The Impact of Cilostazol in Refractory Vasospastic Angina

Vasospastic angina (VSA) is a clinical disorder characterised by transient myocardial ischaemia, attributable to epicardial coronary artery vasospasm [1]. The cornerstone therapy for VSA is the calcium channel blockers (CCBs) with their documented cardioprotective and anti-anginal benefits [1, 2]. Nitrates also demonstrate effective anti-anginal properties for VSA [1]. Despite the optimal use of these well-established treatment options, many patients with refractory VSA continue to experience frequent disabling symptoms [2], thus, additional novel anti-anginal agents must be considered [3].

Cilostazol is a phosphodiesterase-3 inhibitor with both anti-platelet and vasodilating properties, which is currently clinically utilised in the management of peripheral arterial disease [4]. While this medication has compelling randomised controlled data demonstrating its anti-anginal efficacy in refractory VSA [5, 6], it is seldom utilised in contemporary clinical practice as evident by no further publications in the 10 years following the original controlled trial [6]. This study reports our “real-world experience” in the anti-anginal effects of cilostazol in patients with refractory VSA, where angina symptoms were systematically monitored via the Seattle Angina Questionnaire (SAQ) as part of a hospital drug monitoring practice for “off-label” drug use.

This is a real world, observational cohort study where patients with refractory VSA, referred to the Central Adelaide Local Health Network Drugs and Therapeutic Committee for additional pharmacological therapy, were consecutively enrolled for initiation of cilostazol therapy. The prescription of cilostazol in Australia is limited to peripheral arterial disease; hence, use for refractory VSA is considered an off-label indication and thereby restricted. Accordingly, access required application to the local hospital Drugs and Therapeutic Committee (DTC) on a case-by-case basis, utilising the individual patient use medicine request system [7]. Conditional approval for each patient was granted for 3 months with objective monitoring and reporting of treatment outcomes and adverse effects. Dependent upon the initial 3-month response, further use of cilostazol could be extended via repeat application.

Eligible patients fulfilled international standardised VSA diagnostic criteria [8] with the presence of refractory VSA determined by the presence of persisting angina (≥1 episode per week) despite an adequate trial of at least 1 month of maximally tolerated combination first-line therapy (i.e., CCB and nitrate). Exclusion criteria were myocardial infarction in past 3 months, decompensated cardiac failure, malignant ventricular arrhythmias, significant valvular heart disease, baseline heart rate ≥100 beats/minute, systolic blood pressure <90 mm Hg, hepatic or renal impairment, and hypersensitivity to cilostazol.

Response to cilostazol therapy was determined through the Seattle Angina Questionnaire (SAQ), an established and validated tool in assessing the functional status of patients with angina and coronary artery disease [9, 10]. SAQs were completed at baseline (prior to cilostazol) and after 3 months of continuous treatment. The primary endpoint was the rate of a clinically significant response to cilostazol therapy, defined as an increase in the angina frequency domain score of ≥10 after 3 months. Secondary endpoints included the change in other SAQ domains including physical limitation and quality of life, as well as the change in healthcare utilisation, i.e., emergency department (ED) presentations and hospital admissions with chest pain in the 3 months pre- and post-cilostazol initiation. Drug safety was monitored through serial clinical and laboratory evaluation with the safety endpoint being any medication-related adverse event necessitating dose reduction or cessation.

From June 2016 to May 2022, 15 consecutive patients with refractory VSA were approved by the Hospital Drug Committee to initiate cilostazol therapy (starting dose 50 mg twice daily) in addition to optimal conventional therapy. Among these patients (46% male, mean age 51.8 ± 10.4 years, age range 33–67), 13/15 had at least one traditional risk factor for cardiovascular disease (shown in Table 1). All patients fulfilled international diagnostic criteria with nitrate-responsive angina and angiographically confirmed epicardial coronary artery vasospasm (with 60% having multi-vessel spasm demonstrated, shown in Table 1) [8].

All patients had received trials of maximally tolerated CCBs alongside a long-acting nitrate, with 13/15 patients having been prescribed two CCBs (i.e., both a non-dihydropyridine and dihydropyridine CCB) prior to commencement. In addition, many patients had trialled other anti-anginal and anti-spasm agents (conventional and non-conventional therapies) including nicorandil, magnesium, perhexiline, and statins (shown in Table 1). Despite these extensive therapies, patients continued to experience almost daily episodes of angina.

Of 15 patients completing the 3-month treatment, the primary outcome of an improvement in the SAQ angina frequency score by ≥10 points was achieved in 13 patients (86%) with 3 patients (20%) becoming angina-free (shown in Fig. 1). The ≥10-point improvement reflects a median improvement in angina episodes from several times a day to several times per week. The median SAQ angina frequency score (reported as median [25th, 75th centile]) improved from 25 (15, 46) at baseline to 75 (30, 82) after 3 months of cilostazol therapy.

Associated with this was a >10-point improvement in SAQ-reported physical limitation in 11 patients (73%) and the quality of life in 14 patients (93%) (shown in Fig. 1). Correspondingly, the median SAQ scores improved from baseline to 3 months for physical limitation from 53 (44, 67) to 83 (56, 94) and for quality of life from 17 (4, 29) to 50 (35, 58) (shown in Fig. 1).

Prior to initiating cilostazol therapy, healthcare utilisation was high, with 26 chest pain ED attendances and 12 in-patient acute coronary syndrome admissions in the 3 months prior to commencement. Cilostazol therapy was associated with a 54% reduction in ED presentations (from 26 to 12) and a 50% reduction in hospital admissions (from 12 to 6) over the 3-month period.

Concerning the safety outcome, 3 patients (20%) experienced cilostazol-associated palpitations, necessitating a dose reduction in 2 (within 3 months) and cessation of the drug in 1. No serious drug-related adverse effects were encountered, and cilostazol was continued in 14/15 (93%) beyond the 3-month study period (shown in Table 1).

While CCBs and long-acting nitrates are well-established treatment options for VSA, up to 10–20% of patients experience refractory angina despite these evidenced-based therapies [11, 12]. Furthermore, it is estimated only 38% of patients achieve a complete resolution of angina with CCB and nitrate therapy [13], highlighting the need for effective incremental treatment options. Currently suggested options for refractory VSA include very high-dose CCBs, anti-adrenergic drugs (including clonidine and guanethidine), nicorandil, statins, magnesium, and rho-kinase inhibitors (fasudil) and non-pharmacological modalities such as left stellate ganglion blockade; however, few of these have randomised controlled studies supporting their anti-anginal benefits [1, 2].

The STELLA trial [6] is a multi-centre randomised placebo-controlled trial providing compelling evidence for the efficacy of cilostazol in refractory VSA, yet this therapy remains vastly underutilised in contemporary clinical practice. The present study supports the clinical trial data [5, 6] and extends these findings by (a) providing data in a “real-world” scenario, (b) extending the previous 4-week clinical trial data to 3 months, (c) supporting its efficacy in patients with severe, refractory VSA on maximally tolerated conventional therapies, (d) demonstrating its impact on patient health status (i.e., improved quality of life, physical activity, and healthcare utilisation), and (e) providing evidence for its efficacy in a Western/Caucasian cohort. As illustrated in Figure 1, the study patients had severe disabling angina prior to initiating cilostazol, with multiple episodes of angina each day despite multiple conventional anti-anginal agents (often above recommended maximal doses) and associated with poor functional status and quality of life. The initiation of cilostazol in these severely disabled patients has been life changing not only in improving their symptoms and quality of life but also reducing hospital presentations. Hence, this under-recognised and underutilised therapy needs to be considered in patients with refractory VSA.

This real-world study demonstrates that cilostazol can be safely utilised with close clinical monitoring. Important considerations in prescribing cilostazol include its anti-platelet properties [14], necessitating caution when used with other anti-platelet agents; potential for QT interval prolongation, interactions with drugs that inhibit cytochrome 3A4 (e.g., diltiazem); rare side effect of blood dyscrasias (e.g., thrombocytopaenia, leukopenia); and its contraindication in the presence of heart failure. Accordingly, cilostazol should be prescribed by cardiologists with close clinical monitoring, especially considering that multiple (frequently interacting) medications are required.

Our study has several limitations that warrant recognition. Firstly, the observational and non-randomised nature of our study involving a small sample size limits the ability to draw inferences on characteristics that may predict a response to cilostazol. Secondly, while our study represents the longest follow-up duration of cilostazol in refractory VSA, the 3-month study period remains relatively short, and the efficacy and safety profile of cilostazol as a long-term therapy for VSA remains unclear. Finally, our study population represents a cohort of patients with VSA on multiple anti-anginal agents; hence, it is unclear to what degree the efficacy of cilostazol can be attributed to synergistic effects with other anti-anginal therapies. In summary, this observational real-world data further supports the randomised controlled trial data regarding the benefits of cilostazol in refractory vasospastic angina and will hopefully encourage clinicians to utilise this often overlooked life-changing agent in these extremely disabled patients.

This study conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected by approval under the Central Adelaide Local Health Network (CALHN) Drugs and Therapeutic Committee (DTC). As the off-label use of cilostazol necessitated priori approval and governance from the DTC with mandated reporting of clinical outcomes, correspondence with the CALHN Human Research Ethics Committee confirmed that this study was exempt from formal ethical review. Written informed consent was obtained from all patients for commencement of the drug and inclusion in this study.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

R.Z.L., R.T., S.S., and J.F.B. were involved in conception and design of the study and contributed to its review and revision. R.Z.L., R.T., and J.F.B. were involved in data acquisition and analysis. R.Z.L. wrote the manuscript. R.Z.L. and J.F.B. act as guarantors and take responsibility for the overall content of the manuscript.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (J.F.B.) upon reasonable request.