In patients who cannot tolerate aspirin, the platelet aggregate inhibitor clopidogrel or a similar drug can be substituted (see below). Ticlopidine and clopidogrel are considered, on the basis of clinical trials, to be equivalent to or marginally more effective than aspirin for the prevention of stroke. Furthermore, both drugs have potential side effects; ticlopidine may produce neutropenia and clopidogrel may cause thrombotic thrombocytopenic purpura. Dipyridamole in high doses has not been as well tolerated by many of our patients because of dizziness induced by peripheral vasodilatation.
The combined use of dual antiplatelet drugs (with aspirin) given for days or weeks after the stroke has generally been shown to be slightly superior to aspirin alone in secondary stroke prevention, but with an increased risk of cerebral hemorrhage in some trials. In most large trials, the incremental benefits of adding one of these drugs to aspirin has been of the order of 1 to 3 percent (see the ESPRIT study and Bhatt et al and Sacco et al, a trial that failed to show benefit for the addition of extended release of dipyridamole to aspirin). A study with over 5,000 patients from China, the CHANCE trial reported by Wang and coworkers, did demonstrate a reduction in stroke recurrence during the first 90 days after the first minor stroke or TIA by adding clopidogrel to aspirin, either 75 mg or 300 mg, and no increase in major systemic or intracranial hemorrhages. When the use of dual antiplatelet agents was extended to larger, non-Asian, populations, the POINT trial (Johnston et al), there was an excess of major systemic hemorrhages (not cerebral hemorrhages) compared to aspirin alone and somewhat less reduction in rates of stroke compared to the CHANCE trial but treatment was nevertheless effective in reducing 90-day recurrent stroke risk. The overall risk-benefit ratio for stroke reduction versus major system hemorrhage was judged to be favorable. These two antiplatelet trials enrolled patients with minor stroke or TIA that was considered to be high risk for subsequent stroke as gauged by ABCD2 score. Therefore, it applies to patients who are not planned to have thrombolysis, thrombectomy or anticoagulation. One consideration in the understanding hemorrhage rates is that the first trial used dual antiplatelet drugs for only 3 weeks, whereas the latter trial continued dual therapy for 90 days, which may have explained the divergence in hemorrhage rates.
In trials comparing aspirin to anticoagulation for secondary stroke prevention in atrial fibrillation, anticoagulation has still been superior (see ACTIVE Writing Group). These studies notwithstanding, the therapeutic effectiveness of aspirin is still rather slight and the addition of clopidogrel to aspirin in patients who were not deemed suitable for warfarin reduces strokes over several years of observation but increases the risk of major bleeding so that the combination cannot be endorsed (ACTIVE Investigators). Moreover, in each of the trials, a significant number of subsequent ischemic strokes occurred even in patients while they were receiving aspirin.
In a trial of statins, the institution of high doses of drug reduced the incidence of subsequent stroke after a TIA or first stroke by 2 percent over 5 years (see Stroke Prevention by Aggressive Reduction in Cholesterol Investigators [SPARCL trial]). Other large studies with lower doses of statin drugs have not shown this effect. These findings with high doses have, at the moment, been adopted into routine practice. Recent guidelines encourage LDL concentrations of less than 70 mg/dL for secondary stroke prevention.
Early anticoagulation after an acute stroke carries an uncertain risk of hemorrhagic transformation of an ischemic infarct. In particular, patients with very large cerebral infarcts that have a component of deep (basal ganglionic) tissue damage, especially in those patients who are also hypertensive, there may be a risk of anticoagulant-related hemorrhage into the acute infarct—“hemorrhagic conversion” (Shields et al).