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1.
Clin Chem ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225348

RESUMO

BACKGROUND: The use of biomarkers associated with cardiovascular disease (CVD) is established for diagnostic purposes. Cardiac troponins, as specific markers of myocardial injury, and natriuretic peptides, reflecting myocardial dilation, are routinely used for diagnosis in clinical practice. In addition, a substantial body of research has shed light on the ability of biomarkers to reflect the risk of future major cardiovascular events. Among biomarkers, troponin and members of the natriuretic peptide family have been investigated extensively in the general population, in those at higher risk, and in patients with known CVD. Both biomarkers have been shown to contribute substantially to statistical models describing cardiovascular risk, in addition to and independently of important clinical characteristics. The more precise identification of individuals at risk by appropriate use of biomarkers might lead to an earlier initiation of preventive therapies and potentially avoid significant events. CONTENT: We summarize the current evidence concerning risk prediction using cardiac biomarkers at different stages in the development of CVD and provide examples of observational studies and large-scale clinical trials testing such application. Beyond the focus on troponin and natriuretic peptides, we also discuss other important and emerging biomarkers in the field with potential for such application, including growth differentiation factor-15, soluble ST2 (alias for IL1RL1 [interleukin 1 receptor like 1), and galectin-3. SUMMARY: Incorporating biomarkers in risk prediction models might allow more precise identification of individuals at risk. Among the various biomarkers, cardiac troponin appears to be the most promising for prediction of future cardiovascular events in a wide variety of patient populations.

2.
Hypertension ; 76(6): 1945-1952, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33131315

RESUMO

High office blood pressure variability (OBPV) in midlife increases the risk of cardiovascular disease (CVD), but the impact of OBPV in older adults without previous CVD is unknown. We conducted a post hoc analysis of ASPREE trial (Aspirin in Reducing Events in the Elderly) participants aged 70-years and older (65 for US minorities) without history of CVD events at baseline, to examine risk of incident CVD associated with long-term, visit-to-visit OBPV. CVD was a prespecified, adjudicated secondary end point in ASPREE. We estimated OBPV using within-individual SD of mean systolic BP from baseline and first 2 annual visits. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% CI for associations with CVD events. In 16 475 participants who survived to year 2 without events, those in the highest tertile of OBPV had increased risk of CVD events after adjustment for multiple covariates, when compared with participants in the lowest tertile (HR, 1.36 [95% CI, 1.08-1.70]; P=0.01). Similar increased risk was observed for ischemic stroke (HR, 1.56 [95% CI, 1.04-2.33]; P=0.03), heart failure hospitalization, or death (HR, 1.73 [95% CI, 1.07-2.79]; P=0.02), and all-cause mortality (HR, 1.27 [95% CI, 1.04-1.54]; P=0.02). Findings were consistent when stratifying participants by use of antihypertensive drugs, while sensitivity analyses suggested the increased risk was especially for individuals whose BP was uncontrolled during the OBPV estimation period. Our findings support increased OBPV as a risk factor for CVD events in healthy older adults with, or without hypertension, who have not had such events previously. Registration- URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01038583; URL: https://www.isrctn.com; Unique identifiers: ISRCTN83772183.

3.
Stroke ; 51(10): 2901-2909, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32951537

RESUMO

BACKGROUND AND PURPOSE: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. METHODS: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. RESULTS: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. CONCLUSIONS: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.


Assuntos
Aspirina/uso terapêutico , Infarto Encefálico/prevenção & controle , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/prevenção & controle , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Idoso , Infarto Encefálico/complicações , Infarto Encefálico/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Quimioterapia Combinada , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Resultado do Tratamento
4.
Kidney Int ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32920022

RESUMO

The role of aspirin for primary prevention in older adults with chronic kidney disease (CKD) is unclear. Therefore, post hoc analysis of the randomized controlled trial ASPirin in Reducing Events in the Elderly (ASPREE) was undertaken comparing 100 mg of enteric-coated aspirin daily against matching placebo. Participants were community dwelling adults aged 70 years and older in Australia, 65 years and older in the United States, all free of a history of dementia or cardiovascular disease and of any disease expected to lead to death within five years. CKD was defined as present at baseline if either eGFR under 60mL/min/1.73m2 or urine albumin to creatinine ratio 3 mg/mmol or more. In 4758 participants with and 13004 without CKD, the rates of a composite endpoint (dementia, persistent physical disability or death), major adverse cardiovascular events and clinically significant bleeding in the CKD participants were almost double those without CKD. Aspirin's effects as estimated by hazard ratios were generally similar between CKD and non-CKD groups for dementia, persistent physical disability or death; major adverse cardiovascular events and clinically significant bleeding. Thus, in our analysis aspirin did not improve outcomes in older people while increasing the risk of bleeding, with mostly consistent effects in participants with and without CKD.

5.
J Am Coll Cardiol ; 76(1): 17-27, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32616158

RESUMO

BACKGROUND: There is clinical uncertainty regarding the benefits and harms of prescribing statins in healthy subjects ≥70 years of age. OBJECTIVES: The aim of this study was to examine the association among statins, dementia-free and disability-free survival, and cardiovascular disease (CVD) among healthy older adults using data from the ASPREE (Aspirin in Reducing Events in the Elderly) trial. METHODS: ASPREE was a randomized trial of 19,114 community-dwelling persons in Australia and the United States ≥65 years of age and free of documented CVD, dementia, and disability. Data were collected for those ≥70 years of age, and participants who took statins at baseline were compared with those who did not using Cox proportional hazards regression with inverse probability weighting. The primary outcome, referred to as "disability-free survival," was a composite of all-cause mortality, dementia, or persistent physical disability. Other outcomes included the individual components of the composite outcome, major adverse cardiovascular events, fatal CVD, myocardial infarction, and stroke. RESULTS: Of the 18,096 included participants (median age 74.2 years, 56.0% women), 5,629 took statins at baseline. Over a median follow-up period of 4.7 years, baseline statin use was not associated with disability-free survival or with the risk for all-cause mortality or dementia. However, it was associated with lower risks for physical disability and all cardiovascular outcomes. CONCLUSIONS: Among healthy community-dwelling adults ≥70 years of age, statin use may be beneficial for preventing physical disability and CVD but not beneficial for prolonging disability-free survival or avoiding death or dementia. Future clinical trials are needed to confirm these findings.

6.
Genet Med ; 22(11): 1883-1886, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32606442

RESUMO

PURPOSE: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. METHODS: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. RESULTS: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. CONCLUSION: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

7.
Clin Pharmacol Ther ; 108(6): 1289-1298, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32562573

RESUMO

The platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 variant has been identified as a genetic determinant of platelet aggregation in response to antiplatelet therapies, including aspirin. However, association with atherothrombotic cardiovascular events is less clear, with limited evidence from large trials. Here, we tested association of rs12041331 with cardiovascular events and aspirin use in a randomized trial population of healthy older individuals. We undertook post hoc analysis of 13,547 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, median age 74 years. Participants had no previous diagnosis of atherothrombotic cardiovascular disease at enrollment, and were randomized to either 100 mg daily low-dose aspirin or placebo for median 4.7 years follow-up. We used Cox proportional hazard regression to model the relationship between rs12041331 and the ASPREE primary cardiovascular disease (CVD) end point, and composites of major adverse cardiovascular events (MACE) and ischemic stroke (STROKE); and bleeding events; major hemorrhage (MHEM) and intracranial bleeding (ICB). We performed whole-population analysis using additive and dominant inheritance models, then stratified by treatment group. Interaction effects between genotypes and treatment group were examined. We observed no statistically significant association (P < 0.05) in the population, or by treatment group, between rs12041331 and cardiovascular or bleeding events in either model. We also found no significant interaction effects between rs12041331-A and treatment group, for CVD (P = 0.65), MACE (P = 0.32), STROKE (P = 0.56), MHEM (P = 0.59), or ICB (P = 0.56). The genetic variant PEAR1 rs12041331 is not associated with cardiovascular events in response to low-dose aspirin in a healthy elderly population.

9.
Am J Hypertens ; 33(4): 350-361, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31807750

RESUMO

BACKGROUND: Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP. METHODS: We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control. RESULTS: Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US). CONCLUSIONS: High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population. CLINICAL TRIALS REGISTRATION: NCT01038583.

10.
Eur Heart J ; 41(3): 371-380, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31209498

RESUMO

AIMS: Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. METHODS AND RESULTS: Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. CONCLUSION: A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.

11.
J Rheumatol ; 47(5): 748-760, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31154415

RESUMO

OBJECTIVE: Vascular pathology (changes in blood vessels) and osteoarthritis (OA) are both common chronic conditions associated with aging and obesity, but whether vascular pathology is a risk factor for OA is unclear. The aim of this study was to systematically review the evidence for an association between vascular pathology and risk of joint-specific OA. METHODS: Scopus, Ovid Medline, and EMBASE were searched from inception to February 2019. MeSH terms and keywords were used to identify studies examining the association between vascular pathology and OA. Two reviewers independently extracted the data and assessed the methodological quality. Qualitative evidence synthesis was performed. RESULTS: Fifteen studies with high (n = 3), fair (n = 3), or low (n = 9) quality were included. Features of vascular pathology included atherosclerosis, vascular stiffness, and endothelial dysfunction in different vascular beds. There was evidence for an association between vascular pathology and risk of hand OA in women but not men, and between vascular pathology and risk of knee OA in both men and women. Only 2 studies examined hip OA showing no association between vascular pathology and risk of hip OA. CONCLUSION: There is evidence suggesting an association between vascular pathology and risk of hand and knee OA, with a potential causal relationship for knee OA. Based on the limited evidence, it is hard to conclude an association for hip OA. Further stronger evidence is needed to determine whether there is a causal relationship.

12.
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
13.
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
14.
JCI Insight ; 4(13)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31292301

RESUMO

BACKGROUNDStatins have pleiotropic effects on lipid metabolism. The relationship between these effects and future cardiovascular events is unknown. We characterized the changes in lipids upon pravastatin treatment and defined the relationship with risk reduction for future cardiovascular events.METHODSPlasma lipids (n = 342) were measured in baseline and 1-year follow-up samples from a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study subcohort (n = 4991). The associations of changes in lipids with treatment and cardiovascular outcomes were investigated using linear and Cox regression. The effect of treatment on future cardiovascular outcomes was examined by the relative risk reduction (RRR).RESULTSPravastatin treatment was associated with changes in 206 lipids. Species containing arachidonic acid were positively associated while phosphatidylinositol species were negatively associated with pravastatin treatment. The RRR from pravastatin treatment for cardiovascular events decreased from 23.5% to 16.6% after adjustment for clinical risk factors and change in LDL-cholesterol (LDL-C) and to 3.0% after further adjustment for the change in the lipid ratio PI(36:2)/PC(38:4). Change in PI(36:2)/PC(38:4) mediated 58% of the treatment effect. Stratification of patients into quartiles of change in PI(36:2)/PC(38:4) indicated no benefit of pravastatin in the fourth quartile.CONCLUSIONThe change in PI(36:2)/PC(38:4) predicted benefit from pravastatin, independent of change in LDL-C, demonstrating its potential as a biomarker for monitoring the clinical benefit of statin treatment in secondary prevention.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry identifier ACTRN12616000535471.FUNDINGBristol-Myers Squibb; NHMRC grants 211086, 358395, and 1029754; NHMRC program grant 1149987; NHMRC fellowship 108026; and the Operational Infrastructure Support Program of the Victorian government of Australia.

15.
Gastroenterology ; 157(3): 682-691.e2, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31152740

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 × 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 (5 mg 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. ClinicalTrials.gov Number: NCT01776424.


Assuntos
Aspirina/administração & dosagem , Doenças Cardiovasculares/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Hemorragia Gastrointestinal/prevenção & controle , Pantoprazol/administração & dosagem , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Rivaroxabana/administração & dosagem , Idoso , Aspirina/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Método Duplo-Cego , Esquema de Medicação , Enterocolite Pseudomembranosa/induzido quimicamente , Enterocolite Pseudomembranosa/microbiologia , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pantoprazol/efeitos adversos , Doença Arterial Periférica/diagnóstico , Inibidores da Agregação de Plaquetas/efeitos adversos , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
Gastroenterology ; 157(2): 403-412.e5, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31054846

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.gov ID: NCT01776424.


Assuntos
Anticoagulantes/efeitos adversos , Doenças Cardiovasculares/prevenção & controle , Hemorragia Gastrointestinal/prevenção & controle , Pantoprazol/administração & dosagem , Úlcera Péptica/prevenção & controle , Inibidores da Bomba de Prótons/administração & dosagem , Administração Oral , Idoso , Anticoagulantes/administração & dosagem , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/epidemiologia , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Resultado do Tratamento
17.
Med J Aust ; 210(9): 409-415, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30907001

RESUMO

OBJECTIVES: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). DESIGN, SETTING, PARTICIPANTS: Men and women aged 55-60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. METHODS: Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55-60 years; reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball sampling) and by Facebook advertising. MAIN OUTCOME: Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. RESULTS: 21 526 of 154 992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders); early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball sampling did not increase recruitment. CONCLUSIONS: Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.


Assuntos
Publicidade/métodos , Seleção de Pacientes , Mídias Sociais , Austrália , Doenças Cardiovasculares/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Vacinas Pneumocócicas/uso terapêutico , Inquéritos e Questionários
19.
Int J Stroke ; 14(3): 270-281, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30058959

RESUMO

BACKGROUND: Covert vascular disease of the brain manifests as infarcts, white matter hyperintensities, and microbleeds on MRI. Their cumulative effect is often a decline in cognition, motor impairment, and psychiatric disorders. Preventive therapies for covert brain ischemia have not been established but represent a huge unmet clinical need. AIMS: The MRI substudy examines the effects of the antithrombotic regimens in COMPASS on incident covert brain infarcts (the primary outcome), white matter hyperintensities, and cognitive and functional status in a sample of consenting COMPASS participants without contraindications to MRI. METHODS: COMPASS is a randomized superiority trial testing rivaroxaban 2.5 mg bid plus acetylsalicylic acid 100 mg and rivaroxaban 5 mg bid against acetylsalicylic acid 100 mg per day for the combined endpoint of MI, stroke, and cardiovascular death in individuals with stable coronary artery disease or peripheral artery disease. T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near the termination of assigned antithrombotic therapy; biomarker and genetic samples at randomization and one month, and cognitive and functional assessment at randomization, after two years and at the end of study. RESULTS: Between March 2013 and May 2016, 1905 participants were recruited from 86 centers in 16 countries. Of these participants, 1760 underwent baseline MRI scans that were deemed technically adequate for interpretation. The mean age at entry of participants with interpretable MRI was 71 years and 23.5% were women. Coronary artery disease was present in 90.4% and 28.1% had peripheral artery disease. Brain infarcts were present in 34.8%, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities. The median Montreal Cognitive Assessment score was 26 (interquartile range 23-28). CONCLUSIONS: The COMPASS MRI substudy will examine the effect of the antithrombotic interventions on MRI-determined covert brain infarcts and cognition. Demonstration of a therapeutic effect of the antithrombotic regimens on brain infarcts would have implications for prevention of cognitive decline and provide insight into the pathogenesis of vascular cognitive decline.


Assuntos
Anticoagulantes/uso terapêutico , Infarto Encefálico/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/patologia , Transtornos Cognitivos/tratamento farmacológico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Infarto Encefálico/diagnóstico , Isquemia Encefálica/diagnóstico , Cognição , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico , Resultado do Tratamento
20.
Lancet ; 392(10155): 1311-1320, 2018 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-30293769

RESUMO

BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. FINDINGS: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. FUNDING: Novartis Pharma AG.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Lipoproteína(a)/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Lipoproteína(a)/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
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