Chronotherapeutics for cardiovascular disease.

Chronotherapeutics, or delivery of a medication in concentrations that vary according to physiological need at different times during the dosage period, is a relatively new practice in clinical medicine. Epidemiological studies document that the incidence of many cardiovascular diseases, including myocardial infarction and stroke, varies predictably in time over 24 hours (the circadian period). Advanced diagnostic technologies using ambulatory monitoring of the blood pressure and electrocardiogram have also demonstrated that there is marked variability in the level of pressure in hypertensive patients and the degree of myocardial ischaemia in patients with coronary disease. These diagnostic techniques also allow us to study the effects of varying the timing of administration or delivery of a concentration of a drug on end-points such as changes in blood pressure, heart rate or intensity of angina. The first chronotherapeutic agent for hypertension and angina pectoris, controlled onset, extended release (COER-24) verapamil, has recently been developed and registered in the US, Brazil, Canada and Mexico. The theoretical advantage of this formulation is that delivery of the active drug, verapamil, has been tailored to the typical circadian rhythm of blood pressure and heart rate in patients with hypertension and angina to better cover the early morning hours when cardiovascular need appears to be the greatest. An outcome study (CONVINCE) that evaluates primary prevention of cardiovascular events with this chronotherapy versus standard of care therapy is under way in several countries in North and South America and Europe.