Several beta-blocker and diuretic combinations were marketed a number of decades ago when beta-blockers became available in the USA (Figure 12). In most of these fixed combinations, the beta-blocker is combined with 25 mg, or even 50 mg, of HCTZ (or the corresponding dose of a thiazide derivative), a dose that, by today's standard, would have to be considered high. It has been learned that HCTZ doses of 12.5 mg, and even 6.25 mg, lower BP and cause fewer endocrine metabolic adverse effects than the higher doses that were used previously. The dose-response curve with regard to BP plateaus at around 50 mg. However, the dose-response curve with regard to hypokalemia, hyponatremia, hyperuricemia, glucose intolerance, and so on, seems to plateau only at levels of 100-200 mg. Thus, it is in the best interest of the patient to use low-dose diuretics. Indeed, the FDA has approved a very low-dose fixed beta-blocker and diuretic combination (bisoprolol and HCTZ). In this combination, three different dose levels of bisoprolol (2.5 mg, 5 mg, and 10 mg) are combined with only 6.25 mg of HCTZ. The FDA approved this fixed combination for first-line therapy because of solid documentation that it lowered BP more than monotherapy of the same dose of either bisoprolol or HCTZ, and yet all known adverse effects of these two drugs are dose dependent.
Fixed-dose beta-blocker and diuretic combinations
Atenolol 50 or 100 mg/chlorthalidore 25 mg
Bisoprolol 2.5, 5 or 10 mg/HCTZ 6.25 mg
Metoprolol 50 or 100 mg/HCTZ 25 or 50 mg
Nadolol 40 or 80 mg/bendroflumethiazide 5 mg
Propranolol (extended release) 80, 120 or 160 mg/HCTZ 50 mg
Metoprolol 100 mg/HCTZ 12.5 mg
Propanolol 160 mg/bendrofluazide 5 mg
Timolol 10 mg/bendrofluazide 2.5 mg
Acebutolol 200 mg/HCTZ 12.5 mg
Atenolol 25 mg/bendrofluazide 1.25 mg
Atenolol 50 mg/chlorthalidone 1.25 mg
Oxprenolol 160 mg/cyclopenthiazide 0.25 mg
Pindolol 10 mg/clopamide 5 mg
Figure 12 Fixed-dose beta-blocker and diuretic combinations.
Both beta-blockers and diuretics have been documented to lower BP. The Fifth Report of the JNC, released in 1992, labeled diuretics and beta-blockers as the preferred agents for initial therapy of hypertension. This stand was somewhat softened in 1997 by the JNC VI . Nevertheless, the JNC VI still recommended diuretics and beta-blockers as first-line therapy for uncomplicated hypertension because these were, supposedly, the only two drug classes for which a reduction in morbidity or mortality was shown in hypertension. While this is true for diuretics, it is incorrect for beta-blockers. There is no study in which beta-blockers have been shown to reduce morbidity and mortality in hypertension when compared with placebo. In the large UK Medical Research Council (MRC) study, in patients younger than 65 years of age, diuretics reduced the risk of stroke between two and four times better than beta-blockers, despite an equal fall in BP . One can also estimate from this study that, in order to prevent one heart attack or one stroke by beta-blockade, six patients were made impotent and another seven experienced fatigue to the extent that they decided to withdraw from this therapy. This is hardly a risk/benefit ratio that can be considered acceptable for patients with asymptomatic mild essential hypertension. In JNC 7, thiazide diuretics became the preferred drug class for initial therapy .
Does the addition of a beta-blocker to a diuretic enhance the morbidity and mortality benefit of a diuretic? Clearly, the addition of a beta-blocker to a diuretic will lower BP further. However, in the MRC study in elderly patients, whenever a beta-blocker was added to a diuretic, the benefits were diminished, and they vanished completely with beta-blocker monotherapy . Thus, almost in a dose-dependent fashion, the diuretic-induced benefit melted away with an increasing dose of beta-blocker; the more beta-blocker present, the less cardioprotection achieved. Even in the SHEP study, in which many patients received atenolol in addition to baseline diuretic therapy (chlorthalidone), no benefits of this addition were documented . Kostis et al.  scrutinized the effects of beta-blocker addition in this study and clearly stated, "Additional (independent) benefits attributable to atenolol or to reserpine were not identified." It seems that most, if not all, benefits, with regard to cardiovascular morbidity and mortality, observed with diuretic and beta-blocker combinations are due to diuretic therapy. As beta-blockers do not have a benign adverse-effect profile, it seems reasonable to avoid a diuretic/ beta-blocker combination for uncomplicated hypertension. This is particularly true for elderly patients, who often present with systolic hypertension. Beta-blockers will reduce heart rate in these patients, which, in turn, leads to a higher stroke volume (ie, an increased amount of blood is ejected into the aorta per heartbeat). This will invariably cause an increase (or a lesser fall) in systolic pressure and a decrease in diastolic pressure. The simple rule to remember is that bradycardia causes systolic hypertension.
It must be emphasized that there are well-documented indications for beta-blockers; these include certain disease states, such as the post-MI patient with hypertension or the patient with heart failure. In the Carvedilol or Metoprolol European Trial (COMET) - the largest trial to date to be carried out in patients with heart failure - carvedilol was shown to reduce cardiovascular morbidity and mortality better than metoprolol . Numerous studies, carried out 25 years ago, have shown that beta-blockers reduce morbidity and mortality, mostly by reducing reinfarction and sudden death in the post-MI patient. However, in a contemporary patient population, this was only demonstrated with carvedilol. Should such a patient have hyperten sion, or become hypertensive in the post-MI time period, the addition of a low-dose thiazide diuretic to the beta-blocker must be considered a logical therapeutic step. Similarly, in heart failure, beta-blockers and diuretics are a cornerstone of the therapeutic strategy and should be combined in a fixed combination whenever possible. Commonly, physicians fear that they will lose some therapeutic flexibility when using fixed combinations. This is certainly true with regard to downtitration, but not necessarily for uptitration. Thus, there is nothing wrong in telling a patient who is on a fixed diuretic and beta-blocker combination to occasionally take an additional dose of a diuretic if he or she is exposed to an inappropriate dietary salt load. In unstable clinical situations, as a rule, fixed combinations should be avoided.
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