001, corresponding to 143 versus 18.8 cases/1,000 patient years and a relative risk of 0.76 at the end of the trial; 95% confidence interval 0.58-0.98). This difference in risk has potentially important implications for clinical practice because of the large number of hypertensive patients who are at increased risk for coronary events. Because a placebo group, for ethical reasons, could not be included, relative risk can only be expressed in relation to diuretics. There was no difference between the two treatment groups in baseline characteristics, blood pressure during follow-up, or stroke rates. Thus, the difference in risk for coronary events is probably mediated via mechanisms other than blood pressure control. However, present data might suggest that different /3-blockers may have different efficacy in preventing coronary events. The reasons for this possibility are as yet unknown. (Hypertension 1991:17:579-588) C ontrolled studies with thiazide diuretics in mild-to-moderate hypertension have demonstrated an approximately 40% reduction in strokes as compared with placebo.1 However, because pooled analyses of all studies performed with thiazide diuretics have only shown a modest 8-10% beneficial effect on coronary events, 1 comparative trials to assess the effects of other antihypertensive drugs are needed. These are of particular interest since the risk for coronary events is much greater than the risk for stroke.

In a randomized primary prevention trial including 3,234 men with mild to moderate uncomplicated hypertension, the effect of the beta-blocker metoprolol or a thiazide diuretic as an initial antihypertensive therapy was compared regarding the risk of sudden cardiovascular death during a follow-up ranging from 2.3 to 10.8 years (median of 4.2 years). Only men aged 40 to 64 years were included in the study. The randomization of patients into the metoprolol (n = 1,609) or diuretic group (n = 1,625) was performed after stratification for age, smoking habits, serum cholesterol, and systolic blood pressure. At baseline the two treatment groups were well matched. Metoprolol was given in a mean dose of 174 mg daily and the mean dose of thiazide diuretic was either 46 mg hydrochlorothiazide daily or 4.4 mg bendroflumethiazide daily. Identical blood pressure control was achieved using the fixed therapeutic schedule. Total and cardiovascular mortality were significantly lower for metoprolol than for diuretics, owing to fewer deaths from coronary heart disease and stroke. Of the cardiovascular deaths, 78% were classified as sudden cardiovascular deaths (occurred within 24 h after the onset of symptoms). There were significantly fewer sudden cardiovascular deaths in the metoprolol group compared to the diuretic group (32 v 45, P = .017). The present results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of sudden cardiovascular deaths than initial diuretic treatment in uncomplicated hypertension.

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The present primary prevention study aimed at investigating whether metoprolol given as initial antihypertensive treatment would lower cardiovascular complications of high blood pressure to a greater extent than thiazide diuretics. Patients were randomized to metoprolol («=1,609, 8,110 patient-years) or a thiazide diuretic (n=1,625, 8,070 patient-years). At randomization, 535 patients in the metoprolol group and 524 patients in the diuretic group were classified as smokers. Blood pressure control during follow-up was equally effective regardless of smoking habits at randomization. Cardiovascular and coronary heart disease mortality was three to four times higher in smokers than in nonsmokers, underlining the importance of smoking as a risk factor. Total and cardiovascular mortality were significantly lower for the metoprolol group than for the thiazide diuretic group in the whole study population (p=0.028 and p=0.012), as well as in smokers (p=0.013 and/?=0.016). Coronary heart disease mortality was significantly lower for patients on metoprolol than for patients on diuretics in the whole study population (/?=0.048) as well as in smokers (p=0.02l). The results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of total, cardiovascular, and coronary heart disease mortality as compared with initial diuretic treatment, both in the whole study population and in smokers. The favorable effect of metoprolol must be mediated via mechanisms other than the blood pressure-lowering effect of metoprolol because equal blood pressure control was achieved with both types of medication, irrespective of smoking habits at randomization. (Hypertension 1989;13:773-780) S moking is an undisputed major independent risk factor for coronary heart disease. 1 The serious adverse effects of smoking on a spectrum of cardiovascular complications to hypertension have been highlighted in numerous studies, and life table analyses have shown that the incidence of coronary heart disease is at least threefold higher in smoking hypertensive men than in nonsmokers. Thus, for reasons of statistical power, it is extremely difficult to show a reduction in overall mortality in intervention studies in hypertension unless an effect on coronary heart disease is achieved in smoking men. Studies of diuretics and several /3-blockers as first-line treatment for hypertension have failed to provide evidence that they can reduce the increased risk for coronary heart disease in smokers.

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