ACE Inhibitors in Aortic Stenosis
Abstract & Commentary
Synopsis: Enalapril improves effort tolerance and reduces dyspnea in patients with symptomatic aortic stenosis, but may cause hypotension in those with congestive heart failure, left ventricular dysfunction, or systolic blood pressure < 100 mm Hg.
Source: Chockolingam A, et al. Am Heart J. 2004; 147:740.
Caution has been advised for vasodilator use in patients with significant aortic stenosis even in the presence of heart failure, yet there is little data on this issue. Thus, Chockolingam and colleagues enrolled patients with severe aortic stenosis (AS) and NYHA class III or IV dyspnea or angina. Severe AS was defined as valve area < .75 am², mean aortic gradient > 50 mm Hg, or Doppler peak velocity > 4.5 m/s. Exclusion criteria included hypotension (systolic blood pressure < 90 mm Hg or mean < 60) and renal dysfunction (creatinine > 2.5 mg/dL). After initial stabilization, patients were randomized to enalapril 2.5 mg twice daily titrated as tolerated to 10 mg twice daily or placebo in a 2:1 ratio. This was a double-blind study with a 4-week follow-up since most of the patients were awaiting surgery. The primary end points were development of hypotension, the Borg dyspnea index, and the 6-minute walk distance. Of the 61 patients who met eligibility criteria, 6 were eliminated for a variety of other issues. Among the remaining 56 patients, 37 were assigned to enalapril and 19 to placebo. Three patients in the enalapril group were withdrawn within 48 hours due to hypotension on 2.5 mg of enalapril; all 3 were in NYHA class IV heart failure, had moderate left ventricular dysfunction (EF < 40%), and had an initial systolic blood pressure between 90-100 mm Hg. One patient developed pulmonary edema after 2 weeks of enalapril, but was stabilized and continued on the drug. Four of the remaining 34 patients in the enalapril group had cough (11%), but continued the study. In the placebo group, 1 patient withdrew for worsening symptoms and 1 developed pulmonary edema. Despite the fact that many of the patients were taking potassium supplements or spironolactone, hyperkalemia was not observed. The Borg dyspnea index and the 6-minute walk distance improved in both groups, but the magnitude was greater in the enalapril group. Among the 43 patients (28 enalapril, 15 control) who continued on study medication for 12 weeks, the improvement on enalapril was sustained, but the placebo effect waned. Chockolingam et al concluded that enalapril improves effort tolerance and reduces dyspnea in patients with symptomatic aortic stenosis, but may cause hypotension in those with congestive heart failure, left ventricular dysfunction, or systolic blood pressure < 100 mm Hg.
Comment by Michael H. Crawford, MD
There are 2 rationales for using angiotensin converting enzyme inhibitors (ACEI) in patients with AS. First, animal studies of aortic banding have shown reduced LV mass and preservation of systolic LV function. This preventative role may not apply to symptomatic patients near the end of their natural history in need of surgery. Second, patients with severe LV dysfunction and clinical decompensation due to severe AS have been shown to improve on IV nitroprusside. However, the patients in the study under discussion on average had normal LV function (mean EF, 63%) and were not decompensated. So this urgent therapeutic role may not apply. In fact, of the 8 patients in the enalapril group with heart failure symptoms, 5 improved and 3 were withdrawn because of hypotension. These 3 had moderate LV function impairment and systolic blood pressure < 100 mm Hg. Thus, it seems that only patients with angina symptoms (the majority in this study) seemed to benefit from enalapril. It is difficult to understand the mechanism of this finding since more of the traditional measures of myocardial oxygen demand (heart rate, aortic valve gradient) did not change significantly and ACEI have not been shown to be antianginal. Also, this was an unusual AS population compared to the typical US patient in that only 5 patients had coronary artery disease and 9 had rheumatic heart disease. Another explanation is that the medical therapy (diuretics in many and dobutamine in some) made the real therapeutic difference, not the ACEI. The fact that the primary end points in the placebo group also improved supports this possibility. Chockolingam et al note that those with concomitant valvular regurgitation seemed to respond best, and 10 patients had grade 3 aortic regurgitation or more in the enalapril group vs 5 in the placebo group. Perhaps improved aortic regurgitation explains the greater benefit in the ACEI group. Chockolingam et al suggest that ACEI be considered for symptomatic patients with severe AS in whom surgery is delayed or not feasible, with the caution that it may cause hypotension in those with heart failure, low blood pressure, or reduced EF. Unfortunately, those with reduced EF or heart failure are the very patients we would like to get on ACEI. There are other approaches for those with angina. Thus, I don’t see this study greatly changing our current approach to patients with symptomatic AS.
Michael H. Crawford, MD, Professor of Medicine, Associate Chief of Cardiology for Clinical Programs, University of California San Francisco, is Editor of Clinical Cardiology Alert.