Peripheral artery disease (PAD) prevalence and incidence are both age-related. Its prevalence in population older than 60 ranges between 8.6 to 24.2% in women and 5.5 to 24.7% in men [1, 2] and it increases progressively with ageing population [1]. Population studies conducted in Spain have found a prevalence of PAD between 3.7 and 7.6% in general population [3, 4]. PAD causes an impairment in quality of life, decrease in life expectancy and it is an important predictor of morbidity and mortality [5, 6].

Many people with PAD do not have symptoms, but when they occur, intermittent claudication (IC) is the main symptom. Treatment for IC is a combination of preventive measures such as modification of risk factors, physical activity, treatment of symptoms and antiplatelet therapy [7, 8]. Currently, there are two drugs authorized for PAD treatment; pentoxifylline [9] and cilostazol [10]. Cilostazol was approved by European Medicines Agency (EMA) in 2002 and in Spain in 2009 to improve walking distances in patients with IC [10].

Cilostazol is a phosphodiesterase III inhibitor which was first approved for the treatment of symptoms related to IC. It is a potent platelet-aggregation inhibitor and has arterial vasodilatory effects [11]. Cilostazol is contraindicated in patients with severe renal impairment, moderate or severe hepatic impairment, and known predisposition to bleeding and in patients with history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopic beats, or prolongation of the QTc interval. Cilostazol has been associated with a number of spontaneous reports of cardiovascular adverse effects (myocardial infarction, angina, and arrhythmias) and serious bleeding [10, 12]. Haemorrhagic events in elderly patients co-treated with antiplatelets were also reported by the Centro Autonómico de Farmacovigilancia de Cantabria [13].

The EMA evaluated the benefit/risk of cilostazol in a referral and recommended changes in the summary of product characteristics (SmPC), including extension of contraindications to patients with unstable angina pectoris, recent acute myocardial infarction (AMI), or recent coronary intervention. EMA also highlighted cautions and concerns over haemorrhagic and vascular events [12, 14]. Healthcare professionals in Europe have been advised to use cilostazol for IC only in patients where other lifestyle modifications such as smoking cessation and exercise have not provided adequate improvement and to continue use only in those patients who have shown clinically relevant benefit after 3 months of therapy. Other cautions include avoiding cilostazol in patients receiving two or more additional antiplatelet or anticoagulant agents and potentially avoiding use or decreasing the dose in patients concomitantly receiving strong inhibitors of CYP3A4 or CYP2C19 [12].

Cilostazol is recommended by guidelines as an effective therapy in improving symptoms and increasing walking distance in patients with lower extremity PAD [15, 16]. Nevertheless, the effect of cilostazol on morbidity and mortality has not been fully determined. In this population-based primary healthcare (PHC) cohort study, we assess the safety of cilostazol for the treatment of PAD patients in terms of incidence of cardiovascular events, arrhythmias and haemorrhages during the follow-up.

The main objective of the study was to calculate the relative risk of cardiovascular adverse events or bleeding in patients with PAD treated with cilostazol in comparison to pentoxifylline users. The specific objectives were: 1) to calculate risks for cilostazol users versus pentoxifylline users of: ischemic or coronary artery disease (CAD), arrhythmias or haemorrhages; 2) to determine whether the coexistence of type 2 diabetes mellitus (DM) may increase adverse events of cilostazol; and 3) to determine whether concomitant use of antiplatelet agents with cilostazol increases the risk of bleeding.

During the study period, 9129 patients met the inclusion criteria; 3345 were receiving treatment with cilostazol and 5784 with pentoxifylline. Patients in the two groups were different in most baseline characteristics (Table 1).

After PS matching, there were 2905 patients per group. As shown in Table 1, most patients (76%) in both cohorts were men. Their mean ages were similar in both groups. There were differences between groups in the frequency of smokers; more than 25% of patients in both groups were current smokers. The percentages of missing values of this variable were 9.9 and 10.9% in cilostazol and pentoxifylline users, respectively.

We analysed the frequency and incidence of bleeding, cerebrovascular and cardiovascular events comparing the two cohorts (Table 2). There were no statistically significant differences between them for the overall population included.

We also conducted three subgroup analyses for the following groups of patients: 1) older than 65, 2) patients with type 2 DM, and 3) patients co-treated with antiplatelets. We did not find significant differences between the two groups of treatment in the subgroup of people older than 65 or in the patients with type 2 DM. For patients co-treated with antiplatelets, we found differences between cilostazol and pentoxifylline in the rates of other haemorrhages, which include eye bleeding, haemorrhages of the anus and rectum, epistaxis and haemorrhages not elsewhere classified; and in the rates of any haemorrhage. The incidence of these events was higher in pentoxifylline users than in cilostazol users (Table 3).

In this cohort study of the safety of cilostazol in PAD, we identified 9129 patients who initiated cilostazol or pentoxifylline during the study period. They differed in most of socio-demographic and clinical characteristics. After PS matching, the cohort was composed by 2905 cilostazol users and 2905 pentoxifylline users with comparable characteristics between groups.

We analysed the frequency and incidence of bleeding, cerebrovascular and cardiovascular events and we found non-statistically significant differences between cilostazol and pentoxifylline. We also conducted three sub-analyses in the following subgroups of patients: 1) population ≥ 65 years-old, 2) patients diagnosed with type 2 DM and 3) patients co-treated with antiplatelet agents. For patients co-treated with other antiplatelets, pentoxifylline showed higher incidences than cilostazol for overall haemorrhages, and for the group of other haemorrhages, which includes eye bleeding, haemorrhages of the anus and rectum, epistaxis and haemorrhages not elsewhere classified.

Our results are in line with previous studies, which did not find increases in haemorrhages, CAD or arrhythmic events in cilostazol-treated patients. In the clinical trial conducted by Dawson et al. [19] patients were randomized to receive cilostazol, pentoxifylline or placebo and the maximal walking distance was measured after 4, 8, 12, 16, 20 and 24 weeks. They also studied the frequency of common side effects and the group of “serious adverse events” had similar frequencies in the three groups, with non-significant differences.

In a systematic review of clinical trials comparing cilostazol with placebo or other drugs currently known to increase walking distance, such as pentoxifylline, 3718 patients were assessed and there was no clear evidence of a difference between any of the treatment groups and risk of AMI, stroke or all-cause mortality [20].

In the cohort study conducted by Leeper et al. [21], 232 patients with PAD treated with cilostazol were matched by 1:5 PS with 1160 patients not taking this drug. Over a mean follow-up of 4.2 years, they did not find association between cilostazol and cerebrovascular or cardiovascular events (OR for stroke 1.13, 95%CI 0.82–1.55; OR for AMI 1.00, 95%CI 0.71–1.39) or death (OR 0.86, 95%CI 0.63–1.18). They did not find increase in arrhythmic events either.

Previous published data in Spain [13] studied elderly patients with underlying comorbidities and receiving a considerable number of concomitant medications. The small sample size of the study does not allow establishing definite conclusions. Cilostazol should be used for IC only in patients with no contraindications for the treatment and should be used cautiously in elderly polymedicated patients, in those receiving two or more additional antiplatelet or anticoagulant agents and in those receiving strong inhibitors of CYP3A4 or CYP2C19.

Patients treated with cilostazol were clearly different from those treated with pentoxifylline at baseline, so they were matched through PS.

After matching, we did not find differences between treatment groups in the incidence of bleeding or cardiovascular and cerebrovascular events. We did not find differences in specific subgroups either, except an increase in overall haemorrhages rates with pentoxifylline in patients co-treated with additional antiplatelets.

Cilostazol should be used with precaution in elderly polymedicated patients in order to avoid adverse events.