Editor's Note: Commentary based on Takagi Y, Takahashi J, Yasuda S, et al. Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association. J Am Coll Cardiol 2013;62:1144-53.

Background

Vasospastic angina is a term used to define the condition characterized by the occurrence of angina pectoris caused by coronary vasospasm, an important trigger of myocardial ischemia in patients with or without obstructive atherosclerotic coronary artery disease. The terms vasospastic angina and coronary artery spasm are used interchangeably in clinical practice. Vasospatic angina encompasses patients with typical "Variant Angina" ("Prinzmetal's variant angina"), as described originally by Prinzmetal et al. in 1959. Patients with "Variant Angina typically present with typical chest pain at rest, suggestive of myocardial ischemia, associated with transient ST segment elevation which resolves either spontaneously or following the administration of sublingual or intravenous nitrates. Of interest, patients with typical variant angina have a preserved exercise capacity. Angiographically, these patients can have normal coronary arteries or different degrees of coronary atheroma (as originally shown by Prinzmetal et al.).^1-3

Importantly, although patients with Prinzmetal's variant angina who receive treatment with calcium channel blockers generally have a good prognosis, epicardial coronary artery spasm has been reported to be associated with the development of acute coronary syndrome, life-threatening arrhythmias and sudden cardiac death.^4,5 Although studies have reported on clinical outcomes in patients with different forms of epicardial coronary artery spasm, risk stratification in patients with this condition has been problematic.^6-12 Clinical presentation of vasospastic angina differs in different patients and it has become apparent that survivors of out of hospital cardiac arrest and those with multivessel spasm and sustained ventricular arrhythmias during episodes of chest pain or during provocative tests for spasm, tend to have an impaired prognosis.^13,14

Methods

In an attempt to develop a comprehensive clinical risk score for vasospastic angina patients, which could be used in real life clinical practice, Takagi et al.¹⁵ carried out an observational study based on information gathered by the multicenter registry study by the Japanese Coronary Spasm Association (JCSA). Eighty-one Japanese centres contributed to the database and 1,429 patients were included in this registry, with a median age of 66 years and a median follow-up of 32 months. Prospective patient incorporation to the database was carried out between September 1, 2007, and December 31, 2008. However, data collection was conducted in a retrospective fashion for patients seen before September 2007. The diagnosis of vasospastic angina was made on the basis of a positive result of coronary spasm provocation tests and/or the occurrence of "spontaneous" rest angina attacks, as defined in the JCSA guidelines for diagnosis and treatment of patients with vasospastic angina.¹⁶ A provocation test -- using pharmacological or non-pharmacological means -- was defined as "positive" when it resulted in a total or subtotal (> 90%) coronary artery narrowing on angiography associated with chest pain and/or ischemic electrocardiographic changes. Spontaneous attacks of angina at rest were accompanied by transient ST-segment shifts and/ or new negative U-waves on the ECG.¹⁶

The authors used a multivariable Cox proportional hazard model to select seven variables that represented predictors of major adverse cardiac events (MACE). These risk markers included: history of out of hospital cardiac arrest, smoking, angina at rest alone, organic coronary artery stenoses, multivessel coronary artery spasm, ST-segment elevation during episodes of angina, and beta-blocker use. These variables were assigned a value that was proportional to their respective adjusted hazard ratio. The arithmetic sum of the respective values represented the risk score in a given individual. Three different risk categories were identified according to the total score calculated in individual patients. Patients who scored 0 to 2 (n= 598), were considered to be at a low risk of MACE; those with a score of 3 to 5 were individuals at intermediate risk (n= 639) and patient at a high risk of serious events had a score of 6 or more, (n= 192). The incidences of MACE in the low-, intermediate-, and high-risk patients were 2.5%, 7.0%, and 13.0%, respectively (p < 0.001). According to the authors, the Cox model for MACE between the three risk categories also showed prognostic utility of the scoring system in different clinical subgroups. In both the internal training and the validation sets the average prediction rate of the scoring system was above 86%.

Results

Importantly, the Takagi¹⁵ study showed that the proposed JCSA risk score, including 7 predictive variables, correlated with clinical prognosis and identified patients at different degrees of risk among the subjects included in the registry. Taken at face value, the study results suggest that the proposed risk score may be useful in clinical practice. Several prognostic variables had been identified in studies preceding the Takagi study, such as smoking, the presence of organic coronary artery stenosis, and multivessel spasm.^{6-10, 12} The study by Takagi et al confirmed and expanded these findings with the identification of a history of out of hospital cardiac arrest¹³ and angiographic findings during provocation tests¹⁴ as powerful markers of risk. Although the risk stratification tool tested in the Takagi study does not incorporate substantially novel predictors, it allowed a more systematic characterization of risk than individual risk factors considered individually. The novel risk score showed a good correlation with patient outcome and the three risk categories defined in the study were associated with two- to three-fold relative increases in risk for MACE. The score was easily applicable to individual patients. The incorporation of beta-blocker use to the risk panel was based on the suggestion that beta-blockers may exacerbate vasospastic mechanisms^17-19 due to inhibition of beta-adrenergic receptor-mediated coronary vasodilatation unmasking alpha-adrenoceptor-mediated coronary vasoconstriction and increasing vascular permeability to calcium.²⁰

Conclusion

The study has several limitations that deserve consideration and further studies may be required to confirm the interesting findings reported by Takagi et al. regarding risk stratification. First, the study is not fully prospective but based on registry data; second, it addresses the problem of risk stratification in just one ethnic group, i.e., Japanese patients; third, there has been no external independent validation of the proposed risk score; fourth, the assessment of ECG changes and arrhythmias was not carried out in a standardized fashion and therapeutic decisions were left to the discretion of the attending physician; moreover, patient adherence to medications during the follow-up period was not evaluated systematically. Fifth, a broadly encompassing composite study endpoint was used and only clinical variables available in the registry database were considered for analysis. Arguably, prediction of all-cause mortality should be complemented by data on prediction of cardiovascular death, which has not been specifically documented in the Takagi study.

Commentary/Perspective

A substantial proportion of patients with vasospastic angina involving the epicardial coronary arteries also have coronary microvascular spasm as recently reported by Ong et al. in the ACOVA study.²¹ The involvement of the coronary microvessels in this process adds a new diagnostic and therapeutic dimension to the problem, which needs to be considered in future ad hoc studies, as coronary microvessels do not necessarily respond to currently used vasodilator agents in an identical fashion as epicardial coronary arteries.

In summary, Takagi's newly proposed risk stratification score may prove useful for risk stratification in clinical practice but further studies are required to validate the usefulness of this scoring system in different patient populations as well as identifying other variables that could improve the prognostic capability of this tool.

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References

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Keywords: Angina Pectoris, Angina Pectoris, Variant, Coronary Artery Disease, Coronary Vasospasm, Myocardial Ischemia, Spasm

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