We are grateful for the opportunity to address the concerns that may have arisen from the results of the case–control study of Hoes and colleagues [1], which was published shortly after our review appeared [2]. The conclusion of this study suggested an association between ß-blocker therapy and sudden death. Our review advocated the use of ß-blockers to reduce the risk for sudden death.

Case-control studies are designed to detect possible associations, whereas randomized trials are needed to show the effect of an intervention. In the study of Hoes and colleagues [1], case-patients were probably prescribed a ß-blocker more often than were controls because their physicians considered them to have an increased risk for sudden death. Although the authors used several methods to limit this problem, any study that does not use random treatment assignments is subject to potential bias.

Second, it is unreasonable to assume that all ß-blockers are the same. We accept that different penicillins are used for different infections, and recent concerns have suggested that not all calcium antagonists are the same. Data from long-term, randomized clinical trials have shown that ß-blockers—more specifically, lipophilic ß-blockers such as metoprolol, propranolol, and timolol—reduce coronary-related mortality [2], whereas no data indicate that hydrophilic ß-blockers do so [3, 4].

Third, coronary artery disease starts early in adult life and is progressive. For a drug to merit the description "cardioprotective" (in the sense that it reduces the risk for coronary death), it must positively affect atherosclerosis or must reduce the frequency of ventricular fibrillation. Such a drug should reduce the mortality from coronary disease when given to high-risk hypertensive patients. It should also be effective when given for the short term at the time of infarction and for long-term therapy after infarction. Data from animals and humans have shown that lipophilic ß-blockers do affect the underlying mechanisms responsible for coronary artery disease and ventricular fibrillation [2]. They have been shown in primary prevention trials to reduce mortality rates in men. In secondary prevention studies, patients benefit from ß-blockers given at the time of infarction and for long periods after infarction [5]. For no other group of drugs is the evidence so great.

Many reasons have been suggested for the unsatisfactory reduction in coronary artery disease resulting from the treatment of hypertension. Improvement may be seen if the antihypertensive drug chosen has been shown to have cardioprotective effects both in the laboratory and in the clinic.