A multinational, double-blind, randomised study was conducted to investigate the efficacy and safety of a low-dose combination of the angiotensin converting enzyme inhibitor, ramipril, and the calcium antagonist, felodipine ER, in 642 patients with mild to moderate hypertension [supine diastolic blood pressure (DBP) = 95-115 mm Hg]. After a 4-week single-blind placebo run-in, patients were randomly allocated to once-daily felodipine extended release (ER; 2.5 mg), ramipril (2.5 mg) or felodipine ER/ramipril (2.5/2.5 mg) for 12 weeks. In the intention-to-treat analysis, mean DBP decreased significantly (p < 0.0001) after felodipine ER, ramipril and the combination (-9.1, -9.8 and -11.4 mm Hg, respectively). The decrease was significantly greater with the combination than with felodipine ER monotherapy (p = 0.02). The number of responding patients (final DBP < or = 90 mm Hg or a decrease of > or = 10 mm Hg) was also higher with the combination than with felodipine ER or ramipril monotherapy (65.1%, 53.1%, 55.7%, respectively). There were no differences between the three groups with respect to the incidence of adverse events overall or those considered treatment-related. There were fewer cases of peripheral oedema with combination therapy than with felodipine ER monotherapy. Thirty-three patients (5.1%) withdrew from the study because of adverse events, but there was no clear pattern with regard to the specific events leading to withdrawal. There were no clinically relevant changes in laboratory or clinical safety variables. Ramipril/felodipine ER 2.5/2.5 mg is an appropriate starting dosage when initiating combination antihypertensive therapy.
Summary:In an open, multicenter extension of a shortterm study, 159 patients with mild to moderate hypertension were treated with either ramipril monotherapy or a combination of ramipril and hydrochlorothiazide for up to 1 year. Patients started with either 5 mg ramipril once daily (responders in the short-term study) or a combination of ramipril5 mg plus hydrochlorothiazide 25 mg once daily. The dose could be adjusted and nonresponders to ramipril monotherapy could have hydrochlorothiazide added. In the 38 patients treated with ramipril monotherapy, the largest drop in mean blood pressure (BP) had already occurred in the previous short-term study; from Week 2 in the longterm study, the BP remained stable with means below 150/ 90 mmHg. In the 83 patients treated with the combination for 50 weeks or more, mean BP continued to decrease until around Week 10 in the long-term study while therapy was being adjusted. Thereafter, it also remained stable with means below 150/85 mmHg. Both treatment groups showed good mean reductions at end point, as did the group of 38 patients treated with the combination for less than 50 weeks. High response rates (84-95%) were seen in all groups at end point. The combination was well tolerated and the efficacy of ramipril in combination with hydrochlorothiazide was maintained over the 1-year period of investigation.
The aim of the study was to identify the most appropriate dosage combination of ramipril and felodipine ER (an extended release tablet) for mild-to-moderate hypertension. Hypertensive patients (N = 507) with supinediastolic blood pressure (DBP) values between 100-115 mm Hg were included in a randomized, multicenter, double-blind study of 3x4 factorial design with a 2-4 week single-blind, placebo run-in and 6 week active treatment phase. The patients were randomized to 12 groups: placebo, ramipril (2.5, 5, 10 mg), felodipine ER (5, 10 mg), or ramipril-felodipine ER combinations (2.5/5 mg, 2.5/10 mg, 5/5 mg, 5/10 mg, 10/5 mg, 10/10 mg). Although the greatest reductions in blood pressure were observed with ramipril-felodipine ER (10/10 mg), consideration of the antihypertensive efficacy and safety factors suggest that the ramipril-felodipine ER (5/5 mg) combination has the best efficacy/tolerability ratio of the combinations tested. The incidence of adverse events with ramipril-felodipine ER combination therapy was similar to that with felodipine ER monotherapy, but peripheral edema, tachycardia and vasodilatation occurred less frequently with ramipril-felodipine ER (5/5 mg) combination than with felodipine ER monotherapy. The combination of ramipril-felodipine ER (5/5 mg) can be considered to be the most suitable option for hypertensive patients with an inadequate response to either of the monocomponents.
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