Coreg (Carvedilol) for Hypertension
The FDA has granted marketing approval for Smithkline BeechamХs multi-action beta-blocker carvedilol (Coreg) for the treatment of essential hypertension given alone or in combination with other agents, particularly thiazide-type diuretics. The drug exerts its effect through a combination of beta-blocking and vasodilating properties. Carvedilol has been developed in conjunction with Boehringer Mannheim; Smithkline Beecham will market the drug in the US while B-M will market it in several overseas markets.
Carvedilol (Coreg) has been studied in a large number of clinical trials in hypertensives. Two major placebo-controlled studies enrolled 1142 patients who took daily doses of 12.5 to 50 mg. Overall, safety data for the drug used in the FDA application were derived from almost 2200 patients in US studies and about 3000 patients enrolled in non-US studies. At a dose of 50 mg per day, carvedilol reduced sitting 12-hour trough blood pressure by about 9/5.5 mmHg. At 25 mg the effect was about 7.5/3.5 mmHg. The trough-to-peak ratio for blood pressure response was about 65% and heart rate fell about 7.5 beats/min at the 50 mg/day total dose.
Carvedilol (Coreg) has been well tolerated in clinical trials, with 4.9% of treated patients discontinuing due to adverse effects compared to about 5.2% of placebo-treated patients. Postural hypotension (which included syncopal events) occurred in 1.8% of carvedilol-treated patients and 1% of those who discontinued. As with other beta-blockers, carvedilol is contraindicated in patients with asthma or bronchospastic disease (two deaths were reported in asthmatic patients treated with the drug), those with second- or third-degree heart block , cardiogenic shock, severe bradycardia, or hepatic failure. A number of drug interactions have been observed with other cardiovascular drugs, cimetidine, and insulin.
Beta-blockers, including carvedilol, are generally contraindicated or to be used cautiously in patients with severe congestive heart failure (CHF) because of the potential to depress myocardial contractility precipitating more severe failure. However, this drug has been studied in more than 1900 patients with heart failure and some surprising findings have emerged from those studies. Although deaths from all causes of cardiovascular disease are declining in the US population, the incidence of death due to CHF is increasing. Carvedilol has been investigated for its ability to reduce mortality associated with congestive heart failure. A large multicentered US placebo-controlled trial was halted in January 1995 because the effect of carvedilol was so strong that it was deemed unethical to continue to treat control patients with placebo. Carvedilol (Coreg) was subsequently made available to all placebo-treated patients. Interim analyses of that study were reported at the Annual Meeting of the American Heart Association in November 1995. Patients with CHF reduced their risk of dying by 67% (p less than 0.001 compared to placebo) when carvedilol was added to their current best therapy for an average of 6 and one-half months; this reduction in risk was observed across patient groups with varying severity and causes of the disease. The death rate was 3% in the carvedilol group vs 7.8% in the placebo-treated group. Drug therapy also reduced hospitalization by about 45% which was statistically significant compared to placebo. Carvedilol appears to inhibit the proliferation of vascular smooth muscle cells, an effect that appears to be greater than that of other beta-blockers. At present, carvedilol is not indicated for the treatment of congestive heart failure in the US.
The recommended starting dose of carvedilol for hypertension is 6.25 mg twice daily. If patients tolerate this dose, as determined by standing systolic blood pressure measurements one hour after dosing, the dose should be continued for one to 2 weeks then increased to 12.5 mg twice a day. The same procedure should be followed if the dose needs to be increased to 25 mg twice a day. However, if the pulse rate drops below 55 beats/min, the dosage should be decreased. Orthostatic hypotension can occur with this class of drugs, and this event can be minimized by taking the drug with food; furthermore, the drug should be discontinued over a one to 2 week period to prevent difficulties, especially in patients with ischemc heart disease.
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