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A Meta-analysis of the effects of Exercise Training on Left Ventricular Remodeling Following Myocardial… Haykowsky, Mark; Scott, Jessica; Esch, Ben; Schopflocher, Don; Myers, Jonathan; Paterson, Ian; Warburton, Darren; Jones, Lee; Clark, Alexander M Apr 4, 2011

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RESEARCH Open AccessA Meta-analysis of the effects of Exercise Trainingon Left Ventricular Remodeling FollowingMyocardial Infarction: Start early and go longerfor greatest exercise benefits on remodelingMark Haykowsky1*, Jessica Scott2, Ben Esch2, Don Schopflocher3, Jonathan Myers4, Ian Paterson5,Darren Warburton2, Lee Jones6 and Alexander M Clark7AbstractBackground: The effects of variations in exercise training on Left ventricular (LV) remodeling in patients shortlyafter Myocardial Infarction (MI) are important but poorly understood.Methods: Systematic review incorporating meta-analysis using meta-regression. Studies were identified viasystematic searches of: OVID MEDLINE (1950 to 2009), Cochrane Central Register of Controlled Trials (1991 to 2009),AMED (1985 to 2009), EMBASE (1988 to 2009), PUBMED (1966 to 2009), SPORT DISCUS (1975 to 2009), SCOPUS(1950 to 2009) and WEB OF SCIENCE (1950 to 2009) using the medical subject headings: myocardial infarction, postmyocardial infarction, post infarction, heart attack, ventricular remodeling, ventricular volumes, ejection fraction, leftventricular function, exercise, exercise therapy, kinesiotherapy, exercise training. Reference lists of all identifiedstudies were also manually searched for further relevant studies. Studies selected were randomized controlled trialsof exercise training interventions reporting ejection fraction (EF) and/or ventricular volumes in patients followingrecent MI (≤ 3 months) post-MI patients involving control groups. Studies were excluded if they were notrandomized, did not have a ‘usual-care’ control (involving no exercise), evaluated a non-exercise intervention, ordid not involve human subjects. Non-English studies were also excluded.Results: After screening of 1029 trials, trials were identified that reported EF (12 trials, n = 647), End SystolicVolumes (ESV) (9 trials, n = 475) and End Diastolic Volumes (EDV) (10 trials, n = 512). Meta-regression identified thatchanges in EF effect size difference decreased as the time between MI and initiation of the exercise programlengthened, and increased as the duration of the program increased (Q = 25.48, df = 2, p < 0.01, R2 = 0.76).Greater reductions in ESV and EDV (as indicated by effect size decreases) occurred with earlier initiation of exercisetraining and with longer training durations (ESV: Q = 23.89, df = 2, p < 0.05, R2 = 0.79; EDV: Q = 27.42, df = 2, p <0.01, R2 = 0.83). Differences remained following sensitivity analysis. Each week that exercise was delayed requiredan additional month of training to achieve the same level of benefit on LV remodeling.Conclusions: Exercise training has beneficial effects on LV remodeling in clinically stable post-MI patients withgreatest benefits occurring when training starts earlier following MI (from one week) and lasts longer than3 months.* Correspondence: Mark.Haykowsky@ualberta.ca1Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, CanadaFull list of author information is available at the end of the articleHaykowsky et al. Trials 2011, 12:92http://www.trialsjournal.com/content/12/1/92 TRIALS© 2011 Haykowsky et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.BackgroundThere is strong and consistent evidence that exerciseafter a myocardial infarction (MI) improves overall andcardiovascular-related mortality [1,2]. In low, middleand high income countries, patients who exercise regu-larly are over 30% less likely to experience further MI,stroke or death [3]. However, the mechanisms of thesemortality benefits are not well understood.Left ventricular (LV) remodeling is an accurate predictorof cardiac mortality following MI [4] but it is not clearhow exercise effects LV remodeling. In some past trials,aerobic training led to decreases in LV end-diastolic(EDV) and end-systolic volumes (ESV) and increases inejection fraction (EF) [5-7]. In other trials, exercise trainingled to increased LV volumes [8,9] and decreased EF [8].Still further, other trials identified that following MI exer-cise training does not alter LV volumes [10-14] or EF[11-14]. Though the effects of LV remodeling are likely tovary based on the characteristics of populations and exer-cise interventions, it is not known why these variationsoccur [15].Understanding these inconsistencies and the effects ofexercise on LV remodeling is important because thisknowledge could be used to heighten the benefits ofexercise after MI. Though arguably essential for effectivesupport and health services, recent guidelines on physi-cal activity after MI do not provide any recommenda-tions on the key but basic issues of when exerciseshould commence after MI and how long supervisedexercise should continue to ensure or maximize benefits[2]. Information on these design characteristics shouldprovide more effective and useful evidence for healthprofessionals [16]. Consequently we performed a sys-tematic review and meta-analysis to assess the overalleffects of exercise training on LV remodeling in clini-cally stable post-MI patients.MethodsData sourcesA searched was undertaken of OVID MEDLINE (1950to 2009), Cochrane Central Register of Controlled Trials(1991 to 2009), AMED (1985 to 2009), EMBASE (1988to 2009), PUBMED (1966 to 2009), SPORT DISCUS(1975 to 2009), SCOPUS (1950 to 2009) and WEB OFSCIENCE (1950 to 2009) using the following medicalsubject headings: myocardial infarction, post myocardialinfarction, post infarction, heart attack, ventricularremodeling, ventricular volumes, ejection fraction, leftventricular function, exercise, exercise therapy, kine-siotherapy, exercise training. Reference lists of all identi-fied studies were also manually searched for furtherrelevant investigations.Study selectionTwo investigators (MH and AC) independently reviewedthe titles and abstracts of all citations to identify studiesreporting the effect of exercise training on EF and/orventricular volumes in recent (≤ 3 months) post-MIpatients. We excluded trials that were not randomized,did not have a usual care control group, non-exerciseintervention, exercise and other intervention, and non-human studies. We also excluded non-English articles.Data extraction and quality assessmentTwo authors (MH and BE) extracted relevant outcomedata and any disagreement was resolved by consensus indiscussion with AC. When necessary, original investiga-tors were contacted to clarify data or provide additionaldata; authors for 3 studies provided further information.Quality was assessed using the Jadad scale [17].Data synthesis and analysisAll data was entered into SPSS files and analyzed withSPSS v15 software utilizing meta-analysis and meta-regression scripts created by Lipsey and Wilson [18].The review conforms to the requirements of PRISMAreporting standards (Additional file 1). Formulae for cal-culation of outcomes is provided in Additional File 2.ResultsStudy selectionAfter initial review of 1,033 citations (Figure 1), 19papers were reviewed in full; of these, seven wereexcluded. Reasons for this exclusion were: EF dataincomplete or un-extractable (n = 3), non-randomizedFigure 1 Flow of trials through the selection process.Haykowsky et al. Trials 2011, 12:92http://www.trialsjournal.com/content/12/1/92Page 2 of 8design (n = 1), time from MI to initiation of exercisetraining was unreported (n = 1), inclusion of patientsexperiencing MI >3 months (n = 2). One trial [19] ran-domly assigned subjects ‘a priori’ to exercise or controlgroups based on baseline EF (≤ 30 and >30%). Accord-ingly, data for these sub-groups were analyzedseparately.Study characteristicsThe selected studies [5-7,9-14,19-21](Additional File 3)contained 647 post-MI patients (mean age: 55 years) withimpaired LV systolic function (weighted mean EF = 44%).Trials incorporated aerobic training at 60% to 80% ofbaseline peak oxygen uptake (or heart rate) for 20 to 180minutes per session (Table 1). The length of training pro-gram was 1 to 6 months in duration (Table 1). All trialsreported pre and post measures for outcome variable forboth treatment groups and for control groups. No trialdescribed randomization procedures or blinding meth-ods. Consequently, trials tended to be assessed as beingof low to moderate quality.Three outcome variables were chosen for analysis. Theprimary variable was EF for which 12 trials reporteddata (n = 647). The secondary outcome variables wereESV and EDV for which data was only provided for asubset of trials: ESV (9 trials, n = 475) and EDV (10trials, n = 512).Initial analysisAs the studies had high levels of statistical, clinical andmethodological heterogeneity - as evident for examplein the initial meta-analysis of EF (Cochran’s Q = 33.57,df = 12, p < 0.01) and variations in effect size differencesfor each outcome variable, pooling of the results fromthe trials in a sub-analysis was inappropriate [22].Therefore, we performed meta-regression of post-infarctLV remodeling. The effects of elements of the exerciseinterventions identified a priori for analysis were: timepost-MI to initiation of exercise training program andlength of training program [23].Exercise training and ejection fractionMeta-regression identified that change in EF effect sizedifference decreased as the time between MI and initia-tion of the exercise program lengthened, and increasedas the duration of the program increased (Figure 2).Overall, these changes accounted for a significant pro-portion of the variations in outcomes across the studies(Q = 25.48, df = 2, p < 0.01, R2 = 0.76) (Table 2). Thatis, when study level differences in average time to initi-ate and average length of program are considered thetrials become comparable.Exercise training and ventricular volumesA sufficient number of trials reported data on ESV(9 trials, n = 475) [5-7,9-14] and EDV (10 trials, n =512) [5-7,9-14,20] to allow meta-regression of these out-comes. Similar to EF, effects on LV volumes were nothomogeneous across studies (ESV, Q = 30.12, df = 8,p < 0.01; EDV, Q = 33.03, df = 9, p < 0.01). Greaterreductions in ESV and EDV (as indicated by effect sizedecreases) occurred with earlier initiation of exercisetraining and with longer training durations (Tables 3and 4, Figures 3 and 4). These differences accounted fora significant proportion of the heterogeneity for ESV(Q = 23.89, df = 2, p < 0.05, R2 = 0.79) and EDVTable 1 Description of exercise training programStudy Frequency(days/week)Intensity Exercise duration (min/session) Mode Program length (mn)Giallauria et al [6] 3 60-70% VO2peak 30 Cycle 6Giallauria et al [5] 3 60-70% VO2peak 30 Cycle 6Giallauria et al [12] 3 70% VO2peak 30 Cycle 3Giallauria et al [13] 3 60% VO2peak 30 Cycle 3Giannuzzi et al [7] 3-7 80% peak HR 30>30 minCycleWalk6Koizumi et al [14] 7 Moderate speed 30 Walk 3Kubo et al [9] 3 HR at VT 20 min, twice/day CycleWalk3Dubach et al [11] 4 - 7 60-70% HRR 45120CycleWalk2Giannuzzi et al [10] 3-7 80% peak HR 30>30CycleWalk6Heldal et al [20] 5 85% peak HR 120 CycleJogging1Jette et al [19] 7 70-80% peak HR 45-105 Cycle, Jogging Walk, Calisthenics 1Grodzinski et al [21] 5 80% peak HR 30-180 Cycle, Jog Walk, Swim Calisthenics 1(Heart rate; HRR: Heart rate reserve; VO2peak, peak oxygen consumption; VT: Ventilation threshold).Haykowsky et al. Trials 2011, 12:92http://www.trialsjournal.com/content/12/1/92Page 3 of 8(Q = 27.42, df = 2, p < 0.01, R2 = 0.83). As with EFeffect size, when study level differences in average timeto initiate and average length of program were consid-ered, effects on ESV and EDV became comparable.Sensitivity AnalysisThe findings may be influenced strongly by a smallnumber of trials which evaluated exercise training afteraround one week. Analyses were therefore repeatedexcluding the four trials with the shortest latency toinitiation of the exercise program [5,6,12,13]. After thisremoval, the analysis no longer had sufficient power todemonstrate significant effects. However, the regressioncoefficients remained of similar size and direction (Fortime to initiate: -0.119 to -0.178 (p < 0.15); for lengthfrom 0.098 to 0.069 (p < 0.25)) suggesting that thetrends identified in the full analysis remained even whenthese trials are excluded. Removing the same trials fromthe analyses of ESV and EDV reduced the number oftrials in the analyses more dramatically (5 and 6 trialsrespectively). In both re-analyses, the coefficients fortime to initiate again remained in the same directionbut decreased substantially in magnitude (ESV: 0.246 to0.076 and EDV: 0.189 to 0.059) and were no longer sig-nificant. Yet, the coefficients for program length weremore stable (ESV: -0.249 to -0.138, p < 0.10, and EDV:-0.148 to -0.13, p < 0.05). Hence, particularly for LVremodeling, the influence of time to initiation of exer-cise training after MI and subsequent length of trainingprogram remained after removal of the trials.DiscussionThis systematic review found that exercise training hadbeneficial effects on LV remodeling after myocardialinfarction but that the sizes of changes were dependenton time of instigation and duration of the exercise inter-vention. The largest changes in LV remodeling wereobtained when programs began after around 1-weekEffect Size difference (Exercise - Control)-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0Jette 1991aGrodzinski 1987Jette 1991bHeldal 2000Giannuzzi  1993Dubach 1997Kubo 2004Koizumi 2003Giannuzzi 1997Giallauria 2006bGiallauria 2006Giallauria 2008Giallauria 2009Mean time to initiation of exercise program (weeks).Duration of exercise pro gram (months).6.9, 16.5, 16.4, 15.4, 15.4, 65.2, 24.0, 34.0, 33.5, 61.6, 31.4, 31.0, 60.9, 6Figure 2 EF effect size difference for individual trials categorized by time to exercise training and duration of training program.Table 2 Meta-Regression of the change in EF effect sizedifferenceB Standard Error ProbabilityConstant 0.314 0.315 nsTime to Initiate -0.119 0.045 p < 0.05Length 0.098 0.046 p < 0.05Table 3 Meta-Regression of the change in ESV effect sizedifferenceB Standard Error ProbabilityConstant -0.07 0.45 nsTime to Initiate 0.246 0.072 p < 0.01Length -0.249 0.078 p < 0.01Haykowsky et al. Trials 2011, 12:92http://www.trialsjournal.com/content/12/1/92Page 4 of 8post MI hospital discharge and lasted for 6 months. ForESV, a strong predicator of mortality post-MI [4], eachone-week delay in initiating exercise training wouldrequire an additional month of training to obtain a com-parable reduction in ESV. Similarly, delaying exercisetraining by one week after a MI would require an addi-tional month of training to attain the same change inLVEF.As with all systematic reviews, the conclusions of thisreview are only as strong as the quality of the compo-nent studies. The trials included predominantly youngermales with reduced systolic function though there isunlikely to be differences in effects by sex, future trialsshould include a greater proportion of women. In thetrials, the type and location of infarction was not widelyused to stratify results and few studies measured exer-cise capacity. Accordingly, future trials are needed tomeasure and assess the specific effects of these factorson LV remodeling. The trials included were not welldescribed and did not report all of the informationrequired to conduct optimal analysis in the case ofrepeated measures. Here, a conservative alternativenevertheless showed significant findings in the meta-regression. The effect sizes would have been larger ifcorrelations between pre-and-post intervention scoreshad been available.The findings are biologically plausible. Though thephysiological mechanisms responsible for the anti-remo-deling benefits of exercise training following MI are notwell understood, they may arise from favorable improve-ments in coronary and peripheral vascular endothelialfunction, myocardial contractility, autonomic balance, orsystolic and diastolic wall stress [24,25]. Several studieshave also shown that aerobic training can elicit improve-ments in diastolic function and wall stress [5,12,13,26].Post-training decreases in plasma pro-NT-BNP reduceEDV [5] and increase peak early mitral flow velocity[5,12,13] and peak early to late mitral flow velocity ratio[12,13]. Aerobic-training improves autonomic balance[27] and peripheral vascular endothelial function [28].The anti-remodeling benefits arising from exercise pro-grams with a longer training length may explain theeffects of cardiac rehabilitation attendance on survivalafter MI [29].Clinical implicationsThere is no current recommendations [30] or consensus[31] as to when exercise training should commenceTable 4 Meta-Regression of the change in EDV effect sizedifferenceB Standard Error ProbabilityConstant -0.186 0.54 nsTime to Initiate 0.189 0.051 p < 0.01Length -0.148 0.051 p < 0.01Effect Size difference (Exercise - Control)-2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0Giannuzzi  1993Dubach 1997Kubo 2004Koizumi 2003Giannuzzi 1997Giallauria 2006bGiallauria 2006Giallauria 2008Giallauria 20095.4, 65.2, 24.0, 34.0, 33.5, 61.6, 31.4, 31.0, 60.9, 6Mean time to initiation of exercise program (weeks).Duration of exercise program (months).Figure 3 ESV effect size difference for individual trials categorized by time to exercise training and duration of training program.Haykowsky et al. Trials 2011, 12:92http://www.trialsjournal.com/content/12/1/92Page 5 of 8after MI. Most cardiac rehabilitation and secondary pre-vention programs commence at least four to six weeksafter hospital discharge [32]. To achieve maximal anti-remodeling benefits, clinically stable patients afteruncomplicated MI should begin aerobic exercise train-ing earlier after hospital discharge (from one week) andshould continue training for up to 6 months. As thisconclusion represents a potentially significant changefrom current practice, it is important to take intoaccount the size and safety of this.Though understandable, there is no evidence from thetrials in this review or other observational studies thatearly commencement of exercise training is harmful.Trials have indicated that risk of adverse events or com-plications (including: re-infarction, and revascularization) and EF are not raised by earlier physical activity whencompared to activity after 6 weeks - even when pre-discharge (Bruce protocol) stress tests are performed1-week post-MI [33]. Consistent with these findings,pre-discharge exercise (Bruce protocol) stress testing issafe and feasible in the majority of post-MI patients3 days after infarction [34]. In trials in this review, noadverse events occurred during the 6-month exercisetraining sessions initiated at the earliest juncture(around one week post-MI) in people with mild to mod-erate LV systolic dysfunction [5,6]. Moreover, clinicalevents were significantly lower in the trained versuscontrol group during the 6-month period.In addition to benefitting mortality and being safe,earlier commencement of exercise training appears tomarkedly increase participation in secondary preventionservices. Emerging evidence from observational studiesindicates that commencement of cardiac rehabilitationafter one week leads to a 90% increase in participationrates compared to a commencement after four weeks[35] and a faster return to work [33].By providing more specific guidance on basic yet pivo-tal program design characteristics, these findings arealso likely to render existing research evidence on exer-cise after MI more usable to health professionals anddecision-makers [16]. Despite convincing evidence ofthe benefits of exercise after myocardial infarction[1,2,36,37], secondary prevention in clinical populationsremains poor [38] and health services to promote exer-cise are under-utilized and poorly funded [39]. Healthservices, including different forms of cardiac rehabilita-tion [36,37,40] should be used more widely to promoteexercise earlier and for longer after MI.ConclusionsExercise training has beneficial effects on LV remodelingafter myocardial infarction. Exercise earlier after infarction(around 1 week) and for longer improved LV remodeling.There is a need for future high quality randomized con-trolled trials of exercise intervention early post myocardialinfarction on LV remodeling.Effect Size difference (Exercise - Control)-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5Heldal 2000     Giannuzzi  1993 Dubach 1997     Kubo 2004       Koizumi 2003    Giannuzzi 1997  Giallauria 2006bGiallauria 2006 Giallauria2008  Giallauria 20095.4, 15.4, 65.2, 24.0, 34.0, 33.5, 61.6, 31.4, 31.0, 60.9, 6Mean time to initiation of exercise program (weeks).Duration of exercise program (months).Figure 4 EDV effect size difference for individual trials categorized by time to exercise training and duration of training program.Haykowsky et al. Trials 2011, 12:92http://www.trialsjournal.com/content/12/1/92Page 6 of 8Additional materialAdditional file 1: PRISMA Checklist. A checklist of items reported inthe review.Additional file 2: Formulae of calculation of outcomes. A descriptionof the formulae through which outcomes were calculated.Additional file 3: Description of included studies. Studies included inthe review.Acknowledgements and FundingDr. Haykowsky had full access to all of the data in the study and takesresponsibility for the integrity of the data and the accuracy of the dataanalysis.AMC and MH received funding from the Canadian Institutes of HealthResearch via career awards. The organization had no influence orinvolvement in this publication.Author details1Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada.2Cardiovascular Physiology and Rehabilitation Laboratory, University of BritishColumbia, Vancouver, British Columbia, Canada. 3School of Public HealthSciences, University of Alberta, Edmonton, AB, Canada. 4Cardiology Division(111C), VA Palo Alto Health Care System, Stanford University, Palo Alto, CA,USA. 5Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.6Department of Radiation Oncology, Duke University Medical Center,Durham, NC, USA. 7Faculty of Nursing, University of Alberta, Edmonton, AB,Canada.Authors’ contributionsConception: MH, AMC, DS; Design: MH, AMC, DS; Acquisition of data: MH,AMC, DS, JS, BE.; Analysis:: MH, AMC, DS; Interpretation of data: MH, AMC,DS, IP, DW, LJ, JM. All authors read and approve the final manuscript.Competing interestsThe authors declare that they have no competing interests.Received: 19 January 2011 Accepted: 4 April 2011Published: 4 April 2011References1. O’Connor GT, Buring JE, Yusuf S, Goldhaber SZ, Olmstead EM,Paffenbarger RS, Hennekens CH: An overview of randomized trials ofrehabilitation with exercise after myocardial infarction. Circulation 1989,80:234-244.2. Oldridge NB, Guyatt GH, Fischer ME, Rimm AA: Cardiac rehabilitation aftermyocardial infarction. Combined experience of randomized clinical trials.JAMA 1988, 260:945-950.3. Chow CK, Jolly S, Rao-Melacini P, Fox KAA, Anand SS: Association of Diet,Exercise, and Smoking Modification With Risk of Early CardiovascularEvents After Acute Coronary Syndromes. Circulation 2010, 121:750-758.4. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ: Leftventricular end-systolic volume as the major determinant of survivalafter recovery from myocardial infarction. 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T:Attendance in an early discharge clinic with symptom limited maximalexercise testing is safe and improves cardiac rehabilitation participationamong low-risk stemi patients. Eur J Cardiovasc Prev Rehabil 2009, 16.36. Clark AM, Hartling L, Vandermeer B, McAlister FA: Secondary preventionprogram for patients with coronary artery disease: A meta-analysis ofrandomized control trials. Ann Int Med 2005, 143:659-672.37. Taylor RS, Brown A, Ebrahim S, Jolliffe J, Noorani H, Rees K, Skidmore B,Stone J, Thompson DR, Oldridge N: Exercise-based rehabilitation forpatients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med 2004, 116:682-692.38. Kotseva K, D W, De Backer G, De Bacquer D, Pyörälä K, Keil U, ftESG:Cardiovascular prevention guidelines in daily practice: a comparison ofEUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009,373:929-940.39. Bjarnason-Wehrens B, McGee H, Zwisler AD, Piepoli MF, Benzer W,Schmid JP, Dendale P, Pogosova NG, Zdrenghea D, Niebauer J, et al:Cardiac rehabilitation in Europe: results from the European CardiacRehabilitation Inventory Survey. Eur J Cardiovasc Prev Rehabil 2010,17:410-418.40. Dalal HM, Zawada A, Jolly K, Moxham T, Taylor RS: Home-based versuscentre based cardiac rehabiltiation: Cochrane systematic review andmeta-analysis. BMJ 2010, 340:b5631.doi:10.1186/1745-6215-12-92Cite this article as: Haykowsky et al.: A Meta-analysis of the effects ofExercise Training on Left Ventricular Remodeling Following MyocardialInfarction: Start early and go longer for greatest exercise benefits onremodeling. Trials 2011 12:92.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitHaykowsky et al. Trials 2011, 12:92http://www.trialsjournal.com/content/12/1/92Page 8 of 8


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