Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a novel approach for reducing cholesterol and, accordingly, the burden of atherosclerosis. However, limited data are available regarding the possible effects of PCSK9 inhibitors on atherosclerotic plaque. To evaluate the efficacy of PCSK9 inhibitors in reducing carotid plaque progression in individuals with high-risk carotid atherosclerotic disease. We used carotid total plaque area (TPA) to assess the burden of atherosclerosis. Ultrasound imaging of the carotid was acquired before and after the initiation of PCSK9 inhibitor therapy. We selected high-risk cases with atherosclerosis with a minimum of three ultrasound examinations, 1 year before, one at the time of initiation of a PCSK9 inhibitor, and 1 year after initiating a PCSK9 inhibitor. Statistical analysis was conducted using the mixed-effects model with Restricted Maximum Likelihood (REML). We reviewed data from 131 patients with a mean follow-up of 6 (±4) years. Patients were high-risk, with the majority having diabetes or hypertension. There was a decrease in TPA, particularly during the first 3 years after initiating PCSK9 inhibitor therapy ( p  < 0.05). Furthermore, we observed that individuals with higher baseline serum low-density lipoprotein cholesterol (LDL-C) levels experienced a greater decline in TPA ( p  < 0.05). PCSK9 inhibitors are effective in achieving plaque regression in high-risk patients with atherosclerosis. This is important, as plaque regression is associated with a lower risk of stroke, myocardial infarction, or vascular death.

Background: Little is known about the benefits of lipid-lowering medications in those age >= 75 years. We assessed the effect of lipid-lowering medications on progression to severe atherosclerosis in patients age > 75. Methods: Data was retrospectively obtained from the Stroke Prevention & Atherosclerosis Research Centre, Canada. Atherosclerosis burden was measured as carotid total plaque area (TPA), a powerful predictor of cardiovascular risk. Survival time free of severe atherosclerosis (SFSA) was defined as the period when TPA remained <1.19 cm(2). Kaplan-Meier, multiple Cox proportional hazard and hierarchical mixed-effect models were used to determine the effects of lipid-lowering medications on progression to severe atherosclerosis. Results: In total 1404 cases (mean age 81 +/- 4 years; women 52%) were included. Those taking lipid-lowering medications were more likely to have a history of diabetes and a higher burden of atherosclerosis at baseline. In Kaplan-Meier analysis, the SFSA was significantly longer in those receiving lipid-lowering therapy. In multivariable-adjusted analyses, those not receiving lipid lowering therapy (irrespective of their vascular disease at baseline) were more likely to have TPA > 1.19 cm(2) (hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.09,0.71). Similar findings were observed in mixed effects models when plaque progression was defined as any change >0.05 cm(2) per year (odds ratio (OR):2.17, 95% CI:1.38,3.57). Conclusion: Lipid-lowering therapy is effective in controlling the burden of atherosclerosis among older adults with and without vascular disease. The measurement of plaque burden can guide selection and follow-up of those who may benefit from treatment.

Amputation is a dreaded complication of peripheral artery disease (PAD) and diabetes mellitus. In this issue of the Canadian Journal of Cardiology, O’Connor et al. studied secular trends in the incidence of primary lower-extremity amputations (LEAs) associated with PAD or diabetes in the province of Québec, Canada, between the years 2006 and 2019. 1 O’Connor S. Blais C. Leclerc J. et al. Evolution in trends of primary lower-extremity amputations associated with diabetes or peripheral artery disease from 2006 to 2019. Can J Cardiol. 2023; 39: 321-330 Abstract Full Text Full Text PDF Scopus (1) Google Scholar The investigators used large administrative databases linked together in the Quebec Integrated Chronic Disease Surveillance System to capture episodes of LEA, subclassifying these as major and minor, based on the highest level of amputation. 2 Blais C. Jean S. Sirois C. et al. Quebec Integrated Chronic Disease Surveillance System (QICDSS), an innovative approach. Chron Dis Inj Can. 2014; 34: 226-235 Crossref PubMed Google Scholar Amputations related to trauma, cancer, infection, congenital malformation, or venous or lymphatic impairment were excluded. Altogether, just over 10,000 patients with diabetes or PAD underwent primary LEA between 2006 and 2019 (n = 10,287). Evolution in Trends of Primary Lower-Extremity Amputations Associated With Diabetes or Peripheral Artery Disease From 2006 to 2019Canadian Journal of CardiologyVol. 39Issue 3PreviewGiven the importance in prevention of lower extremity amputations (LEAs) associated with diabetes or peripheral artery disease (PAD), we sought to document the trends of primary LEA in Québec, Canada, from years 2006 to 2019. Full-Text PDF

BACKGROUND AND AIMS:Socioeconomic status (SES) is associated with cardiovascular disease. However, the relationship between SES and atherosclerosis is not well documented. This study aims to explore this relationship.METHODS:This is a retrospective cohort study in London, Ontario Canada. It includes 6,907 subjects from a vascular prevention centre at baseline, with long term follow up from 1989 to 2021 (total ultrasound examinations 27,103). Using carotid ultrasound, the burden of atherosclerosis was measured as total plaque area (TPA). The Ontario Marginalization Index (OMI) was used to identify SES of participants' neighborhoods. We used a Bayesian hierarchical regression and mixed effects model to identify associations between SES, baseline TPA and plaque progression. In 2003, we implemented more intensive therapy of vascular risk factors after 2003 (called "Treating arteries instead of risk treating factors"); therefore, we compared our findings before and after 2003.RESULTS:SES was found to have a significant association with TPA, with lower SES associated with higher TPA (adjusted odds ratio [OR] = 2.22, 95% Credible interval [CrI]: 1.37, 3.66). While we observed a higher rate of plaque progression with lower SES in those treated before 2003 (OR = 1.46, 95% CrI:1.04, 2.06), there was no significant association between plaque progression and SES after implementation more intensive therapy (OR = 0.99, 95% CrI: 0.78, 1.27).CONCLUSIONS:SES has a strong association with atherosclerosis and should be considered an important risk factor in clinical practice and vascular disease research. Intensive preventive therapy can prevent plaque progression irrespective of baseline SES.

PURPOSE OF REVIEW:We reviewed lipid-modifying therapies and the risk of stroke and other cerebrovascular outcomes, with a focus on newer therapies.RECENT FINDINGS:Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic stroke risk in statin-treated patients with atherosclerosis without increasing hemorrhagic stroke, even with very low achieved low-density lipoprotein cholesterol levels. Icosapent ethyl reduces the risk of total and first ischemic stroke in patients with established cardiovascular disease or diabetes mellitus. Clinical outcome trials are underway for newer lipid-modifying agents, including inclisiran, bempedoic acid, and pemafibrate. New biologic agents including evinacumab, pelacarsen, olpasiran, and SLN360 are also discussed. In addition to statins and ezetimibe, PCSK9 inhibitors and icosapent ethyl reduce the risk of ischemic stroke without increasing the risk of hemorrhagic stroke. These therapies dramatically expand options for reducing stroke in high-risk settings.

Background and Purpose: Poor mental health and depression are well-recognized sequelae of stroke; however, the association between stroke and subsequent risk of suicide is unknown. Methods: We systematically searched MEDLINE, Embase, PsycINFO, and Google Scholar from their inception to September 15, 2020, using keywords and database-specific subjects. We independently adjudicated and selected observational studies that reported suicide attempts or death by suicide in stroke survivors and a comparison group, consisting either of people without a history of stroke or the general population. We evaluated study quality using the Newcastle Ottawa scale. Using random-effects meta-analysis, we calculated the pooled adjusted risk ratio (RR) of suicide in stroke survivors and separately calculated the pooled adjusted RR of suicide attempt and death by suicide. Using prespecified analyses, we explored study-level factors to explain heterogeneity. Results: We screened 4093 articles and included 23 studies of fair quality, totaling over 2 million stroke survivors, of whom 5563 attempted suicide or died by suicide. Compared to the nonstroke group, the pooled adjusted RR of suicide in stroke survivors was 1.73 (95% CI, 1.53-1.96, I-2=93%), with a significantly (P=0.03) higher adjusted risk of suicide attempt (RR, 2.11 [1.73-2.56]) than of death by suicide (RR, 1.61 [1.41-1.84]). A longer follow-up time in cohort studies was associated with a lower risk of suicide (RR, 0.97 [0.95-0.99] for every 1-year increase). Conclusions: Stroke should be considered as a risk factor for suicide. Comprehensive strategies to screen and treat depression and suicidal ideation in stroke survivors should be developed to reduce the burden of suicide in stroke survivors.

Background: People with neurological conditions are at a higher risk of suicide compared to the general population. Despite the known association of stroke with depression and suicidal ideation, it is unclear if stroke is associated with a higher risk of suicide. Methods: We systematically searched MEDLINE, Embase, PsycINFO, and Google Scholar from their inception to July 26, 2020 using keywords and database-specific subject. We independently adjudicated and selected observational studies that compared the risk of suicide in stroke survivors to a comparison group, consisting either of people without history of stroke or the general population. We evaluated study quality using the Newcastle Ottawa scale. Using random effects meta-analysis, we calculated the pooled adjusted risk ratio (RR) of suicide in stroke survivors, and separately calculated the pooled adjusted RR of death by suicide and suicide attempt. Using prespecified analyses, we explored study-level factors to explain heterogeneity. Results: We screened 4023 articles and included 23 studies, of fair quality, totaling over 2 million stroke survivors, of whom 5563 committed suicide. Compared to the non-stroke group, the pooled adjusted RR of suicide in stroke survivors was 1.73 (95% confidence interval, 1.54-1.95, I 2 = 93%), with a significantly (P=0.03) higher adjusted risk of suicide attempt (RR 2.09, 1.69-2.58) than of death by suicide (RR 1.61, 1.44-1.80). Observed heterogeneity could not be explained by pre-specified meta-regression and subgroup analyses. Conclusions: Stroke should be recognized as an independent risk factor for suicide. Comprehensive strategies to screen and treat depression and suicidal ideation in stroke survivors should be developed to reduce the burden of suicide in stroke survivors.

Asymptomatic carotid stenosis (ACS) due to atherosclerosis is a risk factor for ipsilateral ischemic cerebrovascular events and cognitive impairment. The prognosis of ACS has improved over the past 4 decades due largely to improvements in medical management. Most patients with ACS can be managed without revascularization, but some patients with vulnerable plaque should be considered for revascularization. Regardless of the decision to refer for revascularization, all patients with ACS should receive intensive medical management. This includes lifestyle modification (Mediterranean diet, exercise, and smoking cessation) and pharmacological therapy (antiplatelets, lipid-lowering agents, blood pressure reduction, and glycemic control). Patients with ACS often have atherosclerosis in other critical locations, and thus optimal medical therapy is likely to reduce events outside the carotid arteries. The nature of optimal medical therapy is described.

Background and Purpose: Poor mental health and depression are well-recognized sequelae of stroke; however, the association between stroke and subsequent risk of suicide is unknown. Methods: We systematically searched MEDLINE, Embase, PsycINFO, and Google Scholar from their inception to September 15, 2020, using keywords and database-specific subjects. We independently adjudicated and selected observational studies that reported suicide attempts or death by suicide in stroke survivors and a comparison group, consisting either of people without a history of stroke or the general population. We evaluated study quality using the Newcastle Ottawa scale. Using random-effects meta-analysis, we calculated the pooled adjusted risk ratio (RR) of suicide in stroke survivors and separately calculated the pooled adjusted RR of suicide attempt and death by suicide. Using prespecified analyses, we explored study-level factors to explain heterogeneity. Results: We screened 4093 articles and included 23 studies of fair quality, totaling over 2 million stroke survivors, of whom 5563 attempted suicide or died by suicide. Compared to the nonstroke group, the pooled adjusted RR of suicide in stroke survivors was 1.73 (95% CI, 1.53–1.96, I 2 =93%), with a significantly ( P =0.03) higher adjusted risk of suicide attempt (RR, 2.11 [1.73–2.56]) than of death by suicide (RR, 1.61 [1.41–1.84]). A longer follow-up time in cohort studies was associated with a lower risk of suicide (RR, 0.97 [0.95–0.99] for every 1-year increase). Conclusions: Stroke should be considered as a risk factor for suicide. Comprehensive strategies to screen and treat depression and suicidal ideation in stroke survivors should be developed to reduce the burden of suicide in stroke survivors.

In a recent systematic review it was estimated that the global prevalence of peripheral artery disease (PAD) was 5.6%, with higher prevalence estimates in high-income countries than in low-income countries. 1 Song P Rudan D Zhu Y et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health. 2019; 7 (e1020-30) Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar Worldwide, a total of 237 million people aged 25 years and older were living with PAD in 2015. 1 Song P Rudan D Zhu Y et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health. 2019; 7 (e1020-30) Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar Patients with PAD are at elevated risk of major adverse limb events and major adverse cardiovascular events. 2 Agnelli G Belch JJF Baumgartner I Giovas P Hoffmann U. Morbidity and mortality associated with atherosclerotic peripheral artery disease: a systematic review. Atherosclerosis. 2020; 293: 94-100 Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Extensive evidence suggests that patients with PAD are undertreated with respect to vasculoprotective medications and lifestyle modification. 3 Hackam DG Vyas MV. Utilization of vasculoprotective therapy for peripheral artery disease: a systematic review and meta-analysis. Am J Med. 2018; 131 (e1333): 1332-1339 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Temporal Trends in Hospitalization for Lower Extremity Peripheral Artery Disease in Ontario: The Importance of DiabetesCanadian Journal of CardiologyVol. 37Issue 10PreviewWe sought to assess temporal trends in peripheral artery disease (PAD)-related hospitalization rates in Ontario. Trends in quarterly rates of PAD hospitalization per 100,000 Ontarians between 2006 and 2019 were assessed using autocorrelated linear regression. Stratified analyses according to age, sex, and most responsible diagnosis code type (with vs without diabetes-specific PAD codes) were performed. From 2006 to 2019, overall PAD hospitalizations did not decrease significantly when diabetes-specific codes were included. Full-Text PDF

Objectives: Little is known about the interactions between hyperhomocysteinemia and metabolic syndrome (MetS) in individuals at risk for atherosclerosis. The aim of this study was to assess the burden of atherosclerosis in patients with MetS and hyperhomocysteinemia. Methods: We assessed the interaction of MetS with other risk factors including hyperhomocysteinemia in 972 patients with a history of stroke, transient ischemic attack, or carotid stenosis. MetS was defined as by the International Diabetes Federation as body mass index >30 kg/m2 and two or more of the following: hypertension, high triacylglycerides, and low high-density lipoprotein. We defined hyperhomocysteinemia as plasma total homocysteine >14 mmol/L. Patients with diabetes were excluded. Carotid total plaque area (TPA), a strong predictor of cardiovascular risk, was measured by carotid ultrasound. The association of TPA with MetS, and interaction with related risk factors, was assessed by multiple linear regression. Results: Complete data were available on 972 non-diabetic patients. Of these, 179 (18.4%) had MetS. Patients with MetS and hyperhomocysteinemia (P < 0.001) or smoking (P = 0.02) had a higher TPA compared with those with MetS and normal plasma total homocysteine levels. In linear regression, there was a significant association of MetS (P = 0.004), hyperhomocysteinemia (P = 0.01), and smoking (P = 0.004) with increased TPA. Conclusions: Patients with MetS and smoking or hyperhomocysteinemia are at particularly high cardiovascular risk. Targeted atherosclerosis prevention should include identification and treatment of MetS, smoking, and hyperhomocysteinemia (including that due to unrecognized metabolic vitamin B12 deficiency). (C) 2020 Elsevier Inc. All rights reserved.

An important paradigm in biomedical research is that the results of preclinical animal models should predict the outcome of subsequent human randomized trials. In 2006, we reported that 37% of highly cited animal studies (across all domains) translated at the level of human randomized trials. 1 Hackam DG Redelmeier DA Translation of research evidence from animals to humans. JAMA. 2006; 296: 1731-1732 Crossref PubMed Scopus (441) Google Scholar No such estimate is available exclusively for cardiovascular medicine.

Cardiovascular disease is the leading cause of death and disability in most high-income countries, including Canada. Reports from multiple jurisdictions suggest declining rates of cardiovascular disease over the past 40 years. 1 Virani S.S. Alonso A. Benjamin E.J. et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020; 141: e139-e596 Crossref PubMed Scopus (2236) Google Scholar In this issue of the Canadian Journal of Cardiology, Botly et al. provide timely information on secular trends in hospitalization rates for major cardiovascular diseases in Canada. 2 Botly L.C.P. Lindsay M.P. Hill M.D. et al. Recent trends in hospitalizations for cardiovascular disease, stroke, and vascular cognitive impairment in Canada. Can J Cardiol. 2020; 36: 1081-1090 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar All provinces and territories with the exception of Quebec were included; the time span examined was April 1, 2007 to March 31, 2017. More than 2.6 million hospitalizations were tracked and analyzed. Recent Trends in Hospitalizations for Cardiovascular Disease, Stroke, and Vascular Cognitive Impairment in CanadaCanadian Journal of CardiologyVol. 36Issue 7PreviewWe analyzed hospitalization rates for a broad set of cardiovascular diseases, stroke, and vascular cognitive impairment (VCI) between 2007 and 2016 in Canada to characterize population-level trends and demographic and provincial/territorial variation in inpatient health care utilization. Full-Text PDF Open Access

Objective We sought to assess the current magnitude of the opportunity for secondary stroke prevention with B vitamins. Design A cohort study. Setting The Urgent TIA (Transient Ischaemic Attack) Clinic at an academic medical centre. Main outcome measures We assessed the prevalence of biochemical vitamin B12 deficiency (B12Def, serum B12 <156 pmol/L), hyperhomocysteinaemia (HHcy; plasma total homocysteine [tHcy] >14 µmol/L) and metabolic B12 deficiency (MetB12Def, serum B12 <258 pmol/L and HHcy) between 2002 and 2017, by age group and by stroke subtype. Results Data were available in 4055 patients. B12Def was present in 8.2% of patients overall; it declined from 10.9% of patients referred before 2009 to 5.4% thereafter (p=0.0001). MetB12Def was present in 10.6% of patients, and HHcy was present in 19.1% of patients. Among the patients aged ≥80 years, MetB12Def was present in 18.1% and HHcy in 35%. Among the 3410 patients whose stroke subtype was determined, HHcy was present in 18.4% of patients: 23.3% of large artery atherosclerosis, 18.1% of cardioembolic, 16.3% of small vessel disease, 10.8% of other unusual aetiologies and 13.6% of undetermined subtypes (p=0.0001). Conclusions Despite a decline in our referral area since 2009, B12Def, MetB12Def and HHcy remain common in patients with stroke/TIA. Because these conditions are easily treated and have serious consequences, all patients with stroke/TIA should have their serum B12 and tHcy measured.

HomeStrokeVol. 50, No. 2Cholesterol Lowering and Prevention of Stroke Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBCholesterol Lowering and Prevention of StrokeAn Overview Daniel G. Hackam, MD, PhD and Robert A. Hegele, MD Daniel G. HackamDaniel G. Hackam Correspondence to Daniel G. Hackam, MD, PhD, Division of Clinical Pharmacology, Department of Medicine, Western University, Room 100K-2, Siebens Drake Bldg, 1400 Western Rd, London, Ontario, Canada N6G 2V2. Email E-mail Address: [email protected] From the Division of Clinical Pharmacology, Department of Medicine (D.G.H.), Western University, London, Ontario, Canada. Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute (D.G.H.), Western University, London, Ontario, Canada. Search for more papers by this author and Robert A. HegeleRobert A. Hegele Division of Endocrinology and Metabolism, Department of Medicine (R.A.H.), Western University, London, Ontario, Canada. Molecular Medicine Research Laboratories, Robarts Research Institute (R.A.H.), Western University, London, Ontario, Canada. Search for more papers by this author Originally published3 Jan 2019https://doi.org/10.1161/STROKEAHA.118.023167Stroke. 2019;50:537–541Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 3, 2019: Ahead of Print There is a complex relationship between usual levels of serum cholesterol and the risk of stroke. Low cholesterol is a risk factor for intracerebral hemorrhage, whereas high cholesterol is predictive of atherothrombotic and lacunar cerebral infarction.1 A number of lipid-modifying interventions reduce the risk of ischemic stroke (Table): 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), ezetimibe, purified eicosapentaenoic acid ethyl ester, PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors, gemfibrozil, and possibly nicotinic acid (niacin). This article provides an overview of the epidemiology of stroke and cholesterol, as well as treatment trials showing significant reductions in stroke with lipid-lowering therapies.Table. Lipid-Modifying Therapies With Demonstrated Reductions in Ischemic StrokeTherapyEffect on Ischemic StrokeEffect on Hemorrhagic StrokeStatins2 Statin vs controlRR, 0.80 (95% CI, 0.74–0.86) per 1-mmol/L reduction in LDL-CRR, 1.10 (95% CI, 0.91–1.34) per 1-mmol/L reduction in LDL-C More vs lessRR, 0.69 (95% CI, 0.54–0.88) per 1-mmol/L reduction in LDL-CRR, 1.39 (95% CI, 0.70–2.74) per 1-mmol/L reduction in LDL-C All trialsRR, 0.79 (95% CI, 0.74–0.85) per 1-mmol/L reduction in LDL-CRR, 1.12 (95% CI, 0.93–1.35) per 1-mmol/L reduction in LDL-CEzetimibe3HR, 0.79 (95% CI, 0.67–0.94)HR, 1.38 (95% CI, 0.93–2.04)Eicosapentaenoic acid ethyl ester4HR, 0.64 (95% CI, 0.49–0.85)HR, 1.28 (95% CI, 0.56–2.93)PCSK9 inhibitors Evolocumab5HR, 0.75 (95% CI, 0.62–0.92)HR, 1.16 (95% CI, 0.68–1.98) Alirocumab6HR, 0.73 (95% CI, 0.57–0.93)<0.1% (n=9) vs 0.2% (n=16)*Gemfibrozil7HR, 0.69 (95% CI, 0.48–0.98)n=6 vs n=5†HR indicates hazard ratio; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin-kexin type 9; and RR, relative risk.*Alirocumab group vs placebo group, respectively.†Gemfibrozil group vs placebo group, respectively.Epidemiology of Stroke and CholesterolWhen total stroke is subtyped into ischemic and hemorrhagic stroke, contrasting relationships with serum lipids are found. High levels of total cholesterol (TC) and LDL (low-density lipoprotein) cholesterol (LDL-C) are both associated with an increased risk of ischemic stroke, whereas low levels are associated with an increased risk of intracerebral hemorrhage.1 For example, in a case-control study nested in a health maintenance organization, Tirschwell et al8 found that having a TC in the top quintile (mean, 290 mg/dL or 7.5 mmol/L), versus the lowest quintile, was associated with an increased ischemic stroke risk (odds ratio [OR], 1.6; 95% CI, 1.3–1.9) and a decreased intracerebral hemorrhage risk (OR, 0.6; 95% CI, 0.4–1.0). This contrasting relationship has been reported in multiple studies,9–15 as well as the large Prospective Studies Collaboration meta-analysis.1 Because these associations have also generally been replicated in multiple randomized trials of various lipid-lowering agents, they are probably causal. In addition, a meta-analysis of 185 genome-wide association studies, using a Mendelian randomization design to impute direct causal relationships, showed that 1 SD of genetically elevated LDL-C was associated with an increased risk of ischemic stroke (OR, 1.12; 95% CI, 1.04–1.20).16Within ischemic stroke, the subtype of atherothrombotic or large artery occlusive disease has been most closely tied to higher levels of TC and LDL-C.8,17–20 Tirschwell et al8 found a 3-fold increased risk of atherothrombotic stroke in the highest quintile of serum TC (OR, 3.1; 95% CI, 1.7–5.6). This association has been replicated in Japanese and Chinese populations as well.18–20 In the aforementioned Mendelian randomization meta-analysis, a 1-SD genetically elevated LDL-C was causally associated with large artery atherosclerosis stroke (OR, 1.28; 95% CI, 1.10–1.49) but not with small artery occlusion or cardioembolic stroke.16 Such associations are not entirely surprising because cholesterol has long been recognized as a risk factor for atherosclerosis in other vascular beds (eg, coronary and peripheral).Two case-control studies have identified cholesterol as a risk factor for lacunar stroke.8,17 Similar to atherothrombotic infarction, Tirschwell et al8 found that the highest quintile of TC was associated with a doubling of risk for lacunar infarction (OR, 2.2; 95% CI, 1.4–3.4). Amarenco et al17 found that the OR per SD in LDL-C was 2.71 (95% CI, 1.60–4.55) for lacunar stroke. Bezerra et al21 observed that larger lacunar lesions (8–20 mm on magnetic resonance imaging), which are probably attributable to microatheromata, were associated with LDL-C (prevalence ratio, 1.27 per SD; 95% CI, 1.06–1.52), but smaller lesions (≤7 mm), which are probably attributable to lipohyalinosis, were not. Elevated cholesterol may predispose to lacunar stroke by enhancing formation of microatheromata or plaque rupture. By contrast, there is no association seen between cholesterol and embolic infarction.8,16–18HDL (high-density lipoprotein) cholesterol (HDL-C) is inversely associated with the risk of ischemic stroke.22 Sacco et al22 found a protective effect on ischemic stroke for HDL-C of at least 35 mg/dL (0.91 mmol/L; OR, 0.53; 95% CI, 0.39–0.72). Higher HDL-C was especially protective for the atherosclerotic stroke subtype (OR, 0.20; 95% CI, 0.08–0.50) but also for nonatherosclerotic stroke (OR, 0.60; 95% CI, 0.42–0.85). In the Mendelian randomization meta-analysis, a 1-SD genetically elevated HDL-C was associated with a decreased risk of small artery occlusion stroke (OR, 0.79; 95% CI, 0.67–0.90).16 Genetically elevated triglycerides did not associate with any stroke subtype.In contrast, the Prospective Studies Collaboration found that TC was only weakly related to ischemic and total stroke mortality in middle age (40–59 years), and this finding could be explained by the association of cholesterol with blood pressure.1 A positive relation was seen only in middle age and only in those with below-average blood pressure. Zhang et al23 found that TC was positively associated with ischemic stroke in men and negatively for intracerebral hemorrhage in women. However, the association disappeared in men after adjustment for body mass index, blood pressure, and history of diabetes mellitus.Clinical TrialsStatinsThe Cholesterol Treatment Trialists Collaboration performed a meta-analysis of individual participant data from 26 randomized trials of statin therapy (n=169 138), including 21 trials of statin versus control and 5 trials of more versus less intensive statin regimens.2 For more versus less statin, the relative risk (RR) reduction (RRR) for ischemic stroke per 1 mmol/L reduction in LDL-C was 31% (RR, 0.69; 95% CI, 0.54 – 0.88). For statin versus control, the RRR was 20% (RR, 0.80; 95% CI, 0.74–0.86). Across all 26 trials, there was a 21% reduction in ischemic stroke per 1 mmol/L lower LDL-C (RR, 0.79; 95% CI, 0.74–0.85). Pooling all 26 studies, for hemorrhagic stroke, there was a nonsignificant 12% increase in risk per 1 mmol/L reduction in LDL-C (RR, 1.12; 95% CI, 0.93–1.35).In the SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), patients with a recent stroke or transient ischemic attack but no coronary disease were randomly assigned to receive high-dose atorvastatin (80 mg/d) or placebo.24 Patients were followed for a median of 4.9 years. There was a 16% RRR in the atorvastatin group in the primary end point of first fatal or nonfatal stroke (adjusted hazard ratio [HR], 0.84; 95% CI, 0.71–0.99). This was accounted for by a 22% RRR in ischemic stroke (HR, 0.78; 95% CI, 0.66–0.94) and a 66% increase in hemorrhagic stroke (HR, 1.66; 95% CI, 1.08–2.55). Hemorrhagic stroke was more common in men, in those with advanced age, in those with a previous hemorrhagic stroke as the entry event, and in those with stage 2 hypertension at the last study visit before the hemorrhagic stroke.25 There was no effect of baseline or on-treatment LDL-C level, and LDL-C levels were not lower in patients with hemorrhagic stroke, suggesting that some of them were not actually taking atorvastatin as allocated.25 The difference in absolute risk for hemorrhagic stroke was small: 0.9% (2.3% on atorvastatin versus 1.4% on placebo; P=0.02).Statins clearly reduce the risk of ischemic stroke in diverse populations, and higher statin doses are more effective than lower statin doses at preventing ischemic stroke and other vascular events. As noted, there is a suggestion from SPARCL that in patients with cerebrovascular disease (and especially prior hemorrhagic stroke), a high statin dose may increase the risk of hemorrhagic stroke. Uncontrolled hypertension is a strong risk factor for cerebral hemorrhage, and in patients with uncontrolled blood pressure, it is reasonable to consider deferring initiation of high-dose, potent statins, at least until blood pressure is controlled.15EzetimibeEzetimibe lowers TC and LDL-C by inhibiting the Niemann-Pick C1-like 1 protein, which is a sterol transporter localized to the lumenal surface of gastrointestinal epithelial cells.26 Validation for its efficacy in preventing major vascular events derives from the recent IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).27 In IMPROVE-IT, 18 144 patients stabilized after acute coronary syndrome were randomized to receive either ezetimibe 10 mg/d plus simvastatin 40 mg/d or simvastatin 40 mg/d alone. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. This composite end point was reduced by 6% in the ezetimibe arm (HR, 0.936; 95% CI, 0.89–0.99; P=0.016).During the trial, a total of 641 patients experienced at least 1 stroke during a median follow-up of 6 years.3 Treatment with ezetimibe was protective against ischemic stroke (HR, 0.79; 95% CI, 0.67–0.94), which became more pronounced in the on-treatment analysis.28 There was a nonsignificant increase in hemorrhagic stroke (HR, 1.38; 95% CI, 0.93–2.04; P=0.11). Patients with a history of prior stroke were especially likely to benefit from ezetimibe, with a 40% reduction in total stroke (HR, 0.60; 95% CI, 0.38–0.95) and a number needed to treat of only 12 to prevent any stroke. This subgroup also saw a large benefit in ischemic stroke (HR, 0.52; 95% CI, 0.31–0.86; number needed to treat, 13). This benefit was observed within the first 6 months after the index acute coronary syndrome.Eicosapentaenoic Acid Ethyl EsterRecently, a large, randomized trial studied the effects of highly purified eicosapentaenoic acid ethyl ester on cardiovascular events in patients with established cardiovascular disease or diabetes mellitus plus at least 1 additional risk factor.4 Patients were required to have been receiving statin therapy and had a fasting triglyceride level of 1.52 to 5.63 mmol/L and an LDL-C level of 1.06 to 2.59 mmol/L. Randomization was made to treatment consisting of 2 g BID of icosapent ethyl (total daily dose, 4 g) or placebo. The primary outcome was the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. This outcome was reduced by 25% (HR, 0.75; 95% CI, 0.68–0.83). Of additional note, ischemic stroke was significantly reduced by 36% (HR, 0.64; 95% CI, 0.49–0.85), with no increase observed in hemorrhagic stroke (HR, 1.28; 95% CI, 0.56–2.93). Total fatal or nonfatal stroke was also reduced (HR, 0.72; 95% CI, 0.55–0.93). In addition to triglyceride lowering, the mechanism of action of icosapent ethyl may include plaque stabilization or an antithrombotic effect. Serious adverse bleeding events occurred in 2.7% of patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06).PCSK9 InhibitorsPCSK9 is an enzyme that binds to the LDL receptor and targets it toward lysosomal degradation in liver cells. PCSK9 inhibitors are monoclonal antibodies that block this process, thereby leaving more cell surface LDL receptors available to take up plasma LDL particles.29 Two commercially available PCSK9 inhibitors are evolocumab and alirocumab. In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with atherosclerotic vascular disease and LDL-C of ≥70 mg/dL (1.8 mmol/L) on statin therapy were randomized to receive evolocumab or matching placebo as subcutaneous injections.5 The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. This composite end point was reduced by evolocumab (HR, 0.85; 95% CI, 0.79–0.92; P<0.001). Total stroke (HR, 0.79; 95% CI, 0.66–0.95) and ischemic stroke (HR, 0.75; 95% CI, 0.62–0.92) were also reduced in the evolocumab group. There was a nonsignificant increase in hemorrhagic stroke seen with evolocumab (HR, 1.16; 95% CI, 0.68–1.98). Patients (n=3366) who qualified for the trial on the basis of ischemic stroke alone saw a significant benefit in the primary end point (6.0% in the evolocumab arm versus 8.5% in the placebo arm; HR, 0.70; 95% CI, 0.54–0.90). Recurrent stroke was not reported in this subgroup. Importantly, a preplanned subgroup analysis in FOURIER showed that achievement of very low LDL-C levels (defined as <20 mg/dL or 0.5 mmol/L) was not associated with a greater risk of hemorrhagic stroke compared with those achieving higher LDL-C with evolocumab (defined as >100 mg/dL or 2.6 mmol/L; HR, 0.71; 95% CI, 0.17–2.90).30In the ODYSSEY Outcomes trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), 18 924 patients with recent acute coronary syndrome on high-dose statin therapy were randomized to receive subcutaneous injections of alirocumab or placebo every 2 weeks.6 The primary outcome was time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. This was reduced by 15% (HR, 0.85; 95% CI, 0.78–0.93; P=0.0003).31 All-cause mortality was 3.5% in the alirocumab arm and 4.1% in the control group (HR, 0.85; 95% CI, 0.3–0.98; P=0.026). Ischemic stroke was also reduced (1.2% versus 1.6%; HR, 0.73; 95% CI, 0.57–0.93) as was unstable angina and nonfatal MI. There were fewer hemorrhagic strokes in the alirocumab arm than the placebo arm (9 versus 16 events, respectively).GemfibrozilGemfibrozil is a fibric acid derivative and partial agonist of PPAR (peroxisome proliferator-activated receptor)-α; gemfibrozil reduces serum triglycerides and raises HDL-C by enhancing activity of lipoprotein lipase. Its effect on cardiovascular events, including stroke, was tested in the VA-HIT (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial).32 A total of 2531 men with coronary heart disease, an HDL-C of ≤40 mg/dL (1.0 mmol/L), and an LDL-C of ≤140 mg/dL (3.6 mmol/L), were randomly assigned to receive gemfibrozil 1200 mg/d or placebo. The primary outcome was nonfatal myocardial infarction or death from coronary causes. This was reduced in the gemfibrozil arm (RRR, 22%; 95% CI, 7%–35%; P=0.006). Of note, LDL-C did not differ between groups, although TC was reduced by 4%. The RRR for stroke, adjusted for baseline variables, was 31% (95% CI, 2%–52%; P=0.036).7 There was a 59% reduction in transient ischemic attack (95% CI, 33%–75%; P<0.001) and a 65% reduction in carotid endarterectomy (95% CI, 37%–80%; P<0.001). The effect of gemfibrozil was largely confined to atherothrombotic strokes, with no difference in lacunar or cardioembolic strokes. There were 5 and 6 hemorrhagic strokes in the placebo and gemfibrozil arms, respectively.NiacinIn the Coronary Drug Project—a randomized trial of niacin versus placebo in 8341 men with previous myocardial infarction, niacin 1 g TID reduced the risk of recurrent nonfatal MI by 27% (P<0.004).33 As a secondary end point, niacin reduced the incidence of cerebrovascular events (strokes plus TIAs) by 26%—an absolute reduction of 2.9% (P<0.01). However, no reduction in overall stroke was seen in 2 more modern niacin cardiovascular end point trials; there was also no increase in hemorrhagic stroke with niacin in either trial.34,35ConclusionsHigher levels of TC and LDL-C predict ischemic stroke and in particular, atherothrombotic and lacunar stroke subtypes. Low levels of TC and LDL-C seem to predict a higher risk of intracerebral hemorrhage. Low HDL-C is a strong risk factor for ischemic stroke (both atherothrombotic and nonatherothrombotic). A graded relationship with these outcomes is present across the entire range of TC, LDL-C, and HDL-C levels.Agents with diverse mechanisms of action that share only the property of LDL-C reduction—namely statins, ezetimibe, and PCSK9 inhibitors—reduce incident ischemic stroke. This would suggest a causal relationship between LDL-C reduction and stroke prevention. A signal of increased risk for hemorrhagic stroke in the SPARCL trial and nonsignificant increases in risk in IMPROVE-IT, FOURIER, and the Cholesterol Treatment Trialists meta-analysis suggest that marked lowering of LDL-C could cause hemorrhagic strokes in a vulnerable subset of patients, most likely those with uncontrolled hypertension. This hypothesis needs to be tested in future clinical trials. Hemorrhagic stroke is a rare event compared with ischemic stroke and coronary artery disease, so that possible concerns about increased risk of hemorrhagic stroke should not detract from the large benefits of LDL-C–lowering therapies for other serious vascular disease end points.Sources of FundingDr Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics, and the Martha G. Blackburn Chair in Cardiovascular Research. Dr Hegele has received operating grants from the Canadian Institutes of Health Research (foundation grant) and the Heart and Stroke Foundation of Ontario (G-18-0022147).DisclosuresDr Hegele has received honoraria for membership on advisory boards and speakers’ bureaus for Aegerion, Akcea/Ionis, Amgen, Gemphire, Regeneron, and Sanofi.FootnotesCorrespondence to Daniel G. Hackam, MD, PhD, Division of Clinical Pharmacology, Department of Medicine, Western University, Room 100K-2, Siebens Drake Bldg, 1400 Western Rd, London, Ontario, Canada N6G 2V2. Email [email protected]caReferences1. Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths.Lancet. 2007; 370:1829–1839.CrossrefMedlineGoogle Scholar2. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. 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Zheng X, Fang F, Nong W, Feng D and Yang Y (2021) Development and validation of a model to estimate the risk of acute ischemic stroke in geriatric patients with primary hypertension, BMC Geriatrics, 10.1186/s12877-021-02392-7, 21:1, Online publication date: 1-Dec-2021. Yu Y, Lei D, He Q and Chen W (2021) A cohort study on the relationship between education level and high‐risk population of stroke, Ibrain, 10.1002/j.2769-2795.2021.tb00082.x, 7:3, (181-191), Online publication date: 1-Sep-2021. ISHIKAWA T, YAMAZAKI T, SATO M, KATO N, ISHIKAWA E, MATSUMARU Y and MATSUMURA A (2021) Endovascular Stent Grafting for Recurrent Strokes Due to Fragile Innominate Artery Plaque: A Case Report, NMC Case Report Journal, 10.2176/nmccrj.cr.2020-0007, 8:1, (21-25), . 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Bertrand C, Saulnier P, Potier L, Croyal M, Blanchard V, Gand E, Ragot S, Schneider F, Bocock O, Baillet-Blanco L, Velho G, Marre M, Roussel R, Rigalleau V, Hadjadj S and Mohammedi K (2021) Plasma concentrations of lipoproteins and risk of lower-limb peripheral artery disease in people with type 2 diabetes: the SURDIAGENE study, Diabetologia, 10.1007/s00125-020-05326-x, 64:3, (668-680), Online publication date: 1-Mar-2021. Xiuyun W, Qian W, Minjun X, Weidong L and Lizhen L (2020) Education and stroke: evidence from epidemiology and Mendelian randomization study, Scientific Reports, 10.1038/s41598-020-78248-8, 10:1, Online publication date: 1-Dec-2020. Tate M, Shugart R, Moraney R, Brechtel L, Blum B and Thomas I Nathaniel (2020) Gender and functional outcomes in prestroke depressive patients treated with thrombolytic therapy, Future Neurology, 10.2217/fnl-2019-0030, 15:2, Online publication date: 1-May-2020. Kulesh A, Gorst N, Kuzina N, Drobakha V, Shestakov V and Karakulova Y (2020) Amyloid angiitis and progressive cortical superficial siderosis as aggressive phenotypes of cerebral amyloid angiopathy: principles of rational management, Russian neurological journal, 10.30629/2658-7947-2019-24-6-29-38, 24:6, (29-38) Salgado M, Manchado A, Nieto C, Díez D and Garrido N (2021) Synthesis and Modeling of Ezetimibe Analogues, Molecules, 10.3390/molecules26113107, 26:11, (3107) FIRAT O, KARAKUŞ M, ARSAVA E, TOPÇUOĞLU M and DEMİRKAN K (2021) İskemik İnmelerde Risk Faktörlerinin Yönetiminde Kılavuz Karşılaştırması, STED / Sürekli Tıp Eğitimi Dergisi, 10.17942/sted.890125 Aghamiri S, Mansouri B, Mehrpour M, Karani S, Ghaffari M, Lima B and Komlakh K (2022) Efficacy of mechanical thrombectomy in stroke patients with large vessel involvement, European Journal of Translational Myology, 10.4081/ejtm.2022.10456 February 2019Vol 50, Issue 2 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.118.023167PMID: 30602355 Manuscript receivedAugust 6, 2018Manuscript acceptedDecember 7, 2018Originally publishedJanuary 3, 2019Manuscript revisedNovember 28, 2018 Keywordsclinical trials as topicniacinstrokecholesterolrisk factorsPDF download Advertisement SubjectsAtherosclerosisCerebrovascular Disease/StrokeIntracranial HemorrhageIschemic StrokeLipids and Cholesterol

HomeStrokeVol. 50, No. 3Antiplatelet Therapy in Ischemic Stroke and Transient Ischemic Attack Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAntiplatelet Therapy in Ischemic Stroke and Transient Ischemic AttackAn Overview of Major Trials and Meta-Analyses Daniel G. Hackam, MD, PhD and J. David Spence, MD Daniel G. HackamDaniel G. Hackam Correspondence to Daniel G. Hackam, MD, PhD, Room 100K-2, Siebens Drake Bldg, 1400 Western Rd, London, ON N6G 2V2, Canada. Email E-mail Address: [email protected] From the Division of Clinical Pharmacology, Departments of Medicine, Clinical Neurological Sciences and Epidemiology/Biostatistics and Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, ON, Canada. Search for more papers by this author and J. David SpenceJ. David Spence From the Division of Clinical Pharmacology, Departments of Medicine, Clinical Neurological Sciences and Epidemiology/Biostatistics and Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, ON, Canada. Search for more papers by this author Originally published10 Jan 2019https://doi.org/10.1161/STROKEAHA.118.023954Stroke. 2019;50:773–778Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 10, 2019: Ahead of Print Stroke is a leading cause of mortality and disability worldwide.1 Initial manifestations of acute cerebral ischemia, such as ischemic stroke and transient ischemic attack (TIA), are often followed by recurrent vascular events, including recurrent stroke.2 To reduce this burden, antiplatelet therapy is a key component of the management of noncardioembolic ischemic stroke and TIA.3 This review will focus on the evidence for 4 antiplatelets: aspirin, aspirin-dipyridamole, clopidogrel, and ticagrelor (Table). These were selected because they have been the subject of definitive trials and are the most commonly discussed antiplatelets in practice guidelines.3,4 MEDLINE was searched for randomized trials (N>500) and meta-analyses of antiplatelets in the secondary prevention of cerebrovascular disease.Table. Characteristics of Key Antiplatelet Trials and Meta-Analyses in Stroke/TIATrial or Meta-AnalysisPatient PopulationAntiplatelet InterventionFollow-UpKey ResultsAspirin IST19 435 patients with acute ischemic stroke within 48 h of symptom onsetAspirin 300 mg/d vs avoid aspirin6 mo11 fewer deaths or recurrent strokes per 1000 treated within 14 days CAST21 106 patients with acute ischemic stroke within 48 h of symptom onsetAspirin 160 mg/d vs placebo4 wk6.8 fewer cases of death or nonfatal stroke per 1000 treated at 4 wk IST+CAST pooled analysis40 000 patients with acute ischemic stroke within 48 h of symptom onsetAspirin 160–300 mg/d vs no aspirin3 wk9 fewer cases of stroke or death in hospital per 1000 treated ATC-3 meta-analysis6170 secondary prevention patients in 10 poststroke/TIA aspirin trialsAspirin (various doses)not stated17% (P=0.001) reduction in serious vascular events; 36% (P=0.003) reduction in nonfatal MI; 21% (P=0.01) reduction in major coronary events; 90% (P=0.03) increase in hemorrhagic stroke; 21% (P=0.05) reduction in definite ischemic stroke; 22% (P=0.001) reduction in probable ischemic stroke; 17% (P=0.01) reduction in any strokeASA-dipyridamole ESPS-26602 patients with a completed ischemic stroke or TIA within the past 3 moAspirin 25 mg bid; dipyridamole 200 mg BID; aspirin 25 mg BID+dipyridamole 200 mg BID; or placebo2 yComposite of stroke or death was reduced by 13.2% (P=0.016) with aspirin; by 15.4% (P=0.015) with dipyridamole; and by 24.4% (P<0.001) with aspirin+dipyridamole ESPRIT2739 patients within 6 mo of a TIA or minor ischemic stroke of presumed arterial originAspirin (30–325 mg/d) and dipyridamole (200 mg BID) vs aspirin (30–325 mg/d) alone3.5 yComposite of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complication was reduced by aspirin+dipyridamole (HR, 0.80; 95% CI, 0.66–0.98); no increase in major bleeding complications (HR, 0.67; 95% CI, 0.44–1.03) Aspirin-dipyridamole meta-analysis7795 patients with cerebral ischemia of presumed arterial origin in 6 antiplatelet trialsAspirin+dipyridamole vs aspirin alonenot statedRR=0.82 (95% CI, 0.74–0.91) for composite of vascular death, nonfatal stroke and nonfatal MIClopidogrel CAPRIE19 185 patients with recent ischemic stroke, recent MI, or peripheral arterial disease; included n=6431 with recent ischemic strokeClopidogrel 75 mg/d vs aspirin 325 mg/d1.91 y8.7% (P=0.043) relative risk reduction for composite of ischemic stroke, MI or vascular death; 7.3% (P=0.26) relative risk reduction in stroke subgroup for this end point MATCH7599 patients with recent ischemic stroke or TIA and at least 1 additional vascular risk factorClopidogrel 75 mg/d plus aspirin 75 mg/d vs clopidogrel 75 mg/d alone18 moRRR=6.4% (P=0.244) for primary outcome; ARD 1.26% (P<0.0001) for life-threatening bleeding; ARD 0.40% (P=0.029) for primary intracranial hemorrhage SPS33020 patients with symptomatic lacunar stroke in the preceding 180 daysAspirin 325 mg/d plus clopidogrel 75 mg/d vs aspirin 325 mg/d alone3.4 yHR=0.92 (P=0.48) for recurrent stroke; HR=1.97 (P<0.001) for major hemorrhage; HR=1.52 (P=0.004) for all-cause mortality CHARISMA15 603 patients with cardiovascular disease or multiple risk factors; included n=4320 with TIA or ischemic strokeClopidogrel 75 mg/d plus aspirin 75–162 mg/d vs aspirin 75–162 mg/d28 moRR=0.93 (P=0.22) for primary composite outcome in all patients; RR=0.80 (0.62–1.03) for recurrent stroke in the TIA/stroke subgroup PRoFESS20 332 patients with a recent ischemic stroke (<90 days)Aspirin 25 mg BID plus extended release dipyridamole 200 mg bid (ASA-ERDP) or clopidogrel 75 mg/d2.5 yHR=1.01 (95% CI, 0.92–1.11) for ASA-ERDP and recurrent stroke; HR=0.99 (95% CI, 0.92–1.07) for stroke/MI/vascular death; HR=1.15 (95% CI, 1.00–1.32) for major hemorrhage; HR=1.42 (1.11–1.83) for intracranial hemorrhage CHANCE5170 patients within 24 h after the onset of minor ischemic stroke or high-risk TIAClopidogrel (300 mg load then 75 mg/d) plus aspirin 75 mg/d vs aspirin 75 mg/d. DAPT given for 21 days only.90 dHR=0.68 (P<0.001) for stroke; HR=0.75 (P=0.01) for fatal or disabling stroke; HR=0.67 (P<0.001) for ischemic stroke; HR=0.94 (P=0.94) for severe bleeding POINT4881 patients within 12 h after the onset of minor ischemic stroke or high-risk TIAClopidogrel (600 mg load then 75 mg/d) plus aspirin 50–325 mg/d vs aspirin 50–325 mg alone90 dHR=0.75 (P=0.02) for major ischemic events; HR=0.72 (P=0.01) for ischemic stroke; HR=2.32 (P=0.02) for major hemorrhage; HR=2.45 (P=0.04) for nonintracranial major hemorrhageSOCRATES13 199 patients with nonsevere ischemic stroke or high-risk TIA within 24 hTicagrelor (180 mg load then 90 mg BID) vs aspirin (300 mg load then 100 mg/d)90 dHR=0.89 (P=0.07) for stroke/MI/death; HR=0.87 (P=0.046) for ischemic stroke; HR=0.83 (P=0.45) for major bleedingARD indicates absolute risk difference; ASA, acetylsalicylic acid; ATC, antithrombotic trialists’ collaboration; CAPRIE, Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events; CAST, Chinese Acute Stroke Trial; CHANCE, Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance; ESPRIT, European/Australasian Stroke Prevention in Reversible Ischemia Trial; ESPS-2 European Stroke Prevention Study-2; HR, hazard ratio; IST, International Stroke Trial; MATCH, Management of Atherothrombosis With Clopidogrel in High-Risk Patients; MI, myocardial infarction; POINT, Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; RR, relative risk; RRR, relative risk reduction; SOCRATES, Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes; SPS3, Secondary Prevention of Small Subcortical Strokes; and TIA, transient ischemic attack.AspirinAcetylsalicylic acid (ASA), otherwise known as aspirin, irreversibly inactivates platelet cyclooxygenase, which is responsible for prostaglandin and thromboxane synthesis.5 In particular, aspirin irreversibly blocks production of thromboxane A2.6 Thromboxane A2 is a potent platelet activator and proaggregant; hence by blocking thromboxane A2 synthesis, ASA is able to achieve an antiplatelet effect.Two large randomized trials tested the effects of aspirin in the acute phase of ischemic stroke: the IST (International Stroke Trial) and the CAST (Chinese Acute Stroke Trial).7,8 In IST, patients received 300 mg of aspirin daily, whereas in CAST, 160 mg daily was provided. A combined analysis of 40 000 patients randomized in these 2 trials was published in 2000.9 There was a highly significant decrease of 7 recurrent ischemic strokes per 1000 patients treated and a nominally significant reduction of 4 deaths without further stroke per 1000 patients treated. Overall, there was a net decrease of 9 per 1000 treated in the risk of further stroke or death in hospital. These data indicate strong benefit for acute initiation of aspirin after ischemic stroke but have been largely superceded by trials of dual antiplatelet therapy (DAPT) in the acute setting (Clopidogrel).10,11Ten trials analyzed by the Antithrombotic Trialists’ Collaboration studied the longer-term effects of aspirin started in patients with a history of cerebrovascular ischemic events.12 These trials aggregated 6170 subjects and 1308 serious vascular events for secondary prevention poststroke or TIA. Overall, aspirin reduced the risk of serious vascular events by 19% (95% CI, 7%–25%), nonfatal myocardial infarction by 36% (95% CI, 15%–52%), major coronary events by 21% (95% CI, 5%–34%), and any stroke by 17% (95% CI, 4%–28%). Probable ischemic stroke and definite ischemic stroke were both significantly reduced (by 22% and 21%, respectively). Conversely, hemorrhagic stroke (relative risk, 1.90; 95% CI, 1.06–3.44) and gastrointestinal bleeding (relative risk, 2.69; 95% CI, 1.25–5.76) were both increased. Because absolute risk reductions in serious vascular events and ischemic strokes in secondary prevention outnumber absolute risk increases in bleeding events, the net risk-benefit ratio favors aspirin therapy in this setting. Most patients with ischemic cerebrovascular disease will be started on low-dose aspirin as either monotherapy or as part of a DAPT regimen (discussed in detail below). The optimal dose of aspirin was explored in the second Antithrombotic Trialists’ Collaboration overview, published in 2002.13 Significant risk reductions in serious vascular events were seen in trials where patients received ≥75 mg/d but not in 3 trials where patients received <75 mg/d. Because higher doses are more gastrotoxic, it has been suggested that 75 to 150 mg/d is the optimal dose range for aspirin.13Aspirin-DipyridamoleDipyridamole is a platelet aggregation inhibitor with several mechanisms of action including (1) inhibition of platelet cAMP-phosphodiesterase; (2) potentiation of adenosine inhibition of platelet function by blocking reuptake by vascular and blood cells and subsequent degradation of adenosine; and (3) potentiation of prostacyclin (PGI2) antiaggregatory activity and enhancement of PGI2 biosynthesis.14Dipyridamole is usually given in combination with aspirin. DAPT with aspirin and dipyridamole has been studied in 6 trials in patients with ischemic stroke or TIA; in aggregate, these trials total 7795 patients and 1158 outcomes (composite of vascular death, nonfatal stroke, and nonfatal myocardial infarction).15 The pooled risk ratio was 0.82 (95% CI, 0.74–0.91) with no evidence for heterogeneity (I2=0%). Most of the data (79%) come from 2 trials: the ESPS-2 (European Stroke Prevention Study 2) and the ESPRIT (European/Australasian Stroke Prevention in Reversible Ischemia Trial).16,17 In the ESPS-2 trial, patients in the aspirin-dipyridamole arm received modified-release dipyridamole 200 mg twice daily in a fixed-dose combination with aspirin 25 mg twice daily.17 In ESPRIT, 83% of combination-allocated patients received modified-release dipyridamole and the dose of aspirin was allowed to vary between 30 and 325 mg/d in all patients.16 Both trials were positive for their primary end points.The most significant side effect of dipyridamole-containing preparations is headache, which occurs in ≈40% of patients initiating aspirin-dipyridamole.18 This adverse effect can be minimized by slow uptitration of therapy.19 In addition, headache drops rapidly in intensity for those patients who can push through therapy with ASA-dipyridamole.20 In a recent large randomized trial, 5.9% of patients permanently discontinued ASA-dipyridamole because of headache.21 However, it is likely that in real-world practice, discontinuation because of headache is more frequent; persistence is typically better in clinical trials because of the availability of counseling and close monitoring.In summary, aspirin-dipyridamole is an acceptable antiplatelet therapy for patients with noncardioembolic ischemic stroke or TIA and probably superior to aspirin alone. Disadvantages include twice-daily dosing and headache as a common adverse drug reaction.ClopidogrelClopidogrel is a thienopyridine compound whose active metabolite selectively inhibits the binding of adenosine diphosphate to its platelet P2Y12 receptor and the subsequent adenosine diphosphate-mediated activation of the glycoprotein (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation.22 In the acute setting, a loading dose of 300 to 600 mg is administered for more rapid onset of effect.23Clopidogrel was first tested in patients with cerebrovascular disease in the CAPRIE trial (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events), which enrolled 19 185 patients with atherosclerotic vascular disease, including 6431 with recent ischemic stroke (mean time from stroke onset to randomization, 53 days).24 Clopidogrel 75 mg/d was compared with aspirin 325 mg/d, with a primary outcome of ischemic stroke, myocardial infarction, or vascular death. Overall, there was a relative risk reduction of 8.7% favoring clopidogrel across all patients in the trial (95% CI, 0.3%–16.5%; P=0.043). For patients with stroke, there was a similar relative risk reduction of 7.3% favoring clopidogrel, which was nonsignificant (−5.7% to 18.7%; P=0.26). In all patients, there were similar rates of intracranial hemorrhage with aspirin versus clopidogrel (0.49% versus 0.35%, respectively; P=0.23) and higher rates of gastrointestinal hemorrhage with aspirin (2.66% versus 1.99%, P=0.05).In the MATCH trial (Management of Atherothrombosis With Clopidogrel in High-Risk Patients), the combination of clopidogrel and aspirin was compared with clopidogrel alone in 7599 patients with recent ischemic stroke or TIA and at least 1 additional vascular risk factor.25 The primary end point was the composite of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia (including rehospitalization for TIA, angina pectoris, or worsening peripheral arterial disease). The mean time from qualifying event to randomization was 27 days, and more than half of patients (53%) had small vessel disease as the cause of their qualifying event.In this trial, there was no evidence of significant benefit for the combination of clopidogrel and aspirin compared with clopidogrel alone (relative risk reduction, 6.4%; 95% CI, −4.6% to 16.3%; P=0.244).25 In addition, life-threatening bleeding was more frequent in the group assigned to DAPT versus clopidogrel alone (2.6% versus 1.3%, respectively; P<0.0001), as was major bleeding (2% versus 1%, respectively; P<0.0001). Primary intracranial hemorrhage and gastrointestinal hemorrhage were both more frequent with DAPT.These data are mirrored by the SPS3 trial (Secondary Prevention of Small Subcortical Strokes).26 A total of 3020 patients with recent symptomatic lacunar infarcts were randomized to clopidogrel or placebo; both groups received aspirin 325 mg daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. After a mean follow-up of 3.4 years, there was no reduction in recurrent stroke with DAPT compared with aspirin (hazard ratio, 0.92; 95% CI, 0.72–1.16), or in recurrent ischemic stroke, recurrent lacunar stroke, or disabling or fatal stroke. Major hemorrhage was nearly doubled with DAPT (2.1% per year versus 1.1% per year; P<0.001), and all-cause mortality was increased in the DAPT group (2.1% per year versus 1.4% per year; P=0.004). The increase in all-cause mortality was unexpected and could not be explained by fatal hemorrhage, which occurred in only 13 patients in the trial.In the CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance), 15 603 high-risk vascular patients (including 4320 patients who were enrolled with a qualifying diagnosis of documented cerebrovascular disease) were randomly assigned to receive clopidogrel plus low-dose aspirin (75–162 mg/d) or low-dose aspirin alone.27 The primary outcome was the composite of stroke, myocardial infarction, or vascular death. In the entire trial population, the relative risk for the primary outcome with DAPT versus aspirin monotherapy was 0.93 (95% CI, 0.83–1.05). Among the 4320 patients with a qualifying diagnosis of ischemic stroke or TIA, 233 (5.4%) experienced a stroke during follow-up, of whom 103 were randomly assigned to DAPT and 130 to aspirin monotherapy (relative risk, 0.80; 95% CI, 0.62–1.03).28 There was no evidence that DAPT changed the severity of stroke outcome events during follow-up.28Clopidogrel was compared with aspirin plus extended-release dipyridamole (ASA-ERDP) in the large PRoFESS trial (Prevention Regimen for Effectively Avoiding Second Strokes).21 Patients were enrolled at a median of 15 days from a qualifying ischemic stroke, with 40% of patients randomized within 10 days after the qualifying event. The primary outcome of recurrent stroke of any type occurred at a similar rate in both arms (8.8% in patients receiving clopidogrel and 9.0% in patients receiving ASA-ERDP; hazard ratio, 1.01 for ASA-ERDP; 95% CI, 0.92–1.11). The secondary composite outcome of stroke, myocardial infarction, or vascular death occurred in 13.1% of patients in each group (hazard ratio [HR] for ASA-ERDP, 0.99; 95% CI, 0.92–1.07). There were more major hemorrhagic events in the ASA-ERDP group (HR, 1.15; 95% CI, 1.00–1.32) and more intracranial hemorrhages (HR, 1.42; 95% CI, 1.11–1.83). In summary, although the trial did not meet the predefined criteria for noninferiority, ASA-ERDP and clopidogrel showed broadly similar efficacy at preventing vascular events across a mean follow-up of 2.5 years.The aforementioned trials are largely longer-term studies, with selection of patients at some distance from their acute event.21,24–26,28 Two trials have examined the efficacy of clopidogrel and aspirin DAPT in patients with acute ischemic stroke or TIA.10,11 In the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), combined clopidogrel (initial dose 300 mg, followed by 75 mg/d for 90 days) and low-dose aspirin (75 mg/d for the first 3 weeks) was compared with placebo plus aspirin (75 mg/d for 90 days) in 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA.11 The primary outcome of stroke (ischemic or hemorrhagic) during 90 days of follow-up occurred in 8.2% of patients in the clopidogrel-aspirin group and 11.7% of those in the aspirin monotherapy group (HR, 0.68; 95% CI, 0.57–0.81). Fatal or disabling stroke and ischemic stroke were both reduced. Concomitantly, there was no increase in moderate or severe hemorrhage or hemorrhagic stroke. It should be noted that this trial was conducted entirely in China, and the results might not be generalizable to other regions such as North America or Europe.However, these results are largely mirrored in the recent POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke).10 A total of 4881 patients were enrolled within 12 hours of an acute ischemic stroke with a score of ≤3 on the National Institutes of Health Stroke Scale or a high-risk TIA with a score of ≥4 on the ABCD2 scale. Patients were randomly assigned to receive clopidogrel (with a 600 mg loading dose) plus aspirin or aspirin alone. The primary outcome of major ischemic events (the composite of ischemic stroke, myocardial infarction, or death from an ischemic vascular event) occurred in 5.0% of the DAPT group and 6.5% of the aspirin monotherapy group (HR, 0.75; 95% CI, 0.59–0.95). The secondary outcome of ischemic stroke was also reduced (HR, 0.72; 95% CI, 0.56–0.92). Major hemorrhage occurred in 0.9% of the DAPT group and 0.4% of the aspirin group (HR, 2.32; 95% CI, 1.10–4.87), an increase largely because of nonfatal nonintracranial hemorrhage (HR, 2.45; 95% CI, 1.01–5.90). The benefit of clopidogrel plus aspirin was greater in the first 7 days and in the first 30 days than in the 90 days, whereas the risk of hemorrhage with DAPT was greater during the period from 8 to 90 days than during the first 7 days. The investigators estimate that for every 1000 patients treated with DAPT for a period of 90 days, treatment would prevent 15 ischemic strokes and cause 5 major hemorrhages.These data suggest benefit for DAPT (comprising clopidogrel and aspirin) for acute nondisabling noncardioembolic stroke and TIA, but the other trials reviewed here suggest lack of benefit in the longer term (and probable harm). The risk of recurrent stroke is highest within the first 90 days after an acute ischemic stroke or TIA, which at least partially explains the success of POINT and CHANCE.2TicagrelorTicagrelor is a reversible P2Y12 receptor antagonist, which unlike clopidogrel, does not require conversion from prodrug to active drug in the liver.29 Ticagrelor is reversible and short acting, so must be given twice daily.30 SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) tested the efficacy of ticagrelor (180 mg loading dose then 90 mg twice daily) versus aspirin in 13 199 patients with an acute nonsevere ischemic stroke or high-risk TIA.31 The primary outcome was the time to occurrence of stroke, myocardial infarction, or death within 90 days. The primary end point occurred in 6.7% of patients treated with ticagrelor versus 7.5% treated with aspirin (HR, 0.89; 95% CI, 0.78–1.01; P=0.07). Ischemic stroke occurred in 5.8% in the ticagrelor arm versus 6.7% in the aspirin arm (HR, 0.87; 95% CI, 0.76–1.00; nominal P=0.046). There were no differences in major bleeding, intracranial hemorrhage, or fatal bleeding. There were more discontinuations because of dyspnea and minor bleeding in the ticagrelor group. Permanent discontinuation of study drug occurred in 17.5% in the ticagrelor group, versus 14.7% in the aspirin group.In large artery disease, ticagrelor was substantially more efficacious.32 A total of 6.7% of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9.6%) of 1539 patients with ipsilateral stenosis in the aspirin group had a primary event within 90 days (HR, 0.68; 95% CI, 0.53–0.88). This is likely because of the predominance of white thrombus (rich in platelet aggregates) in the mechanism of stroke/TIA in large artery atherosclerosis.A recently published subgroup analysis from SOCRATES found that ticagrelor was effective at preventing the primary outcome in patients with a background history of aspirin use (HR, 0.76; 95% CI, 0.61–0.95; P=0.02).33 This will be tested in the forthcoming THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death), which is randomly assigning patients with TIA or acute ischemic stroke to combined aspirin and ticagrelor versus aspirin alone. The estimated completion date of this study is December 2019.DiscussionFor acute treatment of nonembolic TIA or ischemic stroke, 2 trials have convincingly demonstrated reductions in recurrent ischemic strokes with the combination of aspirin and clopidogrel (versus aspirin monotherapy), lasting 21 or 90 days.10,11 With a 90-day course of DAPT in POINT, prevention of ischemic stroke was only partially offset by the increase in major hemorrhage.10 These data are likely to change practice recommendations about the treatment of acute cerebrovascular ischemia. The 2018 American Heart Association/ASA guidelines for management of acute ischemic stroke, which were published before the POINT trial, give a IIa recommendation for DAPT in acute minor stroke on the basis of the CHANCE trial.4 This recommendation will likely be strengthened in the aftermath of POINT.For long-term prevention of recurrent vascular events in patients with a history of ischemic stroke or TIA, several options are available. These include aspirin, aspirin-dipyridamole, and clopidogrel. DAPT combining clopidogrel and aspirin has not convincingly demonstrated prevention of recurrent events in long-term prevention trials, whereas major hemorrhage is significantly increased (MATCH, SPS3, CHARISMA).25,26,28 Aspirin monotherapy has a strong track record in acute and chronic cerebrovascular ischemia but clearly does not prevent all recurrent events.9,12 Aspirin-dipyridamole and clopidogrel are acceptable alternatives to aspirin for long-term prevention and were compared directly in the PRoFESS trial (with little evidence of a difference in efficacy between them).21 The clinician should be aware that aspirin-dipyridamole has higher rates of discontinuation and noncompliance (because of headache) and monitor for these in clinical practice.Ticagrelor was compared directly with aspirin in the SOCRATES trial, which showed a strong trend toward lower stroke rates in patients assigned to ticagrelor in the acute setting.31 This difference was magnified in the subgroup of patients with atherosclerotic stroke.32 The ongoing THALES trial should better define the role of ticagrelor in acute cerebrovascular disease (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429). The combination of aspirin and ticagrelor is being compared with aspirin alone. This study is eagerly awaited and may change practice recommendations if it is positive.There are many limitations in the body of randomized trials evaluating antiplatelet therapy for the secondary prevention of ischemic stroke and TIA. There is no evidence on aspirin-dipyridamole or clopidogrel monotherapy in acute stroke/TIA. Similarly, there are no data on ticagrelor beyond 90 days after an ischemic stroke or TIA. There are also no data to answer the question of which antiplatelet to select in a patient who has a breakthrough event (acute stroke or TIA while already on antiplatelet therapy). Strategies are needed to ensure long-term adherence to antiplatelet therapies in patients after stroke or TIA.It is likely that many cases of major hemorrhage in patients taking antiplatelet therapy could be prevented through appropriate medical interventions. First, prompt diagnosis and treatment of Helicobacter pylori infection, as well as proton pump inhibition for those at high risk, is likely to prevent many cases of gastrointestinal hemorrhage. Li et al34 have estimated that half of the major hemorrhages in patients aged 75 years or older are upper gastrointestinal, outnumbering disabling or fatal intracerebral hemorrhage by 2.5:1. Second, most intracerebral hemorrhages could be prevented by effective blood pressure control.35 In the North American Symptomatic Carotid Endarterectomy Trial, strenuous efforts were made to achieve blood pressure control by overcoming therapeutic inertia.36 Every time an investigator failed to intensify antihypertensive therapy in a patient whose blood pressure was above target, the investigator received a reminder that the protocol must be followed. The result of this was that hemorrhagic strokes (including subarachnoid hemorrhages and lobar infarctions, which are not because of high blood pressure) were reduced to 0.5% of stroke, at a time when ≈20% of strokes were hemorrhagic.37DisclosuresDr Spence is an officer and shareholder of Vascularis Inc, a company seeking to market software for vascular risk reclassification based on measurement of carotid plaque burden. He received honoraria from Pfizer and BMS and also receives royalties on books from Vanderbilt University Press and McGraw-Hill Medical publishers. The other author reports no conflicts.FootnotesCorrespondence to Daniel G. Hackam, MD, PhD, Room 100K-2, Siebens Drake Bldg, 1400 Western Rd, London, ON N6G 2V2, Canada. Email [email protected]caReferences1. Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh S, et al; Global Burden of Diseases, Injuries and Risk Factors Study 2013 and Stroke Experts Writing Group. Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet Neurol. 2016; 15:913–924. doi: 10.1016/S1474-4422(16)30073-4CrossrefMedlineGoogle Scholar2. Amarenco P, Lavallée PC, Labreuche J, Albers GW, Bornstein NM, Canhão P, et al; TIAregistry.org Investigators. One-year risk of stroke after transient ischemic attack or minor stroke.N Engl J Med. 2016; 374:1533–1542. doi: 10.1056/NEJMoa1412981CrossrefMedlineGoogle Scholar3. Kernan WN, Ovbiagele B, Black HR, Bravata DM,

INTRODUCTION: Practice guidelines recommend that patients with peripheral artery disease receive antiplatelets, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). We sought to quantify the rates of prescribing these therapies in patients with peripheral artery disease in the literature. METHODS: We performed a systematic review and meta-analysis of treatment prescribing rates in observational studies containing peripheral artery disease patients published on or after the year 2000. We also assessed whether prescribing rates are increasing over time. RESULTS: A total of 86 studies were available for analysis. The aggregate sample size across all studies was 332,555. The pooled estimates for utilization of antiplatelets, statins, and ACE inhibitors or ARBs were 75% (95% confidence interval [CI], 71%-79%), 56% (95% CI, 52%-60%), and 53% (95% CI, 49%-58%), respectively. Stalin use was directly related to publication year (+2.0% per year, P < .001), but this was not the case for antiplatelets (P = .68) or ACE inhibitors or ARBs (P = .066). CONCLUSIONS: Although some improvement in statin prescribing has occurred in recent years, major practice gaps exist in the treatment of peripheral artery disease. Effective measures to close these gaps should be implemented. (C) 2018 Elsevier hug. All lights reserved.