Controlled Multicenter Study of the Antihypertensive Effects of Lisinopril, Hydrochlorothiazide, and Lisinopril plus Hydrochlorothiazide in the Treatment of 394 Patients with Mild to Moderate Essential Hypertension

Lisinopril (LIS) is a lysine analog of enalaprilat, the active metabolite of enalapril, an angiotensin-converting enzyme inhibitor (ACEI). Unlike enalapril, the precursor of enalaprilat, LIS is not a prodrug but has equal ACEI efficacy and potency and a slightly longer duration of action after oral administration. Short-term (12 weeks) and long-term (24 weeks) blood pressure control has been studied with LIS, hydrochlorothiazide (HCTZ), and LIS + HCTZ when given once a day. Drug treatment had three phases: (i) 2–4 weeks of single-blind placebo washout; (ii) 12 weeks of double-blind comparison therapy with LIS 20, 40. and 80 mg vs. HCTZ 12.5, 25, and 50 mg, vs. LIS + HCTZ 20 + 12.5, 40 + 25. and 80 + 50 mg; (iii) 13–24 weeks single-blind LIS vs. LIS + HCTZ. Starting double-blind therapy at the lowest dose, all three groups doubled the dose at weeks 4 and 8 if BP was not controlled with sitting diastolic BP (SDBP) < 90 mm Hg. At the end of 12 weeks of double-blind therapy, uncontrolled HCTZ-only and LIS-only treatment groups were advanced to combination LIS + HCTZ therapy but uncontrolled LIS + HCTZ patients were dropped. Mean BP reductions (systolic/diastolic, mm Hg) for all three groups after 12 weeks of double-blind comparison therapy were: (i) LIS (n = 162), – 16.6/-12.5; (ii) HCTZ (n = 155), – 10.4/-6.8: (iii) LIS + HCTZ (n = 74). −23.9/- 18.2 with p < 0.01 for all groups compared to baseline. Significant (p < 0.01) decreases in SDBP with all therapies were seen regardless of race, but nonblack patients responded better than black patients to LIS alone. During the second treatment period (weeks 13–24), 89% of patients (177/199) at week 24 had SDBP ≤ 85 mm Hg or ≥ 10 mm Hg SDBP reduction. By 24 weeks, 82% (72/88) of LIS-treated patients maintained this BP control, whereas 84% (48/57) of LIS + HCTZ-treated patients and 67% (36/54) of HCTZ-treated patients sustained identical BP control. By 22 weeks, 68% (81/119) of patients maintained BP control on LIS monotherapy. With ≤ 20 mg LIS therapy, 41% (33/81) achieved long-term BP control, whereas 65% and 72% of these patients responded to ≤ 40 mg and ≥ 80 mg LIS doses, respectively. Serious adverse clinical effects in all groups were rare (< s3%) during short-term and long-term therapy. In conclusion, LIS therapy alone (20–80 mg q.d.) is more efficacious than HCTZ therapy alone (12.5–50 mg q.d.). LIS + HCTZ [(20 + 12.5)-(80 + 50) mg q.d.] is more efficacious than either LIS therapy alone (20–80 mg q.d.) or HCTZ therapy alone (12.5–50 mg q.d.). Lisinopril and LIS + HCTZ are effective and well tolerated antihypertensive agents in both short- and long-term therapy.