Objectives We conducted a randomised, double blind, placebo controlled trial to assess the efficacy and safety of cilostazol, a selective inhibitor of phosphodiesterase 3, in patients with vasospastic angina (VSA).
Background Cilostazol has been shown to induce vascular dilatation, but its efficacy in patients with VSA is unknown.
Methods Between October 2011 and July 2012, 50 patients with confirmed VSA who had ≥1 angina episodes/week despite amlodipine therapy (5 mg/day) were randomly assigned to receive either cilostazol (up to 200 mg/day) or placebo for 4 weeks. All patients were given diaries to record the frequency and severity of chest pain (0–10 grading). The primary endpoint was the relative reduction of the weekly incidence of chest pain.
Results Baseline characteristics were similar between the two groups. Among 49 evaluable patients (25 in the cilostazol group, 24 in the placebo group), the primary endpoint was significantly greater in the cilostazol group compared with the placebo group (−66.5±88.6% vs −17.6±140.1%, respectively, p=0.009). The secondary endpoints, including a change in the frequency of chest pain (−3.7±0.5 vs −1.9±0.6, respectively, p=0.029), a change in the chest pain severity scale (−2.8±0.4 vs −1.1±0.4, respectively, p=0.003), and the proportion of chest pain-free patients (76.0% vs 33.3%, respectively, p=0.003) also significantly favoured cilostazol. Headache was the most common adverse event in both groups (40.0% vs 20.8%, respectively, p=0.217).
Conclusions Cilostazol is an effective therapy for patients with VSA uncontrolled by conventional amlodipine therapy, and has no serious side effects.
Trial registration number NCT01444885.
- CORONARY ARTERY DISEASE
Statistics from Altmetric.com
Over the past 30 years, the efficacy of calcium channel blockers (CCBs) in the treatment of vasospastic angina (VSA) has been well documented, and CCBs are now considered the drug of choice for the treatment of VSA. However, 10–20% of patients with VSA are refractory to this treatment or tolerate CCBs poorly.1–5 Furthermore, among poor responders, prolonged spasm can cause life threatening arrhythmias, sudden death, or acute myocardial infarction. Thus, further research is needed to identify new drugs for the treatment of VSA refractory to conventional CCB therapy.
Cilostazol is a selective inhibitor of phosphodiesterase 3 that has several properties, including vasodilation, antiplatelet action, increased blood flow to the limbs, and the inhibition of vascular smooth muscle cell growth.6–8 It is known that cilostazol can reduce the cytosolic calcium concentration, which plays a key role in this vasodilation.9 We recently reported a non-randomised study demonstrating cilostazol as an effective therapy in VSA uncontrolled with conventional medical treatment.10 To confirm this observation, a multicentre, randomised, double blind, placebo controlled, parallel group, therapeutic exploratory trial (STELLA—Study to evaluaTe the Efficacy and safety of Pletaal (ciLostazoL) in subjects with vAsospastic angina) was designed. In this trial, we assessed the efficacy and safety of cilostazol for the treatment of VSA patients who have an insufficient response to conventional treatment with amlodipine.
The STELLA trial was conducted in 10 teaching hospitals in South Korea between October 2011 and July 2012 (ClinicalTrials.gov number, NCT01444885). We included patients who were newly diagnosed with VSA within 3 months of the screening. In addition to the angina symptoms, the following two criteria for diagnosing VSA needed to be satisfied: (1) spontaneous or ergonovine induced coronary artery spasm (producing >90% narrowing of coronary lumen diameter during angiography) associated with chest pain and ischaemic ST segment changes (transient ST elevation or depression ≥0.1 mV, recorded from at least two contiguous leads on the 12-lead ECG); and (2) normal or insignificant (diameter stenosis <50%) coronary artery disease after intracoronary glyceryl trinitrate (GTN, nitroglycerine) injection.11 We excluded patients who had fixed stenosis corresponding to ≥50% of the lumen diameter in the coronary artery and those who had a history of allergic reaction to amlodipine or cilostazol. Other exclusion criteria were: (1) myocardial infarction within 3 months of screening; (2) history of life threatening events associated with previous episodes of coronary artery spasm, such as ventricular tachycardia, ventricular fibrillation, or syncopal episodes; (3) decompensated congestive heart failure; (4) significant valvular heart disease; (5) systolic blood pressure <90 mm Hg; (6) baseline heart rate ≥100 beats/min; (7) ECG abnormalities precluding interpretation of the ST changes; (8) coronary artery bypass surgery or percutaneous coronary intervention within 3 months of screening; (9) women of childbearing potential who refused to use contraception; (10) active hepatic or renal disease; and (11) other major concomitant disease. All patients provided written informed consent. The protocol was approved by the institutional review boards of the participating centres.
Patients with confirmed VSA who had ≥1 angina episodes/week despite amlodipine therapy (5 mg/day) for 2 weeks (amlodipine run-in period) were randomly assigned to receive either cilostazol (50 mg oral tablet twice daily for 2 weeks and then 100 mg oral tablet twice daily for 2 weeks) or placebo for 4 weeks in addition to an amlodipine background regimen. Aspirin and long acting nitrates were stopped from the amlodipine run-in period to the end of the 4 weeks study period. With regard to the safety evaluation, we assessed the adverse events for 1 week after the end of the double blind period (safety follow-up period). The details of trial enrolment and follow-up are shown in figure 1. Participants were allowed to take sublingual GTN as needed for episodes of chest pain.
Assessment of patient responses
Participants were assessed by angina diaries. The diary for detailing the frequency, severity (0–10 grading, where 0 was defined as no pain at all, and 10 was defined as the worst unbearable pain),12 duration, and circumstances of chest pain episodes and intake of sublingual GTN was given to the patients from the initiation of the amlodipine run-in period to the study completion. The contents of the diaries were reviewed and tabulated at biweekly intervals. Safety was monitored by clinical evaluation, with assessment for any adverse events at each visit and laboratory tests at baseline and at the end of the double blind period. Patient compliance was monitored by counts of the unused tablets returned at each visit. Premature termination of the study was considered if the patient had a major adverse event or there was evidence of therapeutic failure, defined as significant worsening of the anginal symptoms, resulting in intolerable symptoms or admission to the hospital to rule out myocardial infarction.
The primary endpoint was the relative reduction of chest pain frequency during the last week of the double blind period compared to the 1-week period before randomisation, defined as: (number of chest pain episodes during the last week − the number of chest pain episodes during baseline week)/(the number of chest pain episodes during baseline week)×100.
The secondary endpoints were: (1) change in weekly chest pain frequency; (2) the proportion of patients without chest pain during the last week; (3) change in the total chest pain intensity; (4) change in the average chest pain intensity (the total chest pain intensity/the frequency of chest pain); (5) change in total GTN consumption during the last week in the double blind period compared to the 1-week period before randomisation. Additionally, this period was considered necessary to observe the development of any adverse events and to record the changes in blood pressure and heart rate.
It was calculated that approximately 22 patients per treatment group would provide 80% power (assuming an SD of 45.0%) to detect a difference of −38.4%, with a significance level of 0.05 using a two-sided test.13 With an anticipated dropout rate of 10%, a final sample size of 25 patients per treatment group (total 50 patients) was specified to provide an adequate number of evaluable patients.
All analyses were based on the intention-to-treat principle, and data analysis was allowed if the patient took the test drug at least once or more. The primary endpoint was analysed by the rank-ANCOVA (analysis of covariance) using the baseline week as a covariate. For the secondary endpoints (change of the total chest pain frequency, total chest pain intensity, average chest pain intensity, and total GTN consumption on the last week between the treatment groups), ANCOVA was performed using baseline week as a covariate. The χ2 test was used to compare the treatment groups for a proportion of patients without chest pain in the last week. The measured values are expressed as mean±SD, and median (Q1(1st quartile), Q3(3rd quartile)) for rank-ANCOVA analysis, and least squares mean±SD and median (Q1, Q3) for the ANCOVA analysis of the secondary endpoints. Subjects who had no chest pain were recorded as having total chest pain intensity and an average chest pain intensity of ‘0’. Patients who did not take GTN were recorded as having taken ‘0’ tablets. All of the tests were performed at the two-tailed 5% level of significance. The statistical software SAS V.9.2 (SAS Institute, Cary, North Carolina, USA) was used to perform the statistical analysis.
A total of 71 patients from 10 hospitals were screened, and the patients who met the eligibility criteria began a 2-week amlodipine run-in period (figure 1). Of these, 50 patients who met the study criteria were randomly assigned to receive either cilostazol (n=25) or placebo (n=25). One patient in the placebo group withdrew her consent without taking any medications after randomisation, and therefore the final study population comprised 49 patients. Forty-seven patients showed complete compliance to study drug administration, but two patients (one in the cilostazol group, one in the placebo group) adhered to <80% of their assigned medications.
The two treatment groups were comparable in regard to age, gender, severity of angina at baseline, history of previous myocardial infarction, and coronary angiography data (table 1). The mean age of the participants was 53.9±8.9 years, 67.3% were men, 53.1% had a history of hypertension, 10.2% had diabetes, and 49% were current smokers. One patient had multivessel spasm of the left anterior descending artery and right coronary artery, and two patients had multifocal spasms in the right coronary artery. Baseline blood pressure and heart rate between the groups were similar.
During the study period, the relative reduction of weekly chest pain frequency was significantly greater in the cilostazol group compared with the placebo group (−66.5±88.6% vs −17.6±140.1%, respectively, p=0.009) (table 2, figure 2).
The change in the weekly chest pain frequency (−3.7±0.5 vs −1.9±0.6, respectively, p=0.029), the change in the average chest pain intensity (−2.8±0.4 vs −1.1±0.4, respectively, p=0.003), and the proportion of patients without chest pain during the last week (76.0% vs 33.3%, respectively, p=0.003) all favoured the use of cilostazol (table 2, figure 3).
The adverse events are presented in table 3. Headache was the most common adverse event. No patient was withdrawn from the protocol because of an adverse event. The administration of cilostazol had no significant effect on heart rate or systolic and diastolic blood pressure (table 4). The profile of adverse events was similar to the short term pattern, consisting of infrequent and mild adverse events.
The STELLA trial demonstrated that cilostazol significantly reduced angina frequency and intensity without serious adverse effects in VSA patients refractory to amlodipine treatment. These findings are consistent with our pilot report,10 showing that there was a 78.9% relative reduction in the score of angina intensity and a 73.5% reduction in the angina frequency after adding cilostazol to conventional medications (all p values <0.001). Furthermore, the magnitude of the treatment effect was substantial with ∼70% reduction in angina attacks, which is similar to that shown in a study with amlodipine.11 Taken together, cilostazol appears to be an effective therapy for VSA that is refractory to conventional medical treatment.
Although the exact mechanism of VSA has not been elucidated, endothelial dysfunction is regarded as one of the most important underlying mechanisms. CCBs or nitrates have been considered the drug of choice for the treatment of VSA. However, 10–20% of patients with VSA are still reported to be refractory or develop poorly tolerated adverse events with these drugs.1–5 Interestingly, with regards to the current treatment of VSA, ﬁrst line drugs such as CCBs or nitrates are not included in the repertoire of drugs that improve the ‘endothelial dysfunction’ per se.14 Cilostazol—6-(4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy)-3, 4-dihydro-2 (1H)-quinolinone—is a selective inhibitor of phosphodiesterase 3, which increases intracellular cyclic adenosine monophosphate (cAMP) concentrations and has been shown to promote vasodilation.15 Although the exact mechanism of this vasodilatory effect is still debateable, it is known that cilostazol can reduce the cytosolic calcium concentration, which plays a key role in vasodilatation.9 In addition, cilostazol induces nitric oxide production via the phosphorylation of endothelial nitric oxide synthase at Ser1177 and the phosphorylation of Akt at Ser473 in association with increased cAMP values, and it enhances endothelial tube formation in human aortic endothelial cells.16 ,17 Additionally, cilostazol increases the coronary flow reserve and the flow dependent coronary dilation attributed to nitric oxide. Therefore, cilostazol may improve coronary vascular endothelial dysfunction and coronary haemodynamics in patients with VSA.18 Recently, Kawanabe et al reported that the dual actions of cilostazol can prevent endothelin induced vasoconstriction and cell proliferation in mouse smooth muscle cells in vitro and ex vivo. They also showed that cilostazol has dual inhibitory effects on endothelin induced vasoconstriction and cellular proliferation.19
Although the clinical benefits of antiplatelet therapy in VSA has been debated, aspirin is the most commonly used agent because its usefulness for primary and secondary prophylaxis of atherothrombotic events has been well documented.20 Watanabe et al studied an acetylcholine provocation test in VSA where the patients were divided into the following three groups: no antiplatelet group, aspirin group, and a cilostazol group. The authors showed no favourable effect from aspirin on vascular endothelial function, but cilostazol significantly increased the coronary diameter and flow reserve attributed to nitric oxide.18 Consistent with the report, our study shows that the decrease in the frequency of angina episodes was evident with cilostazol compared with the placebo (figure 3). Regarding the antiplatelet effect, cilostazol is known to be at least as good as aspirin, and cilostazol has been shown to reduce the risk of haemorrhagic events such as haemorrhagic stroke and gastrointestinal bleeding when compared to aspirin.21 ,22 Cilostazol may be superior to aspirin in terms of preventing stroke recurrence after an ischaemic stroke and inhibiting atheroma progression.23 ,24 In addition, several studies have also reported that adjunctive cilostazol use has a favourable effect in reducing adverse events in ischaemic heart disease.25–27 Based on these considerations, cilostazol appears to be useful in VSA for coronary vasodilation and prevention of thrombotic complications.
Our study also indicates that cilostazol is a relatively safe product with mild adverse events. Headache was the most common adverse event. The mechanism is mainly explained by cerebrovascular dilatation, which occurs with other vasodilators such as nitrates, dipyridamole, sildenafil, and calcium antagonists. However, there was no withdrawal from treatment in patients receiving cilostazol due to headache.28–30 The haemodynamic effects of cilostazol were minimal.
We acknowledge there are limitations in our study. First, the study population size was small. Secondly, the study duration was short (4 weeks) and this period of time may not be sufficient to assess the medium to long term effects of cilostazol for VSA treatment as well as the adverse events from long term therapy. Further trials addressing these limitations are needed to assess the long term efficacy and safety profile of cilostazol.
Cilostazol is effective in treating VSA refractory to conventional amlodipine therapy, and does not cause any serious adverse events. Cilostazol may be considered as an add-on therapy for patients with refractory VSA.
What is known on this subject?
Cilostazol, a selective inhibitor of phosphodiesterase 3, has been shown to induce vascular dilatation, but its efficacy in treating vasospastic angina is unknown.
What might this study add?
In this randomised, double blind, placebo controlled trial, we were able to provide evidence that cilostazol is effective in controlling symptoms of uncontrolled vasospastic angina by conventional amlodipine therapy.
How might this impact on clinical practice?
Cilostazol can be a useful add-on drug for calcium channel blocker refractory vasospastic angina, without any serious side effects. The anti-vasospastic effects of cilostazol combined with its inherent antiplatelet effect appear to make it a plausible selection as an antiplatelet drug for vasospastic angina.
Contributors Design of this study and analysis of data: J-HK. Drafting of the manuscript: E-SS, CWL, J-HK. Revision of the manuscript: all authors. Final approval of the manuscript submitted: all authors.
Funding The STELLA project was managed and sponsored by Korea Otsuka Pharmaceutical Co, Ltd. The Steering Committee designed the study, in collaboration with the sponsor. Randomisation codes were developed by a statistician of a contract research organisation. The sponsor was blinded to the patients’ study assignment. The patient data and information collected for the study was monitored by the assigned sponsor's staff. Members of the Steering Committee wrote the manuscript and confirmed the completeness and accuracy of the data gathering and analysis. The authors were not restricted from disclosing the study results. Collected data analyses, data interpretation, and writing of the report were performed by independent groups, and the sponsor had only the role of oversight of these activities. The corresponding author had full access to all data in the study and the final responsibility to submit for publication.
Competing interests None.
Ethics approval Institutional review boards of the participating centres.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent Obtained.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.