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Background: Treatment of patients diagnosed with angina due to epicardial or microvascular coronary artery spasm (CAS) is challenging because patients often remain symptomatic despite conventional pharmacological therapy. In this prospective, randomized, double-blind, placebo-controlled, sequential cross-over proof-of-concept study, we compared the efficacy and safety of macitentan, a potent inhibitor of the endothelin-1 receptor, to placebo in symptomatic patients with CAS despite background pharmacological treatment. Methods: Patients with CAS diagnosed by invasive spasm provocation testing with >3 anginal attacks per week despite pharmacological treatment were considered for participation. Participants received either 10 mg of macitentan or placebo daily for 28 days as add-on treatment. After a wash-out period patients were crossed over to the alternate treatment arm. The primary endpoint was the difference in anginal burden calculated as [1] the duration (in minutes) * severity (on a Visual Analogue Scale (VAS) pain scale 1-10); and [2] the frequency of angina attacks * severity during medication use compared to the run-in phase. Results: 28 patients of whom 22 females (79%) and a mean age of 55.3 ± 7.6 completed the entire study protocol (epicardial CAS n = 19 (68), microvascular CAS n = 9 (32)). Change in both indices of anginal burden were not different during treatment with add-on macitentan as compared to add-on placebo (duration*severity: -9 [-134 78] vs -45 [-353 11], p = 0.136 and frequency*severity: -1.7 [-5.8 1.2] vs -1.8 [-6.2 0.3], p = 0.767). The occurrence and nature of self-reported adverse events were closely similar between the treatment phase with macitentan and placebo. Conclusion: In patients with angina due to epicardial or microvascular CAS despite background pharmacological treatment, 28 days of add-on treatment with the ET-1 receptor antagonist, macitentan 10 mg daily, did not reduce anginal burden compared to add-on treatment with placebo.Trial Registrationhttps://trialsearch.who.int/, Identifier: EUCTR2018-002623-42-NL. Registration date: 20 February 2019.
RESUMO
BACKGROUND AND PURPOSE: Cardiac thrombi are an important cause of embolic stroke. We studied the diagnostic yield and diagnostic accuracy of cardiac CT angiography (CTA) compared to echocardiography for detection of cardiac thrombi in ischemic stroke patients. METHODS: We performed a systematic review and meta-analysis of the literature on cardiac CTA versus echocardiography for detection of cardiac thrombi in ischemic stroke patients. We included studies (N ≥ 20) in which both cardiac CTA (index test) and echocardiography (reference test) were performed and data on cardiac thrombi were reported. Results were stratified for type of echocardiography: transesophageal (TEE) vs transthoracic (TTE). RESULTS: Out of 1530 studies, 14 were included (all single center cohort studies), with data on 1568 patients. Mean age varied between 52 and 69 years per study and 66% were men. Reported time intervals ranged from 0 to 21 days between stroke and first test, and from 0 to 199 days between tests. In ten studies that compared CTA to TEE, CTA detected cardiac thrombi in 87/1385 (6.3%) patients versus 68/1385 (4.9%) on TEE (p < 0.001). In four studies comparing CTA to TTE, CTA detected thrombi in 23/183 (12.5%) patients versus 12/183 (6.6%) on TTE (p = 0.010). Pooled sensitivity and specificity of CTA versus TEE were 86.0% (95% CI 65.6-95.2) and 97.4% (95% CI 95.0-98.7), respectively. CONCLUSIONS: CTA may be a promising alternative to echocardiography for detection of cardiac thrombi in patients with ischemic stroke, especially now that CTA is standard care for patient selection for endovascular treatment. However, studies were too heterogeneous and of insufficient methodological quality to draw firm conclusions. Large, prospective studies on this topic are warranted.
