Amlodipine Versus Valsartan for Improvement of Diastolic Dysfunction Associated With Hypertension

Approximately half of hypertensive patients have diastolic dysfunction and diastolic dysfunction is associated with development of congestive heart failure and increased mortality. The Framingham study reported that 51% of patients with HF have a preserved left ventricular (LV) ejection fraction and hypertension is the strongest risk factor for HF with preserved ejection fraction, also termed diastolic heart failure. The rates of death and morbidity in these patients are as high as in patients with HF and a low LV ejection fraction. Hypertensive patients are at increased risk of developing LV hypertrophy and myocardial fibrosis, which cause relaxation abnormality and decreased compliance of LV with a rise in the LV diastolic pressure. Although diastolic HF associated with hypertension is a clinically significant problem, few clinical trials have been conducted and there is no proven pharmacological therapy to improve outcomes. Because the activation of rennin-angiotensin-aldosterone system (RAAS) has been shown to induce LV hypertrophy and myocardial fibrosis, the RAAS may play a central role in the pathogenic process from hypertension to diastolic HF. Inhibitors of RAAS have been considered as a treatment option for these patients, and the angiotensin receptor blockers (ARB) have been of interest because they antagonize the effects of angiotensin II more completely. However, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial reported that treatment with irbesartan did not reduce the risk of death or hospitalization for cardiovascular causes among 4,128 patients who had HF with a preserved LV ejection fraction.

The degree of improvement of diastolic dysfunction was associated with the extent of systolic blood pressure reduction, whether a RAAS inhibitor or non-RAAS blood pressure lowering was used. The Systolic Blood Pressure Intervention Trial (SPRINT) compared the benefit of treatment of systolic blood pressure to a target of less than 120 mmHg with treatment to a target of less than 140 mmHg, and recently reported that targeting a systolic blood pressure of less than 120 mmHg, as compared with less than 140 mmHg, resulted in lower rates of fatal and nonfatal major cardiovascular events and all-cause death. Amlodipine is a potent and well-tolerated calcium channel blocker, and seems to be appropriate for achieving more aggressive systolic blood pressure target and improving diastolic dysfunction in hypertensive patients, because amlodipine is clinically very useful for controlling systolic blood pressure. Evaluating the effect of treatments on diastolic dysfunction has been limited by difficulties in non-invasive measure of LV diastolic pressure, but recent advances in echocardiography have made it possible to assess diastolic dysfunction accurately and reproducibly. Thus, assessment of diastolic function by echocardiography will be helpful to determine whether addition of amlodipine or an ARB to standard therapy is more beneficial to hypertensive patients with diastolic dysfunction. To the best of our knowledge, there has been no randomized trial to compare the effect of amlodipine versus an ARB on improving diastolic dysfunction in hypertensive patients. The investigators hypothesize that amlodipine added to standard therapy will be superior to valsartan in improving diastolic dysfunction by lowering systolic blood pressure more effectively in hypertensive patients, and try to examine this hypothesis in a prospective, open-label, randomized comparison study using blinded echocardiographic evaluation for end point.