Terutroban versus aspirin in Patients with Cerebral Ischaemic Events (PREFORM): a Randomized, Double- blind Parallel-group Trial Daniel Wells Mercer University School of Medicine MS-III Journal Club Presentation Dr. Ali Rahimi

Funding: Servier, France Bousser, Marie-Germaine, Pierre Amarenco, Angel Chamorro, Marc Fisher, Ian Ford, Kim M. Fox, Michael G. Hennerici, Heinrich P. Mattle, Peter M. Rothwell, Agnes De Cordoue, and Marie-Dominique Fratacci. "Terutroban versus aspirin in Patients with Cerebral Ischaemic Events (PREFORM):a Randomized, Double-blind Parallel-group Trial." The Lancet 377.June 11 (2011): Print.

Level of Evidence: Ib: Evidence obtained from at least one randomized controlled trial

Objective : To determine if the selective thromboxane- prostaglandin receptor antagonist terutroban is more effective than aspirin at preventing the recurrence of stroke or other cardiovascular events in patients who have suffered a stroke or transient ischemic attack.

Design: Randomized, double-blind parallel-group, multi-center trial 19,428 patients were selected from 802 centers in 46 countries. The study was confirmed by the ethical principles set out in the Declaration of Helsinki and was approved by independent ethics committees in all countries. All patients provided written informed consent before study entry. Setting/Patients:

Inclusions: - Eligible patients included men and women aged 55 and older that had either had an ischemic stroke or arterial retinal ischemic event that lasted greater than 48 h and had occurred in the preceding 3 months, or had suffered a TIA in the preceding 8 days. -Ischemic stroke was defined as a focal ischemic neurological deficit lasting at least 24 h or lasting less than 24 h but confirmed by brain imaging. -TIA was defined as a focal deficit including at least motor weakness in the limbs or aphasia and lasting less than 24 h in the absence of imaging evidence in correspondence with cerebral infarction

Exclusions : -Cognitive impairment or known dementia -Cardiac sources of embolism requiring long-term oral anticoagulation

Interventions: Patients were randomly allocated to receive 30 mg per day terutroban or 100mg per day aspirin in the morning, starting the day after randomization. Investigators were advised to follow guidelines for vascular risk factor management, but not to use aspirin.

Main Outcome: The primary endpoint was a composite of fatal or non-fatal ischemic stroke, fatal or non- fatal myocardial infarction, or other vascular death (excluding hemorrhagic death). Secondary endpoints were: a composite of any stroke, any myocardial infarction, or other vascular death (excluding hemorrhagic death; each component of the primary endpoint separately, all-cause mortality, any stroke, fatal stroke, any ischemic stroke, any myocardial infarction, cognitive decline, and dementia. Tertiary endpoints were: admission to the hospital or prolongation of hospital stay for cardiac reasons, cardiac death, revascularization, major lower-limb amputation, disabling or fatal stroke, and disability. Other adverse affects, notably hemorrhagic events, including intracranial and gastrointestinal bleeding were reported as well.

Results: - 19, 428 patients were randomly assigned to either the group receiving terutroban or the group receiving aspirin. At the conclusion of the study, 1091/9556 (11%) of the patients receiving terutroban had reached the primary composite endpoint, compared to 1062/9554 (11%) of the aspirin. - Similar results were obtained for each secondary and tertiary endpoint cause. Patients were also categorized according to baseline demographics, past medical histories, qualifying event for the study, smoking habits, previous treatments, modified Rankin scale scores, and Mini-mental state examination scores. - No significant difference was observed in any category. No significant difference in terutroban versus aspirin was observed in patients who experienced other adverse effects including intracranial and gastrointestinal bleeding.

Conclusion: The PREFORM trial did not show superiority of terutroban compared with aspirin in the prevention of non-hemorrhagic cardiovascular events.

Comments : The PREFORM trial investigated the use of terutroban, a thomboxane- prostaglandin specific antagonist, as compared to aspirin in patients who suffered a cerebral ischemic event. While terutroban did prove to be as effective as aspirin in preventing non-hemorrhagic events, terutroban use was associated with increased incidence of minor bleeding events. This increase in minor bleeding events suggests that increased doses of terutroban would have been detrimental in PREFORM.

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