The best magazine
In Dr. Pettigrew's recent article, he does not address two issues that may be important for individualizing drug therapy. A precaution was placed in the approved labeling for Aggrenox when treating persons with unstable angina or after myocardial infarction. In these clinical settings, a vasodilator such as dipyridamole may cause sufficient systemic vasodilation to produce coronary stealing and exacerbate cardiac insuffi-ciency. These cardiac conditions as comorbidity are not insignificant in the population receiving secondary stroke prevention.
A second issue is that no other studies of clopidogrel have been reported beyond the CAPRIE trial. Without further prospective study of the subgroups enrolled in CAPRIE, as groups on their own, the question of who actually benefits from clopidogrel goes begging for a proven answer.
Pettigrew LC. Antithrombotic drugs for secondary stroke prophylaxis. Pharmacotherapy 2001;21(4):452-63.
Boehringer Ingelheim Pharmaceuticals Inc. Aggrenox package insert. Ridgefield, CT; November 1999.
Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.
I appreciate the thoughtful comments made by Drs. Inverso, Spinler, and Hansen regarding my review article on secondary stroke prophylaxis. I agree with Drs. Inverso and Spinler that cardiogenic emboli to the brain is an important cause of cerebral infarction. The use of warfarin for the primary prevention of stroke in patients with atrial fibrillation or at high risk of cerebral embolization associated with cardiac valvular prosthesis has been established beyond question. Drs. Inverso and Spinler cite correctly the guidelines for administering warfarin to patients with atrial fibrillation. It must be emphasized, however, that warfarin is the treatment of choice for patients who are at risk for, but have not yet experienced, stroke resulting from atrial fibrillation. Warfarin may be administered to the patient with atrial fibrillation who has suffered a nondisabling stroke, but the most effective use of anticoagulation is in primary prevention.
The role of warfarin in secondary stroke prevention is much more controversial and was the subject of recently performed clinical studies. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) was the first randomized comparison of vigorous oral anticoagulation (international normalized ratio [INR] of 3.0-4.5) with aspirin 30 mg/day for prevention of recurrent, noncardiogenic stroke. The study was stopped prematurely because of a significant increase in the number of major bleeding complications, including intracerebral hemorrhage, in the anticoagulation group.
A second trial conducted in patients with noncardiogenic stroke, the Warfarin-Aspirin Recurrent Stroke Study (WARSS), was reported during the 53rd annual meeting of the American Academy of Neurology in May 2001. Subjects enrolled in WARSS were randomized to receive warfarin to achieve an INR of 1.4-2.8 or aspirin 325 mg/day and were followed prospectively for 2 years. A manuscript describing WARSS has been submitted for review. Unofficial reports of the platform presentation made by the WARSS principal investigator, Dr. J. P. Mohr of Columbia University in New York, stated that there was no difference in the primary outcome measure, recurrent ischemic stroke or death from any cause.
I agree with Dr. Hansen that caution should be advised with use of Aggrenox in patients who have experienced a stroke and have a history of coronary arterial insufficiency. I also agree that targeted use of clopidogrel in patients with peripheral arterial insufficiency, myocardial infarction, or stroke -- the three conditions studied in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial -- should be confirmed in a follow-up clinical trial.
Barnett HJ, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995; 332(4):238-48.
Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999;281(19):1830-5.
SPIRIT Investigators. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The stroke prevention in reversible ischemia trial (SPIRIT) study group. Ann Neurol 1997;42(6):857-65.
WARSS Investigators. The feasibility of a collaborative double-blind study using an anticoagulant. The warfarin-aspirin recurrent stroke study (WARSS), the antiphospholipid antibodies and stroke study (APASS), the patent foramen ovale in cryptogenic stroke study, the hemostatic activation study (HAS), the genes for stroke study (GENESIS). Cerebrovasc Dis 1997;7:100-12.
L. Creed Pettigrew, M.D., M.P.H.
Source: ...