Prevention Regimen for Effectively Avoiding Second Strokes - PRoFESS

Description:

PRoFESS was a double-blinded randomized international clinical trial where patients with a recent (within 3 months) non-cardioembolic ischemic stroke were randomized in a 2 × 2 factorial design to: 1) either fixed combination of low-dose aspirin 25 mg and extended-release dipyridamole 200 mg twice daily or clopidogrel 75 mg once daily, and 2) telmisartan 80 mg daily or placebo.

Hypothesis:

Aspirin plus dipyridamole is noninferior to clopidogrel alone in reducing recurrent strokes in patients with recent strokes. Further, telmisartan is superior to placebo in reducing recurrent strokes in the same patient population.

Study Design

Study Design:

Patients Screened: N/A
Patients Enrolled: 20,332
Mean Follow Up: 2.5 years
Mean Patient Age: 66.1 ± 8.6 years
Female: 36

Patient Populations:

• Age ≥55 years
• Ischemic stroke within 90 days

Patients ages 50-55 years and/or 90-120 days after the qualifying stroke were included if they had at least two of the following risk factors:
• Diabetes mellitus
• Hypertension
• Smoker
• Body mass index >30
• Previous vascular stroke
• Evidence of end-organ damage
• Hyperlipidemia

Exclusions:

• Primary hemorrhagic stroke
• Known brain tumor
• Dementia requiring institutional care
• Modified Rankin score >4 at baseline
• Postprocedural stroke
• Hypersensitivity to study medications
• Unable to swallow medications
• Patient unlikely to be released from the hospital following the qualifying stroke, or presence of a severe disability after the qualifying stroke likely to lead to the patient being bedridden or demented, or a nonvascular disease or condition, which makes it unlikely that the patient will survive to the end of the trial
• Uncontrolled hypertension
• Seated systolic blood pressure ≤120 mm Hg
• Patients already on an angiotensin-receptor blocker
• Patients on heparin or warfarin, or other antiplatelet agents
• Chronic kidney disease (serum creatinine >3.0 mg/dl)
• Known severe hepatic dysfunction
• Hyperkalemia
• Known active peptic ulcer disease
• Severe coronary artery disease including unstable angina or myocardial infarction within 3 months
• Thrombocytopenia
• Nursing or pregnant women
• Planned major surgery, carotid endarterectomy, or angioplasty

Primary Endpoints:

Recurrent stroke of any type

Secondary Endpoints:

• Major vascular events (stroke, myocardial infarction, or vascular death)
• Major vascular events or new or worsening congestive heart failure
• New-onset diabetes mellitus

Drug/Procedures Used:

Patients meeting inclusion and exclusion criteria received either fixed-dose combination of aspirin/dipyridamole 25 mg/200 mg twice daily or clopidogrel 75 mg daily, as well as either telmisartan 80 mg daily or placebo. The medication was administered as a “double dummy,” such that every patient received either matching drug or placebo for all medications.

Concomitant Medications:

Statins (47.2%), angiotensin-converting enzyme inhibitors (36.8%), calcium channel blockers (24.2%), and beta-blockers (20.7%)

Principal Findings:

A total of 20,332 patients from 695 sites in 35 countries were randomized. A 2 × 2 factorial design, as described above, was employed. The median time to randomization from index event was about 15 days. About 51% of patients had no symptoms or no significant disability from the index event. Patients were at high risk for cardiovascular events, with 74% having hypertension, 28.3% with diabetes, 6.7% with prior myocardial infarction, and 24.6% with either prior stroke or transient ischemic attack (before index event). Approximately 52% of the patients with stroke had evidence of small-vessel ischemic disease. Follow-up averaged about 2.5 years.

Aspirin + dipyridamole vs. clopidogrel: The incidence of the primary endpoint of any recurrent stroke was similar between the aspirin + dipyridamole arm (9.0%) and the clopidogrel arm (8.8%) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92-1.11). This failed to meet the predefined noninferiority criteria for aspirin + dipyridamole compared with clopidogrel. The incidence of the main secondary outcome of stroke, myocardial infarction, or vascular death was similar between the two arms as well (13.1% vs. 13.1%, HR 0.99, 95% CI 0.92-1.07, p = 0.83). New or worsening heart failure, a tertiary outcome, was significantly better in the aspirin + dipyridamole arm (HR 0.78, 95% CI 0.62-0.96).

The investigators also noted a significantly higher risk of intracranial hemorrhage with aspirin + dipyridamole compared with clopidogrel (1.4% vs. 1.0%, HR 1.42 95% CI 1.11-1.83, p=0.006); the incidence of ischemic strokes was similar (7.7% vs. 7.9%). Major hemorrhagic events were observed more frequently in the aspirin + dipyridamole arm (4.1%) compared with the clopidogrel arm (3.6%) as well (HR 1.15, 95% CI 1.00-1.32, p = 0.06). Dropouts due to headache were also more common in the aspirin + dipyridamole arm.

Telmisartan vs. placebo: At the end of 1 year, the mean blood pressure difference between telmisartan and placebo was 3.8/2.2 mm Hg. The incidence of the primary endpoint of any recurrent stroke was similar between the telmisartan (8.7%) and placebo (9.2%) arms (HR 0.95, 95% CI 0.86-1.04, p = 0.23). The incidence of major vascular events (cardiovascular death, myocardial infarction, stroke, and new or worsening heart failure) was also similar between the two arms (13.5% vs. 14.4%, HR 0.94, 95% CI 0.87-1.01, p = 0.11). Rates of new-onset diabetes mellitus, also a prespecified secondary endpoint, were similar between the two arms (1.2% vs. 1.5%, HR 0.82, 95% CI 0.65-1.04, p = 0.10).

Further exploratory analysis indicated that there may be a benefit with telmisartan compared with placebo beyond 6 months in reducing the incidence of recurrent stroke (5.3% vs. 6.0%, HR 0.88, 95% CI 0.78-0.99). Adverse events, including hypotension, syncope, diarrhea, nausea, and atrial fibrillation, were more common with telmisartan compared with placebo. Moreover, although the incidence of hyperkalemia was similar between the two arms (0.1% vs. 0.1%, p = 0.07), the proportion of patients with severe hyperkalemia (potassium >5.5 mmol/L) was greater with telmisartan compared with placebo (1.6% vs. 0.8%, p < 0.001).

Interpretation:

The results of this landmark clinical trial, which is the largest secondary prevention trial in patients with ischemic stroke, indicate that the combination of aspirin + dipyridamole is roughly similar to clopidogrel (although it did not meet strict criteria for noninferiority) in reducing the incidence of recurrent strokes, but is associated with an increased risk of intracranial bleeds.

Current ACCP guidelines recommend either aspirin + dipyridamole or clopidogrel over aspirin for secondary prevention in patients with a prior cerebrovascular event. Given the findings of this trial, there is not likely to be a consensus on the use of one agent over the other. Patient preferences and comorbidities (such as co-existing coronary artery disease) will need to be factored in when choosing the appropriate antiplatelet agent in these patients.

Furthermore, telmisartan is not superior to placebo in reducing the incidence of recurrent strokes in this patient population, with a higher incidence of side effects including hypotension, syncope, and serious hyperkalemia compared with placebo. Exploratory analyses indicated that telmisartan may be associated with a reduction in the risk of recurrent stroke after 6 months of treatment. Further studies to corroborate these findings are necessary.

References:

Sacco RL, Diener HC, Yusuf S, et al., on behalf of the PRoFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-51.

Yusuf S, Diener HC, Sacco RL, et al., on behalf of the PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225-37.

Presented by Drs. R. Sacco and S. Yusuf at the European Stroke Conference, Nice, France, May 14, 2008.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Novel Agents, Statins, Acute Heart Failure, Hypertension

Keywords: Coronary Artery Disease, Ischemic Attack, Transient, Follow-Up Studies, Platelet Aggregation Inhibitors, Hyperlipidemias, Comorbidity, Syncope, Hypotension, Ticlopidine, Hyperkalemia, Risk Factors, Headache, Benzoates, Benzimidazoles, Research Personnel, Confidence Intervals, Hypertension, Nausea, Myocardial Infarction, Stroke, Diarrhea, Consensus, Potassium, Intracranial Hemorrhages, Body Mass Index, Heart Failure, Dipyridamole, Diabetes Mellitus


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