Coronary artery disease
Efficacy of Ivabradine, a Selective If Inhibitor, in Patients With Chronic Stable Angina Pectoris and Diabetes Mellitus

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Ivabradine is a specific heart rate-lowering antianginal agent that was evaluated in a clinical development program involving approximately 3,000 patients with stable coronary artery disease, most with angina pectoris. We analyzed the pharmacokinetics, efficacy (evaluated by exercise tolerance testing), safety, and effects on glucose metabolism of ivabradine in patients with diabetes mellitus (DM) in this program. Most analyses included data from 535 patients with DM, approximately 18% of the overall patient sample. Patients with DM were older, more likely to be women, and more likely to have more severe angina pectoris than patients without DM. The pharmacokinetics of ivabradine did not differ in patients with DM versus those without DM. A reduction in the heart rate at rest with ivabradine was similar in those with (15.2%) and without (15.7%) DM. At baseline, the exercise capacity tended to be lower in the patients with DM, but the improvements in most exercise tolerance measures with ivabradine treatment were similar in patients with and without DM. No special safety concerns were associated with ivabradine in those with DM. The rates of sinus bradycardia and visual disturbances, known to be related to the action of ivabradine, showed no relative increase in the patients with DM. Ivabradine treatment was not associated with adverse effects on glucose metabolism. In conclusion, ivabradine was effective in preventing angina in patients with DM and was not associated with particular safety concerns or adverse effects on glucose metabolism. Ivabradine represents an attractive alternative to β blockers in patients with stable angina pectoris and DM.

Section snippets

Methods

Data were drawn from the 8 multicenter, randomized, double-blind, controlled trials designed to assess the efficacy and safety of ivabradine during its clinical development before regulatory approval in Europe (Table 1). In the large efficacy and safety studies (studies 1 to 6), male or female outpatients with chronic stable angina pectoris and documented CAD were treated for ≥3 months. The exclusion criteria included important heart disease other than CAD, Prinzmetal's or microvascular angina,

Results

Patients with DM were approximately 18% of the total patient sample. Thus, the analyses of efficacy and heart rate changes were done using data from 535 patients with and 2,372 patients without DM treated with ivabradine. However, the number of patients varied for the different analyses, depending on data availability. For example, the pharmacokinetic analysis, for which only a subset of patients was tested, involved 788 patients treated with ivabradine (146 with DM). The baseline demographic

Discussion

These analyses have indicated, first, that DM does not affect plasma exposure to ivabradine and its active metabolite as measured by the pharmacokinetic parameters maximum drug concentration. and area under the curve, although it should be noted that patients with severe hepatic and renal failure were excluded in these studies. Second, our data have suggested that DM does not affect the heart rate-lowering effect of ivabradine. Third, DM also does not have a negative effect on the antianginal

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    This study was supported by Servier, Neuilly-sur-Seine, France; Drs. Borer and Tardif are paid consultants to Servier.

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