Clinical trials of single-drug therapy for the cardiac effects of hypertension

The cardiac effects of hypertension were recognized by the great French physician Auguste Laennec, who described a relationship between left ventricular hypertrophy (LVH) and the arterial circulation.1 He noted that “When affecting the left ventricle, I have seen its parietes more than an inch thick … the septum between the two ventricles becomes also notably thickened in the disease of the left ventricle … Symptoms are—a strong full pulse, strong and obvious pulsation of the heart … ” More than 20%2 of the American population (60% of African-Americans > 60 years of age) are hypertensive. Moreover, increased weight (mass) of the LV (ie, LVH) is an independent risk factor for cardiac morbidity and mortality, independent of other risk factors.3,,–6 Further, there is a continuous relation between LV mass and adverse outcome,7 even for values of LV mass within the normal range. Because the prevalence of LVH in hypertension can range from about 20% to 60%,8,–10,11 the population-attributable risk of hypertensive LVH is high given the high prevalence of hypertension in the general population. Importantly, recent studies12,13 have suggested that reduction of LV mass confers clinical benefit, even after statistical adjustment for other factors known to affect outcome. If confirmed by prospective studies, reduction of LV mass may therefore become an important goal in the treatment of hypertension. Although LV mass and the prevalence of LV hypertrophy14,15 are reduced by antihypertensive therapy, not all drugs are equally effective in reducing LV mass,16,,–19 even with an equivalent reduction of blood pressure. Although it has been shown unequivocally that diuretic- and β-blocker–based regimens reduce the cardiac mortality and morbidity of hypertension, some studies have indicated that these agents,20,21,,,–25 as well as vasodilators, may be ineffective in decreasing LV mass. It has been suggested that this may be due to failure to block, or in some cases actual stimulation of, neurohumoral mechanisms responsible for LV hypertrophy.19 However, therapeutic trials of LV mass regression have often been uncontrolled, short-term studies of one or two therapies, with uncertain randomization. Also, there has been a tendency to study relatively small numbers of patients, which is particularly problematic when evaluating a methodologically variable endpoint such as LV mass. Moreover, factors other than drug selection may affect LV mass10,26 and change in LV mass with antihypertensive therapy. These include the extent of systolic blood pressure reduction, obesity, the magnitude of weight loss, race, plasma renin, sodium excretion, and physical activity. Many prior studies have failed to control or adjust for these factors. To overcome some of these shortcomings, the results of many individual studies have been combined in metaanalyses.27,28 However, even the more rigorous28 of these two evaluated clinical trials that were of relatively short duration, included multiple-drug regimens, had subgroup analyses of small numbers of patients, and usually didn’t adjust for relevant covariates. Notably, the metaanalysis included only studies where LV mass reduction (in contrast to blood pressure reduction) was the primary endpoint. Accordingly, the results of the only large multilimb, multicenter trial published before that time (The Treatment of Mild Hypertension Study [TOMHS], described later) were excluded, as the stated purpose of that trial was to compare the efficacy of several single drug regimens with placebo (actually a nondrug, weight loss and nutritional treatment limb) on reduction of blood pressure. However, reduction of LV mass cannot be evaluated as a primary endpoint because patients must achieve blood pressure control to remain in the study. Hence, it is not ethically possible to maintain patients with therapy ineffective for blood pressure control to determine its potential effects on LV mass. Despite the methodologic limitations of studies of LV mass reduction20,29 noted earlier, the Treatment of Mild Hypertension Study avoided many of these. In this double-blind, placebo-controlled trial of 844 patients with mild hypertension and low prevalence of LV hypertrophy, all treatment groups were associated with reduction in LV mass (Figure 1), including placebo, chlorthalidone, and acebutolol.30 However, LV mass decreased more than placebo only in the chlorthalidone group (P = .03).31 Another, relatively recent multicenter trial of single-drug therapy was The Veterans Affairs Trial of Monotherapy in Mild-Moderate Hypertension. This was a placebo-controlled, titration trial of monotherapy, employing six active drugs and placebo to test the comparative efficacy of different classes of drugs for the lowering of diastolic blood pressure.32 The response of LV mass and its structural components to treatment was assessed during 1 year of antihypertensive monotherapy, which consisted of monotherapy with either atenolol, captopril, clonidine, diltiazem, hydrochlorothiazide, prazosin, or placebo. The effects of treatment on the echocardiographic endpoints were statistically adjusted for potentially contributory factors, including body weight, the magnitude of blood pressure reduction, race, and age.33 After adjustment for patient covariates, significant reductions at 1 year in LV mass were seen with hydrochlorothiazide (mean, −42.9; 95% confidence limits, −65.5; −20.2 g), captopril (mean, −38.7; 95% confidence limits, −61.0; −16.4 g), and atenolol (mean, −28.1; 95% confidence limits, −50.9; −5.3 g) for patients in the highest tertile of pretreatment LV mass (Figure 2). These treatment effects differed from those of prazosin, diltiazem, or clonidine. Hydrochlorothiazide was effective for LV mass reduction in another relatively large monotherapy comparison. We analyzed the echocardiograms of 134 patients with mild-moderate hypertension in an 18-center double-blind diastolic blood pressure titration comparison of isradipine (a dihydropyridine calcium blocker) with hydrochlorothiazide.34 Whereas at 6 months (Figure 3), the decrease in LV mass from baseline with isradipine was not statistically significant, LV mass reduction (−43 ± 7 g) was achieved with hydrochlorothiazide, which also differed statistically from isradipine on between-treatment comparison. Both drugs were associated with comparable decreases in septal and posterior wall thickness. By design, an equivalent decrease in diastolic blood pressure was obtained with both drugs, although the decrease in systolic blood pressure on 24-h ambulatory blood pressure recording was greater with hydrochlorothiazide. Nonetheless, on multiple regression analysis, hydrochlorothiazide was superior to isradipine for LV mass reduction even after adjustment for systolic blood pressure, race, age, weight, and gender. Systolic hypertension in the elderly differs in important characteristics from hypertension in younger individuals. Conceivably, LV mass reduction in these older patients may be more difficult to achieve than in younger individuals. However, it was shown35,36 in the Systolic Hypertension in the Elderly Program (SHEP) that blood pressure reduction achieved with a diuretic- or β-blocker–based regimen was effective for reduction of LV mass, and was associated with improved outcome. Thiazides may not be the only diuretics capable of LV mass reduction. One recent study documented reduction of LV wall thickness and LV mass using indapamide.37 Although the absence of a control group makes the conclusions of that study somewhat tentative, a metaanalysis of clinical trials using indapamide also suggested that the drug is associated with reduction of LV mass.38 Additionally, a crossover clinical trial comparing clonidine with indapamide39 noted no reduction in LV mass in patients assigned to clonidine. There was a decrease in LV mass with indapamide, primarily from the decrease in LV wall thickness. Moreover, when patients were switched from clonidine to indapamide, there was subsequent reduction of LV mass. Nonpharmacologic means for reducing blood pressure may also be effective for reduction of LV mass. Patients who modified salt intake and lost weight as part of the placebo intervention in TOMHS30 had a decrease in LV mass. In another study,40 there was a greater decrease in LV mass with weight reduction than with metoprolol. Although exercise can be effective for reduction of blood pressure in patients with hypertension, in normal individuals it has been associated with increased LV mass on echocardiography.41 This physiologic, athletic increase in LV mass is characterized by increased LV cavity size with little or no change in wall thickness, and preservation of diastolic LV function. However, in hypertensive patients exercise training may produce decreases in LV mass, greater than that associated with concomittant drug therapy.42 Dietary salt restriction may also result in reduction of LV mass.30,43,44 Theoretically, the loss of contractile protein accompanying decreases in LV mass might impair LV systolic function. This could be particularly severe if a sudden increase in blood pressure, such as might occur with discontinuing therapy after effective reduction of LV mass, were to load a left ventricle no longer protected by compensatory hypertrophy. Nonetheless, echocardiographic evaluation of the ejection phase indices of LV function14,33,45,46,47 have not produced decreases in systolic function accompanying LV mass reduction during or after antihypertensive therapy. However, measurement of ejection phase indices—such as velocity of circumferential fiber shortening, fractional shortening, and ejection fraction—are highly load dependent, and therefore do not assess myocardial contractility. The tendency for LV function to increase during the initial stages of therapy may in fact reflect the effects of reduced afterload.45 Midwall fractional shortening adjusted for end-systolic stress may be a better way to assess myocardial contractility noninvasively. In this regard, we recently evaluated midwall fractional shortening relationships to end-systolic stress in patients with substantial reductions of LV mass during treatment and found no adverse effects of LV mass reduction on LV contractile function.48 It is also theoretically possible that a decrease in LV mass could produce impairment of diastolic LV function if the decrease in contractile protein was disproportionate to the decrease in connective tissue mass. Then, with the reduction of total LV mass, a relative increase in the collagen/LV weight ratio could result in decreased diastolic distensibility of the left ventricle. Using Doppler echocardiography, however, studies have failed to show worsened diastolic function with LVH regression.14,49,,–52 Indeed, there may be an improvement in diastolic function after reduction of LV mass.49,50 It is a fundamental tenet of logic that the truth of a proposition does not imply that its converse is also true. Nonetheless, it has been tempting in clinical medicine to assume that because a risk factor is associated with adverse outcome, its removal or modification will improve outcome. Probably the best known example of this is the previous clinical practice of attempting to suppress multiform or frequent ventricular premature beats with Type I antiarrhythmic agents, because of strong relationships between ventricular arrhythmia and death in patients with coronary disease. Moreover, such a rationale was well supported by pathophysiologic theory. Subsequently, the results of the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated a lack of benefit with these agents. Moreover, there were actual increases in mortality, particularly with one of the drugs that was most effective for the suppression of arrhythmia. In fact, there are reasons to be concerned about the potentially adverse effects of LVH regression. If the cardiac hypertrophy that occurs in response to hypertension is truly compensatory, then reduction of contractile muscle mass could result in cardiac decompensation, as well as worsened diastolic function, because of a relative increase in the connective tissue. Although a decrease in LV function after LVH regression has not been shown, surrogate endpoints can be misleading. Reassuringly, recent studies have indicated that reduction of LV mass confers benefit in addition to what would be gained by blood pressure reduction alone. In the population-based Framingham study, Levy and colleagues12 reported that serial decline in ECG voltage was associated with a reduction of risk for incident cardiovascular disease (odds ratio, 0.46 for men and 0.56 for women). However, those with a serial increase in voltage had an increased risk for cardiovascular disease (odds ratio, 1.86 for men and 1.61 for women). It should be noted, however, that these subjects were selected for the presence of LVH on ECG, which is relatively insensitive for the detection of LVH. Hence, the participants selected for this study likely had greater severity of LVH than if echocardiography had been used. However, in another study, regression of LVH determined by echocardiography was also associated with benefit.53 Repeat echocardiography was performed in 151 of 215 hypertensive patients, of whom fewer than half had LVH. Patients without regression of LVH had a greater number of nonfatal cardiovascular events over the 10-year average follow-up than those with regression of LVH. Recently, Verdecchia et al13 reported their findings in 430 hypertensive patients studied over 1217 patient-years. In the combined group of patients of whom three-fourths did not have echocardiographic LVH, a decrease in LV mass was associated with a diminished risk for cardiovascular events (hazard ratio, 0.46). There was a particularly marked reduction in events (hazard ratio, 0.18) among the 26% of patients who had echocardiographic LVH at baseline and a decrease in LV mass to less than the partition value for LVH. The relationship between LV mass reduction and improved outcome was statistically independent of baseline LV mass, baseline clinic and ambulatory blood pressure reduction, and the degree of blood pressure reduction with treatment. It is important to consider, however, that these studies were not prospective trials of antihypertensive treatment. It is still uncertain whether drugs of equal efficacy for reduction of LV mass and blood pressure differ in their ability to reduce cardiac morbidity and mortality. Hypertension is associated with increased left atrial size,54,,–57 which in itself is associated with increased risk of atrial fibrillation58,59 and stroke.60 Despite the large number of clinical trials that have evaluated the effects of antihypertensive therapy on LV mass, few studies have assessed the effects of treatment on left atrial size. Although one study of verapamil61 showed a decrease in left atrial size with treatment, another62 failed to show an effect of verapamil therapy on left atrial size—despite reduction of LV wall thickness—but not on LV mass. In another study,63 treatment with labetolol failed to produce a decrease in left atrial size, despite reduction of LV mass. Notably, there are factors other than drug selection that may affect left atrial size in patients with hypertension.56,57 These factors, which include body weight, systolic blood pressure reduction, age, race, sodium excretion, and physical activity, have not been evaluated in studies of left atrial size reduction. We measured left atrial size on echocardiogram for up to 2 years of treatment in a double-masked monotherapy trial of 784 men with mild to moderate hypertension.64 Only hydrochlorothiazide was associated with a reduction in left atrial size at 8 weeks, 1 year, and 2 years of treatment (Figure 4). After adjustment for the covariates described earlier, patients with normal left atrial size had a greater reduction in left atrial size at 2 years with hydrochlorothiazide, whereas in patients with left atrial enlargement, left atrial size decreased significantly with all treatments at 2 years, although the reduction was greater with hydrochlorothiazide than with captopril or prazosin. It is of clinical importance to know whether the reduction of left atrial size is associated with a decrease in incident atrial fibrillation, or stroke. However, the study noted here was not designed to assess the effects of reduction of left atrial size on clinical outcome. Further studies need to be done to determine whether the superior reduction of left atrial size demonstrated in our study with hydrochlorothiazide is associated with improved outcome. Much has been learned in epidemiologic studies and clinical trials about the relationships between hypertension and cardiac anatomic and functional responses, as well as the effects of antihypertensive treatment on those responses. The results of recent multicenter trials have supported initial concerns that not all drugs effective for blood pressure reduction are effective for reduction of LV mass and regression of LVH. However, recent trials of single-drug therapy suggest that those agents initially believed to be ineffective for LV mass reduction (principally diuretics and β-blockers), on the basis of pathophysiologic theory and inadequate clinical trials, may in fact be quite effective for LVH regression, as well as for improving cardiac outcomes.65,66,67,68 Additionally, fears concerning the adverse effects of LV mass reduction on systolic and diastolic LV function have not been justified by the results of clinical trials. In conclusion, the often-assumed lack of efficacy of diuretics and β-blockers for the reduction of LV mass can no longer be used as a reason to disregard the longstanding recommendations of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Hypertension supporting the use of diuretics and β-blockers as the initial drug treatment of hypertension.