Selecting an optimal antiplatelet agent for secondary stroke prevention

Four seminal randomized controlled trials (RCTs) have investigated aspirin, aspirin plus extended release dipyridamole, and clopidogrel for the prevention of recurrent vascular events. Despite studying over 32,000 stroke patients in these trials, the decision which antiplatelet agent to select for secondary stroke prevention remains controversial. Attempts to translate the results of these RCTs into clinical practice are complicated by each trial’s selection of participants and choice of primary outcome. Herein, we argue that by examining RCT results with participant selection limited to patients with ischemic stroke or TIA and by focusing on recurrent stroke as our outcome, we can use the standard epidemiology two-by-two table to assist in selecting an antiplatelet agent for secondary stroke prevention.

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Aspirin in Neurology

ISRN Vascular Medicine ◽

10.5402/2011/912820 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9

Author(s):

Yolanda Aburto-Murrieta ◽

Dulce Bonifacio-Delgadillo ◽

Juan Marquez

Keyword(s):

Extended Release ◽

Individual Patient Data ◽

Recurrent Stroke ◽

Meta Analysis ◽

The Novel ◽

Vascular Events ◽

Randomized Controlled ◽

Sch 530348 ◽

Protease Activated Receptor 1 ◽

Ischaemic Attack

Aspirin is widely used for the prevention of recurrent stroke in patients with transient ischaemic attack (TIA) of arterial origin, because it is effective and inexpensive. Clopidogrel and the combination of aspirin and extended-release dipyridamole are more effective than aspirin, but are also much more expensive. No other antithrombotic regimens provide significant advantages over aspirin, although cilostazol and the novel platelet protease-activated receptor-1 antagonist, SCH 530348, are currently being evaluated. Numerous trials have examined the efficacy of antiplatelet drugs, primarily aspirin for prevention of vascular events in patients with a prior TIA or stroke. Although many were small and inconclusive, the Antiplatelet Trialists’ Collaboration (ATC) individual patient data meta-analysis reported that among more than 23000 patients (from 21 randomized controlled trials), antiplatelet therapy (usually aspirin) compared with placebo or untreated control continued for a mean of 29 months was associated with a 22% reduction in the odds of recurrent ischemic stroke, myocardial infarction (MI), or vascular death (17.8% versus 21.4%, P=0.001).

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Abstract P252: Discharge Antithrombotic Therapy for Ischemic Stroke Patients With Prior Aspirin Failure

Stroke ◽

10.1161/str.52.suppl_1.p252 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Ying Xian ◽

Haolin Xu ◽

Deepak L Bhatt ◽

Gregg C Fonarow ◽

Eric E Smith ◽

...

Keyword(s):

Ischemic Stroke ◽

Stroke Prevention ◽

Antithrombotic Therapy ◽

Recurrent Stroke ◽

Oral Anticoagulants ◽

The United States ◽

Future Research ◽

Large Artery ◽

Secondary Stroke Prevention ◽

Stroke Registry

Introduction: Aspirin is one of the most commonly used medications for cardiovascular disease and stroke prevention. Many older patients who present with a first or recurrent stroke are already on aspirin monotherapy, yet little evidence is available to guide antithrombotic strategies for these patients. Method: Using data from the American Heart Association Get With The Guidelines-Stroke Registry, we described discharge antithrombotic treatment pattern among Medicare beneficiaries without atrial fibrillation who were discharged alive for acute ischemic stroke from 1734 hospitals in the United States between October 2012 and December 2017. Results: Of 261,634 ischemic stroke survivors, 100,016 (38.2%) were on prior aspirin monotherapy (median age 78 years; 53% women; 79.4% initial stroke and 20.6% recurrent stroke). The most common discharge antithrombotics (Figure) were 81 mg aspirin monotherapy (20.9%), 325 mg aspirin monotherapy (18.2%), clopidogrel monotherapy (17.8%), and dual antiplatelet therapy (DAPT) of 81 mg aspirin and clopidogrel (17.1%). Combined, aspirin monotherapy, clopidogrel monotherapy, and DAPT accounted for 86.8% of discharge antithrombotics. The rest of 13.2% were discharged on either aspirin/dipyridamole, warfarin or non-vitamin K antagonist oral anticoagulants with or without antiplatelet, or no antithrombotics at all. Among patients with documented stroke etiology (TOAST criteria), 81 mg aspirin monotherapy (21.2-24.0%) was the most commonly prescribed antithrombotic for secondary stroke prevention. The only exception was those with large-artery atherosclerosis, in which, 25.3% received DAPT of 81 mg aspirin and clopidogrel at discharge. Conclusion: Substantial variations exist in discharge antithrombotic therapy for secondary stroke prevention in ischemic stroke with prior aspirin failure. Future research is needed to identify best management strategies to care for this complex but common clinical scenario.

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Physical activity in secondary stroke prevention

Swiss Sports & Exercise Medicine ◽

10.34045/ssem/2019/33 ◽

2019 ◽

Vol 67 (4) ◽

Keyword(s):

Quality Of Life ◽

Physical Activity ◽

Activities Of Daily Living ◽

Brain Function ◽

Stroke Prevention ◽

Daily Living ◽

Recurrent Stroke ◽

Treatment Strategies ◽

Secondary Stroke Prevention

After having a stroke the main challenges are reducing the risk of recurrent stroke, improving impaired brain function, quality of life, independence in activities of daily living and reintegration into the community. [1] Lesion-induced impairment of brain function also has, besides its effects on e.g. motor, sensory, visual and speech function, an influence on e.g. cognition and mood, all of which are determinants of post-stroke physical activity. The evidence for a benefit of physical activity in secondary stroke prevention is increasing and treatment strategies aimed at factors which are limiting physical activity are more and more recognized.

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Abstract 81: Translesional Pressure Gradient Alters the Relationship Between Blood Pressure and Stroke Recurrence in Symptomatic Intracranial Atherosclerotic Disease

Stroke ◽

10.1161/str.51.suppl_1.81 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Xueyan Feng ◽

Ka Lung Chan ◽

Jill Abrigo ◽

Linda Lan ◽

Yannie Soo ◽

...

Keyword(s):

Blood Pressure ◽

Pressure Gradient ◽

Stroke Prevention ◽

Primary Outcome ◽

Stroke Recurrence ◽

Secondary Stroke Prevention ◽

Cfd Models ◽

Intracranial Atherosclerotic Disease ◽

The Relationship

Objective: Patients with symptomatic intracranial atherosclerotic stenosis (sICAS) have a high risk of stroke recurrence. There is debate over an optimal blood pressure (BP) lowering target in secondary stroke prevention in such patients, when some factors (e.g., impaired cerebral perfusion) may alter the relationship between BP and risk of stroke recurrence. In this study, we investigated whether translesional pressure gradient across sICAS lesions would also alter such relationship. Methods: We recruited patients with sICAS (50-99% stenosis) confirmed in CT angiography (CTA). Computational fluid dynamics (CFD) models were built based on CTA to simulate blood flow across sICAS and calculate the translesional pressure ratio (PR, the ratio of pressures distal and proximal to a lesion). PR ≤ median was defined as low PR, indicating larger translesional pressure gradient and hence restricted downstream perfusion. The primary outcome was recurrent ischemic stroke in the same territory in 1 year. We investigated the interaction of PR and mean systolic BP (SBP) during follow-up in determining the risk of the primary outcome. Results: Among 157 patients, the median PR was 0.93. Multivariate Cox regression revealed significant PR-SBP interaction on the primary outcome (p=0.025): in patients with normal PR, the risk of primary outcome significantly decreased with lower SBP during follow-up (for 10 mmHg decrement: HR 0.46; p=0.018); however, in those with low PR, mean SBP ≤130 mmHg was associated with significantly increased risk of primary outcome, compared with 130<SBP<150mmHg (HR 5.08; p=0.043) (Figure). Conclusion: Intensive BP lowering may increase the risk of stroke recurrence in sICAS patients with a large translesional pressure gradient, warranting further investigation. PR by CFD models may yield a promising indicator to differentiate sICAS patients for different BP management strategies for better secondary stroke prevention.

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Abstract 77: Intensity of Blood Pressure Reduction and Secondary Stroke Prevention: A Systematic Review and Meta-regression Analysis of Randomized Clinical Trials

Stroke ◽

10.1161/str.48.suppl_1.77 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Georgios Tsivgoulis ◽

Aristeidis H Katsanos ◽

Angeliki Filippatou ◽

Efstathios Manios ◽

Spyridon Deftereos ◽

...

Keyword(s):

Systematic Review ◽

Stroke Prevention ◽

Lower Risk ◽

Antihypertensive Treatment ◽

Recurrent Stroke ◽

Cardiovascular Death ◽

Secondary Stroke Prevention ◽

Regression Analyses ◽

Meta Regression ◽

Meta Regression Analysis

Background & Purpose: Current recommendations do not specifically address the optimal blood pressure (BP) cut-off for secondary stroke prevention in patients with previous cerebrovascular events. We conducted a systematic review and meta-regression analysis on the association of BP reduction with recurrent stroke and cardiovascular events using data from randomized-controlled clinical trials (RCTs) of secondary stroke prevention. Methods: For all reported events during each eligible study period we calculated the corresponding risk ratios (RRs) to express the comparison of event occurrence risk between patients randomized to antihypertensive treatment and those randomized to placebo. Based on the reported BP values, we performed univariate meta-regression analyses according to achieved BP values under the random-effects model (Method of Moments) for those outcome events reported in ≥10 total subgroups of included RCTs. Results: In pairwise meta-analyses of 14 RCTs comprising 42,736 patients antihypertensive treatment lowered the risk for recurrent stroke (RR=0.73, 95%CI: 0.62-0.87, p<0.001), disabling or fatal stroke (RR=0.71, 95%CI: 0.59-0.85, p<0.001) and cardiovascular death (RR=0.85, 95%CI: 0.75-0.96, p=0.010). In meta-regression analyses systolic BP reduction was linearly related to lower risk of recurrent stroke (p=0.049; Figure A), myocardial infarction (p=0.024), death from any cause (p=0.001) and cardiovascular death (p<0.001). Similarly, diastolic BP reduction was linearly related to a lower risk of recurrent stroke (p=0.026; Figure B) and all-cause mortality (p=0.009). Funnel plot inspection and Egger’s statistical test revealed no evidence of publication bias. Conclusion: The extent of BP reduction is linearly associated with the magnitude of risk reduction in recurrent cerebro- and cardio-vascular events. Strict and aggressive BP control appears to be essential for effective secondary stroke prevention.

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Family Perceptions of Barriers and Facilitators of Treatment Protocols for Secondary Stroke Prevention in Children with Sickle Cell Disease

Blood ◽

10.1182/blood.v116.21.4805.4805 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4805-4805

Author(s):

Eve S Puffer ◽

Melanie J Bonner ◽

Courtney D Thornburg

Keyword(s):

Iron Overload ◽

Sickle Cell ◽

Stroke Prevention ◽

Recurrent Stroke ◽

Iron Chelation ◽

Secondary Stroke Prevention ◽

Treatment Protocols ◽

History Of ◽

Family Perceptions

Abstract Abstract 4805 Children with sickle cell anemia (SCA) and a primary overt stroke are at high risk of recurrent (secondary) stroke. Chronic blood transfusion (CBT) dramatically reduces but does not eliminate this high risk, and results in transfusion-related hemosiderosis. We previously reported the use of hydroxyurea/phlebotomy as an alternative to CBT to reduce the risk of secondary stroke and improve management of iron overload (Ware et al. J Pediatr 2004). This study examines the caregiver and child experience with secondary stroke prevention. Individual semi-structured interviews were conducted with primary caregivers and children/adolescents (age > 5 years) recruited from the Duke Pediatric Sickle Cell Program. The interviewer (E.P.) asked about perceptions of risk of recurrent stroke and iron overload with and without therapy and facilitators and barriers of therapy. Interviews were coded and analyzed independently by two investigators (E.P and C.T.). The sample included 14 youth (10 males) with a median age of 12.5 years (range 3–17). All primary caregivers were female. Twelve children had a history of overt stroke and 2 had a history of silent stroke. All children had experience with CBT and 9 were receiving CBT at the time of the interview. Eleven children had experience taking hydroxyurea and 5 were taking hydroxyurea at the time of the interview. All caregivers agreed that their child was at risk of recurrent stroke, identified benefit of current treatment and reported high motivation to adhere to treatment protocols. They noted significant impact that stroke had on school functioning, attention, personality, participation in sports and overall quality of life. Caregiver-reported barriers to CBT and hydroxyurea fell into three main categories: (1) missed work and school and related consequences; (2) unexpected resource-related challenges; and (3) inconvenience of clinic appointments, all of which contributed to burden on the family and sometimes missed clinic appointments and treatments. There were higher levels of concern expressed by caregivers of children on CBT related to the higher frequency and longer length of medical appointments compared with those taking hydroxyurea. The primary child-reported barrier was dislike of needles or shots (although this decreased with age as expected); those taking hydroxyurea also noted that they sometimes forgot to take the medication if they were busy with other activities or fell asleep. Caregiver-reported facilitators of CBT and hydroxyurea included: (1) understanding importance of stroke prevention and connection to consistent treatment; (2) ancillary benefits of treatments in addition to stroke prevention; (3) link between treatment and long-term benefits. Caregivers were able to overcome treatment barriers via the following: (1) logistical supports including appointment and medication reminders; (2) shared responsibility with other family members including the child; (3) trust in medical staff; and (4) faith. Although children disliked needles and shots, many enjoyed the clinic visits due to fun activities in the clinic setting and rewards. In addition, iron overload was a significant concern for caregivers. For those with children on CBT, knowledge of the risks of iron overload motivated adherence with oral iron chelation. Automatic refills facilitated adherence with chelation therapy, but the taste of the medication was a major barrier to adequate iron chelation. Caregivers of children taking hydroxyurea noted the benefit of avoiding iron overload. Of those who had undergone phlebotomy, in-home phlebotomy was noted as a facilitator, though requirement for IV contributed to negative perception. In summary, as clinicians review options for secondary stroke prevention with families, they should discuss family perceptions and individual barriers and facilitators which may impact adherence with therapy and long-term outcome. Future research should also investigate whether these family perceptions predict actual adherence to protocols and treatment outcomes. Disclosures: Off Label Use: Hydroxyurea for secondary stroke prevention in sickle cell disease.

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Peer education for secondary stroke prevention in inner-city minorities: Design and methods of the prevent recurrence of all inner-city strokes through education randomized controlled trial

Contemporary Clinical Trials ◽

10.1016/j.cct.2012.06.003 ◽

2012 ◽

Vol 33 (5) ◽

pp. 1065-1073 ◽

Cited By ~ 25

Author(s):

Judith Z. Goldfinger ◽

Ian M. Kronish ◽

Kezhen Fei ◽

Albert Graciani ◽

Peri Rosenfeld ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Inner City ◽

Stroke Prevention ◽

Controlled Trial ◽

Peer Education ◽

Secondary Stroke Prevention ◽

Randomized Controlled ◽

Design And Methods

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Residual Risk and Its Risk Factors for Ischemic Stroke with Adherence to Guideline-Based Secondary Stroke Prevention

Journal of Stroke ◽

10.5853/jos.2020.03391 ◽

2021 ◽

Vol 23 (1) ◽

pp. 51-60

Author(s):

Yuesong Pan ◽

Zixiao Li ◽

Jiejie Li ◽

Aoming Jin ◽

Jinxi Lin ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Secondary Prevention ◽

Acute Ischemic Stroke ◽

Stroke Prevention ◽

Recurrent Stroke ◽

Antihypertensive Agents ◽

Residual Risk ◽

Stroke Recurrence ◽

Secondary Stroke Prevention

Background and Purpose Despite administration of evidence-based therapies, residual risk of stroke recurrence persists. This study aimed to evaluate the residual risk of recurrent stroke in acute ischemic stroke or transient ischemic attack (TIA) with adherence to guideline-based secondary stroke prevention and identify the risk factors of the residual risk.Methods Patients with acute ischemic stroke or TIA within 7 hours were enrolled from 169 hospitals in Third China National Stroke Registry (CNSR-III) in China. Adherence to guideline-based secondary stroke prevention was defined as persistently receiving all of the five secondary prevention medications (antithrombotic, antidiabetic and antihypertensive agents, statin and anticoagulants) during hospitalization, at discharge, at 3, 6, and 12 months if eligible. The primary outcome was a new stroke at 12 months.Results Among 9,022 included patients (median age 63.0 years and 31.7% female), 3,146 (34.9%) were identified as adherence to guideline-based secondary prevention. Of all, 864 (9.6%) patients had recurrent stroke at 12 months, and the residual risk in patients with adherence to guidelinebased secondary prevention was 8.3%. Compared with those without adherence, patients with adherence to guideline-based secondary prevention had lower rate of recurrent stroke (hazard ratio, 0.85; 95% confidence interval, 0.74 to 0.99; P=0.04) at 12 months. Female, history of stroke, interleukin-6 ≥5.63 ng/L, and relevant intracranial artery stenosis were independent risk factors of the residual risk.Conclusions There was still a substantial residual risk of 12-month recurrent stroke even in patients with persistent adherence to guideline-based secondary stroke prevention. Future research should focus on efforts to reduce the residual risk.

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Novel Predictors of Future Vascular Events in Post-stroke Patients—A Pilot Study

Frontiers in Neurology ◽

10.3389/fneur.2021.666994 ◽

2021 ◽

Vol 12 ◽

Author(s):

Diana Schrick ◽

Erzsebet Ezer ◽

Margit Tokes-Fuzesi ◽

Laszlo Szapary ◽

Tihamer Molnar

Keyword(s):

Ex Vivo ◽

Platelet Reactivity ◽

Recurrent Stroke ◽

Stroke Patients ◽

Vascular Events ◽

Post Stroke ◽

Coronary Syndrome ◽

Impedance Aggregometry ◽

Selection Of

Introduction: A modified platelet function test (mPFT) was recently found to be superior compared to impedance aggregometry for selection of post-stroke patients with high on-treatment platelet reactivity (HTPR). We aimed to explore some peripheral blood cell characteristics as predictors of recurrent ischemic episodes. The predictive value of mPFT was also assessed in a cohort followed up to 36 months regarding recurrent ischemic vascular events.Methods: As a novelty, not only whole blood (WB), but after 1-h gravity sedimentation the separated upper (UB) and lower half blood (LB) samples were analyzed including neutrophil antisedimentation rate (NAR) in 52 post-stroke patients taking clopidogrel. Area under the curve (AUC, AUCupper and AUClower, respectively) was separately measured by Multiplate in the WB, UB and LB samples to characterize ex vivo platelet aggregation in the presence of ADP. Next, the occurrence of vascular events (stroke, acute coronary syndrome, ACS) were evaluated during 36-month follow-up.Results: A total of 11 vascular events (stroke n = 5, ACS n = 6) occurred during the follow-up period. The AUCupper was significantly higher in patients with recurrent stroke compared to those with uneventful follow-up (p = 0.03). The AUCupper with a cut-off value ≥70 based on the mPFT, was able to predict all stroke events (p = 0.01), while the total vascular events were independently predicted by NAR with a sensitivity of 82% and specificity of 88%.Conclusions: A combination of NAR reflecting the inflammatory state and AUCupper indicating HTPR may provide a better prediction of recurrent ischemic events suggesting a better selection of patients at risk, thus providing an individually tailored vascular therapy.

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