Nitrendipine and Enalapril Combination Therapy in Mild to Moderate Hypertension: Assessment of Dose-Response Relationship by a Clinical Trial of Factorial Design

Abstract

Hypertension is an important cardiovascular risk factor and the goal of its pharmacologic treatment is to reduce morbidity and mortality. Treatment is usually initiated with a low dose of a single agent and titrated to a higher dose as required. As many as 50% of patients require the addition of a second agent to achieve satisfactory blood pressure control. The aim of this study was to assess the dose-response relationship of nitrendipine and enalapril alone or in fixed combination in the treatment of mild to moderate hypertension. A total of 496 patients were enrolled in a multicenter, randomized, double-blind, factorial-design, parallel-group clinical trial comparing placebo, nitrendipine (5, 10, and 20 mg) and enalapril (5, 10, and 20 mg) alone or in combination. After a single-blind, 2-week placebo run-in period, 414 patients whose diastolic blood pressure ranged between 90-109 mm Hg were randomly assigned to a treatment group. The combination of nitrendipine and enalapril, particularly regimens including nitrendipine 20 mg and enalapril 5 or 10 mg, were significantly superior to both monotherapies; mean diastolic blood pressure reductions from baseline to last visit were -12.5 and -14.3 mm Hg, respectively. Response surface analysis provided further evidence that these combinations were optimal in terms of anti-hypertensive efficacy. All treatments were well tolerated and the incidence of adverse events did not differ significantly between groups. In summary, the anti-hypertensive efficacy of the combination was found to be superior to both monotherapies at any doses. The dose combination achieving the greatest blood pressure reduction was nitrendipine 20 mg and enalapril 10 mg.

Management of High Blood Pressure in African Americans<subtitle>Consensus Statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks</subtitle>

“…1,110 Combination therapy with 2 drugs from the following list may be considered effective in lowering the patient's blood pressure to target: ␤-blocker/diuretic 104 ; ACE inhibitor/diuretic 111 ; ACE inhibitor/ CCB 102,103,105 ; or ARB/diuretic. 101,106,112 Fixed-dose combination products are listed in Table 9. 110 As an alternative, it is also acceptable to increase the dose of the initial monotherapy agent to achieve a blood pressure target, provided the patient tolerates the increased dose.…”

Hypertension‐Related Morbidity and Mortality in African Americans—Why We Need to Do Better

“…71 Based on clinical trial data, the following combinations are considered effective in lowering BP to target levels and potentially in protecting against end-organ damage in African-American patients with hypertension: ACE inhibitor/diuretic, 72 ARB/ diuretic, 51,69,70,73 β blocker/diuretic, 74 and ACE inhibitor/CCB combinations. 64,[75][76][77] Fixed-dose formulations of each of these combinations are approved for use in patients with hypertension and should provide greater convenience to patients. Combination therapy also offers a direct economic benefit to the patient through reduced payment shares toward the cost of the prescription.…”

Comparison of the antihypertensive effects of the fixed dose combination enalapril 10 mg/nitrendipine 20 mg vs losartan 50 mg/hydrochlorothiazide 12.5 mg, assessed by 24-h ambulatory blood pressure monitoring, in essential hypertensive patients

“…15 The fixed-dose combination of enalapril 10 mg/ nitrendipine 20 mg has been selected and developed by Grupo Vita for second-line treatment of hypertension according to current regulatory recommendations. 16,17 The dose combination was selected in a factorial study, 18 and then confirmed in two comparative controlled trials against monotherapy with either enalapril or nitrendipine. 19 Another important factor in the use of new antihypertensive agents is their ability to maintain the antihypertensive effect during the complete dose interval.…”