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ARBs and Diastolic Function
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Solomon SD, 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.
Left ventricular (LV) diastolic dysfunction is believed to be an important mechanism of heart failure in patients with hypertension. However, there are currently no specific treatments for diastolic dysfunction. Thus, the results of the Valsartan in Diastolic Dysfunction (VALIDD) trial are of interest. In VALIDD, 482 patients with mild-to-moderate hypertension, who had no recent heart failure and were not on renin angiotensin aldosterone system (RAAS) inhibitors were screened by echocardiography. Those with LV ejection fraction < 50% were excluded. Diastolic dysfunction was defined as a tissue Doppler lateral mitral annular early relaxation velocity (E') lower than age specific cut-off values: < 10 cm/s for age 45-54 years, < 9 cm/s for age 55-65 and < 8 cm/s for > 65 years. The final population of 384 patients was randomized to valsartan 160 to 320 mg/day or matched placebo, plus standard antihypertensive therapy (no RAAS inhibitors) to achieve blood pressures < 135/80. The primary endpoint was the change in relaxation velocity from baseline to 38 weeks of therapy on an intention to the treat basis.
Results: E' was lower in these hypertensive patients (7.5 cm/s) as compared to historic controls (> 8 cm/s) and declined with increasing age. LV hypertrophy was present in < 3% of the randomized patients. Of the 384 patients randomized, 341 completed the study (89%). Only 10 withdrew for adverse effects and 2 left because of uncontrolled hypertension. The other 31 withdrew for a variety of personal reasons. At the end of 38 weeks, systolic blood pressure fell 13 mmHg in the valsartan group and 10 in the placebo group (p = NS) and diastolic 7 and 6 mmHg, respectively. E' increased 0.60 cm/s in the valsartan group and 0.44 in the placebo group (p = NS). However, this change from baseline was statistically significant (p < 0 .0001). Other echo Doppler parameters also improved on therapy: isovolumic relaxation time, LV mass, left atrial volume, LV volumes and ejection fraction. However, only the improvement in isovolumic relation time was significantly greater on valsartan (-6 ms vs -2 ms, p = 0.03). No pre-specified subgroup did better with regard to the primary endpoint on valsartan. There were no treatment related severe adverse events and no one developed heart failure, myocardial infarction or hyperkalemia. The authors concluded that lowering blood pressure improves diastolic function regardless whether RAAS inhibitors are used.
Since experimental studies have shown greater reduction in LV hypertrophy and fibrosis with RAAS inhibitors compared to other antihypertensive agents, it was reasonable to hypothesize that valsartan may have beneficial effects on diastolic function beyond those seen with blood pressure lowering alone. This study failed to support this hypothesis, at least in terms of the primary endpoint of E' (early diastolic tissue velocity). There were some secondary endpoints that were improved more on valsartan such as isovolumic relaxation time, but valsartan did lower blood pressure slightly more than placebo plus other therapy (p = 0.10), so all the effects seen were probably just due to blood pressure lowering per se. So is this hypothesis dead? Probably not since this was a study of relatively young (mean age 60), obese (BMI 31) individuals with mild hypertension (systolic blood pressure 144, diastolic 86) on therapy at baseline. In addition, the duration of therapy was short (38 weeks). Also, even though 80% of these subjects had diastolic dysfunction, few had LV hypertrophy. Thus, a group with higher pressures and more LV hypertrophy may have done better on a RAAS inhibitor.
The good news from this study is that effective blood pressure lowering by any means improves diastolic function, reduces LV mass and volume, and improves systolic function. All these changes were small, but statistically significant. Whether these small changes are clinically significant and will lead to better outcomes was not tested in this study. However, it is attractive to predict that reducing blood pressure and improving diastolic function will lead to less heart failure.
Although early diastolic lateral mitral annulus Doppler tissue velocity (E') is a robust measure of diastolic function, which is less influenced by loading conditions, it is not perfect. Most echocardiography laboratories evaluate several parameters and then factor in confounders such as age, heart rhythm, mitral regurgitation, etc., before deciding what the diastolic function of a given left ventricle is likely to be. Many of these parameters were assessed as secondary endpoints in this study and their results were consistent with the observed changes in E', but noticeably absent were estimates of LV filling pressure based upon pulmonary vein flow. Also, the small changes observed in E' could have been due to the changes observed in left ventricular systolic pressure, volume and performance. Thus, this study is supportive of a beneficial role of RAAS inhibitors in diastolic dysfunction due to hypertension, but the mechanism could just be their efficacy at lowering blood pressure.