@article {592, title = {Survival versus years of healthy life: which is more powerful as a study outcome?}, journal = {Control Clin Trials}, volume = {20}, year = {1999}, month = {1999 Jun}, pages = {267-79}, abstract = {

Studies of interventions that are intended to improve patients{\textquoteright} health are often evaluated with survival as the primary outcome, even when a measure adjusted for quality of survival, such as years of healthy life (YHL), would seem more appropriate. The purpose of this article is to determine whether studies based on survival are more or less powerful than studies based on YHL in clinical trials where either measure might be appropriate. We used data from the Cardiovascular Health Study (CHS) to estimate the sample size that would be needed in studies of 156 different health conditions, for the two outcome measures. The median sample size for a 5-year study was 687 if survival was the endpoint and 484 for YHL. YHL usually required lower sample sizes than survival, although survival was more powerful for some health conditions. We also found that lengthy studies, and studies with many follow-up measures per person, did not have appreciably higher power than less intensive studies. We conclude that clinical investigations in which the goal is to improve health may often be performed more efficiently with YHL rather than survival as the primary outcome measure. Such studies can be short in duration, with relatively few measures per person of health status.

}, keywords = {Aged, Angina Pectoris, Female, Follow-Up Studies, Health Status, Humans, Life Expectancy, Male, Quality-Adjusted Life Years, Randomized Controlled Trials as Topic, Research Design, Sample Size, Survival Analysis, Time Factors, Treatment Outcome}, issn = {0197-2456}, doi = {10.1016/s0197-2456(98)00062-2}, author = {Diehr, P and Patrick, D L and Burke, G L and Williamson, J} } @article {761, title = {The association between the length of the QT interval and mortality in the Cardiovascular Health Study.}, journal = {Am J Med}, volume = {115}, year = {2003}, month = {2003 Dec 15}, pages = {689-94}, abstract = {

PURPOSE: A long QT interval is a risk factor for arrhythmic events and sudden death. Whether moderate QT prolongation is associated with clinical events in community-dwelling elderly patients is uncertain.

METHODS: We measured the QT interval in a population-based sample of 5888 men and women at least 65 years of age who were participants in the Cardiovascular Health Study. The association between Bazett{\textquoteright}s rate-corrected QT (QTc, in ms) and mortality during the subsequent 10 years was evaluated. We stratified participants by the presence or absence of coronary heart disease status at baseline, and adjusted for coronary heart disease risk factors.

RESULTS: The rates of all-cause and coronary heart disease mortality were greater in participants with longer QTc intervals. Among participants without known coronary heart disease, those whose QTc interval was >450 ms were at increased risk of all-cause mortality (relative risk [RR] = 1.34; 95\% confidence interval [CI]: 1.07 to 1.67) and coronary heart disease mortality (RR = 1.6; 95\% CI: 1.0 to 2.5) when compared with participants whose QTc interval was <410 ms. The associations were stronger among those with known coronary heart disease (RR for all-cause mortality = 2.3; 95\% CI: 1.6 to 3.3; and RR for coronary heart disease mortality = 2.0; 95\% CI: 1.1 to 3.7).

CONCLUSIONS: The QT interval from the standard electrocardiograms is of value for identification of elderly persons at increased risk of coronary heart disease and total mortality. A QTc interval >450 ms should prompt clinical evaluation and possible interventions to reduce the risk of coronary events.

}, keywords = {Aged, Arrhythmias, Cardiac, Cause of Death, Coronary Disease, Electrocardiography, Female, Follow-Up Studies, Heart Rate, Humans, Male, Randomized Controlled Trials as Topic, Risk Factors, Statistics as Topic, Survival Analysis, United States}, issn = {0002-9343}, doi = {10.1016/j.amjmed.2003.07.014}, author = {Robbins, John and Nelson, Jennifer Clark and Rautaharju, Pentti M and Gottdiener, John S} } @article {1113, title = {External validity of the cardiovascular health study: a comparison with the Medicare population.}, journal = {Med Care}, volume = {47}, year = {2009}, month = {2009 Aug}, pages = {916-23}, abstract = {

BACKGROUND: The Cardiovascular Health Study (CHS), a population-based prospective cohort study, has been used to identify major risk factors associated with cardiovascular disease and stroke in the elderly.

OBJECTIVE: To assess the external validity of the CHS.

RESEARCH DESIGN: Comparison of the CHS cohort to a national cohort of Medicare beneficiaries and to Medicare beneficiaries residing in the CHS geographic regions.

SUBJECTS: CHS participants and a 5\% sample of Medicare beneficiaries.

MEASURES: Demographic and administrative characteristics, comorbid conditions, resource use, and mortality.

RESULTS: Compared with both Medicare cohorts, the CHS cohort was older and included more men and African American participants. CHS participants were more likely to be enrolled in Medicare managed care than beneficiaries in the national Medicare cohort. Compared with the Medicare cohorts, mortality in the CHS was more than 40\% lower at 1 year, approximately 25\% lower at 5 years, and approximately 15\% lower at 10 years. There were minimal differences in comorbid conditions and health care resource use.

CONCLUSION: The CHS cohort is comparable with the Medicare population, particularly with regard to comorbid conditions and resource use, but had lower mortality. The difference in mortality may reflect the CHS recruitment strategy or volunteer bias. These findings suggest it may not be appropriate to project absolute rates of disease and outcomes based on CHS data to the entire Medicare population. However, there is no reason to expect that the relative risks associated with physiologic processes identified by CHS data would differ for nonparticipants.

}, keywords = {Aged, Cardiovascular Diseases, Cohort Studies, Comorbidity, Female, Humans, Male, Medicare, Randomized Controlled Trials as Topic, Reproducibility of Results, Socioeconomic Factors, United States}, issn = {1537-1948}, doi = {10.1097/MLR.0b013e318197b104}, author = {DiMartino, Lisa D and Hammill, Bradley G and Curtis, Lesley H and Gottdiener, John S and Manolio, Teri A and Powe, Neil R and Schulman, Kevin A} } @article {1173, title = {Intravenous tissue plasminogen activator and stroke in the elderly.}, journal = {Am J Emerg Med}, volume = {28}, year = {2010}, month = {2010 Mar}, pages = {359-63}, abstract = {

OBJECTIVE: Since publication in 1995 of the National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke, the benefit and frequency of use of IV tPA in the elderly have remained uncertain.

METHODS: We obtained data from the NINDS trial to summarize outcomes for randomized subjects older than 80 years. We used data from the Cardiovascular Health Study, a cohort study of 5888 elderly participants from 4 US communities followed longitudinally for stroke since 1989 to estimate the use of and hospital outcome after IV tPA in older adults following publication of the trial in 1995.

RESULTS: In the NINDS trial, 44 subjects older than 80 years were randomized, and their 3-month functional outcomes were not significantly improved with IV tPA. Of 25 randomized to IV tPA, 4 experienced symptomatic intracranial hemorrhages within 36 hours of treatment. Compared with younger patients, older patients were 2.87 times more likely to experience a symptomatic intracranial hemorrhage within 36 hours of IV tPA (95\% confidence interval, 1.04-7.93). Of 227 Cardiovascular Health Study participants hospitalized for ischemic stroke between 1995 and 2002, seven, whose mean age was 84 years, were treated with IV tPA (3.1\%; 95\% confidence interval 1.2-6.2). Two had symptomatic intracranial hemorrhages, 3 failed to improve, and 2 of the 7 had good outcomes.

CONCLUSIONS: These data highlight the need to clarify the risk-benefit profile of IV tPA in ischemic stroke victims who are older than 80 years.

}, keywords = {Aged, 80 and over, Female, Fibrinolytic Agents, Humans, Longitudinal Studies, Male, Placebos, Randomized Controlled Trials as Topic, Stroke, Tissue Plasminogen Activator, Treatment Outcome, United States}, issn = {1532-8171}, doi = {10.1016/j.ajem.2009.01.025}, author = {Longstreth, W T and Katz, Ronit and Tirschwell, David L and Cushman, Mary and Psaty, Bruce M} } @article {6340, title = {Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials.}, journal = {Am J Kidney Dis}, volume = {64}, year = {2014}, month = {2014 Aug}, pages = {187-97}, abstract = {

BACKGROUND: Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs.

STUDY DESIGN: Cross-sectional study.

SETTING \& PARTICIPANTS: 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).

PREDICTOR: eGFR.

OUTCOME: Circulating 24,25(OH)2D3 concentration.

MEASUREMENTS: GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.

RESULTS: Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95\% CI, 2.01-2.10), 1.77 (95\% CI, 1.74-1.81), 1.55 (95\% CI, 1.48-1.62), 1.17 (95\% CI, 1.05-1.29), 0.92 (95\% CI, 0.74-1.10), 0.61 (95\% CI, 0.22-1.00), and 0.37 (95\% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs>=90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95\% CI, 2.87-2.96), 2.68 (95\% CI, 2.64-2.72), 2.35 (95\% CI, 2.26-2.45), 1.92 (95\% CI, 1.74-2.10), 1.69 (95\% CI, 1.43-1.95), 1.14 (95\% CI, 0.62-1.66), and 1.04 (95\% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.

LIMITATIONS: Lack of direct pharmacokinetic measurements of vitamin D catabolism.

CONCLUSIONS: Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.

}, keywords = {24,25-Dihydroxyvitamin D 3, Adult, Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Observational Studies as Topic, Randomized Controlled Trials as Topic, Young Adult}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2014.02.015}, author = {de Boer, Ian H and Sachs, Michael C and Chonchol, Michel and Himmelfarb, Jonathan and Hoofnagle, Andrew N and Ix, Joachim H and Kremsdorf, Robin A and Lin, Yvonne S and Mehrotra, Rajnish and Robinson-Cohen, Cassianne and Siscovick, David S and Steffes, Michael W and Thummel, Kenneth E and Tracy, Russell P and Wang, Zhican and Kestenbaum, Bryan} } @article {6863, title = {HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.}, journal = {Lancet}, volume = {385}, year = {2015}, month = {2015 Jan 24}, pages = {351-61}, abstract = {

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.

FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0{\textperiodcentered}06 mmol/L (95\% CI 0{\textperiodcentered}05-0{\textperiodcentered}07) lower LDL cholesterol and higher body weight (0{\textperiodcentered}30 kg, 0{\textperiodcentered}18-0{\textperiodcentered}43), waist circumference (0{\textperiodcentered}32 cm, 0{\textperiodcentered}16-0{\textperiodcentered}47), plasma insulin concentration (1{\textperiodcentered}62\%, 0{\textperiodcentered}53-2{\textperiodcentered}72), and plasma glucose concentration (0{\textperiodcentered}23\%, 0{\textperiodcentered}02-0{\textperiodcentered}44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1{\textperiodcentered}02, 95\% CI 1{\textperiodcentered}00-1{\textperiodcentered}05); the rs12916-T allele association was consistent (1{\textperiodcentered}06, 1{\textperiodcentered}03-1{\textperiodcentered}09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0{\textperiodcentered}92 mmol/L (95\% CI 0{\textperiodcentered}18-1{\textperiodcentered}67) at 1-year of follow-up, increased bodyweight by 0{\textperiodcentered}24 kg (95\% CI 0{\textperiodcentered}10-0{\textperiodcentered}38 in all trials; 0{\textperiodcentered}33 kg, 95\% CI 0{\textperiodcentered}24-0{\textperiodcentered}42 in placebo or standard care controlled trials and -0{\textperiodcentered}15 kg, 95\% CI -0{\textperiodcentered}39 to 0{\textperiodcentered}08 in intensive-dose vs moderate-dose trials) at a mean of 4{\textperiodcentered}2 years (range 1{\textperiodcentered}9-6{\textperiodcentered}7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1{\textperiodcentered}12, 95\% CI 1{\textperiodcentered}06-1{\textperiodcentered}18 in all trials; 1{\textperiodcentered}11, 95\% CI 1{\textperiodcentered}03-1{\textperiodcentered}20 in placebo or standard care controlled trials and 1{\textperiodcentered}12, 95\% CI 1{\textperiodcentered}04-1{\textperiodcentered}22 in intensive-dose vs moderate dose trials).

INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.

FUNDING: The funding sources are cited at the end of the paper.

}, keywords = {Aged, Body Mass Index, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)61183-1}, author = {Swerdlow, Daniel I and Preiss, David and Kuchenbaecker, Karoline B and Holmes, Michael V and Engmann, Jorgen E L and Shah, Tina and Sofat, Reecha and Stender, Stefan and Johnson, Paul C D and Scott, Robert A and Leusink, Maarten and Verweij, Niek and Sharp, Stephen J and Guo, Yiran and Giambartolomei, Claudia and Chung, Christina and Peasey, Anne and Amuzu, Antoinette and Li, KaWah and Palmen, Jutta and Howard, Philip and Cooper, Jackie A and Drenos, Fotios and Li, Yun R and Lowe, Gordon and Gallacher, John and Stewart, Marlene C W and Tzoulaki, Ioanna and Buxbaum, Sarah G and van der A, Daphne L and Forouhi, Nita G and Onland-Moret, N Charlotte and van der Schouw, Yvonne T and Schnabel, Renate B and Hubacek, Jaroslav A and Kubinova, Ruzena and Baceviciene, Migle and Tamosiunas, Abdonas and Pajak, Andrzej and Topor-Madry, Roman and Stepaniak, Urszula and Malyutina, Sofia and Baldassarre, Damiano and Sennblad, Bengt and Tremoli, Elena and de Faire, Ulf and Veglia, Fabrizio and Ford, Ian and Jukema, J Wouter and Westendorp, Rudi G J and de Borst, Gert Jan and de Jong, Pim A and Algra, Ale and Spiering, Wilko and Maitland-van der Zee, Anke H and Klungel, Olaf H and de Boer, Anthonius and Doevendans, Pieter A and Eaton, Charles B and Robinson, Jennifer G and Duggan, David and Kjekshus, John and Downs, John R and Gotto, Antonio M and Keech, Anthony C and Marchioli, Roberto and Tognoni, Gianni and Sever, Peter S and Poulter, Neil R and Waters, David D and Pedersen, Terje R and Amarenco, Pierre and Nakamura, Haruo and McMurray, John J V and Lewsey, James D and Chasman, Daniel I and Ridker, Paul M and Maggioni, Aldo P and Tavazzi, Luigi and Ray, Kausik K and Seshasai, Sreenivasa Rao Kondapally and Manson, JoAnn E and Price, Jackie F and Whincup, Peter H and Morris, Richard W and Lawlor, Debbie A and Smith, George Davey and Ben-Shlomo, Yoav and Schreiner, Pamela J and Fornage, Myriam and Siscovick, David S and Cushman, Mary and Kumari, Meena and Wareham, Nick J and Verschuren, W M Monique and Redline, Susan and Patel, Sanjay R and Whittaker, John C and Hamsten, Anders and Delaney, Joseph A and Dale, Caroline and Gaunt, Tom R and Wong, Andrew and Kuh, Diana and Hardy, Rebecca and Kathiresan, Sekar and Castillo, Berta A and van der Harst, Pim and Brunner, Eric J and Tybjaerg-Hansen, Anne and Marmot, Michael G and Krauss, Ronald M and Tsai, Michael and Coresh, Josef and Hoogeveen, Ronald C and Psaty, Bruce M and Lange, Leslie A and Hakonarson, Hakon and Dudbridge, Frank and Humphries, Steve E and Talmud, Philippa J and Kivimaki, Mika and Timpson, Nicholas J and Langenberg, Claudia and Asselbergs, Folkert W and Voevoda, Mikhail and Bobak, Martin and Pikhart, Hynek and Wilson, James G and Reiner, Alex P and Keating, Brendan J and Hingorani, Aroon D and Sattar, Naveed} } @article {7452, title = {Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study.}, journal = {BMJ}, volume = {356}, year = {2017}, month = {2017 03 16}, pages = {j1000}, abstract = {

Objective~To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal.Design~Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable.Setting~CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.Participants~Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis.Main outcome measures~The instrumental variable estimation was conducted using the ratio of coefficients approach. Using meta-analysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized.Results~Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95\% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95\% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95\% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (β=1.35, 95\% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: β=-0.21, 95\% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95\% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11).Conclusion~The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.

}, keywords = {Blood Pressure, Dairy Products, Feeding Behavior, Genetic Predisposition to Disease, Humans, Hypertension, Lactase, Mendelian Randomization Analysis, Observational Studies as Topic, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic}, issn = {1756-1833}, doi = {10.1136/bmj.j1000}, author = {Ding, Ming and Huang, Tao and Bergholdt, Helle Km and Nordestgaard, B{\o}rge G and Ellervik, Christina and Qi, Lu} }