Efficacy of the long-acting nitro vasodilator pentaerithrityl tetranitrate in patients with chronic stable angina pectoris receiving anti-anginal background therapy with beta-blockers: a 12-week, randomized, double-blind, placebo-controlled trial

Abstract

BackgroundThe organic nitrate pentaerithrityl tetranitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study (‘CLEOPATRA’ study) was designed to investigate the anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over placebo in patients with chronic stable angina pectoris.Methods and resultsA total of 655 patients were evaluated in the intention-to-treat population, randomized to PETN (80 mg b.i.d., n = 328) or placebo (n = 327) and completed the study. Patients underwent treadmill exercise tests at randomization, after 6 and 12 weeks of treatment. Treatment with PETN over 12 weeks did not modify the primary endpoint total exercise duration (TED, P = 0.423). In a pre-specified sub-analysis of patients with reduced exercise capacity (TED at baseline ≤9 min, n = 257), PETN appeared more effective than placebo treatment (P = 0.054). Superiority of PETN over placebo was evident in patients who were symptomatic at low exercise levels (n = 120; P = 0.017). Pentaerithrityl tetranitrate 80 mg b.i.d. was well tolerated, and the overall safety profile was comparable with placebo.ConclusionAlthough providing no additional benefit in unselected patients with known coronary artery disease, PETN therapy, administered in addition to modern anti-ischaemic therapy, could increase exercise tolerance in symptomatic patients with reduced exercise capacity.

The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

“…Pre-clinical data suggested that pentaerythrityl tetranitrate may not cause nitrate tolerance (see below) or endothelial dysfunction. However, the drug is not currently commonly used as clinical studies have not shown any clear benefit in patients with chronic, stable angina (60). …”

Medical treatment of stable angina: A tailored therapeutic approach

“…Combination of first line drugs in the treatment of stable angina is more effective than monotherapy in controlling symptoms [26], however depending on baseline systolic blood pressure, and it is important to avoid the combination of beta-blockers with diltiazem or verapamil because of the risk of bradycardia or atrioventicular block [26,27].…”

Nitrates

“…For the same reason, PETN was removed in 2012 from the list of reimbursable drugs in Germany, the major market for this drug. The recently concluded Cleopatra study addressed this issue by randomizing 655 patients with coronary artery disease to receive placebo or two daily doses of 80 mg of PETN, demonstrating a benefit of PETN on exercise tolerance during a 12-weeks treatment [ 76 ]. These data will hopefully lead to reconsider the use of (and further research on) this drug in clinical practice worldwide.…”