Blood Pressure Reduction After the First Dose of Captopril and Perindopril

To the Editor: Initiation of treatment with angiotensin-converting enzyme (ACE) inhibitors is frequently complicated by the occurrence of (sometimes severe) hypotension after the first dose. Profound hypotension, requiring termination of the treatment, was present in about 5% of the patients after the first dose of 6.25 mg captopril and of 10 mg enalapril.1,2 First-dose hypotension (FDH) increases the risk of falls, myocardial infarction, and stroke. A positive correlation between FDH and mortality was found.3 Older patients are especially at risk, presumably because of impaired adaptive and autoregulation functions. To prevent FDH, it is advised to stop diuretics for 24 to 48 hours and to give a low dose of 6.25 mg captopril or 2.5 mg enalapril. However, in older people, a delicate treatment equilibrium often exists, and discontinuation of diuretics is not always possible. In general practice, the advice to stop diuretics is not always followed up.4 Clinically relevant differences between ACE inhibitors in the magnitude of FDH might exist. Studies showed that perindopril caused less FDH than did captopril, enalapril, or lisinopril.5–7 We studied 10 patients age 70 and older with chronic stable heart failure and proven severe FDH, defined as a decrease of mean arterial blood pressure (MAP)> 25 mmHg, after 6.25 mg captopril. A consent was obtained from each patient. Blood pressure was measured supine with an automatic ambulatory device (Spacelab®, SpaceLabs, Inc., Workingham, Beckshire, England) every 15 minutes from 8 a.m. on for 5 hours and in sitting position every hour for the next 8 hours. During the whole study period, patients were closely monitored for clinical signs of FDH. Blood pressure was measured on 3 different days: at baseline; the following day, receiving 6.25 mg captopril at 9 a.m.; and, in the case of severe FDH, receiving 2 mg perindopril at 9 a.m. after a 3-day washout period. All other drugs, including diuretics, were not changed from 72 hours before the study until the end of the study period. The difference between the lowest MAP measured in the hour before captopril or perindopril and the lowest of 24 MAPs measured within 12 hours after captopril or perindopril was calculated. The differences in blood pressure reduction after captopril and perindopril were tested with Wilcoxon signed rank test. Effects with a P-value < .05 were regarded as significant. Of 25 patients, 10 (mean ± standard deviation (SD) age 84 ± 6 years) suffered a blood pressure reduction openface> 25 mmHg MAP after 6.25 mg captopril. No differences were found for age, gender, serum creatinine level, or New York Heart Association class between patients with and without severe FDH. The 10 patients with severe FDH used at mean a lower dose of furosemide (44 ± 13 mg) than did the 15 patients without severe FDH (77 ± 53 mg). The mean ± SD maximum fall of MAP in these 10 patients was 31.3 ± 4.5 mmHg (range 27–40). Two patients became drowsy for a short period. No intervention was needed. After the first dose of perindopril, mean ± SD maximum fall of MAP was 18.5 ± 10.6 mmHg (range 5–38) in the 10 patients. Two patients had a fall openface> 25mmHg MAP. None of the patients had symptomatic FDH. The difference in blood pressure reduction after the first dose of captopril and perindopril was statistically significant (P = .007). Figure 1 shows the course of the MAP at baseline, after captopril, and after perindopril. On all 3 days, a marked and comparable blood pressure reduction was present between 8:00 a.m. and 9:00 a.m. A further blood pressure reduction was found 1 hour after use of captopril, between 10:00 and 11:00 a.m. After 12:00 noon, the blood pressure–lowering effect of captopril disappeared again. Captopril was not continued after the first dose. The blood pressure reduction caused by perindopril started gradually, 4 to 5 hours after the dose, and persisted until the last measurements. The median time to the lowest MAP after captopril was 2 hours (range 0.75–5 hours) and after perindopril was 5 hours (range 0.25–10 hours). Plasma ACE values before the first dose of captopril or perindopril were both 0.62 ± 0.2 U/l. Course of blood pressure at baseline, after 6.25 mg captopril and 2 mg perindopril. MAP = mean arterial blood pressure. *P < .05 captopril compared with perindopril and baseline; †P < .05 perindopril compared with captopril and baseline. The present findings confirm that 2 mg perindopril causes less blood pressure reduction after the first dose than does captopril. Even in a high-risk group of older patients with heart failure with proven FDH (>25 Hg MAP) after 6.25 captopril, blood pressure reduction after perindopril was gradual and mild and caused no symptoms, even when diuretics were not withdrawn.