THERAPY

Verapamil - benefits in MI and hypertension

The cardioprotective effects of verapamil were recently reviewed at the Second International Symposium entitled "Calcium Antagonists in Cardiovascular Care" which was held in Basel, Switzerland.

The double blind, placebo-controlled Danish Verapamil Infarction Trials I and II (DAVIT I and II) [see Inpharma 763: I, 17 No\' 1990] both demonstrated that verapamil therapy given after acute myocardial infarction (MI) resulted in significant reductions in total mortality, and the incidence of major events, cardiac events and reinfarction. These reductions were most apparent in patients with a history of heart failure . Dr J Fischer Hansen from Hvidovre Hospital, Denmark, and the Danish Study Group on Verapamil in Myocardial Infarction thus concluded that verapamil can be recommended for treating patients after an acute MI to provide these beneficial cardioprotective effects.

After myocardial infarction

Long term verapamil improves outcome. Verapamil (n = 671) or placebo (679) were administered from the time of admission for 6 months in the DAVIT [ trial as it was ~ypothesised that early initiation of therapy may Improve prognosis of patients with acute MI. Verapamil recipients received IV verapamil 0.1 mg/kg and 120mg orally on admission. followed by an oral maintenance dose of 120mg tid.

A significant reduction in 6-month mortality was observed in patients who commenced v~rapamil therapy 7-24 hours after MI compared with placebo recipients (9.4 \ 's 17%), however, 6-month mortality was not significantly different between placebo and verapamil recipients who commenced therapy within 6 hours of symptom onset.

A significant reduction in the rate of reinfarction was observed in verapamil recipients from day IS to study end. However reinfarction rates and mortality were slightly higher in verapamil compared with placebo recipients during the first weeks of therapy. The incidence of ventricular fibrillation was slightly lower in verapamil than in placebo recipients (NS), suggesting that verapamil may also prevent arrhythmias.

In the DAVIT II trial, verapamil 120mg tid (n = 878) or placebo (897) were initiated in the second week after admission and patients were observed for a mean of 16 months. The 18-month mortality and the incidence of first major events, reinfarction and cardiac events were significantly lower in verapamil than placebo recipients in patients with heart failure ,

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however no significant between-group differences were observed in patients without heart failure.

Meta-analysis of results from the DAVIT I and II trials showed verapamil to result in significant reductions in the pooled odds ratio of death. reinfarction and major events (22, 27 and 27%. respectively).

Anti-ischaemic effect may explain cardioprotection. Reductions in the incidences of major events and angina pectoris observed with verapamil administration after acute MI may be explained by reductions in myocardial ischaemia and a significant reduction in 24-hour HR which could reduce myocardial oxygen demand. The beneficial effects of verapamil could also be attributed to its anti-arrhythmic properties.

A substudy of DA VIT II involving 85 patients was conducted by Dr M Vaage-Nilsen and colleagues from Denmark in conjunction with the DA VIT II study group. Significant reductions in HR and the incidence of transient ischaemic episodes were observed in verapamil compared with placebo recipients; the 18-month major event rate was higher in patients with, than in those without. ischaemia (40 \'s 24%). A significant increase in ventricular ectopic beats was observed in placebo recipients during the first 16 months post-MI. however this was not observed in verapamil recipients. A mean HR of 80 beats/min and> 10 ventricular ectopic beats/ hour occurring early (1 week) after MI were both found to be independent predictors of major events.

Results from another substudy of DA VIT II conducted by Dr eM Jespersen from Copenhagen. Denmark and The Danish Studv Group on Verapamil in Myocardial Infarctio~ involving 155 verapamil and 143 placebo recipients suggested that patients with exercise­induced myocardial ischaemia after MI would benefit from verapamil therapy.

Although not significant, verapamil recipients with ST-segment depression (indicative of myocardial ischaemia) experienced the lowest number of major events: the highest rate of major events occurred in placebo recipients with ST-segment depression,

Dr Jespersen and colleagues consider that the results of this substudy lacked significance possibly because of a type II error. Other possible reasons for the lack of significance may be that verapamil does not suppress myocardial ischaemia, suppression of ST-segment depression may not reduce the number of major events and that ST-segment depression may not have prognostic value.

In conclusion. Dr Fischer Hansen comments that .it remains unclear whether pharmacological. surgIcal. or a combination of these treatments is the optimal approach for patient management after MI. However. he does state that verapamil. and beta blockers. do improve the prognosis after acute MI.

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In hypertension

Verapamil more effective than hydrochlorothiazide. Dr H Holzgreve and colleagues from Germany. on behalf of the Verapamil Versus Diuretic (VERDI) Trial Research group, conducted a study comparing hydrochlorothiazide with verapamil in 369 patients with mild to moderate hypertension.

THERAPY

They concluded that 'verapamil must be regarded as clearly superior to the diuretic hydrochlorothiazide in doses of the drugs commonly used in antihypertensive therapy'. Target BP was achieved in more verapamil than hydrochlorothiazide recipients at 8, 24 and 48 weeks.

Patients unresponsive to either therapy were changed to a combination of the 2 agents. Combination therapy was also superior to hydrochlorothiazide monotherapy.

In conclusion. In view of these results the researchers question the current recommendation in Germany and in the US that diuretics, beta­blockers. calcium antagonists and ACE inhibitors are first line agents in the treatment of hypertension. Vcrapamil- a cardioprotective strategy. Journal of Cardiovascular Pharmacology 18 (Suppl. 6): 1991 [5 papers) ""

18 Apr 1992 INPHARMA8 ISSN 0156-2703/92/0418-0018/$1.00/0 © Adis Intwnational lid