Antithrombotic Therapy for Prevention of Pneumonia

To the Editor: Patients with cerebral infarction, regardless of whether it is symptomatic or silent, are susceptible to the development of aspiration pneumonia.1,2 Therefore, it is conceivable that treatment aimed at reducing the incidence and severity of cerebral infarction (anti-hypertensive therapy, or anticoagulation and anti-platelet therapy in selected populations) may prevent the recurrence of stroke and may reduce the incidence of aspiration pneumonia.3 Cilostazol (Otsuka Pharmaceutical Co Ltd., Tokushima, Japan), a novel cyclic adenosine monophosphate phosphodiesterase inhibitor, has multiple actions, including inhibition of platelet aggregation and cerebral vasodilation, and is useful for treating chronic arterial diseases.4,5 We therefore investigated whether cilostazol reduces the recurrence of stroke and lowers the incidence of pneumonia in patients with cerebral infarctions. Eligible patients had a history of stroke but were not bedridden. We excluded patients if they were immunocompromised, such as those with active malignant disease, renal dialysis, or human immunodefiency virus-1 infection. The Tohoku University Ethics Committee approved the study and subjects gave informed consent. Before the study, all patients underwent a physical examination and chest radiography. Randomization was performed using a random-numbers table and the list was held independently of the investigators. All patients had received antihypertensive drugs (calcium channel blocker or beta-blocker). Patients were randomly assigned cilostazol 100 mg per day or no active treatment in April 1996, and were investigated for 3 years. Criteria for diagnosis of pneumonia were a new pulmonary infiltrate seen on a chest radiograph and one of the following features: cough, temperature higher than 37.8°C, or subjective dyspnea. Two radiologists not involved in the study diagnosed pneumonia. Thirty-one patients were excluded from analysis because they died from causes other than pneumonia during follow-up. Of the remaining 297 patients, 152 (with a mean ± standard error (SE) age of 76 ± 2 years) received cilostazol at study entry and 145 (with a mean (±SE) age of 77 ± 2 years) received no active treatment. Although 270 patients completed the trial, 27 patients who received cilostazol suffered side effects of bleeding (12 patients), palpitation and/or tachycardia (11 patients), diarrhea (one patient), and headache (two patients) and were dropped from the study. During follow-up, new pneumonia and recurrence of cerebral infarction, including transient ischemic attack, were diagnosed in 35 (24%) and 24 (16%), respectively, of 145 patients who received no active treatment, and 12 (10%) and nine (7%), respectively, of 125 patients who received cilostazol. According to the Cox regression model, these findings corresponded to a relative risk for patients who did not receive cilostazol compared with those receiving cilostazol of 2.15 (95% confidence interval (CI) = 1.37–4.63, P < .002) for developing pneumonia and 2.30 (95% CI = 1.10–4.85, P < .02) for recurrence of cerebral infarction, respectively. Pneumonia did not occur at least 6 months after recurrence of stroke in patients receiving cilostazol. Our findings suggest that the risk of pneumonia is lowered about 40% if cilostazol is used in patients with previous stroke. Antithrombotic therapy may, therefore, have beneficial effects on the prevention of pneumonia associated with cerebrovascular disease in these patients.