E-Science Station

Guideline of JCS 2013 stated that nitrates administration for patients with stable coronary spastic angina (CSA) was the evidence level of Ⅱa. However, recent studies in Japan showed the deleterious, at least ineffective, impact of long-term nitrates administration for the improvement of the occurrence of cardiac events (CE) in patients with CSA when nitrates were added on the calcium channel blocker (CCB).Chronic long-acting nitrates administration leads to increased reactive oxygen species (ROSs), endothelial dysfunction, and nitrate tolerance and may thereby increase cardiac events including CSA.The aim of the current study was to perform a systematic review and a meta-analysis to assess how the long-term nitrates administration raised the risk for CE occurrence in Japanese patients with stable CSA who were treated with CCB.

We comprehensively searched the databases of PubMed for eligible studies comparing the clinical outcomes of nitrates versus non-nitrates more than 1 year in patients with CSA, by combining the keywords of coronary spasm and nitrate (530), CSA and nitrate (32), and vasospastic angina and nitrate (266) in April 2020. CE was a composite of cardiac death, non-fatal myocardial infarction, unstable angina, admission due to the medically-resistant frequent chest pain, and operation of implantable cardioverter-defibrillator. A pooled hazard ratio (HR) and 95% confidence interval (CI) were used to summary the estimates. Data from each study were combined using the random-effects to calculate risk ratios and 95% confidence intervals, and heterogeneity analysis was also performed by using STATA version 16.

Of the cumulative 828 reports, we identified 4 retrospective studies involving 2020 patients with CSA with nitrates (n=727) and without nitrates (n=1293) with the mean follow-up duration ranging from 32 to 70.5 months. The percentage administration of CCB in entire cohort was 96.7%, and those of ACE-I and / or ARB and statin in 3 studies were 20-25%, and 29-38%, respectively. The mean percentage of current smoker was 51.3%. The frequency of cardiac death was 0.54%. Nitrates administration was associated with higher risk of CE (relative risk [RR], 1.69; 95% CI, 1.22-2.34; I² = 26.8%) compared without nitrates administration.

The present meta-analysis showed that when nitrates were added on CCB in Japanese patients with CSA, the long-term nitrates administration raised approximately 70% of the risk of CE.