Prognostic Impact of Chronic Nitrate Therapy in Patients With Vasospastic Angina: Multicentre Registry Study of the Japanese Coronary Spasm Association

Study Questions:

What is the prognostic impact of chronic nitrate therapy in patients with vasospastic angina (VSA)?


A total of 1,429 VSA patients (median, 66 years; male/female, 1,090/339) were enrolled in a registry. Over 85% had no significant coronary stenosis. The primary endpoint was defined as major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, hospitalization due to unstable angina pectoris, and heart failure and appropriate implantable cardioverter-defibrillator (ICD) shocks. The propensity score matching and multivariable Cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Among the study patients, 695 (49%) were treated with nitrates, including conventional nitrates (e.g., nitroglycerin [GTN], isosorbide mono- and dinitrate) in 551 and nicorandil in 306. Calcium channel blockers (CCBs) were used in >90% of patients.


During the median follow-up period of 32 months, 85 patients (5.9%) reached the primary endpoint. Propensity score-matched analysis demonstrated that the cumulative incidence of MACE was comparable between the patients with and those without nitrates (11 vs. 8% at 5 years; hazard ratio [HR], 1.28; 95% confidence interval [CI], 0.72-2.28; p = 0.40). Although nicorandil itself had a neutral prognostic effect on VSA (HR, 0.80; 95% CI, 0.28-2.27; p = 0.67), multivariable Cox model revealed the potential harm of concomitant use of conventional nitrates and nicorandil (HR, 2.14; 95% CI, 1.02-4.47; p = 0.044), particularly when GTN and nicorandil were simultaneously administered.


Chronic nitrate therapy did not improve the long-term prognosis of VSA patients when combined with CCBs. Furthermore, the VSA patients with multiple nitrates had potential for an increased risk for cardiac events.


The title and study question should not be taken at face value. Nitrates can be given safely with CCBs in VSA, but are not the drug of first choice because of nitrate tolerance. Controlled trials show them to be inferior to CCBs. Nicorandil, which is available in Europe and Asia, is safe alone and with CCBs; however, the combination of conventional nitrates and nicorandil is harmful. Nicorandil belongs to the class of compounds known as potassium channel activators, which are characterized by their arterial vasodilator properties and venodilating properties, which are attributable to a nitrate group in its chemical structure.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure

Keywords: Spasm, Myocardial Infarction, Potassium Channels, Nicorandil, Isosorbide, Vasodilator Agents, Calcium Channel Blockers, Prognosis, Proportional Hazards Models, Coronary Stenosis, Nitrates, Heart Failure, Confidence Intervals, Defibrillators, Implantable

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