Dose Response Relationship Between Physical Activity ... - Circulation

DOI: 10.1161/CIRCULATIONAHA.115.015853

Dose Response Relationship Between Physical Activity and Risk of Heart Failure: A Meta-Analysis

Running title: Pandey et al.; Physical activity and heart failure risk

Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2017

Ambarish Pandey, MD1; Sushil Garg, MD2; Monica Khunger, MD3; Douglas Darden, MD4; Colby Ayers, MS1,5; Dharam J. Kumbhani, MD, SM1; Helen G. Mayo, MLS6; James A. de Lemos, MD1; Jarett D. Berry, MD, MS1,5

1

Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX; 2Dept oof Internal Medicine, School Minneapolis, Inte In ternall M te e iccin ed ine, University of Minnesota Sc Scho hool off Medicine, ho e Min nneapolis, MN; 3Dept of In Internal nternal Medicine, Med diccinee, Cleveland Cle leve eve vellan andd Clinic, Clin Cl inic in ic, Clevel ic Cleveland, e and, O OH; H; 4De Dept pt off In IInternal tern te rnal rn al M Medicine, ed dic icin ine, in e, U University nive ni v rs rsit ityy of it o

T Tex Texas exas xa Southw Southwestern weste terrn M Medical edicaal C Center, enter er, Da er D Dallas, allass, T TX; X; 5D Dept ept pt ooff Cl Clinic Clinical cal Scien Sciences, encess, U University niveers rsityy ooff Tex Texas exas Southwestern Medical Center, Dallas, TX; Sout uthw ut hweest hw estern nM edic ed ical ic al C enteer, D allas, s T X; 6Un University Uni iversi iver sity ooff Te Texass So Sout Southwestern uthhwe ut hwesteern M Medical ediccal C Center ente en terr Library, Dallas, Library Dallas TX

Address for Correspondence: Jarett D. Berry, MD, MS University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas, TX 75390-9047 Tel: 214-645-7500 Fax: 214-645-75201 E-mail: [email protected] Journal Subject Terms: Congestive; Epidemiology

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Abstract

Background—Prior studies have reported an inverse association between physical activity (PA) and risk of heart failure (HF). However, a comprehensive assessment of the quantitative doseresponse association between PA and HF risk has not been reported previously. Methods and Results—Prospective cohort studies with participants >18 years of age that reported association of baseline PA levels and incident HF were included. Categorical dose Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2017

response relationships between PA and HF risk were assessed using random effects models. Generalized least squares regression models were used to assess the quantitative relationship between PA (MET-min/week) and HF risk across studies reporting quantitative PA eestimates. s im st imat ates at es. es Twelve prospective cohort studies with 20,203 HF events among 370,460 participants (53.5% women; 13 years) were included. wome men; me n; median med edia i n follow-up: fo includ uded ud ed. The highest levelss ooff PA were associated ed with w ith h significantly significanttly reduced red duc uced ed risk rissk of HF HF [Pooled [ oole [P led Hazard le Hazzarrd Ratio Rat atio io (HR) (HR HR)) HHighest 0.70 .700 (0 .7 (0.67(0.6 677 ighes estt vs. vs. lowest low west PA: P :0 PA 0.73)]. 0.73 73)] 73 )]. Comp )] Compared mpaared mp ed dw with ithh pparticipants artic iccip pan a tss rreporting ep porrting ng nno o le leisure eissurre ttime im me P me PA, A, tho those hose ho s w who ho o en engaged ng ged in gu ngag guideline uideelin ne recommended eco comm mmen mm ende en dedd mi de mini minimum nimu ni mum m le leve levels vels els ooff PA ((500 5000 ME 50 MET MET-min/week, T-mi min/ mi n/we n/ week eek ek, 20 2008 08 U US S Fe Fede Federal dera de rall Gu ra G Guidelines) uid idel id elin el ines in es)) ha es hadd modest reductions in HF risk [RR: 0.90 (0.87 – 0.92)]. In contrast, a substantial risk reduction was observed among individuals who engaged in PA at twice [HR for 1000 MET-min/week: 0.81(0.77 – 0.86)] and four times [HR for 2000 MET-min/week: 0.65 (0.58 – 0.73)] the minimum guideline recommended levels. Conclusions—There is an inverse, dose-response relationship between PA and HF risk. Doses of PA in excess of the guideline recommended minimum PA levels may be required for more substantial reductions in HF risk.

Key words: heart failure; physical exercise; prevention; meta-analysis

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Introduction Heart failure (HF) affects over 5.1 million adults in United States, accounts for a significant proportion of hospitalizations and deaths among older Americans, and consumes over $30 billion per year in healthcare cost.1,2 The prevalence of HF is expected to increase by 25% from 2010 to 2030. 3 As a result, novel preventive approaches focused on modifying risk factors for HF are urgently needed to combat this growing epidemic. Physical inactivity and low fitness have been identified as significant contributing factors Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2017

for cardiovascular diseases (CVD). 4-10 Over the past three decades, the inverse, dose-response relationship between physical activity (PA) and risk coronary heart disease (CHD) has been well established. 8, 9, 11-13 Thus, physical inactivity is considered a major, modifiable ri risk isk ffactor acto ac torr fo to forr CHD, 14 and current American Heart Association (AHA) guidelines recommend at least 150 mins nss/w /wee eekk of moderate ee mod oder od e ate intensity aerobic PA to reduce redu re duce the burdenn of CHD du CH HD risk factors and the mins/week 15,16, 5,16 5, 16, 17 16 risk iskk of CHD. 15,

In con contrast, ontras on a t,, thee rrole ole ooff P PA A in re reducing eduucin ng riskk ooff HF ha has as nnot o bee ot been eenn em ee eemphasized mph phaasiz i ed iin n exist existing ting g guid gu idel id elin el ines in es aand nd ppublic ub ubli bli licc he heal alth al th rrecommendations. ecom ec omme om mend me ndat nd atio at ions io ns.15 A ns Although ltho lt houg ho ugh gh ob obse observational serv se rvat atio at iona io nall co na coho cohort hort ho rt sstudies tudi tu dies di es have hav avee guidelines health reported an inverse association between higher levels of PA and HF risk,18-32 a comprehensive assessment of the quantitative dose response association between PA and HF risk has not been previously reported. Understanding this relationship is important since recent studies suggest that there may be important differences in the mechanisms through which PA modifies HF risk and CHD risk,20 and the dose of PA needed to significantly lower HF risk may differ from that currently recommended to reduce CHD risk.25 Previous studies have used dose response metaanalysis of epidemiological studies to better understand the quantitative association between lifestyle risk factors such as coffee intake, dietary patterns and cardiovascular outcomes.33-35 In

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the present study we have utilized a similar approach and performed a dose-response metaanalysis of prospective cohort studies to determine the categorical and quantitative dose response association between PA and risk of HF. We hypothesized that there would be a dose-dependent, inverse association between PA and risk of HF.

Methods: Literature search strategy Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2017

We followed the meta-analysis of observational studies in epidemiology protocol for performing and reporting the present meta-analysis. 36 We searched for all prospective cohort studies that examined the associations between PA and incident HF among adult participants (> 118 8 ye year years arss ooff ar age at baseline). We systematically searchedd electronic databases (Medline, EMBASE and Cochrane Coch ch hra rane ne ddatabase) atabaase) at e and performed additional ma manu manual nual searches throughh th nu the reference list of publications review Wee uused words, among ooriginal rig ginal publi icaati tioonss an andd re revi view vi ew aarticles. rttic icle les. W le sed d tthe he ffollowing ollo ol lowi lo wing wi ng key ey w o ds, am or amon on ng ot oothers, herss, to he perform search “exercise pe erf rfoorm or thee se sear rch “physical “phhysical all activity,” act c ivit ityy,”” ““walking”, it wallkiing ng”, ““exercise”, ex xerrcise see”, ”, “e exeerci c see ttraining”, rain inin in in ng” g , “cardiorespiratory “heart risk”, failure risk” (full search “car “c ardi ar dior di ores or espi es pira pi rato ra tory to ry ffitness”, itne it ness ne ss””, ““fitness”, ss fitn fi tnes tn ess” es s”, “h s” “hea eart ea rt ffailure ailu ai lure re ri risk sk””, ““cardiac sk card ca rdia rd iacc fa ia fail ilur il ure re ri risk sk”” (f sk (ful ull ll se sear arch ar ch tterm erm er m available on request). The search was restricted to articles that focused on human participants and were published between January 1st, 1995 and September 24th 2014. The time restriction was applied to reflect likely changes in PA categorization for analyses by investigators after publication of the 1995 US Centers for Disease Control and Prevention/American College of Sports Medicine guideline. 37 Study Selection Prospective cohort studies that reported the association between baseline PA levels and incident HF were included. Studies with all types of PA (leisure time PA, walking time, occupational PA,

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total PA) were included in the initial study selection process. If multiple articles were published from the same cohort, we included data from the study with the most detailed report of PA levels and/or the larger sample size. Two independent investigators (AP, MK) conducted the initial screening of all titles or abstracts and then evaluated all potentially relevant articles based on full text reviews. Studies were excluded if they failed to meet all the criteria detailed above. All discrepancies regarding study inclusions were adjudicated by the senior author (JB). The study quality was assessed using the Newcastle-Ottawa quality assessment scale that allowed a total Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2017

score of up to 9 points (9 representing the highest quality) summarizing eight aspects of each study. 38 Data Collection Two authors (AP, MK) independently performed the data collection using a standardized form. Thee fo foll following llow ll owin ow ingg in in information nfo formation was recorded for eac each ch st study: author, year off ppublication, ublication, cohort/study nname, am me, geographic geograph hic ic location, loc occatio ion, n, proportion pro ropo port po rtio rt ionn of women, io wom omen, prevalence prev val alen ence en ce of of HF F risk ris iskk factors facttor orss such such aass hypertension, baseline, types PA, PA levels, hy ype pert r ension onn, diabetes, diab abetess, smoking, ab smokkin ng, coronary cor oronnary ary artery arteery disease diseaasee att ba ase s linne,, ty ypees ooff P A, P A le eveels, method meth me thod th od use used sed se d to eestimate stim st imat im atee PA at PA, to tota total tall nu ta nnumber umb mber mb er ooff pa part participants, rtic rt icip ic ipan ip ants an ts, to ts tota total tall nu ta nnumber umb mber mb er ooff H HF F ev eevents, ven ents en ts, me ts meth method thod th od ooff ascertainment of outcomes, follow up duration, hazard ratio/relative risk of HF and confidence intervals, and variables that were entered into the multivariable model as potential confounders. Information on quantitative dose of PA and/or duration and intensity of PA performed per week was also recorded, as reported in the study. Statistical Analysis For the present meta-analysis we used hazard ratio (HR) or relative risk (as available) and 95% confidence intervals as a measure of the effect size associated with each category of PA for all studies. In articles that studied more than one type of PA, only leisure time PA was preferentially

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included for analysis. The primary aim of our analysis is to quantify the risk of HF that is associated with different PA levels independent of other cardiovascular and non-cardiovascular risk factor burden. Therefore, we used the results of the original studies from multivariable adjusted models with the most complete adjustment for potential baseline confounders including presence of risk factors such as hypertension (HTN), diabetes (DM), and body mass index (BMI) for primary analysis. One study (Bell, et al.) reported separate hazard ratios for HF risk associated with different PA levels for African Americans and whites. 19As a result, we included Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2017

data from both the African American and the white cohort separately in the pooled analysis. The categorical dose response analysis was performed with STATA 10.0 (STATA Corp, College Station, TX). For this, we generated four categories of physical activity: lo lowe lowest, west we stt, li ligh light, ghtt, gh moderate, and highest. For each study that was included, the lowest and the highest PA categories catego gori go ries ess ccorresponded o resp or spon sp o ded to the lowest and highest st ggroups, roups, respectively.. F For or studies with at least 3 oorr m more ore exposu exposure ure categories, catteg e or orie ies, ie s,, the the h second sec e onnd andd third th hirdd highest highhes estt PA P categories cat ateg t gorie ies corresponded ie corrres espo pond nded nd ed tto o th thee moderate mode mo derate and de nd light lig ghtt groups, grou oups, respectively. reesppecti tiive v ly y. The Th he pool ppooled o led d hhazard azardd ra az ratios ati t os aand nd 95 95% CI for H HF F as associated ssoociaateed wiith different with dif iffe fere fe rent re nt categories cat ateg egor eg orie or iess of PA ie PA were weere calculated cal alcu cula late la tedd by te by comparing com ompa pari pa ring ri ng each eac achh PA category cat ateg egor eg ory (highest, or (hig (h ighe ig hest he st, st moderate and light PA) with the lowest PA category using the random effects modeling technique as described by Dersimonian and Laird. 39 Maximally adjusted HRs, when reported, were used for the primary analysis to account for confounding variables. Pooled analysis comparing highest vs. lowest PA levels included all available studies (n=12) while comparisons of moderate (2nd highest PA category) and light PA (3rd highest PA category) vs. the lowest PA category included studies that stratified participants into at least 3 (n=10) and 4 PA (n=4) categories, respectively. We assessed for heterogeneity using the I2 test (I2> 50% was assumed to be a result of significant heterogeneity). We performed several sensitivity and subgroup analyses

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based on sex, age, geographical region, study population characteristics, CHD prevalence at baseline, HF incidence rates on follow-up, and multivariable adjustment strategy used in analyses (using HR associated with models without adjustment for cardiovascular risk factors) to test for the robustness of the observed associations. Publication bias was assessed using contourenhanced funnel plots, Egger’s linear regression test, and Begg’s rank correlation test at the P 30min Moderate to vigorous PA Cat 1: 5-7 times/week Cat 2: 1-4 times/week Cat 3: 1-3 times/month Cat 4: Inactive

Self-reported HF

Cat 1:0.73(0.59-0.90) Cat 2: 0.86(0.73-1.01) Cat 3: 0.78(0.63-0.97) Cat 4: Ref

Age; smoking; alcohol; family Hx of MI; treatment group; cardiovascular comorbidities; BMI

Wang 2010 27

Cat 1 > 3 Hr./week VIPA Cat 2 > 4 Hr./week MIPA Cat 3: Inactive

ICD-9 codes for HF admission

Cat 1:0.69(0.60-0.79) Cat 2: 0.83 (0.77-0.89) Cat 3: Ref

Age; sex; year; education, smoking, alcohol use; CVD risk factors, CAD, lung disease, anti-HTN use; BP, total chol, BMI

Bell 201319

Cat 1 > 150 min/week MIPA Cat 2: 1-149 min/week of MIPA or 1-44min/week of VIPA Cat 3: Inactive


Cat 1: A: 0.59 (0.47-0.74) W: 0.64 (0.54 – 0.75) Cat 2: A: 0.62 (0.51-0.75) W: 0.76 (0.65 – 0.88) Cat 3: Ref

Age; sex; smoking; alcohol; diet; education; hormone therapy

Patel 2013 25

Cat 1: High PA (>1,000 MET-min/week) Cat 2: medium PA (500 - 999 MET-min/week) Cat 3: low PA (1 – 499 MET-min/week) Cat 4: Inactive

Adjudication based on chart review

Cat 1:0.79 (0.64-0.97) Cat 2: 0.86 (0.69-1.08) Cat 3: 0.97 (0.79-1.20) Cat 4: Ref

Age; sex; race; SE factors; alcohol; smoking; BMI; CV risk factors; BP; Cr, CRP, Cholesterol, Albumin; MMSE score, depression.

Young 2014 28

Cat 1: high (>1585 MET-min/week) Cat 2:medium (471-1584 MET-min/week) Cat 3: 3: Low L (< (< 470 470 MET-min/week)


Cat 1: Ref Cat 2: 1.15 (1.04-1.26) Cat 3: 1.52(1.38-1.67)

Age;; race; race race ace;; SE E factors; fact fact actors ors;; BMI; ors BMII BMI smoking; Hx of HTN, DM, CAD, anti HTN use; levels of alcohol HDL, Glucose; diet; alcoho

Saevereid aever ae ereid 2014 26 C er Cat at 1: m moderate oderatte tto o hhigh igh Cat at 2: 2: Light Light ht Cat 3: 3: Sedentary Sedenttary y

ICD-8 & 10 code codes es ffor or HF admission F adm dmiss dm i ion

Cat Ca 1:0.888 (0.75-1.03) (0.7 0.75-1.03) Cat 2: 0.80 80 (0.69-0.92) (0..69 69-0.992) Cat att 3: Ref

Age, Age g , sex, alcoh alcohol, hol, o education, educa ed u tio income, history income inc ome,, ffamily ome ami milly his mi histor tory tor y of o CVD D

Andersen Ander An errsen 2014 18 Quintiles Q inttilees of PA Qu PA Cat Cat 1: 1: highest highesst Quintile Quintilee Qu Cat Quintile att 2: 2: Fourth Fourt Fo urth urt h Quin Q uintile uin Cat 3: Third Quintile Cat 4:Second Quintile Cat Lowestt Q Quintile C t 55: L i til

ICD D-9 & 10 0 code es ffor or ICD-9 codes missiion HF adm admission

Cat 1: 0.65 (0.53-0.81) (0..53-0.81 1) Cat att 2: 0.73 0..73 7 (0.60-0.89) (0..6060-0.8 0 9) Cat 0. (0.67-0.94) (0.67(0. 67-0 670.994) 4) Cat 3: 0.79 Cat 4: 0.93 (0.79-1.09) Cat 5: Ref

Age; sex; sex BMI; MI; Alcohol Alcoh holl and an t acc tob ccco use; u cardiovascular carrdiovascu rd scular scu tobacco comorb com orbiditie orb iess ie comorbidities

Agha 2014 31

Cat 1: > 150 min/week MIPA Cat 2: 1-149 min/week MIPA Cat 3: Inactive

Self-reported HF with clinical adjudication from medical records

Cat 1: 0.69 (0.61-0.79) Cat 2: 0.77 (0.67 -0.87) Cat 3: Ref

Age; race; education; Hx of HTN, DM CAD, US region

He 2001 22

Recreational PA Cat 1: High PA Cat 2: Medium or low PA


Cat 1: Ref Cat 2: 1.23 (1.09-1.38)

Age; sex; race; education; income; BMI; smoking; Hx. of HTN, DM, CAD, valvular heart disease; alcohol use

Lewis 2003 30

Recreational PA Cat 1: > 3 times/week MIPA Cat 2: 55 years US cohort European Cohort

No. of studies 12 4 5 6 6 8 4

Pooled Hazard Ratio (95% Confidence Interval) Highest vs. lowest PA 0.70 (0.67 to 0.73) 0.75 (0.63 to 0.87) 0.73 (0.68 to 0.78) 0.71 (0.64 to 0.79) 0.69 (0.65 to 0.73) 0.69 (0.65 to 0.73) 0.73 (0.65 to 0.81)

2

I %

P-value for heterogeneity

36 74 0 60 0 28 53

0.10 0.01 0.80 0.02 0.68 019 0.10


Figure Legends:

Figure 1. Flowchart of Study Selection for the Meta-analysis.

Fi igu gure r 2. P ooled estimates of the relative risk of incident oo inccident HF associated asso socciated with different categories so Figure Pooled o pphysical of hysical activity. activvity y. The The high gh physical physiicall activi activity ity y gro group oup rep represents epre ep rese re s nts pa particip participants pantss inn each ch sstudy tudy dyy wit with th highest high hes estt do dos dose se off ph phys physical ysic ys ical ic al aactivity ctivit ityy wh it while th thee mo mode moderate derrate de rate and and light lig ight ht physical phy hy ysi sica call activity ca acti ac tivity ti ty y groups gro rouups represent repr re pres esen entt participants i i with i h progressively i l llower llevels l off physical h i l activity i i iin each h study. d Pooled l d analysis l i for high physical activity included all available studies while that for moderate and light physical activity included only those studies that stratified participants into at least 3 and 4 physical activity categories, respectively. Participants with the lowest dose of physical activity in each study have been used as the referent group. I2 represents the degree of heterogeneity.

Figure 3. Dose response association between physical activity and heart failure risk. The graph here shows spline (smoothed fit) and 95% confidence interval of pooled relative risk of heart failure by MET-min/week.

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Figure 1


Figure 2


Figure 3

Dose Response Relationship Between Physical Activity and Risk of Heart Failure: A Meta-Analysis Ambarish Pandey, Sushil Garg, Monica Khunger, Douglas Darden, Colby Ayers, Dharam J. Kumbhani, Helen G. Mayo, James A. de Lemos and Jarett D. Berry Downloaded from http://circ.ahajournals.org/ by guest on November 21, 2017

Circulation. published online October 5, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2015/09/18/CIRCULATIONAHA.115.015853

Data Supplement (unedited) at: http://circ.ahajournals.org/content/suppl/2015/09/18/CIRCULATIONAHA.115.015853.DC1

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SUPPLEMENTAL MATERIAL

Supplementary Methods:

Dose calculation for different physical activity categories: Based on available literature1, we used following mean energy expenditure rates for different intensities of physical activity (PA): 3 METs for Light, 5 METs for moderate and 9 METs for vigorous intensity PA. PA dose for each category was calculated as the product of duration of light/moderate/vigorous intensity PA per week and respective mean energy expenditure rate. In one study by Kenchaiah et al 2, PA levels were ascertained among study participants using the question “How often do you exercise vigorously enough to work up a sweat?” Previous studies have shown that “exercise vigorous enough to work up a sweat” is equivalent to 30 mins or more of moderate to vigorous intensity PA. 3 We used a dose based on an energy expenditure rate that is an average of MIPA and VIPA (~7 METS) and duration of at least 30 min per episode reported for each PA group.

Supplemental Figure legends Supplemental Figure 1: Forest plot showing pooled estimate of the relative risk for incident HF comparing high dose physical activity to the lowest category of physical activity (references: 2, 4-14). Supplemental Figure 2: Forest plot showing pooled estimate of the relative risk for incident HF associated with moderate dose physical activity compared to the lowest category of physical activity (references: 2, 4-11, 14). Supplemental Figure 3: Forest plot showing pooled estimate of the relative risk for incident HF associated with light dose physical activity compared to the lowest category of physical activity(references: 2,6,9,14). Supplemental Figure 4: Inverted funnel plot for assessment of publication bias.

Supplemental Table 1: Estimated mean leisure time physical activity doses (in METmin/week) associated with different physical activity categories among studies that allowed a quantitative estimation of physical activity levels

Study

Categories of Physical activity/Fitness

Estimated Leisure Time PA dose (MET-min/week)

>30min Moderate to vigorous PA

Kenchaiah 2009

2

Cat 1: 5-7 times/week

Cat 1: 1,260

Cat 2: 1-4 times/week

Cat 2: 525

Cat 3: 1-3 times/month

Cat 3: 105

Cat 4: Inactive

Cat 4: 0

Cat 1 > 3 Hr./week VIPA 4

Wang 2010

Cat 1:1,830 Cat 2 > 4 Hr./week MIPA Cat 2: 1,410 Cat 3: Inactive Cat 3: 210 Cat 1 > 150 min/week MIPA Cat 2: 1-149 min/week of MIPA

Bell 20135

or 1-44min/week of VIPA Cat 3: Inactive

Cat 1: 1,125 Cat 2: 375 Cat 3: 0

Cat 1: High PA (>1,000 MET-min/week) Cat 2: medium PA 6

Patel 2013

(500 - 999 MET-min/week) Cat 3: low PA

Cat 1: 1,250 Cat 2: 750 Cat 3: 250 Cat 4: 0

(1 – 499 MET-min/week) Cat 4: Inactive Cat 1: high (>1585 MET-min/week) Young 20147

Cat 2:medium

Cat 1: 2,142 Cat 2: 1,027 Cat 3: 235

(471-1584 MET-min/week) Cat 3: Low (< 474 MET-min/week) Cat 1: moderate to high Saevereid 20148

Cat 1: 1,200

Cat 2: Light

Cat 2: 540

Cat 3: Sedentary

Cat 3: 180

Andersen 2014

9

Cat 1: >1,638 MET-min/week

Cat 1: 2,331

Cat 2: 1,092 -1,638 MET-min/week

Cat 2: 1,617

Cat 3: 672-1,092 MET-min/week

Cat 3: 1,029

Cat 4: 378-672 MET-min/week

Cat 4: 651

Cat 5: < 378 MET-min/week)

Cat 5: 252

Cat 1: > 150 min/week MIPA Agha 201410

Cat 1: 1,125 Cat 2: 1-149 min/week MIPA Cat 2: 375 Cat 3: Inactive Cat 3: 0

Cat: Category; MIPA: moderate intensity physical activity; VIPA: vigorous intensity physical activity

Supplemental Table 2: Quality assessment of included studies

Bell 20135

Wang 20124

Young 20147

Kenchaia h 20092

K-krainer 201311

He 200112

Lewis 200313

Patel 20136

Saevereid 20148

Rahman 201414

Agha 201410

Andersen 20149

Exposed cohort representativen ess

1

1

1

0

0

0

0

1

1

1

1

1

Non exposed cohort selection

1

1

1

1

1

1

1

1

1

1

1

1

Exposure Ascertainment

1

1

1

1

1

1

0

1

1

1

1

1

Absence of outcome at baseline Comparability of cohorts

1

1

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

1

2

2

Outcome Ascertainment

1

1

1

0

1

1

0

1

1

1

1

1

Long enough follow up

1

1

1

1

1

1

1

1

1

1

1

1

Follow up adequacy

1

1

1

1

1

1

1

1

1

1

1

1

Total Score

9

9

9

7

8

8

6

9

9

9

9

9

Supplemental Table 3: Sensitivity analyses among different study subgroups

No. of studies

Hazard Ratio (95% CI) Highest vs. lowest PA

2

I

P-value for Heterogeneity

All Studies

12

0.70 (0.67 to 0.73)

36%

0.10

Studies with quantitative estimates of LTPA levels

8

0.68 (0.65 to 0.72)

37%

0.12

Studies without CAD among participants at baseline

5

0.70 (0.63 to 0.78)

54%

0.05

Studies with low incidence of HF on f/u (< 10%)

8

0.70 (0.66 to 0.73)

23%

0.24

Studies with high incidence of HF on f/u (>10%)

4

0.70 (0.60 to 0.79)

59%

0.045

Excluding Bell, et al African American Cohort

12

0.71 (0.68 to 0.74)

32%

0.14

Excluding CARE study 13 (Lewis, et al )

11

0.70 (0.67 to 0.73)

41%

0.07

Pooled analysis of HR from models without adjustment for CVD risk factors such as DM, HTN, and BMI

11

0.66 (0.61 to 0.71)

62%

0.002

Studies with adjustment for Socioeconomic Factors

7

0.73 (0.68 to 0.79)

55%

0.04

5

LTPA: leisure time physical activity; CAD: coronary artery disease; HF: heart failure; f/u: follow up; CVD: cardiovascular disease; HTN: hypertension; DM: diabetes mellitus; BMI: body mass index

Supplemental Fig 1

Supplemental Fig 2

Supplemental Fig 3

Supplemental Fig 4

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Godin G, Shephard RJ. A simple method to assess exercise behavior in the community. can J Appl Sports Sci. 1985;10:141-146

2.

Kenchaiah S, Sesso HD, Gaziano JM. Body mass index and vigorous physical activity and the risk of heart failure among men. Circulation. 2009;119:44-52

3.

Gruner C, Alig F, Muntwyler J. Validity of self-reported exercise-induced sweating as a measure of physical activity among patients with coronary artery disease. Swiss Med wkly. 2002;132:629-632

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