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1.
Lancet ; 396(10260): 1443-1451, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129395

RESUMO

The burden of stroke is higher in low-income and middle-income countries (LMICs) than in high-income countries and is rising. Even though there are global policies and guidelines for implementing stroke care, there are many challenges in setting up stroke services in LMICs. Despite these challenges, there are many models of stroke care available in LMICs-eg, multidisciplinary team care led by a stroke neurologist, specialist-led care by neurologists, physician-led care, hub and spoke models incorporating stroke telemedicine (ie, telestroke), and task sharing involving community health workers. Alternative strategies have been developed, such as reorganising the existing hospital infrastructure by training health professionals to implement protocol-driven care. The future challenge is to identify what elements of organised stroke care can be implemented to make the largest gain. Simple interventions such as swallowing assessments, bowel and bladder care, mobility assessments, and consistent secondary prevention can prove to be key elements to improving post-discharge morbidity and mortality in LMICs.

2.
N Engl J Med ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33186492

RESUMO

BACKGROUND: A polypill comprising statins, multiple blood-pressure-lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease. METHODS: Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly. We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed. RESULTS: A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo. The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10). The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups. CONCLUSIONS: Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk. (Funded by the Wellcome Trust and others; TIPS-3 ClinicalTrials.gov number, NCT01646437.).

3.
Eur. j. prev. cardiol ; 27(3): 1-12, Ago. 2020. gráfico, tabela
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1050001

RESUMO

Abstract Aims: Secondary prevention in patients with coronary artery disease and peripheral artery disease involves antithrombotic therapy and optimal control of cardiovascular risk factors. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study, adding low-dose rivaroxaban on top of aspirin lowered cardiovascular events, but there is limited data about risk factor control in secondary prevention. We studied the association between risk factor status and outcomes, and the impact of risk factor status on the treatment effect of rivaroxaban, in a large contemporary population of patients with coronary artery disease or peripheral artery disease. Methods and results: We reported ischemic events (cardiovascular death, stroke, or myocardial infarction) in participants from the randomized, double-blind COMPASS study by individual risk factor (blood pressure, smoking status, cholesterol level, presence of diabetes, body mass index, and level of physical activity), and by number of risk factors. We compared rates and hazard ratios of patients treated with rivaroxaban plus aspirin vs aspirin alone within each risk factor category and tested for interaction between risk factor status and antithrombotic regimen. Complete baseline risk factor status was available in 27,117 (99%) patients. Status and number of risk factors were both associated with increased risk of ischemic events. Rates of ischemic events (hazard ratio 2.2; 95% confidence interval 1.8­2.6) and cardiovascular death (hazard ratio 2.0; 1.5­2.7) were more than twofold higher in patients with 4­6 compared with 0­1 risk factors (p<0.0001 for both). Rivaroxaban reduced event rates independently of the number of risk factors (p interaction 0.93), with the largest absolute benefit in patients with the highest number of risk factors. Conclusion: More favorable risk factor status and low-dose rivaroxaban were independently associated with lower risk of cardiovascular events. (AU)


Assuntos
Doença da Artéria Coronariana , Prevenção Secundária
4.
Can J Anaesth ; 67(11): 1497-1506, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32767054

RESUMO

PURPOSE: Function describes an individual's ability to perform everyday activities. In the context of cardiac surgery, functional changes quantify the effect of surgery on one's day-to-day life. Decreases in regional cerebral oxygen saturation (rScO2) measured using near-infrared spectroscopy (NIRS) has been associated with postoperative cognitive decline but its relationship with function has not been studied. We sought to determine the feasibility of conducting a large observational study examining the relationship between decreases in rScO2 during cardiac surgery and postoperative functional decline. METHODS: We undertook a single-centre, pilot sub-study of the NeuroVISION-Cardiac Surgery pilot study, which included adults undergoing isolated coronary artery bypass grafting on cardiopulmonary bypass; all patients enrolled in NeuroVISION-Cardiac Surgery were included. Function was evaluated at baseline, 30 days, and three months using the Standardized Assessment of Global activities in the Elderly (SAGE) scale. Blinded NIRS monitors were affixed for the duration of surgery. Our feasibility outcomes were to recruit one patient per week, obtain complete NIRS data in ≥ 90%, obtain SAGE at all time-points in ≥ 90%, and determine the time required for NIRS data to be transcribed into case report forms. RESULTS: 49/50 patients enrolled in NeuroVISION-Cardiac Surgery were recruited over 48 weeks (1.02 patients/week). Of the 49 included patients, 49 (100%) had complete NIRS data and 44 (90%) had complete SAGE data. The time required for NIRS data collection was a mean (standard deviation) of 5.5 (1.8) min per patient. CONCLUSION: This pilot study shows the feasibility of conducting a large observational study examining the relationship between decreases in cerebral saturation during cardiac surgery and postoperative functional decline. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT04241289); registered 27 January 2020.

5.
Neurology ; 95(5): e480-e487, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32651298

RESUMO

OBJECTIVE: Subdural hematomas (SDHs) are an uncommon, but important, complication of anticoagulation therapy. We hypothesized that the risks of SDH would be similar during treatment with oral factor Xa inhibitors compared with aspirin. METHODS: We assessed the frequency and the effects of antithrombotic treatments on SDHs in the recent international Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial comparing aspirin 100 mg daily, rivaroxaban 5 mg twice daily, and rivaroxaban 2.5 mg twice daily plus aspirin. A systematic review/meta-analysis of randomized trials comparing oral factor Xa inhibitors vs aspirin on SDH risk was undertaken. RESULTS: Among 27,395 COMPASS participants, 28 patients with SDHs were identified (mean age 72 years). SDH-associated mortality was 7%. Incidence was 0.06 per 100 patient-years (11 SDH/17,492 years observation) during the mean 23-month follow-up among aspirin-assigned patients and did not differ significantly between treatments. Three additional randomized controlled trials including 16,177 participants reported a total of 14 SDHs with an incidence ranging from 0.06 to 0.1 per 100 patient-years. Factor Xa inhibitor use was not associated with an increased risk of SDH compared to aspirin (odds ratio, 0.97; 95% confidence interval, 0.52-1.81; I2 = 0%). CONCLUSION: The frequency of SDH was similar in all 3 treatment arms of the COMPASS trial. The COMPASS trial results markedly increase the available evidence from randomized comparisons of oral factor Xa inhibitors with aspirin regarding SDH. From available, albeit limited, evidence from 4 randomized trials, therapeutic dosages of factor Xa inhibitors do not appear to increase the risk of SDH compared with aspirin. CLINICAL TRIAL IDENTIFIER NUMBER: NCT01776424.


Assuntos
Inibidores do Fator Xa/efeitos adversos , Hematoma Subdural Intracraniano/induzido quimicamente , Rivaroxabana/efeitos adversos , Idoso , Aspirina/uso terapêutico , Aterosclerose/tratamento farmacológico , Feminino , Hematoma Subdural Intracraniano/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
JAMA ; 323(19): 1934-1944, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427305

RESUMO

Importance: The benefit of blood pressure lowering for the prevention of dementia or cognitive impairment is unclear. Objective: To determine the association of blood pressure lowering with dementia or cognitive impairment. Data Sources and Study Selection: Search of PubMed, EMBASE, and CENTRAL for randomized clinical trials published from database inception through December 31, 2019, that evaluated the association of blood pressure lowering on cognitive outcomes. The control groups consisted of either placebo, alternative antihypertensive agents, or higher blood pressure targets. Data Extraction and Synthesis: Data were screened and extracted independently by 2 authors. Random-effects meta-analysis models were used to report pooled treatment effects and CIs. Main Outcomes and Measures: The primary outcome was dementia or cognitive impairment. The secondary outcomes were cognitive decline and changes in cognitive test scores. Results: Fourteen randomized clinical trials were eligible for inclusion (96 158 participants), of which 12 reported the incidence of dementia (or composite of dementia and cognitive impairment [3 trials]) on follow-up and were included in the primary meta-analysis, 8 reported cognitive decline, and 8 reported changes in cognitive test scores. The mean (SD) age of trial participants was 69 (5.4) years and 40 617 (42.2%) were women. The mean systolic baseline blood pressure was 154 (14.9) mm Hg and the mean diastolic blood pressure was 83.3 (9.9) mm Hg. The mean duration of follow-up was 49.2 months. Blood pressure lowering with antihypertensive agents compared with control was significantly associated with a reduced risk of dementia or cognitive impairment (12 trials; 92 135 participants) (7.0% vs 7.5% of patients over a mean trial follow-up of 4.1 years; odds ratio [OR], 0.93 [95% CI, 0.88-0.98]; absolute risk reduction, 0.39% [95% CI, 0.09%-0.68%]; I2 = 0.0%) and cognitive decline (8 trials) (20.2% vs 21.1% of participants over a mean trial follow-up of 4.1 years; OR, 0.93 [95% CI, 0.88-0.99]; absolute risk reduction, 0.71% [95% CI, 0.19%-1.2%]; I2 = 36.1%). Blood pressure lowering was not significantly associated with a change in cognitive test scores. Conclusions and Relevance: In this meta-analysis of randomized clinical trials, blood pressure lowering with antihypertensive agents compared with control was significantly associated with a lower risk of incident dementia or cognitive impairment.


Assuntos
Anti-Hipertensivos/uso terapêutico , Disfunção Cognitiva/prevenção & controle , Demência/prevenção & controle , Hipertensão/tratamento farmacológico , Idoso , Pressão Sanguínea/efeitos dos fármacos , Disfunção Cognitiva/epidemiologia , Demência/epidemiologia , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco
7.
Circulation ; 141(23): 1841-1854, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32223318

RESUMO

BACKGROUND: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events. METHODS: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding. RESULTS: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P=0.002; and hazard ratio, 0.77, P=0.005, respectively, Pinteraction=0.77) and all-cause mortality (hazard ratio, 0.81, P=0.05; and hazard ratio, 0.84, P=0.09, respectively; Pinteraction=0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative Pinteraction<0.0001; 1.9% versus 0.6% for all-cause mortality, Pinteraction=0.02; 2.7% versus 1.7% for major vascular events, Pinteraction<0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative Pinteraction=0.001). CONCLUSIONS: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

8.
Cardiovasc Res ; 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32289159

RESUMO

AIMS: The COMPASS trial demonstrated that the combination of rivaroxaban 2.5mg twice-daily and aspirin 100mg once daily compared with aspirin 100 mg once daily reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD) by 24% during a mean follow-up of 23 months. We explored whether this effect varies by sex. METHODS AND RESULTS: The effects were examined in women and men using log-rank tests and Kaplan-Meier curve. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were obtained from stratified Cox proportional hazards models to explore subgroup effects including subgroup of women and men according to baseline modified REACH risk score. Of 27,395 patients randomized, 18,278 were allocated to receive rivaroxaban plus aspirin (n = 9,152) or aspirin alone (n = 9,126), and of these 22.1% were women. Women compared with men had similar incidence rates for MACE and major bleeding but borderline lower rates for MI (1.7% vs. 2.2%, p = 0.05). The effect of combination therapy compared with aspirin in women and men were consistent for MACE (women: 3.8% vs. 5.2%, HR 0.72, 95% CI 0.54-0.97; men: 4.2% vs. 5.5%, HR 0.76, 95% CI 0.66-0.89; p interaction 0.75) and major bleeding (women: 3.1% vs. 1.4%, HR 2.22, 95% CI 1.42-3.46; men: 3.2% vs. 2.0%, HR 1.60, 95% CI 1.29-1.97; p interaction 0.19). There was no significant interaction between randomized treatment and baseline modified REACH score above or below the median for MACE or major bleeding. CONCLUSIONS: In patients with stable CAD or PAD, the combination of rivaroxaban (2x2.5mg twice-daily) and aspirin compared with aspirin alone appears to produce consistent benefits in women and men, independent of baseline cardiovascular risk.

9.
Cardiovasc Res ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32142099

RESUMO

AIM: To examine the rates of VTE in high-income, upper middle-income and lower middle/low-income countries (World Bank Classification). METHODS AND RESULTS: We examined the rates of VTE in high-income, upper middle-income and lower middle/low-income countries (World Bank Classification) in a cohort derived from four prospective international studies (PURE, HOPE-3, ORIGIN, COMPASS). The primary outcome was a composite of pulmonary embolism, deep vein thrombosis and thrombophlebitis. We calculated age- and sex- standardized incidence rates (per 1000 person-years) and used a Cox frailty model adjusted for covariates to examine associations between the incidence of VTE and country income level. A total of 215,307 individuals (1·5 million person-years of follow-up) from high-income (n = 60,403), upper middle-income (n = 42,066) and lower middle/low-income (n = 112,838) countries were included. The age- and sex-standardized incidence rates of VTE per 1000 person-years in high-, upper middle- and lower middle/low-income countries were 0·87, 0·25 and 0·06, respectively. After adjusting for age, body mass index, smoking, antiplatelet therapy, anticoagulant therapy, education level, ethnicity, and incident cancer diagnosis or hospitalization, individuals from high-income and upper middle-income countries had a significantly higher risk of VTE than those from lower middle/low-income countries (hazard ratio [HR] 3·57, 95% confidence interval [CI] 2·40-5·30 and HR 2·27, 95%CI 1·59-3·23, respectively). The effect of country income level on VTE risk was markedly stronger in people with a lower BMI, hypertension, diabetes, non-white ethnicity and higher education. CONCLUSION: The rates of VTE are substantially higher in high-income than low-income countries. The factors underlying the increased VTE risk in higher income countries remain unknown. TRANSLATIONAL PERSPECTIVE: We investigated the burden of VTE by country income by combining information from 4 large prospective studies (215,307 individuals from 53 countries). This is the largest study on the global incidence of VTE published to date. We observed a higher incidence of VTE in richer compared to poorer countries. We also demonstrated that differences in rates of VTE are not explained by risk factors commonly associated with VTE. Further study is needed to understand whether these findings can be explained by differences in genetic or other markers, or whether they are due to differences in access to health care.

10.
Circulation ; 141(14): 1141-1151, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32178526

RESUMO

BACKGROUND: The COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies) demonstrated that dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily reduced the primary major adverse cardiovascular event (MACE) outcome of cardiovascular death, myocardial infarction, or stroke, as well as, mortality, in patients with chronic coronary syndromes or peripheral arterial disease. Whether this remains true in patients with a history of percutaneous coronary intervention (PCI) is unknown. METHODS: In a prespecified subgroup analysis from COMPASS, we examined the outcomes of patients with chronic coronary syndrome with or without a previous PCI treated with DPI versus aspirin alone. Among patients with a previous PCI, we studied the effects of treatment according to the timing of the previous PCI. RESULTS: Of the 27 395 patients in COMPASS, 16 560 patients with a chronic coronary syndrome were randomly assigned to DPI or aspirin, and, of these, 9862 (59.6%) had previous PCI (mean age 68.2±7.8, female 19.4%, diabetes mellitus 35.7%, previous myocardial infarction 74.8%, multivessel PCI 38.0%). Average time from PCI to randomization was 5.4 years (SD, 4.4) and follow-up was 1.98 (SD, 0.72) years. Regardless of previous PCI, DPI versus aspirin produced consistent reductions in MACE (PCI: 4.0% versus 5.5%; hazard ratio [HR], 0.74 [95% CI, 0.61-0.88]; no PCI: 4.4% versus 5.7%; HR, 0.76 [95% CI, 0.61-0.94], P-interaction=0.85) and mortality (PCI: 2.5% versus 3.5%; HR, 0.73 [95% CI, 0.58-0.92]; no PCI: 4.1% versus 5.0%; HR, 0.80 [95% CI, 0.64-1.00], P-interaction=0.59), but increased major bleeding (PCI: 3.3% versus 2.0%; HR, 1.72 [95% CI, 1.34-2.21]; no PCI: 2.9% versus 1.8%; HR, 1.58 [95% CI, 1.15-2.17], P-interaction=0.68). In those with previous PCI, DPI compared with aspirin produced consistent (robust) reductions in MACE irrespective of time since previous PCI (as early as 1 year and as far as 10 years; P-interaction=0.65), irrespective of having a previous myocardial infarction (P-interaction=0.64). CONCLUSIONS: DPI compared with aspirin produced consistent reductions in MACE and mortality but with increased major bleeding with or without previous PCI. Among those with previous PCI 1 year and beyond, the effects on MACE and mortality were consistent irrespective of time since last PCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

11.
J Bone Joint Surg Am ; 102(10): 880-888, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32118652

RESUMO

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is common and of prognostic importance. Little is known about MINS in orthopaedic surgery. The diagnostic criterion for MINS was a level of ≥0.03 ng/mL on a non-high-sensitivity troponin T (TnT) assay due to myocardial ischemia. METHODS: We undertook an international, prospective study of 15,103 patients ≥45 years of age who had inpatient noncardiac surgery; 3,092 underwent orthopaedic surgery. Non-high-sensitivity TnT assays were performed on postoperative days 0, 1, 2, and 3. Among orthopaedic patients, we determined (1) the prognostic relevance of the MINS diagnostic criteria, (2) the 30-day mortality rate for those with and without MINS, and (3) the probable proportion of MINS cases that would go undetected without troponin monitoring because of a lack of an ischemic symptom. RESULTS: Three hundred and sixty-seven orthopaedic patients (11.9%) had MINS. MINS was associated independently with 30-day mortality including among those who had had orthopaedic surgery. Orthopaedic patients without and with MINS had a 30-day mortality rate of 1.0% and 9.8%, respectively (odds ratio [OR], 11.28; 95% confidence interval [CI], 6.72 to 18.92). The 30-day mortality rate was increased for patients with MINS who had an ischemic feature (i.e., symptoms, or evidence of ischemia on electrocardiography or imaging) (OR, 18.25; 95% CI, 10.06 to 33.10) and for those who did not have an ischemic feature (OR, 7.35; 95% CI, 3.37 to 16.01). The proportion of orthopaedic patients with MINS who were asymptomatic and in whom the myocardial injury would have probably gone undetected without TnT monitoring was 81.3% (95% CI, 76.3% to 85.4%). CONCLUSIONS: One in 8 orthopaedic patients in our study had MINS, and MINS was associated with a higher mortality rate regardless of symptoms. Troponin levels should be measured after surgery in at-risk patients because most MINS cases (>80%) are asymptomatic and would go undetected without routine measurements. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

12.
Diabetes Care ; 43(4): 835-842, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019855

RESUMO

OBJECTIVE: To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS: A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n = 31,200). RESULTS: Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89-0.95]; P = 1.79 × 10-7). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; P = 8.73 × 10-4). After standardization, the ACE GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07-0.51] vs. 0.76 [0.60-0.97], respectively; P = 0.007 for difference). CONCLUSIONS: These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice.

13.
Eur J Prev Cardiol ; 27(3): 296-307, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31615291

RESUMO

AIMS: Secondary prevention in patients with coronary artery disease and peripheral artery disease involves antithrombotic therapy and optimal control of cardiovascular risk factors. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study, adding low-dose rivaroxaban on top of aspirin lowered cardiovascular events, but there is limited data about risk factor control in secondary prevention. We studied the association between risk factor status and outcomes, and the impact of risk factor status on the treatment effect of rivaroxaban, in a large contemporary population of patients with coronary artery disease or peripheral artery disease. METHODS AND RESULTS: We reported ischemic events (cardiovascular death, stroke, or myocardial infarction) in participants from the randomized, double-blind COMPASS study by individual risk factor (blood pressure, smoking status, cholesterol level, presence of diabetes, body mass index, and level of physical activity), and by number of risk factors. We compared rates and hazard ratios of patients treated with rivaroxaban plus aspirin vs aspirin alone within each risk factor category and tested for interaction between risk factor status and antithrombotic regimen. Complete baseline risk factor status was available in 27,117 (99%) patients. Status and number of risk factors were both associated with increased risk of ischemic events. Rates of ischemic events (hazard ratio 2.2; 95% confidence interval 1.8-2.6) and cardiovascular death (hazard ratio 2.0; 1.5-2.7) were more than twofold higher in patients with 4-6 compared with 0-1 risk factors (p < 0.0001 for both). Rivaroxaban reduced event rates independently of the number of risk factors (p interaction 0.93), with the largest absolute benefit in patients with the highest number of risk factors. CONCLUSION: More favorable risk factor status and low-dose rivaroxaban were independently associated with lower risk of cardiovascular events.

14.
Age Ageing ; 49(2): 154-160, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31830268

RESUMO

New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, cardiovascular trials have successfully discovered treatments with moderate but worthwhile effects to prevent heart attack and stroke. The design of these trials may hold lessons for the dementia prevention. Here we outline suitable populations, interventions and outcomes for large simple trials in dementia prevention. We consider what features are needed to maximise efficiency. Populations could be selected by age, clinical or genetic risk factors or clinical presentation. Patients and their families prioritise functional and clinical outcomes over cognitive scores and levels of biomarkers. Loss of particular functions or dementia diagnoses therefore are most meaningful to participants and potential patients and can be measured in large trials. The size of the population and duration of follow-up needed for dementia prevention trials will be a major challenge and will need collaboration between many clinical investigators, funders and patient organisations.

15.
JAMA Neurol ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31524941

RESUMO

Importance: The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized clinical trial was stopped early owing to the efficacy of low-dose rivaroxaban plus aspirin in preventing major cardiovascular events. The main reason for early trial termination was the effect of combination therapy on reducing ischemic strokes. Objective: To analyze the association between low-dose rivaroxaban with or without aspirin and different ischemic stroke subtypes. Design, Setting, and Participants: This is a secondary analysis of a multicenter, double-blind, randomized, placebo-controlled study that was performed in 33 countries from March 12, 2013, to May 10, 2016. Patients with stable atherosclerotic vascular disease were eligible, and a total of 27 395 participants were randomized and followed up to February 6, 2017. All first ischemic strokes and uncertain strokes that occurred by this date were adjudicated using TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. The analysis of ischemic stroke subtypes was evaluated using an intention-to-treat principle. Statistical analysis was performed from March 12, 2013, to February 6, 2017. Interventions: Participants received rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day). Main Outcomes and Measures: Risk of ischemic stroke subtypes during follow-up. Results: A total of 291 patients (66 women; mean [SD] age, 69.4 [8.5] years; 43 [14.8%] had a previous nonlacunar stroke) experienced an ischemic stroke. During the study, 49 patients (16.8%) received a diagnosis of atrial fibrillation. Applying TOAST criteria, 59 strokes (20.3%) were cardioembolic, 54 strokes (18.6%) were secondary to greater than 50% stenosis of the ipsilateral internal carotid artery, 42 strokes (14.4%) had a negative evaluation that met criteria for embolic stroke of undetermined source, and 21 strokes (7.2%) were secondary to small vessel disease. There were significantly fewer cardioembolic strokes (hazard ratio [HR], 0.40 [95% CI, 0.20-0.78]; P = .005) and embolic strokes of undetermined source (HR, 0.30 [95% CI, 0.12-0.74]; P = .006) in the combination therapy group compared with the aspirin-only group. A trend for reduction in strokes secondary to small vessel disease (HR, 0.36 [95% CI, 0.12-1.14]; P = .07) was not statistically significant. No significant difference was observed between the 2 groups in strokes secondary to greater than 50% carotid artery stenosis (HR, 0.85 [95% CI, 0.45-1.60]; P = .61). Rivaroxaban, 5 mg, twice daily showed a trend for reducing cardioembolic strokes compared with aspirin (HR, 0.57 [95% CI, 0.31-1.03]; P = .06) but was not associated with reducing other stroke subtypes. Conclusions and Relevance: For patients with systemic atherosclerosis, low-dose rivaroxaban plus aspirin was associated with large, significant reductions in cardioembolic strokes and embolic strokes of undetermined source. However, these results of exploratory analysis need to be independently confirmed before influencing clinical practice. Trial Registration: ClinicalTrials.gov identifier: NCT01776424.

16.
Eur Heart J ; 40(46): 3771-3778a, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31504399

RESUMO

AIMS : Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease. METHODS AND RESULTS : Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months). CONCLUSION : There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.

17.
Circulation ; 140(7): 529-537, Aug. 13, 2019. ilus, tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1015340

RESUMO

BACKGROUND: Patients with chronic coronary artery disease or peripheral artery disease and history of heart failure (HF) are at high risk for major adverse cardiovascular events. We explored the effects of rivaroxaban with or without aspirin in these patients. METHODS: The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized 27 395 participants with chronic coronary artery disease or peripheral artery disease to rivaroxaban 2.5mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg alone. Patients with New York Heart Association functional class III or IV HF or left ventricular ejection fraction (EF) <30% were excluded. The primary major adverse cardiovascular events outcome comprised cardiovascular death, stroke, or myocardial infarction, and the primary safety outcome was major bleeding using modified International Society of Thrombosis and Haemostasis criteria. Investigators recorded a history of HF and EF at baseline, if available. We examined the effects of rivaroxaban on major adverse cardiovascular events and major bleeding in patients with or without a history of HF and an EF <40% or >/=40% at baseline. RESULTS: Of the 5902 participants (22%) with a history of HF, 4971 (84%) had EF recorded at baseline, and 12% had EF <40%. Rivaroxaban and aspirin had similar relative reduction in major adverse cardiovascular events compared with aspirin in participants with HF (5.5% versus 7.9%; hazard ratio [HR], 0.68; 95% CI, 0.53-0.86) and those without HF (3.8% versus 4.7%; HR, 0.79; 95% CI, 0.68-0.93; P for interaction 0.28) but larger absolute risk reduction in those with HF (HF absolute risk reduction 2.4%, number needed to treat=42; no HF absolute risk reduction 1.0%, number needed to treat=103). The primary major adverse cardiovascular events outcome was not statistically different between those with EF <40% (HR, 0.88; 95% CI, 0.55-1.42) and >/=40% (HR, 0.81; 95% CI, 0.67-0.98; P for interaction 0.36). The excesso hazard for major bleeding was not different in participants with HF (2.5% versus 1.8%; HR, 1.36; 95% CI, 0.88-2.09) than in those without HF (3.3% versus 1.9%; HR, 1.79; 95% CI, 1.45-2.21; P for interaction 0.26). There were no significant differences in the primary outcomes with rivaroxaban alone. CONCLUSIONS: In patients with chronic coronary artery disease or peripheral artery disease and a history of mild or moderate HF, combination rivaroxaban and aspirin compared with aspirin alone produces similar relative but larger absolute benefits than in those without HF.(AU)


Assuntos
Doenças Cardiovasculares , Aspirina , Doença das Coronárias , Doença Arterial Periférica , Rivaroxabana , Insuficiência Cardíaca
18.
Gastroenterology ; 157(2): 403-412, Aug., 2019. tabela, grafico
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1022748

RESUMO

BACKGROUND & AIMS: Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk. METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation. RESULTS: There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528).CONCLUSIONS: In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials. (AU)


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/prevenção & controle , Aspirina/administração & dosagem , Método Duplo-Cego , Relação Dose-Resposta a Droga , Hemorragia Gastrointestinal/prevenção & controle , Anticoagulantes/administração & dosagem
19.
Gastroenterology ; 157(3): 682-691, ago., 30 2019. ilus, tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1015771

RESUMO

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial. METHODS: We performed a 3 x 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up. RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant. CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. (AU)


Assuntos
Bactérias , Doenças Cardiovasculares , Aspirina
20.
J Am Coll Cardiol ; 73(25): 3271-3280, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31248548

RESUMO

BACKGROUND: The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease. OBJECTIVES: The purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy. METHODS: COMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit. RESULTS: High-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months. CONCLUSIONS: In patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.


Assuntos
Aspirina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Inibidores do Fator Xa/uso terapêutico , Fibrinolíticos/uso terapêutico , Rivaroxabana/uso terapêutico , Idoso , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco
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