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Does Lowering Low-Density Lipoprotein Cholesterol With Statin Restore Low Risk in Middle-Aged Adults? Analysis of the Observational MESA Study.
Liu, K, Wilkins, JT, Colangelo, LA, Lloyd-Jones, DM
Journal of the American Heart Association. 2021;(11):e019695
Abstract
Background It is unclear if statin therapy in midlife can restore low cardiovascular risk in hypercholesterolemic individuals. Methods and Results At baseline, we grouped 5687 MESA (Multi-Ethnic Study of Atherosclerosis) participants aged ≥50 years without clinical cardiovascular disease (CVD) by Adult Treatment Panel III statin treatment recommendation and statin treatment status. We used Cox regression to compare the risks for coronary heart disease and CVD between the untreated group with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL (reference) and other groups, adjusting for CVD risk factors. We also grouped participants by LDL-C level (< or ≥100 mg/dL), coronary artery calcium score (0 or >0 Agatston units), and statin status (untreated or treated) with the untreated LDL-C <100 mg/dL and coronary artery calcium=0 Agatston units as the reference. There were 567 coronary heart disease and 848 CVD events over 15 years of follow-up. The hazard ratios (HRs) for coronary heart disease and CVD in the group with statin-treated LDL-C <100 mg/dL were 1.16 (95% CI, 0.85-1.58) and 1.02 (95% CI, 0.78-1.32), respectively. However, participants with coronary artery calcium >0 Agatston units, treated to LDL-C <100 mg/dL had HRs of 2.6 (95% CI, 1.7-4.2) for coronary heart disease and 1.8 (95% CI, 1.2-2.6) for CVD. Conclusions Individuals treated with statins to LDL-C <100 mg/dL had similar levels of risk for atherosclerotic CVD as individuals with untreated LDL-C <100 mg/dL. However, individuals with coronary artery calcium >0 Agatston units have substantially higher risks despite lipid-lowering therapy, suggesting that statin treatment in midlife may not restore a low-risk state in primary prevention patients with established coronary atherosclerosis.
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Hypertensive Retinopathy and the Risk of Stroke Among Hypertensive Adults in China.
Chen, X, Liu, L, Liu, M, Huang, X, Meng, Y, She, H, Zhao, L, Zhang, J, Zhang, Y, Gu, X, et al
Investigative ophthalmology & visual science. 2021;(9):28
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PURPOSE This study aimed to investigate the association between hypertensive retinopathy and the risk of first stroke, examine possible effect modifiers in hypertensive patients, and test the appropriateness of the Keith-Wagener-Barker (KWB) classification for predicting stroke risk. METHODS In total, 9793 hypertensive participants (3727 males and 6066 females) without stroke history from the China Stroke Primary Prevention Trial were included in this study. The primary outcome was first stroke. RESULTS Over a median follow-up of 4.4 years, 592 participants experienced their first stroke (509 ischemic, 77 hemorrhagic, and six unclassifiable strokes). In total, 5590 participants were diagnosed with grade 1 retinopathy (57.08%), 1466 with grade 2 retinopathy (14.97%), 231 with grade 3 retinopathy (2.36%), and three with grade 4 retinopathy (0.03%). Grades 1 and 2 were merged and classified as mild retinopathy, and grades 3 and 4 were merged and classified as severe retinopathy. There was a significant positive association between hypertensive retinopathy and the risk of first stroke and first ischemic stroke, and no effect modifiers were found. The hazard ratios (HRs) for first stroke were as follows: mild versus no retinopathy, 1.26 (95% confidence interval [CI], 1.01-1.58, P = 0.040), and severe versus no retinopathy, 2.40 (95% CI, 1.49-3.84, P < 0.001). The HRs for ischemic stroke were as follows: severe versus no retinopathy, 2.35 (95% CI, 1.41-3.90, P = 0.001), and nonsignificantly increased HRs for mild versus no retinopathy, 1.26 (95% CI, 0.99-1.60, P = 0.057). CONCLUSIONS There was a significant positive association between hypertensive retinopathy and the risk of first stroke in patients with hypertension, indicating that hypertensive retinopathy may be a predictor of the risk of stroke. A simplified two-grade classification system based on the KWB classification is recommended for predicting stroke risk.
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Antihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Trial.
Bosch, J, Lonn, EM, Dagenais, GR, Gao, P, Lopez-Jaramillo, P, Zhu, J, Pais, P, Avezum, A, Sliwa, K, Chazova, IE, et al
Stroke. 2021;(8):2494-2501
Abstract
BACKGROUND AND PURPOSE The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups. METHODS Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed. RESULTS Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59–1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55–1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34–1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41–2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52–0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37–0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59–2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57–2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36–0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23–0.72]). CONCLUSIONS Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT00468923.
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Statin Trials, Cardiovascular Events, and Coronary Artery Calcification: Implications for a Trial-Based Approach to Statin Therapy in MESA.
Mortensen, MB, Falk, E, Li, D, Nasir, K, Blaha, MJ, Sandfort, V, Rodriguez, CJ, Ouyang, P, Budoff, M
JACC. Cardiovascular imaging. 2018;(2 Pt 1):221-230
Abstract
OBJECTIVES This study sought to determine whether coronary artery calcium (CAC) could be used to optimize statin allocation among individuals for whom trial-based evidence supports efficacy of statin therapy. BACKGROUND Recently, allocation of statins was proposed for primary prevention of atherosclerotic cardiovascular disease (ASCVD) based on proven efficacy from randomized controlled trials (RCTs) of statin therapy, a so-called trial-based approach. METHODS The study used data from MESA (Multi-Ethnic Study of Atherosclerosis) with 5,600 men and women, 45 to 84 years of age, and free of clinical ASCVD, lipid-lowering therapy, or missing information for risk factors at baseline examination. RESULTS During 10 years' follow-up, 354 ASCVD and 219 hard coronary heart disease (CHD) events occurred. Based on enrollment criteria for 7 RCTs of statin therapy in primary prevention, 73% of MESA participants (91% of those >55 years of age) were eligible for statin therapy according to a trial-based approach. Among those individuals, CAC = 0 was common (44%) and was associated with low rates of ASCVD and CHD (3.9 and 1.7, respectively, per 1,000 person-years). There was a graded increase in event rates with increasing CAC score, and in individuals with CAC >100 (27% of participants) the rates of ASCVD and CHD were 18.9 and 12.7, respectively. Consequently, the estimated number needed to treat (NNT) in 10 years to prevent 1 event varied greatly according to CAC score. For ASCVD events, the NNT was 87 for CAC = 0 and 19 for CAC >100. For CHD events, the NNT was 197 for CAC = 0 and 28 for CAC >100. CONCLUSIONS Most MESA participants qualified for trial-based primary prevention with statins. Among the individuals for whom trial-based evidence supports efficacy of statin therapy, CAC = 0 and CAC >100 were common and associated with low and high cardiovascular risks, respectively. This information may guide shared decision making aimed at targeting evidence-based statins to those who are likely to benefit the most.
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The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct.
Joseph, P, Pais, P, Dans, AL, Bosch, J, Xavier, D, Lopez-Jaramillo, P, Yusoff, K, Santoso, A, Talukder, S, Gamra, H, et al
American heart journal. 2018;:72-79
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BACKGROUND It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood-pressure agents and a statin [with or without aspirin]) in a single "polypill". However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial. METHODS TIPS-3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events. RESULTS The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk. CONCLUSION Results of the TIP-3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD.
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Effects of Lipid-Lowering and Antihypertensive Treatments in Addition to Healthy Lifestyles in Primary Prevention: An Analysis of the HOPE-3 Trial.
Dagenais, GR, Jung, H, Lonn, E, Bogaty, PM, Dehghan, M, Held, C, Avezum, A, Jansky, P, Keltai, M, Leiter, LA, et al
Journal of the American Heart Association. 2018;(15)
Abstract
BACKGROUND It is not clear whether the effects of lipid-lowering or antihypertensive medications are influenced by adherence to healthy lifestyle factors. We assessed the effects of both drug interventions in subgroups by the number of healthy lifestyle factors in participants in the HOPE-3 (Heart Outcomes Prevention Evaluation) trial. METHODS AND RESULTS In this primary prevention trial, 4 healthy lifestyle factors (nonsmoking status, physical activity, optimal body weight, and healthy diet) were recorded in 12 521 participants who were at intermediate risk of cardiovascular disease (CVD) and were randomized to rosuvastatin, candesartan/hydrochlorothiazide, their combination, or matched placebos. Median follow-up was 5.6 years. The outcome was a composite of CVD events. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. Participants with ≥2 healthy lifestyle factors had a lower rate of CVD compared with those with fewer factors (HR: 0.85; 95% CI, 0.73-1.00). Rosuvastatin reduced CVD events in participants with ≥2 healthy lifestyle factors (HR: 0.74; 95% CI, 0.62-0.90) and in participants with <2 factors (HR: 0.79; 95% CI, 0.61-1.01). Consistent results were observed with combination therapy (≥2 factors: HR: 0.74; 95% CI, 0.57-0.97; <2 factors: HR: 0.61; 95% CI, 0.43-0.88). Candesartan/hydrochlorothiazide tends to reduce CVD only in participants with <2 healthy lifestyle factors (HR: 0.78; 95% CI, 0.61-1.00). CONCLUSIONS Healthy lifestyles are associated with lower CVD. Rosuvastatin alone and combined with candesartan/hydrochlorothiazide is beneficial regardless of healthy lifestyle status; however, the benefit of antihypertensive treatment appears to be limited to patients with less healthy lifestyles. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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Assessing gaps in cholesterol treatment guidelines for primary prevention of cardiovascular disease based on available randomised clinical trial evidence: The Rotterdam Study.
Pavlović, J, Greenland, P, Deckers, JW, Kavousi, M, Hofman, A, Ikram, MA, Franco, OH, Leening, MJ
European journal of preventive cardiology. 2018;(4):420-431
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Background The purpose of this study was to determine how American College of Cardiology/American Heart Association (ACC/AHA) 2013 and European Society of Cardiology 2016 guidelines for the primary prevention of atherosclerotic cardiovascular disease (CVD) compare in reflecting the totality of accrued randomised clinical trial evidence for statin treatment at population level. Methods From 1997-2008, 7279 participants aged 45-75 years, free of atherosclerotic cardiovascular disease, from the population-based Rotterdam Study were included. For each participant, we compared eligibility for each one of 11 randomised clinical trials on statin use in primary prevention of CVD, with recommendations on lipid-lowering therapy from the ACC/AHA and European Society of Cardiology (ESC) guidelines. Atherosclerotic cardiovascular disease incidence and cardiovascular disease mortality rates were calculated. Results The proportion of participants eligible for each trial ranged from 0.4% for ALLHAT-LLT to 30.8% for MEGA. The likelihood of being recommended for lipid-lowering treatment was lowest for those eligible for low-to-intermediate risk RCTs (HOPE-3, MEGA, and JUPITER), and highest for high-risk individuals with diabetes (MRC/BHF HPS, CARDS, and ASPEN) or elderly PROSPER. Eligibility for an increasing number of randomised clinical trials correlated with a greater likelihood of being recommended lipid-lowering treatment by either guideline ( p < 0.001 for both guidelines). Conclusion Compared to RCTs done in high risk populations, randomised clinical trials targeting low-to-intermediate risk populations are less well-reflected in the ACC/AHA, and even less so in the ESC guideline recommendations. Importantly, the low-to-intermediate risk population targeted by HOPE-3, the most recent randomised clinical trial in this field, is not well-captured by the current European prevention guidelines and should be specifically considered in future iterations of the guidelines.
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Effect of Residential Lead-Hazard Interventions on Childhood Blood Lead Concentrations and Neurobehavioral Outcomes: A Randomized Clinical Trial.
Braun, JM, Hornung, R, Chen, A, Dietrich, KN, Jacobs, DE, Jones, R, Khoury, JC, Liddy-Hicks, S, Morgan, S, Vanderbeek, SB, et al
JAMA pediatrics. 2018;(10):934-942
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IMPORTANCE Childhood lead exposure is associated with neurobehavioral deficits. The effect of a residential lead hazard intervention on blood lead concentrations and neurobehavioral development remains unknown. OBJECTIVE To determine whether a comprehensive residential lead-exposure reduction intervention completed during pregnancy could decrease residential dust lead loadings, prevent elevated blood lead concentrations, and improve childhood neurobehavioral outcomes. DESIGN, SETTING, AND PARTICIPANTS This longitudinal, community-based randomized clinical trial of pregnant women and their children, the Health Outcomes and Measures of the Environment (HOME) Study, was conducted between March 1, 2003, and January 31, 2006. Pregnant women attending 1 of 9 prenatal care clinics affiliated with 3 hospitals in the Cincinnati, Ohio, metropolitan area were recruited. Of the 1263 eligible women, 468 (37.0%) agreed to participate and 355 women (75.8%) were randomized in this intention-to-treat analysis. Participants were randomly assigned to receive 1 of 2 interventions designed to reduce residential lead or injury hazards. Follow-up on children took place at 1, 2, 3, 4, 5, and 8 years of age. Data analysis was performed from September 2, 2017, to May 6, 2018. MAIN OUTCOMES AND MEASURES Residential dust lead loadings were measured at baseline and when children were 1 and 2 years of age. At 1, 2, 3, 4, 5, and 8 years of age, the children's blood lead concentrations as well as behavior, cognition, and executive functions were assessed. RESULTS Of the 355 women randomized, 174 (49.0%) were assigned to the intervention group (mean [SD] age at delivery, 30.1 (5.5) years; 119 [68.3%] self-identified as non-Hispanic white) and 181 (50.9%) to the control group (mean [SD] age at delivery, 29.2 [5.7] years; 123 [67.9%] self-identified as non-Hispanic white). The intervention reduced the dust lead loadings for the floor (24%; 95% CI, -43% to 1%), windowsill (40%; 95% CI, -60% to -11%), and window trough (47%; 95% CI, -68% to -10%) surfaces. The intervention did not statistically significantly reduce childhood blood lead concentrations (-6%; 95% CI, -17% to 6%; P = .29). Neurobehavioral test scores were not statistically different between children in the intervention group than those in the control group except for a reduction in anxiety scores in the intervention group (β = -1.6; 95% CI, -3.2 to -0.1; P = .04). CONCLUSIONS AND RELEVANCE Residential lead exposures, as well as blood lead concentrations in non-Hispanic black children, were reduced through a comprehensive lead-hazard intervention without elevating the lead body burden. However, this decrease did not result in substantive neurobehavioral improvements in children. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00129324.
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Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study).
Mahaffey, KW, Neal, B, Perkovic, V, de Zeeuw, D, Fulcher, G, Erondu, N, Shaw, W, Fabbrini, E, Sun, T, Li, Q, et al
Circulation. 2018;(4):323-334
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BACKGROUND Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation. METHODS The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death). RESULTS Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63). CONCLUSIONS Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.
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China Stroke Primary Prevention Trial: Visit-to-Visit Systolic Blood Pressure Variability Is an Independent Predictor of Primary Stroke in Hypertensive Patients.
Men, X, Sun, W, Fan, F, Zhao, M, Huang, X, Wang, Y, Liu, L, Liu, R, Sun, W, Peng, Q, et al
Journal of the American Heart Association. 2017;(3)
Abstract
BACKGROUND The optimal range of blood pressure variability remains unclear. We aimed to stratify the degree of risk of stroke based on visit-to-visit systolic blood pressure (SBP) variability in a large Chinese hypertensive population in 32 communities. METHODS AND RESULTS We retrospectively analyzed the data of 20 702 hypertensive patients from the China Stroke Primary Prevention Trial. The participants were randomized into 2 treatment groups to receive either enalapril or enalapril plus folic acid. Their blood pressures were measured every 3 months. The outcome was the first stroke. Three parameters of SBP variability were calculated: standard deviation, coefficient of variation, and average real variability. The records of first 4, 6, 8, 10 and 12 visits at which SBP was measured were used to calculate SBP variability and to predict subsequent stroke risk in adjusted Cox regression models. After median follow-up of 4.5 years, 597 patients had experienced stroke. Visit-to-visit SBP variability was an independent predictor of subsequent stroke (eg, the hazard ratio for the highest quintile of average real variability [22.67-61.07 mm Hg] over 6 visits was 1.55, 95% CI 1.07-2.25, P=0.021), independent of mean SBP over the follow-up period. Its value was more predictive when more blood pressure records were used. CONCLUSIONS Visit-to-visit SBP variability is an independent predictor of primary stroke in Chinese hypertensive patients. This predictive value depends on the number of blood pressure measurements used to calculate variability but is independent of mean SBP. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.