Update on Stroke Prevention: News from National Meetings—The WARSS and PROGRESS Trials

Conference Coverage

Source: Mohr JP for the warfarin-aspirin recurrent stroke study (WARSS) study group. Presented at the American Academy of Neurology, May 1999, Philadelphia, Pa.

The WARSS trial was designed to compare warfarin therapy with antiplatelet therapy (aspirin) in the prevention of recurrent stroke. The trial was a randomized, double-blind, multicenter trial of 2206 patients at 47 US centers. The trial had 4 substudies: PICSS, APASS, HAS, and GENESIS, examining issues such as the risk of stroke with patent foramen ovale (PFO) and antiphospholipid antibodies. Data from the substudies have not yet been presented.

The inclusion criterion for WARSS was an ischemic stroke within the prior 30 days. Patients with a cardioembolic source of stroke, such as atrial fibrillation (AF) or a symptomatic, operable carotid stenosis, were excluded. Patients were randomized to receive either aspirin (325 mg/d) or warfarin (INR 1.4-2.8) for at least 2 years. Adjustments of warfarin were based on either real or computer-generated INR values.

Among warfarin-treated patients, a mean INR 2.0- 2.1 was sustained over 2-year follow-up. There were no statistical differences in the risk of recurrent stroke or in major hemorrhage. No statistical differences were found in subgroups defined by sex, race, or stroke subtype.

Commentary

We eagerly await the upcoming formal publication of the WARSS data to provide further insight into this landmark study. These preliminary findings alone already portend a major decrease in the empiric use of warfarin post-stroke. The WARSS data, however, are open to at least 3 major criticisms that may still justify the use of coumadin by those who wish to use it.

1. The INR range chosen, 1.4-2.8, may have been too low. INRs in the range of 1.5-2.0 have been shown to be inadequate for stroke prevention in the setting of AF. It is possible that if all patients were maintained with INRs above 2.0, an advantage for warfarin may have been found.

2. The WARSS study was comprised of a large proportion of patients (> 50%), with lacunar disease. Since antiplatelet therapy rather than warfarin has traditionally been considered optimal for these small vessel lesions, inclusion of a these patients may have skewed the results toward aspirin. Data from the warfarin aspirin study of intracranial disease (WASID) comparing these therapies among patients with large vessel intracranial stenoses may yield different results.

3. Finally, while the WARSS study did not show an advantage for warfarin over aspirin, neither did it show a detriment. Under study conditions, with strict control of warfarin therapy, no increase in hemorrhage among warfarin patients was observed. If one is willing to accept the added inconvenience of warfarin therapy, its use remains justifiable based on the WARSS data.

J Chalmers for the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). Presented at the 11th European Meeting on Hypertension, June 2001, Milan, Italy.

Hypertension is a well-recognized stroke risk factor. The immediate reduction of blood pressure in the post-stroke setting is, however, a matter of some controversy as perfusion may be augmented by higher blood pressures. Blood pressure control beyond the acute setting is a uniform goal in stroke survivors.

In the PROGRESS study, 6105 patients with a history of a stroke within the previous 5 years were randomized to a regimen of perindopril 4 mg along with indapamide 2.5 mg compared with placebo. All patients were treated with other antihypertensives as deemed necessary by their physicians along with medications such as aspirin and statin drugs.

The overall stroke risk was reduced by 28% in treated patients compared with placebo. The risk of fatal or disabling stroke was reduced by 38%. This benefit applied to both ischemic and hemorrhagic stroke. While patients with either hypertension or diabetes showed the most striking reduction (approximately 33%), a benefit of 22% was observed in patients without high blood pressure.

Commentary

These data indicate that angiotensin converting enzyme (ACE) inhibitors have potent benefits in recurrent stroke prevention. This benefit applies irrespective of whether hypertension is actually present. These data parallel those of the heart outcomes prevention (HOPE) study (Yusuf S, et al. N Engl J Med. 2000;342:145-153) showing that the ACE inhibitor ramipril (Altace) provided marked reductions of both cardiac risk and stroke. The relative risk of stroke with ramipril treatment was 0.68 (P < 0.001) compared with placebo.

The accumulating data from studies such as PROGRESS and HOPE indicate that ACE inhibitors have vascular benefits extending far beyond blood pressure control. These effects may include anti-atherogenesis, arteriolar remodeling, endothelial cell modulation, platelet inhibition, and alterations in atrial naturetic peptide and other hormones. Most likely, this is a class effect applying to all ACE inhibitors. Perindopril is marketed in the United States under the trade name Aceon. The PROGRESS investigators specifically chose this drug for study as this agent is thought to maintain cerebral autoregulation and blood flow even in the setting of blood pressure reduction.

It is likely that future stroke prevention guidelines will include ACE inhibitor therapy regardless of whether hypertension is present. —Alan Z. Segal