Analysis of Recent Papers in Hypertension
Jan Basile, MD, Senior Editor

Diastolic dysfunction is predominantly characterized by abnormalities of left ventricular (LV) filling, with impairments in both ventricular distensibility and ventricular relaxation. It occurs in up to 50% of patients with hypertension and is often associated with clinical heart failure. Antihypertensive agents that inhibit the renin-angiotensin-aldosterone system (RAAS) have been shown to improve diastolic function, but whether this is related to their blood pressure (BP)-lowering effect or another unique action independent of BP reduction remains unclear. One problem in evaluating any specific antihypertensive agent's effect on diastolic function has been the lack of an effective noninvasive method for measurement. Fortunately, recent advances have overcome this limitation, allowing for direct measurement of myocardial relaxation velocities through the use of tissue Doppler imaging. The aim of the present study was to determine whether lowering BP with an angiotensin receptor blocker (ARB) would improve diastolic function to a greater extent than non-RAAS antihypertensive therapy. The Valsartan in Diastolic Dysfunction (VALIDD) study, an industry-sponsored study by the maker of valsartan, was a randomized, double-blind, placebo-controlled multicenter trial performed in 41 centers in the United States and Canada. Between September 2004 and March 2005, 482 men and women aged 45 years and older were screened for inclusion by assessing echocardiographic evidence of systolic and diastolic function. To be screened, patients had to have a history of stage 1 or 2 hypertension (mean BP of >140 and <180 mm Hg systolic or >90 and <110 mm Hg diastolic), no history of admission for heart failure within the past year, and no history of taking an RAAS inhibitor within the previous 3 months. The main criteria for exclusion were an LV ejection fraction ≥50%, previous intolerance or contraindication to an angiotensin-converting enzyme (ACE) inhibitor or ARB, mean sitting systolic BP ≥180 mm Hg, mean sitting diastolic BP ≥110 mm Hg, chronic kidney disease, or uncontrolled diabetes (glycated hemoglobin A1c >8.5%). Diastolic function was assessed by tissue Doppler imaging of lateral mitral annular relaxation velocities. Patients were included in the study if they had age-specific reductions in relaxation velocities indicative of diastolic dysfunction. A total of 80% (384) of the patients screened were randomized to either valsartan (160 mg once daily, force-titrated 1 week later to 320 mg once daily) or matching placebo to achieve a target systolic BP <135 mm Hg and a diastolic BP <80 mm Hg. To achieve this target BP, add-on treatment was systematically added with a diuretic, a β-blocker, or calcium channel blocker and then an α-blocker for the 38-week study duration. Patients in the valsartan arm (97%) were given the 320-mg dose even if the targeted BP level was reached on the 160-mg dose. Patients in both groups could not receive concomitant antihypertensive therapy that inhibited the RAAS, including treatment with either an ACE inhibitor, ARB (other than the study drug), or an aldosterone antagonist. Baseline characteristics and baseline medication use were similar in the valsartan (n=186) and placebo (n=198) groups. Mean age was 61 years, 51% were women, and 24% were nonwhite. Baseline BP was similar between the 2 groups (144/86 mm Hg). Patients were clinically assessed every 1 to 6 weeks for 38 weeks. They underwent echocardiographic assessment performed in a core laboratory on entry and at the end of the study. The primary end point was the change in diastolic myocardial relaxation velocity of the lateral mitral annulus (E') from baseline to follow-up. Secondary efficacy measures included differences between treatment groups in BP, LV wall thickness, LV mass, and the ratio of mitral inflow velocity to annular relaxation (E/E'). LV hypertrophy (LVH) was considered to be present based on sex-specific LV mass indices >115 g/m2 for men and >95 g/m2 for women. LVH was present in 3% of patients screened. On follow-up, systolic BP decreased more in the valsartan group (12.8 mm Hg) than in the placebo group (9.7 mm Hg). The final BP in the valsartan group was significantly lower than in the placebo group (130.5/78.6 mm Hg vs 134.6/81.9 mm Hg, valsartan vs placebo, respectively). Heart rate reduction was not different between the 2 groups. Concomitant nonstudy BP medications were more likely to be used in the placebo group than in the valsartan group, including treatment with a calcium channel blocker (78% placebo vs 51% valsartan) and diuretic (81% placebo vs 69% valsartan). There were small but significant increases in diastolic relaxation velocities (E'), the primary end point, in both treatment groups from baseline to follow-up but no difference between groups. In addition, improvement was noted in both groups in isovolumic relaxation time, septal and posterior wall thickness, LV mass, LV end-diastolic and end-systolic volume, as well as ejection fraction. Isovolumetric relaxation time improved more in the valsartan group, and systolic longitudinal velocity improved in the valsartan group and worsened in the placebo group. There were no differences between treatment groups in the primary end point for any of the prespecified subgroups based on age, sex, diabetic status, or renal function. Reducing BP was associated with improvement in diastolic function regardless of whether BP was lowered by RAAS inhibition using the ARB valsartan or other non-RAAS-blocking antihypertensive agents. While greater improvement in isovolumetric relaxation time and systolic longitudinal velocity were achieved with valsartan, these improvements may have been related to the additional reduction in BP achieved in the valsartan group. Lowering BP improves diastolic function irrespective of the type of antihypertensive agent used.—Solomon S, Janardhanan R, Verma A, et al. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomized trial. Lancet. 2007;369:2079–2087. Heart failure can occur in patients with a normal ejection fraction. Often referred to as LV diastolic dysfunction, patients with this condition are usually older and female and more likely to have a history of hypertension. These individuals may present to the emergency department with heart failure, often with severe BP elevations. Heart failure with diastolic dysfunction may account for as much as 50% of all heart failure hospitalizations. Its prognosis remains intermediate between patients with normal heart function and those with abnormalities in systolic pump function. The mortality risk is increased as well. While diastolic dysfunction is more likely to occur in patients with LVH, hypertensive patients without LVH can also develop diastolic dysfunction. It may represent an important pathophysiologic intermediate between hypertension and clinical heart failure. Despite small studies that have tested a variety of drugs based mainly on pathophysiologic principles, no major clinical trial has found any specific antihypertensive agent to preferentially improve diastolic function, independent of its effect on reducing BP. In the preserved LV function arm of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial, use of the ARB candesartan was associated with a decrease in the risk of hospitalization but no change in the risk of mortality compared with placebo. Since there was no active treatment control group, it is not possible to know whether this benefit was secondary to the improved BP reduction that occurred in the candesartan arm. In the present 38-week study, a slightly but not significantly greater BP reduction was seen in the valsartan group than in the placebo group (13/7 vs 10/6 mm Hg, respectively). The lower BP level in the valsartan group was related to study design because valsartan was force-titrated to a maximum dose of 320 mg regardless of whether the BP goal of <135/80 mm Hg was achieved, whereas the placebo group was titrated to the BP goal. Compared with baseline, diastolic relaxation velocity significantly increased in both groups (P<.0001), but the between-group difference was not significant (0.60 cm/s in the valsartan group vs 0.44 cm/s in the placebo group). It should be emphasized that improvement in diastolic function was related to lowering of BP even in the setting of RAAS blockade with the maximum clinical dose of valsartan currently in use. These results suggest that optimum BP control improves diastolic function regardless of the type of antihypertensive medication used. The finding that valsartan conferred no significant advantage over other drugs, however, must be interpreted in the context of the trial's design: patients were relatively young and had mild stage 1 hypertension and few had evidence of LVH. It has been hypothesized that because so few of the patients who were randomized had LVH, the degree of myocardial fibrosis and ventricular remodeling may have been minimal, not allowing an RAAS blocker to demonstrate a preferential effect on this “mild degree” of diastolic dysfunction. Until larger studies with longer follow-up are conducted, it remains to be determined whether an ARB, such as valsartan, or any agent that preferentially inhibits the RAAS, including an ACE inhibitor, will improve cardiac function and cardiovascular outcomes independent of BP control in patients with more advanced stages of ventricular remodeling. Results of the Irbesartan in Heart Failure Preserved Systolic Function (I-PRESERVE) study are eagerly anticipated. In this study, the ARB irbesartan is being compared with placebo in patients with preserved LV function and heart failure. Since it also does not employ an active comparator control group, it suffers from some of the same trial design flaws as the CHARM study. For now, early detection and effective control of BP needs to occur as soon as possible to prevent initial abnormalities in diastolic function. This should be done to prevent the eventual development of clinical heart failure. Drs Bloch and Basile receive research support, consulting fees, and honoraria and are members of the Speakers' Bureau for Novartis, the makers of valsartan.

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