Prevention Regimen For Effectively Avoiding Second Strokes Research Articles

Blood pressure, blood pressure variability and the risk of poststroke dementia.

High blood pressure and blood pressure variability are potential, modifiable risk factors of poststroke dementia. We aimed to investigate the association between achieved blood pressure, blood pressure variability and poststroke dementia. We studied 17 064 patients with noncardioembolic ischemic stroke included in the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) trial. We analysed the data as a single observational cohort. We studied mean achieved SBP and DBP and blood pressure variability defined as coefficient of variation (SD/mean∗100). The association between blood pressure and dementia was investigated with logistic regression analysis, correcting for sociodemographic factors and cardiovascular risk factors. During 39 818 person-years of follow-up, 817 patients were diagnosed with dementia (2.1 per 100 person-years). We found a significant nonlinear association between mean SBP and the risk of dementia, implying a U-shaped association between mean SBP and dementia. Mean SBP of 120-129 mmHg was associated with a significantly higher risk of dementia than 130-139 mmHg [odds ratio (OR) 1.28; 95% confidence interval (95% CI) 1.03-1.58]. There was no indication of a U-shaped association between mean DBP and dementia, and no significant association between mean DBP categories and dementia. Higher blood pressure variability was associated with an increased risk of dementia (OR 1.06 per point increase, 95% CI 1.02-1.04), independent of mean SBP. Among patients with a recent noncardioembolic ischemic stroke, there appears to be a U-shaped association between achieved SBP and dementia. High blood pressure variability is associated with an increased risk of poststroke dementia.

Blood Pressure Variability and Cardiovascular Outcomes in Patients With Prior Stroke: A Secondary Analysis of PRoFESS.

Background and Purpose- Every year in the United States, almost 185 000 ischemic strokes occur in patients with a prior stroke. Recurrent stroke has significantly higher morbidity and mortality. Among modifiable risk factors for recurrent stroke, hypertension is the most prevalent. Reducing systolic blood pressure is standard of care for secondary stroke prevention. Recent literature suggests that increased blood pressure variability (BPV) is associated with primary stroke, although studies have not convincingly shown that it is associated with recurrent stroke, which was the goal of this analysis. Methods- We conducted a secondary analysis of 17 916 patients in the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial, which is the largest trial of patients with potential recurrent stroke. We calculated BPV and evaluated its effect on recurrent stroke (composite and stratified by ischemic or hemorrhagic stroke), major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure), and all-cause death. Results- Both systolic and diastolic BPV were associated with recurrent stroke, major cardiovascular events, and all-cause death. The association with stroke was significant for ischemic, but not hemorrhagic, stroke. For every 10-point increase in BPV (systolic SD, range =0-54.2), the hazard ratio for a recurrent ischemic stroke was 1.15 (95% CI, 1.02-1.32; P=0.02), for major cardiovascular events was 1.19 (95% CI, 1.09-1.31; P<0.001), and for all-cause death was 1.24 (95% CI, 1.10-1.39; P<0.001). Conclusions- Our study adds to the growing body of literature suggesting that BPV is an important and potentially modifiable risk factor for ischemic stroke, cardiovascular events, and all-cause death. Specifically, it is the first study to demonstrate that increased BPV is associated with recurrent ischemic stroke and that diastolic BPV can be as important as systolic BPV. Future work should focus on evaluating whether actively reducing BPV, using widely available and inexpensive antihypertensive medications, reduces the risk of cardiovascular disease.

Determining the Joint Effect of Obesity and Diabetes on All-Cause Mortality and Cardiovascular-Related Mortality following an Ischemic Stroke.

Although obesity and diabetes mellitus, or diabetes, are independently associated with mortality-related events (e.g., all-cause mortality and cardiovascular-related mortality) following an ischemic stroke, little is known about the joint effect of obesity and diabetes on mortality-related events following an ischemic stroke. The aim of this study is to evaluate the joint effect of obesity and diabetes on mortality-related events in subjects with a recent ischemic stroke. Data from the multicenter Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial was analyzed for this study. The joint effect of obesity and diabetes on mortality-related events was estimated via Cox proportional hazards regression models. No difference in the hazard of all-cause mortality following an ischemic stroke was observed between obese subjects with diabetes and underweight/normal-weight subjects without diabetes. In contrast, obese subjects with diabetes had an increased hazard of cardiovascular-related mortality following an ischemic stroke compared with underweight/normal-weight subjects without diabetes. Additionally, there was evidence of an attributable proportion due to interaction as well as evidence of a highly statistically significant interaction on the multiplicative scale for cardiovascular-related mortality. In this clinical trial cohort of ischemic stroke survivors, obesity and diabetes synergistically interacted to increase the hazard of cardiovascular-related mortality.

Blood pressure levels and the risk of intracerebral hemorrhage after ischemic stroke.

To investigate the association between blood pressure (BP) levels and risk of intracerebral hemorrhage (ICH) after ischemic stroke. We performed a post hoc analysis of data from the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, a randomized clinical trial including 20,332 patients with recent noncardioembolic ischemic stroke. BP measurements were divided into predefined categories. We calculated incidence rates per BP category and performed multivariable Cox regression analysis with systolic blood pressure (SBP) and diastolic blood pressure (DBP) categories as time-dependent covariables. One hundred thirty-three ICHs occurred during 50,778 person-years of follow-up, resulting in an incidence rate of 2.6 per 1,000 person-years. The incidence rate of ICH increased with increasing SBP and DBP categories. Risk of ICH was significantly higher in patients with SBP ≥160 mm Hg (hazard ratio 2.27, 95% confidence interval 1.34-3.86) compared with those with SBP of 130-<140 mm Hg and in patients with DBP ≥100 mm Hg (hazard ratio 3.08, 95% confidence interval 1.78-5.34) compared with those with DBP of 80-<90 mm Hg. The association between SBP or DBP and ICH did not differ by ischemic stroke subtype (p = 0.55 and 0.93). Among patients with recent noncardioembolic ischemic stroke, the risk of ICH is high. High SBP and DBP are associated with an increased risk of ICH. The association between BP and ICH is not dependent on ischemic stroke subtype.

Discontinuation of Antiplatelet Study Medication and Risk of Recurrent Stroke and Cardiovascular Events: Results from the PRoFESS Study

Background: Several case control studies have reported an increased risk of cardiovascular events following discontinuation of antiplatelet agents in high-risk patients. We therefore sought to investigate the risk of recurrent stroke and cardiovascular events following discontinuation of antiplatelet study medication in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, a large randomized secondary stroke prevention study. Methods: The recurrent stroke and cardiovascular event rates following discontinuation of aspirin plus extended-release dipyridamole (ASA + ERDP) or clopidogrel were compared to the event rates in the on-treatment populations (patients who had discontinued their antiplatelet medication due to an outcome event were kept in the on-treatment population in order not to underestimate the on-treatment stroke rate). Results: In 7,212 treated ASA + ERDP patients, the stroke incidence rate for the on-treatment group was 729 strokes with an average exposure of 17,048 person-years (0.12 per 1,000 person-days). For 7,864 treated clopidogrel patients, the stroke incidence rate for the on-treatment group was 737 strokes with an average exposure of 18,715 person-years (0.11 per 1,000 person-days). ASA + ERDP was discontinued in 2,843 patients (in 57.7% due to an adverse event, 28.2% noncompliance, 1.4% loss to follow-up, 4.5% withdrawal of consent and 8.1% other/nonspecified reasons) and clopidogrel was permanently discontinued in 2,176 patients (49.0% due to an adverse event, 34.2% noncompliance, 1.8% loss to follow-up, 5.3% withdrawal of consent and 9.7% other/nonspecified reasons). Within 30 days, a recurrent stroke occurred in 31 patients (0.37 per 1,000 person-days) after discontinuation of ASA + ERDP and in 15 patients (0.24 per 1,000 person-days) after discontinuation of clopidogrel. This corresponds to an absolute excess risk of 0.77% within 30 days after discontinuation of ASA + ERDP and 0.40% within 30 days after discontinuation of clopidogrel compared with the on-treatment study populations. A combined vascular endpoint (stroke, myocardial infarction, vascular death) occurred in 68 patients (0.82 per 1,000 person-days) within 30 days after discontinuation of ASA + ERDP and in 47 patients (0.75 per 1,000 person-days) within 30 days after discontinuation of clopidogrel. This corresponds to an absolute excess risk of 2.02% within 30 days after discontinuation of ASA + ERDP and 1.83% within 30 days after discontinuation of clopidogrel compared with the on-treatment study populations. Conclusion: Discontinuation of antiplatelet medication after ischemic stroke should be advocated only when the risk and severity of bleeding clearly outweigh the risk of cardiovascular events.

Telmisartan on Top of Antihypertensive Treatment Does Not Prevent Progression of Cerebral White Matter Lesions in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) MRI Substudy

High blood pressure is one of the main risk factors for cerebral white matter lesions (WMLs). There is limited evidence from one randomized trial that blood pressure-lowering is able to slow WML progression. We investigated whether telmisartan prevents WML progression in the imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. This predefined substudy comprised 771 patients (mean age, 65 years) with recent ischemic stroke of noncardioembolic origin who received telmisartan or placebo during a mean follow-up of 27.9 (SD, 7.6) months and had 2 evaluable MRI examinations after index stroke and at study closeout. All MRI scans were centrally adjudicated for progression of periventricular and subcortical WML by 2 neuroradiologists blinded to treatment allocation. Mean blood pressure was 3.0/1.3 mm Hg lower with telmisartan compared with placebo at follow-up MRI. There was no statistically significant difference in progression of the mean periventricular WML score (least squares mean difference, 0.14; 95% CI, -0.12 to 0.39; P=0.29) and mean subcortical WML diameter (least squares mean difference, -0.35 mm; 95% CI, -1.00 to 0.31 mm; P=0.30) during follow-up between patients on telmisartan and placebo. Treatment with telmisartan on top of existing antihypertensive medication did not result in significant blood pressure-lowering and did not prevent the progression of WML in patients with a recent ischemic stroke in this patient cohort. Our analysis is limited by the relatively short follow-up period. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT00153062.

Risk of Recurrent Stroke in Patients With Silent Brain Infarction in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Imaging Substudy

Silent brain infarctions are associated with an increased risk of stroke in healthy individuals. Risk of recurrent stroke in patients with both symptomatic and silent brain infarction (SBI) has only been investigated in patients with cardioembolic stroke in the European Atrial Fibrillation Trial. We assessed whether patients with recent noncardioembolic stroke and SBI detected on MRI are at increased risk for recurrent stroke, other cardiovascular events, and mortality. The prevalence of SBI detected on MRI was assessed in 1014 patients enrolled in the imaging substudy of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. The primary outcome was first recurrence of stroke in patients with both symptomatic stroke and SBI in comparison with age- and sex-matched patients with stroke without SBI. Secondary outcomes were a combined vascular end point, other vascular events, and mortality. The 2 groups were compared using conditional logistic regression. Silent brain infarction was detected in 207 (20.4%) of the 1014 patients. Twenty-seven (13.0%) patients with SBI and 19 (9.2%) without SBI had a recurrent stroke (OR, 1.42; 95% CI, 0.79-2.56; P=0.24) during a mean follow-up of 2.5 years. Similarly, there was no statistically significant difference for all secondary outcome parameters between patients with SBI and matched patients without SBI. The presence of SBI in patients with recent mild noncardioembolic ischemic stroke could not be shown to be an independent risk factor for recurrent stroke, other vascular events, or a higher mortality rate. URL: http://clinicaltrials.gov. Unique identifier: NCT00153062.

Antithrombotic Therapy for Secondary Stroke Prevention

: Antithrombotic therapy is a key component of any strategy for the secondary prevention of ischemic stroke. A better understanding of the various therapeutic options will lead to improved stroke prevention, better medication adherence, and fewer complications. : Antiplatelet agents and anticoagulants are the two major classes of antithrombotic therapy used for stroke prevention. The etiology and mechanism of the stroke must be considered in order to make the best decision regarding which agent(s) to use for secondary stroke prevention. The recent Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study showed that clopidogrel and aspirin plus extended-release dipyridamole had similar event rates in terms of recurrent stroke, but clopidogrel was better tolerated, with fewer bleeding events. Several new anticoagulants are poised to replace warfarin for stroke prevention in the setting of atrial fibrillation. These include dabigatran (a new oral direct thrombin inhibitor) and possibly apixaban (a new oral factor Xa inhibitor). These new medications are much easier to use than warfarin and may be more effective and safer, with fewer drug and food interactions and no need for routine blood monitoring. Thus, these new medications may improve adherence as well as clinicians' inclination to treat with anticoagulation. : Because each antiplatelet agent or anticoagulant has certain advantages and disadvantages, clinicians must choose an agent that the patient can afford and tolerate in terms of side effects and adherence. The hope and expectation is that the proper use of these medications in accordance with current guidelines will reduce the risk of a recurrent stroke.

Dipyridamole

Dipyridamole

Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of Technology Appraisal No. 90): a systematic review and economic analysis

Occlusive vascular events such as myocardial infarction (MI), ischaemic stroke and transient ischaemic attack (TIA) are the result of a reduction in blood flow associated with an artery becoming narrow or blocked through atherosclerosis and atherothrombosis. Peripheral arterial disease is the result of narrowing of the arteries that supply blood to the muscles and other tissues, usually in the lower extremities. The primary objective in the treatment of all patients with a history of occlusive vascular events and peripheral arterial disease is to prevent the occurrence of new occlusive vascular events. To assess the clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole (MRD) alone or with aspirin (ASA) compared with ASA (and each other where appropriate) in the prevention of occlusive vascular events in patients with a history of MI, ischaemic stroke/TIA or established peripheral arterial disease. To consider the clinical effectiveness and cost-effectiveness of clopidogrel in patients with multivascular disease. This review is an update of the evidence base for the National Institute for Health and Clinical Excellence (NICE) guidance Technology Appraisal No. 90 (TA90) entitled Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (2005). Four electronic databases (EMBASE, MEDLINE, Web of Science and The Cochrane Library) were searched for randomised controlled trials (RCTs) and economic evaluations. Submissions to NICE by the manufacturers of the interventions were also considered. A systematic review of clinical effectiveness and cost-effectiveness was conducted. To manage heterogeneity between trials, indirect analysis (using a mixed-treatment methodology) was performed on selected clinical outcomes. A new economic model was developed to assess incremental costs per life-year gained [quality-adjusted life-years (QALYs)]. For evidence of clinical effectiveness, four RCTs were identified: CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events), ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial), PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) and ESPS-2 (Second European Stroke Prevention Study). In CAPRIE (patients with MI, ischaemic stroke or peripheral arterial disease), statistically significant outcomes in favour of clopidogrel were noted for the primary outcome (first occurrence of ischaemic stroke, MI or vascular death) compared with ASA [relative risk reduction 8.7%; 95% confidence interval (CI) 0.3% to 16.5%; p = 0.043]. In ESPRIT (patients with ischaemic stroke/TIA) for the primary outcome (first occurrence of death from all vascular causes, non-fatal stroke, non-fatal MI or major bleeding complication), the risk of event occurrence was statistically significantly lower in the MRD + ASA arm than in the ASA arm [hazard ratio (HR) 0.80; 95% CI 0.66 to 0.98], with no statistically significant difference in bleeding events between the two arms. In PRoFESS (patients with ischaemic stroke) the rate of recurrent stroke of any type (primary outcome) was similar in the MRD + ASA and clopidogrel groups, and the null hypothesis (that MRD + ASA was inferior to clopidogrel) could not be rejected. In ESPS-2 (patients with ischaemic stroke/TIA), on the primary outcome of stroke, statistically significant differences in favour of MRD + ASA were observed compared with ASA and MRD alone (relative risk 0.76; 95% CI 0.63 to 0.93). The outcomes addressed in the mixed-treatment comparisons (limited by the available data) for the ischaemic stroke/TIA population confirmed the results of the direct comparisons. The 11 economic evaluations included in the review of cost-effectiveness indicated that for patients with previous peripheral arterial disease, ischaemic stroke or MI, clopidogrel is cost-effective compared with ASA, and for patients with previous ischaemic stroke/TIA, treatment with MRD + ASA is cost-effective compared with any other treatment in patients in the secondary prevention of occlusive vascular events. The relevance of the review was limited as the economic evaluations were not based on the most current clinical data. Cost-effectiveness results generated from the Assessment Group's de novo economic model suggested that the most cost-effective approach for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA then ASA. For patients with MI, the most cost-effective approach is ASA followed by clopidogrel. For patients with established peripheral arterial disease, the most cost-effective approach is clopidogrel followed by ASA. For patients with multivascular disease, clopidogrel followed by ASA is the most cost-effective approach. Incremental cost-effectiveness ratios (ICERs) were also calculated for patients who are intolerant to ASA. Assuming that the branded price for clopidogrel is used and TA90 guidance is not applied, all of the ICERs range between £2189 and £13,558 per QALY gained. Probabilistic sensitivity analyses were fully consistent with these findings. The evidence suggests that the most cost-effective treatment for patients with ischaemic stroke/TIA is clopidogrel followed by MRD + ASA followed by ASA; for patients with MI, ASA followed by clopidogrel; and for patients with established peripheral arterial disease or multivascular disease, clopidogrel followed by ASA. The National Institute for Health Research Health Technology Assessment programme.

Inhibitors of the Platelet Thrombin Receptor

Not that long ago, aspirin, heparin, and warfarin were the only available antithrombotic agents for treating cardiovascular disease patients at risk of thrombotic events. These agents are still used in several places around the world, and it is remarkable how difficult it was to discover other agents that are more effective and/or safer. Since the mid-1980s we have been witnessing an explosion of research on new antithrombotic therapies, resulting in the availability of ticlopidine and clopidogrel (thienopyridine P2Y12-receptor inhibitors), low–molecular-weight heparins (eg, enoxaparin), and intravenous GPIIb/IIIa-receptor inhibitors (abciximab, eptifibatide, and tirofiban), later followed by fondaparinux (a synthetic indirect intravenous anti-Xa agent), bivalirudin (an intravenous direct anti-IIa agent), and more recently, prasugrel (a more potent thienopyridine) (Figure). Figure. The coagulation cascade, platelet activation pathways, and targets of antithrombotic agents. inhib indicates inhibition; LMWH, low–molecular-weight heparin; AT, antithrombin; vWF, von Willebrandt factor; TxA2, thromboxane A2; and ADP, adenosine diphosphate. Articles see pp 1843 and 1854 In the near future, several new oral antithrombotic agents may become available for treating patients with cardiovascular diseases: ticagrelor (the first direct reversible P2Y12 antagonist), dabigatran (an oral direct anti-IIa agent), rivaroxaban (an oral direct anti-Xa agent), and apixaban (also an oral direct anti-Xa agent). Other P2Y12 antagonists (eg, elinogrel) and oral anti-Xa agents (edoxaban, betrixaban, YM150, and TAK-442) are being studied or will be studied in phase-III programs (Figure). New antiplatelet therapies that target pathways not affected by aspirin or P2Y12-receptor antagonists could provide more comprehensive inhibition of platelet activation, and contribute to a greater inhibition of platelet-mediated thrombosis. Inhibition of protease-activated receptor-1 (PAR-1), a receptor for thrombin, is a new attractive approach in the development of better and safer antiplatelet therapy. As shown in the Figure, thrombin is the key effector of the coagulation cascade, but is also …

Inclusion of Stroke as an Outcome and Risk Equivalent in Risk Scores for Primary and Secondary Prevention of Vascular Disease

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

Current Guidelines on Antiplatelet Agents for Secondary Prevention of Noncardiogenic Stroke: An Evidence-Based Review

Antiplatelet therapy is a mainstay of secondary prevention of ischemic strokes. Recent studies, such as Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS), the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, and the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), have added much to our understanding about how best to utilize the various antiplatelet agents available. Aspirin has been shown to reduce the risk of recurrent strokes, and the combination of aspirin and dipyridamole has repeatedly been shown to outperform aspirin alone. Recently, clopidogrel was demonstrated to be “noninferior” to an aspirin/dipyridamole combination, and can be considered as a first-line agent. The American Stroke Association and American Heart Association have clear recommendations on how to utilize these agents.

Antihypertensive treatment and stroke prevention: From recent meta-analyses to the PRoFESS trial

Blood pressure control is the cornerstone of therapeutic interventions aimed at preventing first strokes and recurrent strokes. All antihypertensive drug classes may be useful in preventing cerebrovascular events, depending on their efficacy in lowering elevated blood pressure values and achieving blood pressure control. However, recent findings indicate that drugs acting on the renin-angiotensin system (-angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) may exert cerebrovascular protective effects in addition to blood pressure reduction. This article examines the cerebrovascular protection provided by antihypertensive drug treatment in the light of the results of recent meta-analyses and of the findings of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

Preventing stroke: the PRoFESS, ONTARGET, and TRANSCEND trial programs

Renin-angiotensin system blockers have been shown to reduce stroke risk, partly independent of their blood pressure-lowering effect. The PReventiOn regimen For Effectively avoiding Second Strokes (PRoFESS) trial, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant subjects with cardiovascular Disease (TRANSCEND) recently showed potential benefits of the angiotensin II receptor blocker, telmisartan, in reducing secondary strokes. In PRoFESS, 20 332 ischemic stroke patients were randomized to telmisartan 80 mg versus placebo and to two antiplatelets in a 2 x 2 factorial design. After a mean exposure of 2 years, telmisartan showed a nonsignificant lower rate of recurrent stroke versus placebo [880 versus 934; hazard ratio 0.95; 95% confidence interval (CI) 0.86-1.04]. In a post-hoc analysis, from 6 months, telmisartan significantly reduced the number of strokes versus placebo (533 versus 608; hazard ratio 0.88; 95% CI 0.78-0.99; P = 0.042). In the stroke subgroup of ONTARGET, telmisartan 80 mg showed a trend toward reducing recurrent stroke versus ramipril 10 mg (hazard ratio 0.91; 95% CI 0.79-1.05). In the TRANSCEND study, 5926 patients who were intolerant to angiotensin-converting enzyme inhibitors were treated with 80 mg telmisartan or placebo. In a combined analysis of PRoFESS and TRANSCEND, the incidence of the composite of stroke, myocardial infarction, or vascular death was 12.8% for telmisartan versus 13.8% for placebo (hazard ratio 0.91; 95% CI 0.85-0.98; P = 0.013).

Understanding the PRoFESS study for secondary stroke prevention

The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is the largest secondary stroke prevention study completed to date. It compared extended-release dipyridamole plus aspirin (eDYP-ASA) versus clopidogrel and telmisartan versus antihypertensive regimens excluding angiotensin receptor blockers (ARBs). No statistical differences were found in either arm for the primary outcome of fatal or nonfatal stroke or prespecified secondary end points. eDYP-ASA also was associated with increases in major hemorrhagic events but not with statistical increases in combined rates of stroke recurrence or hemorrhage. Despite PRoFESS, the role of ARBs post stroke remains unclear, as concomitant angiotensin-converting enzyme inhibitor use in PRoFESS obscured whether just blood pressure lowering or renin-angiotensin system blockade is important. The resulting interpretation that eDYP-ASA is "not noninferior" has raised questions about how to interpret noninferiority analyses. Also, although the PRoFESS editorialists suggested that aspirin, the historical bystander control, was the "winner," a review of prior antiplatelet studies suggests that the benefits of aspirin, either as combination or monotherapy, are outweighed by its bleeding hazards. The benefits of clopidogrel or eDYP-ASA, compared with aspirin, are small but real, and both remain preferred agents in secondary stroke prevention.

Treatment of atherosclerotic intracranial arterial stenosis.

David Pelz MD L. Nelson Hopkins MD Elad Levy MD Section Editors: Atherosclerotic stenosis of the major intracranial arteries (intracranial internal carotid artery, middle cerebral artery, vertebral artery, basilar artery) is probably the most common cause of stroke worldwide.1 Intracranial atherosclerosis causes 30% to 50% of strokes in Asia2 and 8% to 10% of strokes in North America.3 This review focuses on the medical and endovascular treatment of atherosclerotic intracranial arterial stenosis. Initially, a retrospective study suggested that warfarin was superior to aspirin for stroke prevention in patients with symptomatic intracranial arterial stenosis.4 This retrospective data combined with a proposed pathophysiological rationale for anticoagulation5 made warfarin a common treatment choice for symptomatic intracranial stenosis.6 However, the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that aspirin was safer and as effective as warfarin for stroke prevention in patients with symptomatic intracranial stenosis. WASID was stopped early after a mean follow-up of 1.8 years because of higher rates of death and major hemorrhage in the warfarin arm. The primary end point of ischemic stroke, brain hemorrhage or vascular death, occurred in 22.1% of patients assigned aspirin and 21.8% of those in the warfarin group.7 The rates of myocardial infarction or sudden death were also higher in the warfarin arm. Certain high-risk subgroups of patients with intracranial stenosis were previously thought to benefit from anticoagulation, such as those with severe stenosis,4 vertebrobasilar disease,4 and those who have failed antithrombotic therapy.8 In WASID, however, patients with severe stenosis9 or those previously on antithrombotic therapy9,10 did not benefit from warfarin. Patients with basilar artery stenosis in WASID did appear to have a lower rate of the primary end point on warfarin, but there was no difference in the rate of stroke in the …

Management of Blood Pressure for Acute and Recurrent Stroke

Marc Fisher MD Kennedy Lees MD Section Editors: Hypertension is the most important modifiable risk factor for stroke.1,2 It is estimated that 25% or more of strokes may be attributable to hypertension. Because many patients with stroke have mild hypertension or prehypertension, we have shifted our focus and now think of stroke on a continuum of risk based on blood pressure (BP) level rather than on a threshold effect.3 Because high BP may not exist in isolation, a wider definition of hypertension has been proposed that also takes into account the absolute risk of cardiovascular events and associated metabolic factors or early disease markers.3 Lowering BP reduces the risk of stroke. Epidemiological studies have shown that for each 10 mm Hg lower systolic blood pressure (SBP), there is a decrease in risk of stroke of approximately one third in persons aged 60 to 79 years. This association is continuous down to levels of at least 115/75 mm Hg and is consistent across sexes, regions, stroke subtypes, and for fatal and nonfatal events.4 Lowering diastolic blood pressure (DBP) was once the main target to achieve stroke and other cardiovascular event reduction, but SBP has now become the target.3 As recently shown, even the elderly with sustained SBP elevation may gain from BP reduction in relation to less fatal or nonfatal stroke, death, and heart failure.5 Although the role of longer-term BP control to improve outcomes in patients with stroke is undisputed, BP management immediately after a stroke remains controversial. In an effort to resolve this controversy, several pilot clinical trials have been initiated. In this review, we discuss the results of some of these trials and available evidence-based guidelines for BP control in the settings of acute ischemic and hemorrhagic stroke (excluding subarachnoid hemorrhage) and …

Blockage of the Renin-Angiotensin System in the Secondary Prevention of Stroke: Beneficial Effects Beyond Blood Pressure Reduction?

HomeStrokeVol. 40, No. 3Blockage of the Renin-Angiotensin System in the Secondary Prevention of Stroke: Beneficial Effects Beyond Blood Pressure Reduction? Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBBlockage of the Renin-Angiotensin System in the Secondary Prevention of Stroke: Beneficial Effects Beyond Blood Pressure Reduction? Luis Castilla-Guerra María del Carmen Fernández-Moreno Maria Dolores Jiménez-Hernandez Luis Castilla-GuerraLuis Castilla-Guerra Department of Internal Medicine, Hospital de Osuna, Seville, Spain Search for more papers by this author María del Carmen Fernández-MorenoMaría del Carmen Fernández-Moreno Department of Neurology, Hospital de Valme, Seville, Spain Search for more papers by this author Maria Dolores Jiménez-HernandezMaria Dolores Jiménez-Hernandez Department of Neurology, Hospital Virgen del Rocio, Seville, Spain Search for more papers by this author Originally published29 Jan 2009https://doi.org/10.1161/STROKEAHA.108.537639Stroke. 2009;40:e75Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 29, 2009: Previous Version 1 To the Editor:In the last few years, evidence from experimental and clinical studies have supported the hypothesis that angiotensin II might exert detrimental effects beyond the mechanical damage of high blood pressure (BP) and be a risk factor for ischemic stroke independent of its effect on BP. Thus, data from the HOPE and LIFE studies suggested that ACE inhibitors and angiotensin receptors blockers (ARB) may have protective effects for stroke that are independent of BP reduction.1 However, in view of recent published trials, data on the particular benefits of these specific antihypertensive agents for secondary stroke prevention are largely lacking. First, the Perindopril Protection against Recurrent Stroke Study (PROGRESS) trial provided no evidence of perindopril alone for preventing recurrent stroke. In fact, only the subgroup receiving both perindopril in combination with indapamide had reduced stroke recurrence.2 Furthermore, there is no evidence to date that using perindopril in combination with indapamide is more beneficial than using indapamide alone. Thus, the BP reduction with indapamide alone in the Poststroke Antihypertensive Treatment Study (PATS) trial was only 5/2 mm Hg, similar to the reduction seen with perindopril alone in the PROGRESS, and, on the contrary, significantly associated with stroke reduction.2,3 In addition, a systematic review on BP reduction in secondary prevention of stroke showed that calcium channel blockers were found to be better than ACE inhibitors in stroke prevention.4Recently, the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, a multicenter trial involving more than 20 000 patients, has shown that termisaltan initiated soon after ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke or major cardiovascular events against placebo.5 This trial has important lessons for clinical practice and also illustrates that the extrapolation of the benefits of these drugs to the prevention of vascular recurrences after stroke may be inappropriate.Therefore, currently the question of whether agents that block the rennin–angiotensin system offer additional benefits independent of their effects on BP in patients with stroke seems to be a matter of faith.DisclosuresNone.1 Hankey GJ. Angiotensin-converting enzyme inhibitors for stroke prevention. Is there hope for progress after life? Stroke. 2003; 34: 354–356.LinkGoogle Scholar2 Wennberg R, Zimmermann C. The progress trial three years later: time for a balanced report of effectiveness. BMJ. 2004; 329: 968–970.CrossrefMedlineGoogle Scholar3 PATS Collaborating Group. Post-stroke antihypertensive treatment study. A preliminary result. Chin Med J. 1995; 108: 710–717.MedlineGoogle Scholar4 Zhang H, Thijs L, Staessen JA. Blood pressure lowering for primary and secondary prevention of stroke. Hypertension. 2006; 48: 187–195.LinkGoogle Scholar5 Yusuf S, Diener HC, Sacco RL, Cotton D, Ôunpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BPL, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Markku Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voigt T, Weber M, Yoon BW, for the PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008; 359.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Pandit A (2015) Evidence base for secondary prevention – Antihypertensive therapy in cerebrovascular disease, Apollo Medicine, 10.1016/j.apme.2015.03.001, 12:2, (100-102), Online publication date: 1-Jun-2015. Castilla-Guerra L, Fernández-Moreno M, Romera-Tellado M and Álvarez-Suero J (2012) Prevención primaria del ictus en el anciano: evidencias actuales en el tratamiento de la hipertensión arterial, Revista Española de Geriatría y Gerontología, 10.1016/j.regg.2011.06.014, 47:3, (119-124), Online publication date: 1-May-2012. March 2009Vol 40, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/STROKEAHA.108.537639PMID: 19182077 Originally publishedJanuary 29, 2009 PDF download Advertisement

Drugs Prove Equal Against Recurring Strokes

Drugs Prove Equal Against Recurring Strokes