Editor’s Note: Commentary based on Takahashi J, Nihei T, Takagi Y et al. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association. Eur Heart J 2015;36:228-37.

Study Aim:

The study by Takahashi et al.¹ was designed to study the long-term prognosis of patients taking nitrates for vasospastic angina.

Background:

Nitrate drugs have been used in the treatment of vasospastic angina because of the potential role of these drugs in decreasing vasospasm by increasing local nitric oxide levels. However, the clinical benefits of these drugs in long-term prognosis are unclear and were thus investigated in this study.

Methods:

Patients with a confirmed diagnosis of vasospastic angina between April, 2003 and December, 2008 were enrolled from September, 2007 to December, 2008. Patients enrolled prior to September, 2008 and after this date were followed in a retrospective and prospective manner, respectively. Nitrate therapy consisted of nitroglycerin, nicornadil or isosorbide mono or dinitrate or any combination of these. The primary endpoint was defined as major adverse cardiac events (MACE) and included cardiac death, myocardial infarction, hospitalization related to heart failure or angina or ICD shocks. The secondary endpoint was defined as all-cause mortality. Multinomial propensity matched scoring system was used for adjusting for selection bias. The results were verified using inverse probability of treatment weighting (IPTW) to assess for the effect of chronic nitrate therapy. Hazard ratios (HR) with univariate and multivariate Cox-proportional hazards models and Kaplan-Meier curves were used to compare MACE between the two groups.

Results:

Total of 1429 patients from 47 sites meeting the inclusion criteria were included and of these 695 (49%) of the patients were on chronic nitrate therapy. The nitrate group patients were older and had higher prevalence of ST-elevation during angina events, spasm of the left anterior descending artery, multi-vessel spasm and use of antiplatelet agents. The non-nitrate group patients had a higher prevalence of previous myocardial infarctions and coronary stenotic lesions. The remainder of the baseline characteristics was similar in both the groups. Concomitant calcium channel blockers were used in > 90% of the patients in both the groups and the medial follow up time was 32 months.

Incidence of MACE was 10% and 8% prior to propensity matched and 11% and 8% after propensity matching in the nitrate and non-nitrate groups, respectively. The hazard ratio (HR) for major adverse cardiac events (MACE) in the nitrate group was higher but non-significant compared to the non-nitrate group in the non-adjusted (1.35, 95% CI 0.88 – 2.07) and the adjusted analysis (1.28, 95% CI 0.72 – 2.28). The HR for MACE was also similar in the various clinical subgroups. The secondary endpoint was not different in the two groups.

Nicorandil, nitrates and combination therapy was used in 10%, 27% and 11% of the patients respectively. Nicorandil use was associated with slightly lower risk of MACE on both adjusted (HR 0.8, 95% CI 0.28 – 2.27) and IPTW analysis (HR 0.83, 95% CI 0.54 – 1.28) but this did not reach statistical significance. On the IPTW propensity matched analysis, use of multiple nitrate agents (HR 2.7, 95% CI 1.92 – 3.78), combination with nicorandil (HR 2.34, 95% CI 1.65 – 3.31), use of patch nitrates (HR 1.69, 95% CI 1.17 – 2.45) and combining oral and patch nitrates (HR 2.18, 95% CI 1.52 – 3.11) were associated with higher risk of MACE. Among the nitrates, nitroglycerin in combination with nicorandil was associated with a significantly increased risk of MACE (HR 4.47, 95% CI 1.47 – 13.6).

Conclusion:

This study concludes that chronic use of nitrates is not associated with improved outcomes compared to calcium channel blockers alone in patients with vasospastic angina. Combination of multiple nitrates is associated with worse outcomes. However, there may be a potential clinical benefit with the use of nicorandil in these patients.

Commentary/Perspective:

The current ACC/AHA guidelines recommend the use of calcium channel blockers and or nitrates for vasospastic angina.² However, the observations made in this study question the current practice pattern of using nitrates in vasospastic angina. There was no clinical benefit observed with the use of nitrates in combination with calcium channel blockers and more importantly worsened clinical outcomes when the patient was taking multiple nitrate drugs. This study being largely retrospective in nature did not report if there was any improvement in patient's symptoms with the use of nitrates. The study also suggested the likelihood of potential benefit with the use of nicorandil however this conclusion also did not reach statistical significance and this drug is not currently available in the United States. Further, prospective studies with adequate power are warranted to assess if nicorandil would improve long-term outcomes in patients with vasospastic angina.

References

1. Takahashi J, Nihei T, Takagi Y et al. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association. Eur Heart J 2015;36:228-37.
2. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44-e164.

Keywords: Angina Pectoris, Angina Pectoris, Variant, Arteries, Calcium Channel Blockers, Heart Failure, Hospitalization, Incidence, Isosorbide, Myocardial Infarction, Nicorandil, Nitrates, Nitric Oxide, Nitroglycerin, Platelet Aggregation Inhibitors, Prevalence, Prognosis, Proportional Hazards Models, Prospective Studies, Registries, Retrospective Studies, Selection Bias, Spasm

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