More Good News for Stroke Prevention — Statins and ACE Inhibitors Really Work!

Abstracts & Commentary

By Matthew E. Fink, MD, Vice Chairman, Professor of Clinical Neurology, Weill Cornell Medical College; Chief, Division of Stroke and Critical Care Neurology, NewYork-Presbyterian Hospital. Dr. Fink reports no financial relationship relevant to this field of study.

Synopsis: The SPARCL study showed that 80 mg per day of atorvastatin reduced the overall incidence of recurrent stroke, and a meta-analysis of several large studies of ACE inhibitors showed a reduction in all stroke types, as well as a reduction in overall cardiovascular mortality.

Sources: Amarenco P, et al (SPARCL). High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. N Engl J Med. 2006;355:613-615; Dagenais GR, et al. Angiotensin-Converting-Enzyme Inhibitors in Stable Vascular Disease without Left Ventricular Systolic Dysfunction or Heart Failure: A Combined Analysis of Three Trials. Lancet. 2006;368:581-588.

Until now, neurologists have relied on large studies of patients with coronary atherosclerosis and hyperlipidemia who were treated with statins and were found, as a secondary outcome, to have a reduced risk of ischemic stroke. While the role of cholesterol as a stroke risk factor has remained controversial, the benefit of statins in reducing the risk of ischemic stroke has been compelling. Other mechanisms than reduction of LDL cholesterol have been postulated, such as the antithrombotic, anti-inflammatory, and plaque-stabilizing effects of statins.

Now, Amarenco and colleagues have reported for the first time convincing evidence regarding the efficacy of atorvastatin in a direct study of secondary prevention of ischemic stroke in a selected population of patients with stroke or TIA. In a double-blind, placebo-controlled trial of atorvastatin 80 mg. per day, 4731 patients who had a stroke or transient ischemic attack (TIA) within one to 6 months had low-density lipoprotein cholesterol levels (LDL) of 100 to 190 mg/dL, and no known coronary disease, were enrolled in the study, and followed for a median of 4.9 years. During the trial, the mean LDL cholesterol was reduced to 73 mg/dL among patients receiving atorvastatin and 129 mg/dL in those receiving placebo. Two hundred sixty-five patients (11.2 %) receiving atorvastatin and 311 patients (13.1%) receiving placebo had a fatal or non-fatal stroke (5-year absolute RR = 2.2%; adjusted hazard ratio, 0.84; 95% CI = 0.71-0.99; P = 0.03). The 5-year absolute risk reduction for all cardiovascular events was 3.5% (HR = 0.80; 95% CI = 0.69-0.92; P = 0.002). There was a small increase in hemorrhagic stroke, and elevated liver enzymes were more common in the atorvastatin group.

In a complementary study reported in Lancet by Dagenais and colleagues, the benefit of using an angiotensin-converting-enzyme inhibitor (ACEI) to prevent stroke in a population of patients with stable coronary artery disease was supported by a meta-analysis of 3 large clinical trials (HOPE, EUROPA, PEACE) that looked at cardiovascular outcomes and total mortality in 29,805 patients randomized to treatment with an ACEI (ramipril, perindopril, trandolapril). In prior studies of patients with overt heart failure, use of an ACEI did not demonstrate a significant reduction in stroke risk. The lack of efficacy was attributed to the relatively low blood pressures that these patients had at time of enrollment. Because high blood pressure is such a powerful risk factor for stroke, use of an ACEI without a significant lowering of blood pressure would not be expected to have much benefit.

Degenais et al's analysis, however, demonstrated that when the findings of the studies were combined, ACEI significantly reduced all-cause mortality (7.8% vs 8.9%, P = 0.0004), cardiovascular mortality (4.3% vs 5.2%, P = 0.0002), and all stroke (2.2% vs 2.8%, P = 0.0004). The baseline mean blood pressures, before treatment, ranged from 134-139 systolic and 78-82 diastolic, and were reduced during treatment by 4-6 systolic and 3-4 diastolic.

Commentary

We are entering a Golden Age for stroke prevention and treatment, and these 2 studies will add to our confidence as neurologists, that we can really help our patients who have had a stroke, or are at high risk for a stroke.

The study by Amarenco et al confirms other data that statins reduce stroke risk. Using 80 mg of atorvastatin, there was a large reduction in LDL cholesterol levels and a relative risk reduction for stroke of 16%, with a relative risk reduction for all major cardiovascular events of 20%. We are still not sure if the mechanism of stroke reduction is lowering of LDL, and it is likely that there are multiple mechanisms at play. In any case, statin treatment has a profound effect, and should be an important part of our armamentarium to prevent stroke.

Dagenais et al's paper in Lancet also adds to our list of effective treatments by confirming that ACEI, as a category of antihypertensive medications, reduce stroke risk with even very small reductions in blood pressure. Many of us have felt that this group of agents might have a selective benefit over other antihypertensive medications because of the widespread presence of ACE receptors in the brain, and the ability of ACEI to maintain cerebral perfusion in the setting of severe heart failure. Dagenais et al's meta-analysis lends more support to this hypothesis, and gives us a compelling reason to select an ACEI over other medications when treating our stroke patients who have hypertension.

Of interest, the World Congress of Cardiology has recently proposed the development of a combination pill that would contain aspirin, a statin, and an ACEI to prevent cardiovascular disease. Such a combination pill would have a very positive impact in reducing stroke risk, since all 3 agents have now been shown to significantly reduce the risk of ischemic stroke.