ACE inhibitors: review of four new agents - angiotensin converting enzyme inhibitors benazepril, fos

Author: S. Bruce Binder
Date: Oct, 1993

Captopril (Capoten) was the first angiotensin converting enzyme (ACE) inhibitor to be developed and marketed in the United States. It was followed closely by two longer-acting agents - enalapril (Vasotec) and lisinopril (Prinivil, Zestril). Multiple studies found that when these agents were used alone, they effectively controlled blood pressure in 50 percent of hypertensive patients; when used in combination within a diuretic, they were effective in 80 to 90 percent of patients with hypertension.[1] Consequently, the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure[1] in 1988 recommended that ACE inhibitors be added to the list of first-line agents for the treatment of essential hypertension.

The available ACE inhibitors have also been shown to be effective in treating congestive heart failure. Improvement has been demonstrated in symptoms,[2,3] hemodynamic parameters[4,5] and New York Heart Association (NYHA) functional class.[6,7] Some studies have also shown a decrease in mortality among patients with severe congestive heart failure who are treated with ACE inhibitors.[2,8,9] However, the precise role of these agents in the treatment of congestive heart failure, relative to the role of other available therapies, is still being defined.

Because of their effectiveness, as well as their excellent side effect and safety profiles, ACE inhibitors now are widely used. In 1992, both captropril and enlapril were among the 20 most frequently prescribed drugs in the United States.[10] In the past several years, the U.S. Food and Drug Administration has approved four new ACE inhibitors: benazepril (Lotensin), fosinopril (Monopril), quinapril (Accupril) and ramipril (Altace). All four agents are converted in vivo to their active forms: benazeprilat, fosinoprilat, quinaprilat and ramiprilat, respectively.

Therapeutic Effectiveness

BENAZEPRIL

In one study[11] of 17 patients with essential hypertension (diastolic blood pressure of 95 to 110 mm Hg), the administration of 10 mg of benazepril per day was shown to decrease diastolic blood pressure to less than 95 mm Hg in seven patients. When the dosage was increased to 10 mg twice daily, 12 (70 percent) of the 17 patients responded to the drug, with an average decrease in diastolic blood pressure of 12 mm Hg.

In a large multicenter study,[12] 206 patients with essential hypertension (diastolic blood pressure of 95 to 114 mm Hg) were randomized to receive once-daily doses of placebo, benazepril or hydrochlorothiazide. The response rates for daily doses of 2, 5 and 10 mg of benazepril were noted to be no greater than the response rate for placebo (25 percent). Overall, the response rate for 20 mg of benazepril (46 percent) was comparable to the response rate for 25 mg of hydrochlorothiazide alone (42 percent). The average reduction in blood pressure with benazepril was 13 mm Hg systolic and8 mm Hg diastolic. In black patients, however, benazepril was found to be less effective than hydrochlorothiazide. (A similar effect has been noted for other ACE inhibitors.). The side effect experienced by study subjects who were given benazepril were no different that those experienced by subjects who were given placebo. Increasing the dosage to 40 and 80 mg of benazepril per day resulted in minimal further improvement in blood pressure.[13]

Benazepril has also been tested at dosages of 2, 5 and 10 mg per day in a small group of patients with NYHA class III or IV congestive heart failure.[14] After four weeks of treatment, symptoms of dyspnea on exertion were improved in 76 percent of patients, and more than 50 percent of patients reported that they no longer had symptoms. Several patients also noted improvement in dyspnea at rest, paroxysmal nocturnal dyspnea and pedal edema. The presence of jugular venous distention and an S3 gallop was noted in fewer patients following treatment with benazepril.

FOSINOPRIL

The response to fosinopril in patients with mild to moderate hypertension has been evaluated in two large multicenter trials.[15,16] The first was three-month double-blind trial followed by an additional 10 to 13 months of open-label study.[15] The initial dosage of 10 mg of fosinopril per day was titrated up to a maximum of 80 mg per day. Twenty-five mg of chlorthalidone was added in patients whose diastolic blood pressure was still greater than 90 mm Hg following treatment with the maximum dosage of fosinopril.

This study found that fosinopril in dosages of 40 and 80 mg per day was significantly more effective than placebo in lowering diastolic blood pressure. Blood pressure control was maintained during the long-term phase of the study, with no evidence of drug tolerance. However, 50 percent of patients required a diuretic for adequate blood pressure control (Table 1).[15] The most common adverse effects reported were dizziness or lightheadedness, cough and gastrointestinal disturbances, which are similar to the symptoms reported with other ACE inhibitors. The discontinuation rate due to side effects was 6.1 percent, which is also comparable to the discontinuation rates for other drugs in this class. Similar results were obtained in a second large study involving more than 400 white patients.[16]

[TABULAR DATA OMITTED]

Fosinopril has also been compared with other antihypertensive agents in two double-blind studies of patients with mild to moderate hypertension.[17,18] When fosinopril was compared with enalapril, no differences were found in response rates, degree of reduction of diastolic blood pressure or reported adverse effects.[17] When fosinopril was compared with sustained-release nifedipine in patients 60 to 80 years of age, no differences were noted in the reduction of either systolic or diastolic blood pressure.[18] The most common adverse effects were the same as the ones reported in other studies.[15,16]

QUINAPRIL

Quinapril has been extensively studied in the treatment of both hypertension and congestive heart failure. A large, multicenter, placebo-controlled trial[19] found that once-daily quinapril therapy was as efficacious as twice-daily therapy, and both regimens were shown to be significantly more effective than placebo. Hypertensive patients (diastolic blood pressure of 95 to 115 mm Hg) in this single-blinded trial were treated with quinapril in a dosage of 20 mg per day for the first four weeks, 40 mg per day for the next four weeks and 80 mg per day for weeks 8 to 12. The response rate for 40 mg of quinapril was greater than 50 percent (average decrease in diastolic blood pressure of 10 to 12 mm Hg). The response rate for 80 mg of quinapril was greater than 65 percent (average decrease in diastolic blood pressure of 12 to 13 mm Hg). The response rate for placebo was 20 percent (average decrease in diastolic blood pressure of 7 mm Hg). There were no significant differences between one- and twice-daily dosing.

A second study[20] compared quinapril with enalapril in the treatment of mild to moderate hypertension. Patients were started on either drug in a dosage of 10 mg per day. Responders were defined as those in whom diastolic blood pressure decreased to 90 mm Hg or less or decreased from their baseline level by 10 mm Hg. Dosages were doubled at four-week intervals in nonresponders. Patients who still did not respond after 12 weeks of ACE therapy were also given hydrochlorothiazide in a dosage of 25 mg per day. No differences were noted between quinapril and enalapril - either alone or in combination with hydrochlorothiazide - in the degree of response achieved (decrease in diastolic blood pressure) or in the response rate.

In this study, adverse effects were reported by 40 percent of the patients who received enalapril and by 31 percent of those who received quinapril. However, none of the side effects were reported as being severe. Headache, cough and dizziness were the most common adverse effects in each group. Differences in symptoms between the two groups were not statistically significant.

Finally, the efficacy of quinapril, 10 to 40 mg twice daily, was compared with the efficacy of captopril, 25 to 100 mg twice daily, in 172 patients with moderate to severe hypertension (diastolic blood pressure of 110 to 120 mm Hg).[21] Overall response rates, degrees of response and adverse effect profiles did not differ significantly between the treatment groups.

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