A specific α2 agonist, mivazerol, known to be effective in reducing myocardial ischaemia when given intravenously immediately before an exercise tolerance test, produced a significant increase in exercise duration and time to the onset of angina when given orally over a two week period to 25 patients with stable angina. A non-significant trend to reduction in electrocardiographic signs of ischaemia was also noted. The clinical relevance of this improvement now needs to be tested in larger numbers.
- α2 agonist
- sympathetic activity
- myocardial ischaemia
- stable angina
- exercise tolerance test
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The hyperadrenergic response to stress and exercise can precipitate angina in patients with critically reduced myocardial blood flow resulting from advanced coronary atherosclerosis. Reduction of sympathetic outflow together with reduced myocardial demand, such as may be achieved through β receptor blockade, can modify the extent of myocardial ischaemia and hence ameliorate anginal symptoms. However, drugs which block β receptors can also depress myocardial function and lead to a number of adverse effects such as exhaustion, reduction of mental acuity, and breathlessness.
The possibility that reduction of sympathetic activity could also be achieved by activation of α2 receptors deserves investigation. A new agent, mivazerol, which appears to act experimentally on peripheral α2 receptors and at the spinal level, has this therapeutic potential. Studies of this specific α2 agonist have shown, in conscious dogs in which transient occlusion of the left anterior descending coronary artery was induced, that electrocardiographic signs of myocardial ischaemia and coronary sinus lactate output were reduced.1 As these dogs were maintained at a constant heart rate through pacing, this apparent beneficial effect was not a function of reduced heart rate.
Anti-ischaemic effects have been shown when mivazerol was given intravenously and orally to patients with stable angina immediately before treadmill exercise tolerance tests.2 In these patients, all parameters of myocardial ischaemia were improved during the exercise tests. Heart rate increases during exercise were unaffected by the α2 agonist.
These data suggest that mivazerol may inhibit increases in sympathetic tone and that it might be a valuable antianginal drug in patients. This report describes the effects of daily administration of mivazerol in 25 patients with stable angina.
Study design and conduct
Three centres were invited to participate in the study. The plan was to recruit 36 male patients, 12 from each centre, in order to provide 90% power for statistical analyses. In two of the centres it was not possible to identify an appropriate number of eligible patients; therefore the intention to treat analysis comprises 25 eligible patients.
The patients selected had stable angina for at least three months, myocardial ischaemia was documented by a positive exercise tolerance test (ST depression of 1.5 mm or more). No episode of unstable angina or myocardial infarction had occurred within the preceding three months.
Two “training” exercise tolerance tests and qualification exercise tolerance tests were given one week apart, the last on the day before the start of the study. Patients who fulfilled this qualification phase, with the development of myocardial ischaemia, entered a four week double blind crossover treatment phase (either two weeks on mivazerol or two weeks on placebo, or vice versa). Two further exercise tolerance tests were then undertaken on the 14th and 28th days of the study. Randomisation of treatment was done for each centre. A tablet of mivazerol 1200 μg, or an identical placebo, was taken twice daily over this two week period.
Total exercise duration was the primary efficacy end point. Time to 1 mm ST depression and time to the onset of angina were secondary end points. Haemodynamic parameters, number of angina attacks, and the number of glyceryl trinitrate tablets taken each week were also considered as secondary end points.
Informed consent was given and the study was approved by all three ethics committees.
For total exercise duration, time to 1 mm ST depression, and time to onset of angina, parametric and non-parametric analyses were made. The analysis carried out on the patients’ results in the two centres with small numbers implies a large confidence interval (CI) but, despite this, similar results were found for all patients analysed.
Heart rate, systolic blood pressure, and rate– pressure product were lower during the two weeks of exercise tolerance tests in the mivazerol treated group (table 1).
TOTAL EXERCISE DURATION
Total exercise duration was longer in the mivazerol treated group compared with the placebo treated group (table 2). In parametric analysis the difference between the mivazerol and placebo treated groups was 38 seconds (95% CI 17 to 60 seconds) (p < 0.002); in non-parametric analysis, the difference was 40 seconds (95% CI 13.5 to 63.5 seconds) (p = 0.004).
TIME TO ST DEPRESSION
There was no significant difference between the mivazerol and placebo treated groups in the time before ST depression of 1 mm developed during the exercise tolerance test at two weeks (table 2).
TIME TO ONSET OF ANGINA
Time to onset of angina was 32 seconds longer in the mivazerol treated group during the exercise tolerance (non-parametric analysis p = 0.03). Figure 1 shows the number of patients having not developed angina pectoris at each minute of exercise tolerance test under mivazerol and placebo. There was no significant period nor interaction effect for all these parameters.
Oral administration of the α2 adrenergic agonist, mivazerol, for two weeks at a dose of 1200 μg daily to patients with stable angina led to an increase in the total duration of exercise during a standardised exercise tolerance test. There was also improvement in the time before the onset of angina but no improvement in the time for the development of 1 mm ST depression during exercise.
These results, although highly significant, are in absolute terms consistent with a small improvement in exercise capacity. They support the earlier finding that the intravenous and oral administration of mivazerol given acutely had a positive effect in patients with angina.2
Whether these results can be translated into clinical benefit, or could be improved by a different dose schedule or dose, remains to be evaluated by longer clinical studies.
Recently, the European mivazerol trial (EMIT)3 has shown that mivazerol, administered during anaesthesia and surgery on a double blind placebo controlled basis, led to a significant reduction in all cause and cardiac mortality in patients undergoing major reconstructive vascular surgery.
The collaborating centres were Royal Brompton Hospital, London, Western Infirmary, Glasgow, and Glenfield Hospital, Leicester. This study was supported by a scientific grant from UCB SA Pharma Sector, Belgium.
Professor de Bono died since this article was submitted for publication.