- Email: [email protected]
Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design, and Participants' Baseline Characteristics
Accepted Manuscript Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design and Participants’ Baseline Characteristics Eva Lonn, MD, Jackie Bosch, PhD, Janice Pogue, PhD, Alvaro Avezum, MD, Irina Chazova, MD, PhD, Antonio Dans, MD, Rafael Diaz, MD, George J. Fodor, MD, PhD, Claes Held, MD, PhD, Petr Jansky, MD, Matyas Keltai, MD, PhD, Katalin Keltai, MD, PhD, Kamlesh Kunti, MD, PhD, Jae-Hyung Kim, MD, PhD, Lawrence Leiter, MD, Basil Lewis, MD, Lisheng Liu, MD, Patricio Lopez-Jaramillo, MD, PhD, Prem Pais, MD, Alexandr Parkhomenko, MD, PhD, Ron J.G. Peters, MD, PhD, Leopoldo S. Piegas, MD, Christopher M. Reid, PhD, Karen Sliwa-Hahnle, MD, PhD, William D. Toff, MD, John Varigos, BSc, Denis Xavier, MD, Khalid Yusoff, MD, Jun Zhu, MD, Gilles Dagenais, MD, Salim Yusuf, MD, DPhil PII:
S0828-282X(15)00512-7
DOI:
10.1016/j.cjca.2015.07.001
Reference:
CJCA 1738
To appear in:
Canadian Journal of Cardiology
Received Date: 24 June 2015 Revised Date:
1 July 2015
Accepted Date: 1 July 2015
Please cite this article as: Lonn E, Bosch J, Pogue J, Avezum A, Chazova I, Dans A, Diaz R, Fodor GJ, Held C, Jansky P, Keltai M, Keltai K, Kunti K, Kim J-H, Leiter L, Lewis B, Liu L, Lopez-Jaramillo P, Pais P, Parkhomenko A, Peters RJG, Piegas LS, Reid CM, Sliwa-Hahnle K, Toff WD, Varigos J, Xavier D, Yusoff K, Zhu J, Dagenais G, Yusuf S, for the HOPE-3 Investigators, Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design and Participants’ Baseline Characteristics, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.07.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design and Participants’ Baseline Characteristics
RI PT
Eva Lonn, MD,a,b Jackie Bosch PhD,b Janice Pogue, PhD,b Alvaro Avezum, MD,c Irina Chazova, MD, PhD,d Antonio Dans, MD,e Rafael Diaz, MD,f George J. Fodor, MD, PhD,g Claes Held, MD, PhD,h Petr Jansky, MD,i Matyas Keltai, MD, PhD,j Katalin
SC
Keltai, MD, PhD,j Kamlesh Kunti,k MD, PhD, Jae-Hyung Kim, MD, PhD,l Lawrence
Leiter, MD,m Basil Lewis, MD,n Lisheng Liu, MD,o Patricio Lopez-Jaramillo, MD, PhD,p
M AN U
Prem Pais, MD,q Alexandr Parkhomenko MD, PhD,r Ron J.G. Peters, MD, PhD,s Leopoldo S. Piegas, MD, t Christopher M Reid, PhD,u Karen Sliwa-Hahnle, MD, PhD,v William D. Toff,w MD, John Varigos, BSc,u Denis Xavier, MD,q Khalid Yusoff, MD,x Jun Zhu, MD,y Gilles Dagenais, MD,z Salim Yusuf, MD, DPhil,a,b for the HOPE-3
TE D
Investigators
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
b
Population Health Research Institute, Hamilton Health Sciences and McMaster
EP
a
University, Hamilton, Ontario, Canada Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
d
Russian Cardiology Research Complex, Moscow, Russian Federation
e
College of Medicine of the University of the Philippines, Manula, Philippines
f
Fundacion ECLA, Rosario, Argentina
g
University of Ottawa Heart Institute, Ottawa, Ontario, Canada
h
Department of Medical Sciences, Uppsala University, Uppsala, Sweden
AC C
c
ACCEPTED MANUSCRIPT 2 University Hospital Motol, Prague, Czech Republic
j
Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary
k
Diabetes Research Centre, University of Leicester, United Kingdom
l
St. Paul’s Hospital, The Catholic University of Korea, Seoul, Korea
m
Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science,
St. Michael's Hospital, University of Toronto, Ontario, Canada n
RI PT
i
SC
Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of
Medicine, Technion-Israel Institute of Technology, Haifa
Fu Wai Hospital, Chinese Academy of Medical Sciences Beijing, China
P
Fundacion Oftalmolgica de Santander (FOSCAL) and Instituto Masira, Medical School,
M AN U
o
Universidad de Santander, Bucaramanga, Colombia q
Division of Clinical Research and Training, St. John’s Research Institute, Bangalore,
TE D
India r
Ukranian Strazhesko Institute of Cardiology, Kiev, Ukraine
s
Professor of Cardiology, Department of Cardiology, Academic Medical Center,
EP
Amsterdam, the Netherlands.
Hospital do Coração, São Paulo, Brazil
u
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne,
AC C
t
Australia
The HOPE-3 Investigators are listed in the online Appendix. v
Hatter Institute for Cardiovascular Research in Africa, Department of Medicine,
University of Cape Town and Soweto Cardiovascular Research Group, University of the Witwatersrand, Johannesburg, South Africa
ACCEPTED MANUSCRIPT 3 w
Department of Cardiovascular Sciences, University of Leicester, Leicester, United
Kingdom Universiti Teknologi MARA, Selangor, Malaysia
y
Fuwai Hospital, Chinese Adcademy of medical Sciences and Peking Union Medical
RI PT
x
College, Beijing, China z
Institut Universitaire de Cardiologie et Pneumologie de Québec, Université Laval,
SC
Québec, Canada.
Address for correspondence: Eva Lonn
M AN U
Short Title: The HOPE-3 Trial: Study Design and Baseline Characteristics
TE D
David Braley Cardiac Vascular and Stroke Research Institute Hamilton Health Sciences General Site
237 Barton Street East, Hamilton Ontario, Canada L8L 2X2
EP
Tel: (905) 526-0970; Fax: (905) 577-8261; E-mail: [email protected]
AC C
Word Count: 4913 (excluding title page)
ACCEPTED MANUSCRIPT 4 Abstract
Background: Cholesterol and blood pressure (BP) can be effectively and safely lowered
RI PT
with statins and with BP lowering drugs and reduce major cardiovascular (CV) events by 20%-30% within 5 years in high-risk people. However, there are limited data in lower risk populations. The HOPE-3 trial is evaluating whether cholesterol lowering with a
SC
statin, BP lowering with low doses of two antihypertensives and their combination safely reduce major CV events in people at intermediate risk, with no previous vascular events
M AN U
and with average cholesterol and BP levels.
Methods: 12,705 women 65 years or older and men 55 years or older with at least one CV risk factor, no known CV disease and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/day or placebo and to candesartan/hydrocholorothiazide (HCTZ) 16/12.5 mg/day or placebo (2x2 factorial
TE D
design) and will be followed for a mean of 5.8 years. The co-primary study outcomes are the composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke and
EP
the composite of CV death, non-fatal MI, non-fatal stroke, resuscitated cardiac arrest, heart failure and revascularizations.
AC C
Results: Participants were recruited from 21 countries in North America, South America, Europe, Asia and Australia. Mean age at randomization was 66 years and 46% were women.
Conclusions: The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.gov number, NCT00468923).
ACCEPTED MANUSCRIPT 5
AC C
EP
TE D
M AN U
SC
RI PT
Word Count: 248
ACCEPTED MANUSCRIPT 6 Brief Summary: The HOPE-3 trial is a large international randomized trial evaluating whether cholesterol lowering with a statin, BP lowering with low doses of two antihypertensives and their
RI PT
combination safely reduce major CV events in people at intermediate risk, with no
previous vascular events and with average cholesterol and BP levels. The trial enrolled 12,705 participants and is expected to inform approaches to primary cardiovascular
SC
disease prevention.
AC C
EP
TE D
M AN U
Word Count: 65 words
ACCEPTED MANUSCRIPT 7 Cardiovascular diseases (CVD) are major causes of mortality, morbidity and health care expenditure worldwide and affect over 50% of men and 40% of women over their lifetimes.1,2 Current primary prevention strategies are suboptimal. The HOPE-3 trial
RI PT
is testing novel approaches to primary prevention. This article summarizes the trial rationale and design and the baseline characteristics of the study population.
SC
Rationale for the HOPE trial
A substantial proportion of CVD events occur in average risk populations with
M AN U
no prior vascular disease and often without major elevations in cardiovascular (CV) risk factors. Prevention in such populations may have a big impact, a concept known as the "prevention paradox".3 Moreover, “mildly” abnormal CV risk factor levels are common. In the Framingham study fewer than 5% had optimal CV risk factor levels,2 in the U.S.A.
TE D
National Health and Nutrition Examination Surveys I, II, and III, the prevalence of low cardiovascular (CV) risk factors was only 4.4% during 1971–1975, 10.5% during 1988– 1994, and 7.5% during 1999–20044 and in the INTERHEART study 99% of control
EP
subjects had at least one abnormal CV risk factor.5 Therefore, in order to substantially reduce the population burden of CVD, the majority of individuals in most urban
AC C
populations may require modification of their risk factors. An important barrier to reducing the population burden of CV disease is the lack
of simple and widely applicable approaches to prevention. Guidelines for primary prevention vary by region, change often, extrapolate beyond data available from randomized trials and frequently involve complex algorithms for selection of people requiring drug therapies to reduce risk factor levels such as cholesterol and BP and for
ACCEPTED MANUSCRIPT 8 applying and monitoring the effects of therapy. These factors may contribute to the low rates of adoption of cholesterol and BP lowering strategies.6-9 Simplifying the selection of individuals who should receive preventive interventions using simple risk criteria instead
RI PT
of strict lipid or BP thresholds, generating evidence globally in multiple ethnic groups,
avoiding rigid “targets” and using less frequent monitoring may reduce the complexity and the cost of primary prevention and increase its uptake.
SC
Lifestyle interventions are considered to be the preferred approach in primary
prevention because of perceived low cost, apparent simplicity and safety. However, most
M AN U
lifestyle intervention trials have failed to show reductions in CV events, largely because substantial lifestyle changes are difficult to achieve and to sustain long-term.10-12 While specific risk factors were lowered in studies involving intensive and costly lifestyle interventions in selected groups (such as preventing diabetes in people with impaired
TE D
glucose tolerance by exercise and diet,13 or lowering BP by strict dietary changes in short term trials),14 these approaches are neither widely applicable to populations, nor affordable.15 A Mediterranean diet reduced CV events,16 but it is costly and cannot be
EP
easily implemented in many parts of the world. A complementary approach may be the use of inexpensive drugs proven to safely reduce events in people with established CVD
AC C
and/or with substantially elevated risk factor levels in a broad range of at-risk people. This is the basis for the polypill concept, which theorized large reductions in major CV events using a combination of such drugs.17-19 The drugs most likely to safely reduce CV events are statins and BP lowering drugs. Epidemiological data identify cholesterol and BP (along with smoking) as the most potent modifiable risk factors for atherosclerotic CVD and show that these are related “continuously” to CV risk over a wide range,
ACCEPTED MANUSCRIPT 9 including levels considered to be “normal” and without clear thresholds.5,20-22 Statins and BP lowering drugs can substantially and safely lower low-density lipoprotein cholesterol (LDL-C) and BP, and are therefore expected to cause large reductions in major CV
RI PT
events when used alone or in combination. To-date most evidence comes from studies in high-risk individuals with established CVD or diabetes or with substantially elevated
LDL-C or BP levels. Such trials have confirmed the efficacy and safety of these drugs in
SC
high-risk populations.23,24
Based on these considerations the HOPE-3 trial was initiated in 2007 to evaluate
M AN U
the effects of a low dose potent statin to lower LDL-C, a low dose fixed combination of an angiotensin-receptor blocker (ARB) plus diuretic and their combination to prevent major CV events in a wide range of people at intermediate risk without prior CVD, without strictly defined cholesterol or BP entry levels, and who are all receiving lifestyle
TE D
advice.
HOPE-3 differs significantly from previous statin and BP lowering trials in primary prevention. The Justification for the Use of Statins in Prevention: an Intervention
EP
Trial Evaluating Rosuvastatin (JUPITER), published after initiation of HOPE-3, evaluated treatment with rosuvastatin 20 mg/day in a highly selected population of
AC C
largely white Caucasian men and women with increased high-sensitivity C-reactive protein (hs-CRP) and reported a 44% reduction in major CV events after a median of 1.9 years of follow-up.25 However, because of the trial’s restrictive eligibility criteria (only 20% of participants screened were eligible), it is unclear whether these findings can be generalized. Other trials of statins in primary prevention also used restrictive eligibility criteria and were conducted in middle-aged Scottish men with hypercholesterolemia,26
ACCEPTED MANUSCRIPT 10
people with high LDL-C and low high-density lipoprotein cholesterol (HDL-C),27 Japanese subjects with hypercholesterolemia,28 hypertensives with additional CV risk factors29 and people with diabetes.30,31 Two trials included people targeted for both
RI PT
primary and secondary prevention, although study participants without prior CV events had high-risk profiles.32,33 Compared to these trials, HOPE-3 uses wider eligibility
criteria, a longer duration of follow-up, wider ethnic diversity and simpler monitoring
SC
procedures. The Cholesterol Treatment Trialists' (CTT) meta-analysis reported large relative risk reductions (RRR) in major CVD events in low and intermediate risk
M AN U
groups.34 However, in this meta-analysis, data in the lowest risk group (major yearly CV event rate of ≤1%) were provided by the aforementioned trials, which used narrow eligibility criteria. Moreover these data are based on a modest number of events, only 71 vascular deaths among those without CVD, 138 major coronary events, 161strokes, 208
TE D
revascularizations and a total of 377 major CV events. The HOPE-3 trial is expected to accrue almost twice as many events and will thus add substantially to the available information in this population. Similarly, BP lowering trials published before and after
EP
the start of HOPE-3, were conducted in individuals with hypertension defined as BP ≥160/100 mmHg or with pre-existing CVD, diabetes and/ or renal disease.24 Whether BP
AC C
lowering drugs will benefit a wider range of individuals without CVD, including those with “normal” entry BP levels, remains uncertain. Recent critical appraisals of the available data suggest than even for patients with "mild" hypertension (systolic BP of 140-160 mmHg) the evidence for benefit with BP lowering drugs is not robust. Some of these uncertainties in BP management in primary prevention in the absence of end organ damage are reflected in recent guidelines for BP management.35
ACCEPTED MANUSCRIPT 11
Study Design Study Objectives, Design and Interventions
RI PT
HOPE-3 is a large, multicentre, international double-blind randomized placebocontrolled trial, utilizing a 2 x 2 factorial design and evaluating LDL-C lowering with
rosuvastatin 10 mg/day vs. placebo, BP lowering with candesartan/ hydrochlorothiazide
SC
(HCTZ) 16/12.5 mg/day vs. placebo and the combination of rosuvastatin 10 mg/day and candesartan/HCTZ 16/12.5 mg/day vs. double placebo in preventing major CV events in
Patient Eligibility Criteria
M AN U
a population at intermediate CV risk (Table 1).
A wide range of people at intermediate risk were eligible for trial participation (Table 2). Men over 55 years and in women over 65 years with at least one additional CV
TE D
risk factor, among moderately elevated waist-to-hip ratio, history of low HDLcholesterol, recent tobacco use, dysglycemia, family history of premature coronary heart disease or early renal dysfunction were included. Participants with a clear clinical
EP
indication or contraindication for a statin, an ARB, an angiotensin-converting enzyme inhibitor (ACE-I) or a thiazide diuretic were excluded, including individuals with any
AC C
pre-existing CVD. The trial did not mandate strict cholesterol and BP entry levels. However, a local blood test for fasting lipids and glucose was obtained to inform physicians about participants’ risk and ultimately trial eligibility was based on the uncertainty principle,36 where among those who met inclusion criteria only those considered to have clear indication(s) or contraindications to the study drugs were excluded by informed local physicians with thorough knowledge of participants’ risk
ACCEPTED MANUSCRIPT 12
profile and of local guidelines and standards of practice. This approach is more relevant to clinical practice as it reflects the individual and collective equipoise of clinicians than
Primary, Secondary and Additional Outcome
RI PT
strict protocol-driven eligibility criteria.
In the original study design the primary outcome was the composite of CV death, non-fatal MI and non-fatal stroke. Based on in-trial blinded overall observed event rates,
SC
which were slightly lower than expected, the International Steering Committee for the trial decided to amend the trial to include two co-primary outcomes, the original
M AN U
composite of CV death, non-fatal MI and non-fatal stroke and the broader composite of CV death, non-fatal MI, non-fatal stroke, resuscitated cardiac arrest, heart failure and arterial revascularizations. Secondary outcomes are the composite of CV death, non-fatal MI, non-fatal stroke, resuscitated cardiac arrest, heart failure, arterial revascularizations
TE D
and angina with objective evidence of ischemia for both study arms and fatal and nonfatal stroke for the BP lowering arm of the trial. Additional outcomes include total mortality, the components of the co-primary outcomes, new diagnosis of diabetes,
EP
cognitive function in participants 70 years or older and erectile dysfunction in men. Sample Size and Data Analysis
AC C
The CTT meta-analysis of individual patient data from over 176,000 people in 27
statin RCTs, showed that for each 1 mmol/L reduction in LDL cholesterol over 5 years, there was a 21% RRR in major CV events,37 so an expected slightly larger reduction in LDC-C in the trial would reduce the risk for major CV events by about 25%. The BP Lowering Treatment Trialists Collaboration (BPLTTC) meta-analysis of individual patient data from over 100,000 participants in 29 trials showed that lowering systolic BP
ACCEPTED MANUSCRIPT 13
by 5 mmHg over 5 years with most drugs reduced the risk of major CV events by about 25%.25 The trial was originally planned to start in the spring of 2007, to recruit 11,000
RI PT
participants and to complete follow-up by March 2013. Original power calculations
considered the factorial design of the trial, estimated yearly placebo event rates of 1% for the original primary outcome, anticipated recruitment completion by the end of 2009, a
SC
mean follow-up of 5 years, 25% relative risk reduction for each intervention alone
(comparisons at the margins of the factorial design; these are independent comparisons,
M AN U
with no effect on the type I error rate; the effect of a modest, 10%, subadditivity was included in the sample size estimates), cumulative non-adherence rates of 6% in year one,11% by 2 years, 15% by 3 years and 23% by 5 years, drop-in rates of 3% in the first year and 2%/year in subsequent years (11% over 5 years) and rates of lost to follow-up of
TE D
<1%. These original calculations estimated also that the trial had >90% power to detect 40-50% relative reductions in risk for the double active (i.e. rosuvastatin 10 mg/day plus candesartan/HCTZ 16/12.5 mg/day) vs. the double placebo comparison.
EP
Recruitment started in May 2007, lasted 3.66 years and was skewed, with higher enrolment rates during the last year of recruitment. Due to the delay in recruitment and
AC C
the lower than expected in trial observed event rates, additional 1,705 study participants were enrolled for a total sample size of 12,705 and the Steering Committee amended the protocol twice. The first amendment approved on February 29th, 2012 allowed for two co-primary outcomes (see above). The second amendment approved on June 30th, 2013 was for an extension of follow-up of 2.5 years to October 2015 to ensure accrual of at least 500 first co-primary events. This will result in a mean follow-up of 5.8 years. To
ACCEPTED MANUSCRIPT 14
preserve alpha for testing of both co-primary outcomes and for testing at the margins of the factorial and the diagonal comparisons, the first co-primary outcome will be tested at a p value of 0.04 and the second co-primary at 0.02 at the margins and both co-primaries
RI PT
will be tested at a p value of 0.0044 for the diagonal comparisons (calculated via
simulation based on 80% overlap between the co-primary outcomes). We estimate that
the current amended sample size, co-primary study outcomes and revised timelines will
SC
allow the detection of relative risk reductions of at least 22.5% with each intervention
alone vs. its placebo with over 80% power and of at least 35% for the combined effects of
M AN U
cholesterol and BP lowering vs. double placebo with over 90% power. The study is expected to accrue at least 500 events for the first co-primary outcome and at least 600 for the second co-primary outcome.
The main analyses will use an intention to treat approach. Survival curves will be
TE D
estimated for the co-primary and the secondary outcomes using the Kaplan-Meier procedure. The main efficacy analyses will be the comparisons at the margins (i.e. separately for the rosuvastatin vs. rosuvastatin placebo and for candesartan/HCTZ vs. the
EP
candesartan/HCTZ placebo) and for the double active vs. the double placebo cells of the factorial design. The Cox model stratified by the opposite arm of the factorial design will
AC C
be used for treatment effect estimates and to evaluate effects in subgroups. A possible interaction between the two treatments will be assessed by inclusion of an interaction term in the model. In the very unlikely event of a significant interaction between the two treatment arms, the effects of rosuvastatin vs. placebo will be reported separately in those randomized and those not randomized to candesartan/HCTZ, and conversely the effects of candesartan/HCTZ will be reported separately in strata defined by rosuvastatin use.
ACCEPTED MANUSCRIPT 15
The main pre-defined hypothesis testing subgroup analyses will be conducted in subgroups defined by baseline risk, LDL-C and systolic BP. Additional analyses will be conducted to test the consistency of the trial results in subgroups defined by sex, age,
RI PT
additional lipid parameters, diastolic BP, waist to hip ratio, and geographic region.
Study Procedures
SC
Among 15,469 people screened, 14,665 eligible study participants entered an
active single blind run-in phase of 4 weeks, during which they received both active study
M AN U
drugs. A fasting blood sample and a first morning urine sample were obtained before administration of any study drugs for central analyses of lipids and other biomarkers and for local review of eligibility. Adherent participants who tolerated the study drugs were randomized using central concealed randomization, stratified by center (with fixed
TE D
randomization blocks). A total of 505 (3.4%) participants were not randomized after runin due to side effects. The majority of run-in failures were due to participants’ unwillingness to continue, 595 (4.0%) or poor adherence, 860 (5.9%). Individualized
EP
lifestyle advice was provided at randomization and in follow-up. Follow-up visits occurred at 6 weeks post randomization and every 6 months thereafter and assessed
AC C
adherence, side effects, use of concomitant drugs and outcome events. Data on BP, lipids and other biomarkers, lifestyle, cognitive function, erectile dysfunction, health care utilization and quality of life were obtained at baseline and in follow-up. Study Organization
HOPE-3 is an investigator-initiated trial conducted in 228 centers in 21 countries, led by an independent International Steering Committee and sponsored by the Canadian Institutes of Health Research and Astra-Zeneca (online Appendix). Ethics approvals were
ACCEPTED MANUSCRIPT 16
obtained at all centers and all participants signed informed consent. The Coordinating Center is the Population Health Research Institute, Hamilton Health Sciences and McMaster University in Hamilton, Ontario, Canada. A blinded Event Adjudication
RI PT
Committee adjudicates all primary and secondary events using pre-specified criteria. An independent Data and Safety Monitoring Board (DSMB) oversees the trial. Three formal interim efficacy analyses were planned, equally spaced with respect to accumulating
M AN U
Baseline Characteristics
SC
numbers of events.
Key baseline characteristics are shown in Table 3.
Discussion
TE D
Unanswered questions remain regarding possible benefits of cholesterol and BP lowering in people with average levels of both these risk factors and without CVD, which represent a large proportion of the population. The HOPE-3 trial is testing a novel
EP
approach based on the use of a statin and combination BP lowering drugs in a wide range of easily identifiable individuals at intermediate risk. In addition to evaluating each
AC C
intervention alone, the trial is assessing the efficacy and safety of statin plus combination BP lowering drugs and may therefore provide proof of concept for the use of fixed dose combinations (polypills) in primary prevention. The trial enrolled 12,705 participants, will have a long duration of follow-up and will provide robust data on the efficacy of the study interventions and also on their safety and impact on quality of life and health care costs. Drug safety and tolerability are essential in primary prevention, as true and
ACCEPTED MANUSCRIPT 17
perceived side effects adversely affect adherence and persistence and limit the potential benefits of preventive therapies. For example, statins are reported to increase the risk of incident diabetes, based mainly on post-hoc analyses of unadjudicated data.37 Similarly,
RI PT
thiazide diuretics may increase the risk of developing diabetes, but ARBs may have the opposite effect. Concerns have been raised also about the impact of statins and
antihypertensive drugs on cancer, cognitive decline, erectile dysfunction, visual acuity
SC
and overall quality of life,37,38 although it may be hypothesized that improved vascular health associated with cholesterol and BP lowering may actually benefit some of these
M AN U
outcomes. These and other safety outcomes are prospectively and carefully evaluated in the trial. As planned, participants’ mean LDL-C and BP at baseline were at levels for which considerable uncertainty regarding best management exists (3.2 mmol/L and 136.6/81.6 mmHg, respectively). Importantly, the trial randomized a large number of
TE D
women (46%) and has broad geographic and ethnic representation including large numbers of participants from Asia, South America, India and Africa (81% of the study population), regions of the world with increasing CV disease burden but
EP
underrepresented in previous primary prevention trials. HOPE-3 is large, simple, global trial that addresses the next frontier in CVD
AC C
prevention and its findings are expected to have a worldwide impact.
ACCEPTED MANUSCRIPT 18
References: 1.
The top 10 causes of death. Fact sheet N°310. Updated July 2013. http://www.who.int/mediacentre/factsheets/fs310/en/-accessed February 16, 2014 Lloyd-Jones, DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for
RI PT
2.
cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113:791-98.
Rose G. Strategy of prevention: lessons from cardiovascular disease. BMJ
SC
3.
1981;282:1847-51.
Ford ES, Li C, Zhao G, Pearson WS, Capewell S. Trends in the prevalence of low
M AN U
4.
risk factor burden for cardiovascular disease among United States adults. Circulation 2009;120:1181-88. 5.
Yusuf S, Hawken S, Ounpuu S, et al.; INTERHEART Study Investigators. Effect
TE D
of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:93752.
Chow CK, TeoKK, RangarajanS, et al.; PURE Investigators. Prevalence,
EP
6.
awareness, treatment, and control of hypertension in rural and urban communities
7.
AC C
in high-, middle-, and low-income countries. JAMA 2013;310:959-68. Lemstra M, Blackburn D, Crawley A, Fung R. Proportion and risk indicators of nonadherence to statin therapy: a meta-analysis. Can J Cardiol 2012;28:574-80.
8.
Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent cardiovascular disease: meta-analysis on 376,162 patients. Am J Med 2012;125:882-87.
ACCEPTED MANUSCRIPT 19
9.
Chowdhury R, Khan H, Heydon E, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J 2013;34:29408. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple
RI PT
10.
risk factor interventions for primary prevention of coronary heart disease Cochrane Database Syst Rev 2011;1:CD001561.
Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and risk of
SC
11.
cardiovascular disease: the Women's Health Initiative Randomized Controlled
12.
M AN U
Dietary Modification Trial. JAMA 2006;295:655-66.
Wing RR, Bolin P, Brancati FL, et al; Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-54.
Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program
TE D
13.
Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. Sacks FM, Svetkey LP, Vollmer WM, et al.; DASH-Sodium Collaborative
EP
14.
Research Group. Effects on blood pressure of reduced dietary sodium and the
AC C
Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.N Engl J Med 2001;344:3-10.
15.
Miller RR, Sales AE, Kopjar B, Fihn SD, Bryson CL. Adherence to heart-healthy behaviors in a sample of the US population. Prev Chronic Dis 2005;2:A18.
16.
Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
ACCEPTED MANUSCRIPT 20
17.
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419-24.
18.
Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The Polypill in the
and future directions. Circulation 2010;122:2078-88. 19.
RI PT
Prevention of cardiovascular diseases: key concepts, current status, challenges,
Yusuf S, Attaran A, Bosch J, et al.; Working Group on the Summit on
SC
Combination Therapy for CVD. Combination pharmacotherapy to prevent
cardiovascular disease: present status and challenges. Eur Heart J 2014;35:353Lewington S, Whitlock G, Clarke R, et al.; Prospective Studies Collaboration.
M AN U
20.
Blood cholesterol and vascular mortality by age, sex, and blood pressure: a metaanalysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829-39.
Prospective Studies Collaboration. Age-specific relevance of usual blood pressure
TE D
21.
to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-13. Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ
EP
22.
2002;324:1570-77.
Baigent C, Blackwell L, Emberson J, et al.; Cholesterol Treatment Trialists’
AC C
23.
(CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
24.
Turnbull F. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events:
ACCEPTED MANUSCRIPT 21
results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527-35. 25.
Ridker PM, Danielson E, Fonseca FA, et al.; JUPITER Study Group.
reactive protein N Engl J Med 2008;359:2195-207. 26.
RI PT
Rosuvastatin to prevent vascular events in men and women with elevated C-
Shepherd J, Cobbe S, Ford I, et al for the West of Scotland Coronary Prevention
SC
Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995 Nov. 20;333.1301-7.
Downs J, Clearfield M, Weis S, et al for the AFCAPS/TexCAPS Research Group.
M AN U
27.
Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998 May 20;279:1615-22. 28.
Nakamura H, Arakawa K, Itakura H, et al.; MEGA Study Group.Primary
TE D
prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368:1155-63. 29.
Server P, Dahlof B, Poulter N, et al for the ASCOT investigators. Prevention of
EP
coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-
AC C
Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58.
30.
Colhoun H, Betteridge J, Durrington P, et al for the CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet 2004;364: 685-96.
ACCEPTED MANUSCRIPT 22
31.
Knopp R, d’Emden M, Smilde J, Pocock S for the ASPEN Study Group. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes. Diabetes Care 2006;29:1478-85. Shepherd J, Blauw G, Murphy M, et al. Pravastatin in elderly individuals at risk
RI PT
32.
of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study
SC
33.
of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a
34.
M AN U
randomised placebo-controlled trial. Lancet 2002;360:7-22.
Mihaylova B, Emberson J, Blackwell L, et al.; Cholesterol Treatment Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27
35.
TE D
randomised trials. Lancet 2012;380:581-90.
Kjeldsen S, Feldman RD, Lisheng L, et al. Updated national and international hypertension guidelines: a review of current recommendations. Drugs.
36.
EP
2014;74:2033-2051.
Sackett DL. Why randomized controlled trials fail but needn’t: 1. Failure to gain
AC C
“coal-face” commitment and to use the uncertainty principle. CMAJ 2000;162:1311-1314.
37.
Mancini GB, Gosselin G, Chow B et al; Canadian Cardiovascular Society. Can J Cardiol 2014;3:837-849.
38.
Bakris G, Sarafidis P, Agarwal R, Ruilope L. Review of blood pressure control rates and outcomes. J Am Soc Hypertens 2014;8:127-141.
ACCEPTED MANUSCRIPT 24
Funding Sources: The Canadian Institutes of Health Research, Funding Reference Number IR2-91038 and
AC C
EP
TE D
M AN U
SC
RI PT
Astra Zeneca.
ACCEPTED MANUSCRIPT 25
Tables Table 1: The HOPE-3 Factorial Study Design (N=12,705):
Rosuvastatin Active/ Candesartan/HCTZ Placebo n=3,176
Rosuvastatin Placebo/ Candesartan/HCTZ Active n=3,176 Candesartan/HCTZ Active n=6,352
Rosuvastatin Placebo/ Candesartan/HCTZ Placebo n=3,177 Candesartan/HCTZ Placebo n=6,353
Candesartan/HCTZ Margins
AC C
EP
TE D
HCTZ=hydrochlorothiazide
M AN U
Placebo
SC
Rosuvastatin Active/ Candesartan/HCTZ Active n=3,176
Active
Rosuvastatin Margins
RI PT
Candesartan/HCTZ Active Placebo
Rosuvastatin
Rosuvastatin Active n=6,352
Rosuvastatin Placebo n=6,353
ACCEPTED MANUSCRIPT 26
Table 2: HOPE-3 Eligibility Criteria Inclusion Criteria
At least one of the following additional CV risk factors: Waist/hip ratio ≥ 0.85 in women and ≥ 0.90 in men
RI PT
Women aged ≥ 65 years* and men aged ≥ 55 years
History of current or recent smoking (regular tobacco use within 5 years)
SC
Low HDL-C ( HDL-C < 1.0 mmol/L in men and <1.3 mmol/L in women)
diabetes treated with diet only) Early renal dysfunction**
M AN U
Dysglycemia (impaired fasting glucose, impaired glucose tolerance or uncomplicated
Family history of premature coronary heart disease in first degree relatives (age < 55 years in men or <65 years in women)
Exclusion Criteria
TE D
Provision of informed consent
Documented clinically manifest atherothrombotic CVD
EP
Indication for statin and/or ARB, ACE inhibitor or thiazide diuretics
AC C
Contraindications for statin and/or ARB or thiazide diuretics1 Symptomatic hypotension Chronic liver disease (cirrhosis or persistent hepatitis) or abnormal liver function (ALT or
1
Subjects with persistently elevated blood pressure and who are considered by the recruiting /local physician to require antihypertensive therapy can be entered in the trial after BP control is attained with lifestyle interventions or with non-study drugs such as beta-blockers, calcium channel blockers or alpha blockers. Subjects on lipid lowering therapy other than a statin or a fibrate can also be considered for the trial.
ACCEPTED MANUSCRIPT 27
AST > 3 x ULN) Inflammatory muscle disease (such as dermatomyositis or polymyositis) or creatine kinase (CK) > 3 x ULN)
RI PT
Moderate renal dysfunction defined as serum creatinine >180µmol/L (2.0 mg/dL) or eGFR <45ml/min/1.73m² Treatment with cyclosporine or fibrates
SC
Other serious condition(s) likely to interfere with study participation or with the ability to complete the trial
M AN U
Concurrent use of any experimental pharmacological agent
* women ≥ 60 years with at least two additional risk factors were also eligible **microalbuminuria or estimated GFR<60ml/min/1.73m² or creatinine>124µmol/L
AC C
EP
TE D
(1.4mg/dL), unless the participant has proteinuria or blood pressure >130/80mmHg
ACCEPTED MANUSCRIPT 28
Table 3: Key Baseline Characteristics of the 12,705 HOPE-3 Study Participants N (%) Demographic Data 5,873 (46.2)
RI PT
Women Geographic Region South America
3,870 (30.5)
1,156 (9.1)
SC
North America Europe
1,169 (9.2)
3,677 (28.9)
India
1,824 (14.4)
Other Asian countries South Africa
TE D
Australia Race
EP
Chinese Latin
M AN U
China
AC C
European/ Caucasian
753 (5.9) 211 (1.7) 45 (0.4)
3,691 (29.1) 3,496 (27.5) 2,546 (20.0)
South Asian
1,854 (14.6)
Other Asian
696 (5.5)
Black African
225 (1.8)
Other
197 (1.6)
Risk Factors Accounting for Trial Eligibility Elevated waist/hip ratio
11,022 (86.8)
ACCEPTED MANUSCRIPT 29
4,581 (36.1)
Recent or current smoking
3,516 (27.7)
Dysglycemia
2,342 (18.4)
Family history of premature coronary heart disease
3,327 (26.2)
Renal dysfunction
348 (2.7)
Participants with 2 risk factors
5,915 (46.5)
3,063 (24.1)
SC
Participants with > 3 risk factors
Aspirin Beta-Blocker Calcium-Channel Blocker Alpha Blocker
TE D
Niacin
EP
Physical and Laboratory Measures Age
M AN U
Medication Use:
Ezetimibe
RI PT
Low HDL-cholesterol
AC C
Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg)
1,392 (11.0) 1,017 (8.0)
1,884 (14.8) 140 (1.1) 17 (0.1) 11 (0.1) Mean (SD) 65.6 (6.4) 136.6 (14.6) 81.6 (9.3)
Heart Rate (beats/minute)
72.7 (10.4)
Body mass index (kg/m2)(
27.1 (4.7)
Waist/Hip ratio (cm)
0.94 (0.1)
Total cholesterol (mmol/L)
5.2 (1.0)
Triglycerides (mmol/L)
1.6 (0.9)
ACCEPTED MANUSCRIPT 30
3.2 (0.9)
HDL-cholesterol mmol/L (mmol/L)
1.3 (0.4)
Fasting plasma glucose (mmol/L)
5.5 (1.2)
Apolipoprotein B (mg/L)
1.0 (0.3)
RI PT
LDL-cholesterol (mmol/L)
Apolipoprotein A (mg/L)
1.5 (0.3)
hs- CRP (mg/L) – median (IQR)
1.9 (1.0-3.8)
AC C
EP
TE D
M AN U
Reactive Protein; IQR = interquartile range
SC
LDL=low density lipoprotein; HDL=high density lipoprotein; hs-CRP=high sensitivity C
ACCEPTED MANUSCRIPT
Appendix: The HOPE-3 Investigators
RI PT
Steering Committee: S Yusuf (Chair and Principal Investigator), E Lonn (Co-Chair and CoPrincipal Investigator), A Avezum, J Bosch, I Chazova, G. Dagenais, A Dans, R Diaz, G Fodor, C Held, P Jansky, M Keltai, K Khunti, J-H Kim, L Leiter, B Lewis, L Loss, L Liu, P LopezJaramillo, P Pais, A Parkhomenko, R Peters, L Piegas, J Pogue, C Reid, K Sliwa, W Toff, J Varigos, D Xavier, K Yusoff, J Zhu.
SC
Event Adjudication Committee: G Dagenais (Chair), R McKelvie (Co-Chair), N Anderson, A Avezum, P Bogaty, I Chazova, M Corson, G Fodor, D Halon, R Hart, C Held, P Hildebrandt, M Keltai, Y Liang, P Magloire, J Mann, M Naufal, R Peters, Z Punthakee, M Sharma, J Silva, B Tsang, J Wilkinson, N Yakubovich, K Yusoff.
M AN U
Data and Safety Monitoring Board: D Sackett (Chair), D DeMets (Interim Chair), C Baigent, C Hennekens, J Mancini. Study Statisticians: J Pogue, H Jung, G Wong, K Balasubramanian Project Office Study Coordination: J Bosch, J Wilkinson, J Miller, K Brettell, A Rogge, C Choppick, A Kuptsova, S. Owens, S MacRae, A Mead, J Gibson, N Barkhordari.
AC C
EP
TE D
National Leader Office Coordination and Monitoring by Country: Argentina: R Diaz, M Cabezon, B Dellavedova, A Pascual Australia: C Reid, J Varigos, L Shiel Brazil: L Piegas, A Avezum, M Steiner Marroni, D Nova, L Pini Tanabe, Canada: E. Lonn, L Leiter, L Baetz, S Kulkarni, T Newman China: L Liu, J Zhu, Y Liang, L Ma, H Tan, Y Ge Colombia & Ecuador: P Lopez-Jaramillo, M Lopez Czech Republic: P Jansky, J Vanova Hungary: M Keltai, K Keltai India: P Pais, D Xavier, A Sigamani, F Xavier, S G, R Gupta Israel: B Lewis, Y Marmor*, R Yuval Korea: J-H Kim Malaysia: K Yusoff, S Muhamad-Yunus Netherlands: R Peters, N Bruinsma, P Ebbinkhuijsen Philippines: A Dans, J Sanchez, E Villarruz-Sulit Russia: I Chazova, A Aksenova, N Blinova, E Helis Slovakia: G Fodor, S. Africa: K Sliwa-Hahnle Sweden: C Held, G Lindstrom, E Svensson UK: K Khunti, W Toff, E Parker, S Legi, E Wadey Ukraine: A, Parkhomenko, L Parkhomenko, O Skarzhevsky. *deceased Site Principal Investigators and Co-Investigators by Country: Argentina: M Alzogaray, M Aparici, M Berli, M Bevacqua, M Bustamante Labarta, B Bustos, A Caccavo, A Candiello, M Carignano, N Carrillo, N Carro, L Cartasegna, W Casali, A Cassettari, G Ceconi, M Centeno, J Cuello, Sandra Cusimano, C Cuneo, C Damonte, M De Landaluc, E De Martino, R Diez, R Duran, A Fernandez, A Ferrari, L Forti, M Galello, C Garcia, F Giachello, M Garrido, F Guerlloy, R Guerrero, A Hrabar, H Imposti, M Hominal, G Liniado, P Lanchiotti, C Laugle, A Longhi, M-R Litvak, H Luciardi, I Mackinnon, J Marino, R Manzano, B Merlo, R Milesi, C Mulazzi, S Nemi, S Orio, M Pelaggage, S Raimondi, L Rodino, C Rodriguez, L Sago, S Salazar, J Sala, A Sanchez, R Sanchez, D Santos, P Schygiel, V Sernia, T Smith, F Sokn, L Soso, M Toledo, M Trivi, M Vico, O Vilamajo, A Villamil, D Vogel, C Zaidman, Australia: W
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Abhayaratna, J Canalese, P Groenestein, H Krum, A Patel, D Sullivan Brazil: C Amaro, J-C Ayoub, M Blacher, L Bondanese, J Braga, C Brasil, M Costa, O Costa, C De Melo Novelli, M Del Monaco, A Do Valle, L Fabian Restelatto, F Filho, R Franco, M Furtado, M Hernandes, P Leaes, A Leite, L Maia, D Mion, D Mota, F Mothe, G Oliveira, L Oliveira, E Pelloso, C Polanczyk, A Rabelo, L Rabelo, P Raupp Da Rosa, A Rodrigues, C Rodrigues, J Saraiva, A Schmidt, A Sobral Sousa, V Silva Canada: B Abramson, S Anand, J Aw, W Baxter, S Brulotte, J Berlingieri, R Casey, M Crete, J Cha, R Chaulk, T Chetty, G Dagenais, D Dattani, M Degrace, F Delage, D Dion, M Dominguez, R Gallo, K Glendinning, H Goldman, G Grosselin, A Greenspoon, F Grondin, Q Hungly, M Juneau, P Keegan, A Kelly, H Kilby, R Labonte, M Lavoie, P Magloire, P Mehta, A Mente, N Mercante, H Miscescu, G Moran, S Nawaz, A Nigam, W Nisker, P Pang, E Papp, R Petrella, C Poirier, P Poirier, R Rabasa-Lhoret, Q Rizvi, R St-Hilaire, D Saulnier, M Sharma, P Sohal, S Stern, S Tobe, P Walsh, R Ward, W Watson, V Woo, H Yamamoto, J Yellin, P Zuliani China: X Bai, M Baobin, L Dajun, L Dong, P Dong, S Doufei, J-Z Feng, M Feng-Ling, L Fengying, P Fu, P Gao, Y Ge, S Hong, Z Hong, Z Hui, Q Hua, Y Husheng, T Jialun, C Jianguo, A Kaying, N Liu, L Liu, F Lu, T Lv, S Ma, R Man, L Minge, Z Qingtan, G Quing Ling, Z Run Ping, J Shi, K Song, H Tanabe, B Wang, S-Y Wang, J Wang, Q Wang, Y Wang, Y Wei, S Ziandon, Y Ziaohong, L Xiaolin, L Xiumei, N Yang, X Yang, M Yanhua, K Yu, S Yunai, B Zhang, H Zhang, J Zhang, F Zhang, L Zengyan, J Zhao, Y Zhao Colombia: J Accini, G Aroca, E Arcos, N Cabrera Lopez, M Casanova, C Celemin, A Cervantes, B Collante, J Coronel, C Cotes, C Cure, A Duarte, D Escobar, M Figueredo, H Garcia, L Garcia, M Grisales, Z Hernandez, D Ines, K Martinez, B Nino Castellanos, M Olite, N Ospina Rendon, I Posada, A Quintero, F Quiros, G Sanchez, A Sotomayor, M Suarez, M Urina, T Valencia Czech Republic: V Adamkova, R Cifkova, R Ferkl, M Galovcova, J Hartman, M Jozifova, K Linhart, T Linhart, D Moravcikova, B Nussbaumerova, M Plachy, H Rosolova, B Seifert, M Soucek Ecuador: Y Duarte-Vera, M Espinel, M Lopez, J McDermont, E Penaherrera, F Plascencia, F Pow-Chon-Long, D Tettamanti Hungary: L Bajnok, E Baranyior, E Bartfai, K Beck, Z Bedo, E Bod, B Bodis, I Czuriga, H Eleonora, R Janosne, E Mezosi, E Monostori, F Poor, E Somos, Z Tarjanyi, T Tatrai, J Tomcsanyi, A Tumpek, A Vertes, A Zsary India: DK Agarwal, KG Alexander, V Ayyars, B Bosco, N Chidambaram, N Deshpande, HR Devendra, B Ganapathi, S George, D Ghosh Roy, S Gnanasekaran, R Gupta, S Joshi, SP Kalantri, CB Keshavamurthy, A Khan, C Kocherlakaota, S Kulkarni, S Kumar, AR Manjunath, K Mehta, A Modi, V Mohan, S Murthy, A Nambiar, J Narendra, S Paul, A Purshit, MA Qureshi, D Rajasekaran, M Ramu, R Ranjani, RL Ranka, S Roy, MR Satyanarayana, K Selvam, M Shunmugavelu, G Sidhu, R Singh, R Singh Khedar, J Drinivas, B Srinivasulu, S Suresh, R Razyeem Khan, N Thomas, R Tongia, R Umarani, K Varghese, S Varma, S Yelwatkar, B Yerrathota Israel: A Biton, A Goldhaber, S Ivri, R Kaminsky, I Lentsisky, A Lubov, T Pugacsov, B Punchik, T Rozenthal, A Schlesinger, A Seidman, I Shapiro, E Shveydel, N Shveydel, D Tsalihin, N Viliky, S Vinker, A Weinar, C Yosefy Korea: S Kil Kim Malaysia: A Abdullah, D Ambigga, A Ghapar, C Krishnan, H Liew, M Maizatullifah, Y Mazapuspavina, M Mo Aris, U Muthukumaru, L Ramanathan, K Selvaraj, A Shah Mohd Shah Netherlands: JH
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Bonarius, A De Jong, ZDG De Ruiter, R De Vos, HA Dirkse, E Drenth, H Ferguson, R Jansen, H Rol, A Schilder, I Spelt, P Van Leeuwen Philippines: M Abola, H Co, A Loyola, J Mercado, D Morales, N Nicodemus, D Padi, L Padua, L Palileo, A Patanao, G Rogelio, A Roxas, D Sulit, A Tang-Manga, B Tumanan-Mendoza Russia: F Ageev, S. Boytsov, I Chukaeva, J Grinishina, Y Karpov, D Kirakozov, O Kisliak, Z Kobalava, I Kolos, L Krilova, A Ledyacva, T Lobzhanidze, Y Lopatin, M Markova, T Myshlyaeva, S Nedogoda, M Pokichenko, S Postnikova, S Serdyuk, G Soboleva, M Solovieva, I Teupko, Z Tigay, V Tsoma, T Tyurina Slovakia: M Hranai, S Stevikova S. Africa: A Badat Sweden: F Al-Khalili, B Carlberg, A Dotevall, P Nilsson, A Olsson, A Rosengren, S Soderberg UK: W Toff Ukraine: D Artomov, T Babanina, A Bagriy, G Chobotko, S Danyliuk, N Doretska, O Dorovska, N Dovgan, G Dzyak, L Glushko, I Gorbas, T Ilashchuk, P Ivanchuk, K Karapetyan, I Karavanska, L Khimion, A Khorsun, L Kononenko, O Kuryata, S Lazareva, D Loktyev, V Martynyuk, N Miroshnchenko, O Onyschenko, D Palianichko, N Petryk, S Pivovarova, O Polishchuk, I Rakytskay, L Sapozhnychenko, V Serneniaka, T Shandra, I Sichkaruk, I Smymova, O Soya, V Tashchuk, N Turubarova-Leunova, O Vasilkova, L Vasilyeva, N Velichko, O Verbovska, A Yagensky, S Zborovskyy, S Zhurba, A Zhukova, R Zubyk UK: I Loke,
S0828-282X(15)00512-7
DOI:
10.1016/j.cjca.2015.07.001
Reference:
CJCA 1738
To appear in:
Canadian Journal of Cardiology
Received Date: 24 June 2015 Revised Date:
1 July 2015
Accepted Date: 1 July 2015
Please cite this article as: Lonn E, Bosch J, Pogue J, Avezum A, Chazova I, Dans A, Diaz R, Fodor GJ, Held C, Jansky P, Keltai M, Keltai K, Kunti K, Kim J-H, Leiter L, Lewis B, Liu L, Lopez-Jaramillo P, Pais P, Parkhomenko A, Peters RJG, Piegas LS, Reid CM, Sliwa-Hahnle K, Toff WD, Varigos J, Xavier D, Yusoff K, Zhu J, Dagenais G, Yusuf S, for the HOPE-3 Investigators, Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design and Participants’ Baseline Characteristics, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.07.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design and Participants’ Baseline Characteristics
RI PT
Eva Lonn, MD,a,b Jackie Bosch PhD,b Janice Pogue, PhD,b Alvaro Avezum, MD,c Irina Chazova, MD, PhD,d Antonio Dans, MD,e Rafael Diaz, MD,f George J. Fodor, MD, PhD,g Claes Held, MD, PhD,h Petr Jansky, MD,i Matyas Keltai, MD, PhD,j Katalin
SC
Keltai, MD, PhD,j Kamlesh Kunti,k MD, PhD, Jae-Hyung Kim, MD, PhD,l Lawrence
Leiter, MD,m Basil Lewis, MD,n Lisheng Liu, MD,o Patricio Lopez-Jaramillo, MD, PhD,p
M AN U
Prem Pais, MD,q Alexandr Parkhomenko MD, PhD,r Ron J.G. Peters, MD, PhD,s Leopoldo S. Piegas, MD, t Christopher M Reid, PhD,u Karen Sliwa-Hahnle, MD, PhD,v William D. Toff,w MD, John Varigos, BSc,u Denis Xavier, MD,q Khalid Yusoff, MD,x Jun Zhu, MD,y Gilles Dagenais, MD,z Salim Yusuf, MD, DPhil,a,b for the HOPE-3
TE D
Investigators
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
b
Population Health Research Institute, Hamilton Health Sciences and McMaster
EP
a
University, Hamilton, Ontario, Canada Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
d
Russian Cardiology Research Complex, Moscow, Russian Federation
e
College of Medicine of the University of the Philippines, Manula, Philippines
f
Fundacion ECLA, Rosario, Argentina
g
University of Ottawa Heart Institute, Ottawa, Ontario, Canada
h
Department of Medical Sciences, Uppsala University, Uppsala, Sweden
AC C
c
ACCEPTED MANUSCRIPT 2 University Hospital Motol, Prague, Czech Republic
j
Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary
k
Diabetes Research Centre, University of Leicester, United Kingdom
l
St. Paul’s Hospital, The Catholic University of Korea, Seoul, Korea
m
Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science,
St. Michael's Hospital, University of Toronto, Ontario, Canada n
RI PT
i
SC
Lady Davis Carmel Medical Center and the Ruth and Bruce Rappaport School of
Medicine, Technion-Israel Institute of Technology, Haifa
Fu Wai Hospital, Chinese Academy of Medical Sciences Beijing, China
P
Fundacion Oftalmolgica de Santander (FOSCAL) and Instituto Masira, Medical School,
M AN U
o
Universidad de Santander, Bucaramanga, Colombia q
Division of Clinical Research and Training, St. John’s Research Institute, Bangalore,
TE D
India r
Ukranian Strazhesko Institute of Cardiology, Kiev, Ukraine
s
Professor of Cardiology, Department of Cardiology, Academic Medical Center,
EP
Amsterdam, the Netherlands.
Hospital do Coração, São Paulo, Brazil
u
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne,
AC C
t
Australia
The HOPE-3 Investigators are listed in the online Appendix. v
Hatter Institute for Cardiovascular Research in Africa, Department of Medicine,
University of Cape Town and Soweto Cardiovascular Research Group, University of the Witwatersrand, Johannesburg, South Africa
ACCEPTED MANUSCRIPT 3 w
Department of Cardiovascular Sciences, University of Leicester, Leicester, United
Kingdom Universiti Teknologi MARA, Selangor, Malaysia
y
Fuwai Hospital, Chinese Adcademy of medical Sciences and Peking Union Medical
RI PT
x
College, Beijing, China z
Institut Universitaire de Cardiologie et Pneumologie de Québec, Université Laval,
SC
Québec, Canada.
Address for correspondence: Eva Lonn
M AN U
Short Title: The HOPE-3 Trial: Study Design and Baseline Characteristics
TE D
David Braley Cardiac Vascular and Stroke Research Institute Hamilton Health Sciences General Site
237 Barton Street East, Hamilton Ontario, Canada L8L 2X2
EP
Tel: (905) 526-0970; Fax: (905) 577-8261; E-mail: [email protected]
AC C
Word Count: 4913 (excluding title page)
ACCEPTED MANUSCRIPT 4 Abstract
Background: Cholesterol and blood pressure (BP) can be effectively and safely lowered
RI PT
with statins and with BP lowering drugs and reduce major cardiovascular (CV) events by 20%-30% within 5 years in high-risk people. However, there are limited data in lower risk populations. The HOPE-3 trial is evaluating whether cholesterol lowering with a
SC
statin, BP lowering with low doses of two antihypertensives and their combination safely reduce major CV events in people at intermediate risk, with no previous vascular events
M AN U
and with average cholesterol and BP levels.
Methods: 12,705 women 65 years or older and men 55 years or older with at least one CV risk factor, no known CV disease and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/day or placebo and to candesartan/hydrocholorothiazide (HCTZ) 16/12.5 mg/day or placebo (2x2 factorial
TE D
design) and will be followed for a mean of 5.8 years. The co-primary study outcomes are the composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke and
EP
the composite of CV death, non-fatal MI, non-fatal stroke, resuscitated cardiac arrest, heart failure and revascularizations.
AC C
Results: Participants were recruited from 21 countries in North America, South America, Europe, Asia and Australia. Mean age at randomization was 66 years and 46% were women.
Conclusions: The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.gov number, NCT00468923).
ACCEPTED MANUSCRIPT 5
AC C
EP
TE D
M AN U
SC
RI PT
Word Count: 248
ACCEPTED MANUSCRIPT 6 Brief Summary: The HOPE-3 trial is a large international randomized trial evaluating whether cholesterol lowering with a statin, BP lowering with low doses of two antihypertensives and their
RI PT
combination safely reduce major CV events in people at intermediate risk, with no
previous vascular events and with average cholesterol and BP levels. The trial enrolled 12,705 participants and is expected to inform approaches to primary cardiovascular
SC
disease prevention.
AC C
EP
TE D
M AN U
Word Count: 65 words
ACCEPTED MANUSCRIPT 7 Cardiovascular diseases (CVD) are major causes of mortality, morbidity and health care expenditure worldwide and affect over 50% of men and 40% of women over their lifetimes.1,2 Current primary prevention strategies are suboptimal. The HOPE-3 trial
RI PT
is testing novel approaches to primary prevention. This article summarizes the trial rationale and design and the baseline characteristics of the study population.
SC
Rationale for the HOPE trial
A substantial proportion of CVD events occur in average risk populations with
M AN U
no prior vascular disease and often without major elevations in cardiovascular (CV) risk factors. Prevention in such populations may have a big impact, a concept known as the "prevention paradox".3 Moreover, “mildly” abnormal CV risk factor levels are common. In the Framingham study fewer than 5% had optimal CV risk factor levels,2 in the U.S.A.
TE D
National Health and Nutrition Examination Surveys I, II, and III, the prevalence of low cardiovascular (CV) risk factors was only 4.4% during 1971–1975, 10.5% during 1988– 1994, and 7.5% during 1999–20044 and in the INTERHEART study 99% of control
EP
subjects had at least one abnormal CV risk factor.5 Therefore, in order to substantially reduce the population burden of CVD, the majority of individuals in most urban
AC C
populations may require modification of their risk factors. An important barrier to reducing the population burden of CV disease is the lack
of simple and widely applicable approaches to prevention. Guidelines for primary prevention vary by region, change often, extrapolate beyond data available from randomized trials and frequently involve complex algorithms for selection of people requiring drug therapies to reduce risk factor levels such as cholesterol and BP and for
ACCEPTED MANUSCRIPT 8 applying and monitoring the effects of therapy. These factors may contribute to the low rates of adoption of cholesterol and BP lowering strategies.6-9 Simplifying the selection of individuals who should receive preventive interventions using simple risk criteria instead
RI PT
of strict lipid or BP thresholds, generating evidence globally in multiple ethnic groups,
avoiding rigid “targets” and using less frequent monitoring may reduce the complexity and the cost of primary prevention and increase its uptake.
SC
Lifestyle interventions are considered to be the preferred approach in primary
prevention because of perceived low cost, apparent simplicity and safety. However, most
M AN U
lifestyle intervention trials have failed to show reductions in CV events, largely because substantial lifestyle changes are difficult to achieve and to sustain long-term.10-12 While specific risk factors were lowered in studies involving intensive and costly lifestyle interventions in selected groups (such as preventing diabetes in people with impaired
TE D
glucose tolerance by exercise and diet,13 or lowering BP by strict dietary changes in short term trials),14 these approaches are neither widely applicable to populations, nor affordable.15 A Mediterranean diet reduced CV events,16 but it is costly and cannot be
EP
easily implemented in many parts of the world. A complementary approach may be the use of inexpensive drugs proven to safely reduce events in people with established CVD
AC C
and/or with substantially elevated risk factor levels in a broad range of at-risk people. This is the basis for the polypill concept, which theorized large reductions in major CV events using a combination of such drugs.17-19 The drugs most likely to safely reduce CV events are statins and BP lowering drugs. Epidemiological data identify cholesterol and BP (along with smoking) as the most potent modifiable risk factors for atherosclerotic CVD and show that these are related “continuously” to CV risk over a wide range,
ACCEPTED MANUSCRIPT 9 including levels considered to be “normal” and without clear thresholds.5,20-22 Statins and BP lowering drugs can substantially and safely lower low-density lipoprotein cholesterol (LDL-C) and BP, and are therefore expected to cause large reductions in major CV
RI PT
events when used alone or in combination. To-date most evidence comes from studies in high-risk individuals with established CVD or diabetes or with substantially elevated
LDL-C or BP levels. Such trials have confirmed the efficacy and safety of these drugs in
SC
high-risk populations.23,24
Based on these considerations the HOPE-3 trial was initiated in 2007 to evaluate
M AN U
the effects of a low dose potent statin to lower LDL-C, a low dose fixed combination of an angiotensin-receptor blocker (ARB) plus diuretic and their combination to prevent major CV events in a wide range of people at intermediate risk without prior CVD, without strictly defined cholesterol or BP entry levels, and who are all receiving lifestyle
TE D
advice.
HOPE-3 differs significantly from previous statin and BP lowering trials in primary prevention. The Justification for the Use of Statins in Prevention: an Intervention
EP
Trial Evaluating Rosuvastatin (JUPITER), published after initiation of HOPE-3, evaluated treatment with rosuvastatin 20 mg/day in a highly selected population of
AC C
largely white Caucasian men and women with increased high-sensitivity C-reactive protein (hs-CRP) and reported a 44% reduction in major CV events after a median of 1.9 years of follow-up.25 However, because of the trial’s restrictive eligibility criteria (only 20% of participants screened were eligible), it is unclear whether these findings can be generalized. Other trials of statins in primary prevention also used restrictive eligibility criteria and were conducted in middle-aged Scottish men with hypercholesterolemia,26
ACCEPTED MANUSCRIPT 10
people with high LDL-C and low high-density lipoprotein cholesterol (HDL-C),27 Japanese subjects with hypercholesterolemia,28 hypertensives with additional CV risk factors29 and people with diabetes.30,31 Two trials included people targeted for both
RI PT
primary and secondary prevention, although study participants without prior CV events had high-risk profiles.32,33 Compared to these trials, HOPE-3 uses wider eligibility
criteria, a longer duration of follow-up, wider ethnic diversity and simpler monitoring
SC
procedures. The Cholesterol Treatment Trialists' (CTT) meta-analysis reported large relative risk reductions (RRR) in major CVD events in low and intermediate risk
M AN U
groups.34 However, in this meta-analysis, data in the lowest risk group (major yearly CV event rate of ≤1%) were provided by the aforementioned trials, which used narrow eligibility criteria. Moreover these data are based on a modest number of events, only 71 vascular deaths among those without CVD, 138 major coronary events, 161strokes, 208
TE D
revascularizations and a total of 377 major CV events. The HOPE-3 trial is expected to accrue almost twice as many events and will thus add substantially to the available information in this population. Similarly, BP lowering trials published before and after
EP
the start of HOPE-3, were conducted in individuals with hypertension defined as BP ≥160/100 mmHg or with pre-existing CVD, diabetes and/ or renal disease.24 Whether BP
AC C
lowering drugs will benefit a wider range of individuals without CVD, including those with “normal” entry BP levels, remains uncertain. Recent critical appraisals of the available data suggest than even for patients with "mild" hypertension (systolic BP of 140-160 mmHg) the evidence for benefit with BP lowering drugs is not robust. Some of these uncertainties in BP management in primary prevention in the absence of end organ damage are reflected in recent guidelines for BP management.35
ACCEPTED MANUSCRIPT 11
Study Design Study Objectives, Design and Interventions
RI PT
HOPE-3 is a large, multicentre, international double-blind randomized placebocontrolled trial, utilizing a 2 x 2 factorial design and evaluating LDL-C lowering with
rosuvastatin 10 mg/day vs. placebo, BP lowering with candesartan/ hydrochlorothiazide
SC
(HCTZ) 16/12.5 mg/day vs. placebo and the combination of rosuvastatin 10 mg/day and candesartan/HCTZ 16/12.5 mg/day vs. double placebo in preventing major CV events in
Patient Eligibility Criteria
M AN U
a population at intermediate CV risk (Table 1).
A wide range of people at intermediate risk were eligible for trial participation (Table 2). Men over 55 years and in women over 65 years with at least one additional CV
TE D
risk factor, among moderately elevated waist-to-hip ratio, history of low HDLcholesterol, recent tobacco use, dysglycemia, family history of premature coronary heart disease or early renal dysfunction were included. Participants with a clear clinical
EP
indication or contraindication for a statin, an ARB, an angiotensin-converting enzyme inhibitor (ACE-I) or a thiazide diuretic were excluded, including individuals with any
AC C
pre-existing CVD. The trial did not mandate strict cholesterol and BP entry levels. However, a local blood test for fasting lipids and glucose was obtained to inform physicians about participants’ risk and ultimately trial eligibility was based on the uncertainty principle,36 where among those who met inclusion criteria only those considered to have clear indication(s) or contraindications to the study drugs were excluded by informed local physicians with thorough knowledge of participants’ risk
ACCEPTED MANUSCRIPT 12
profile and of local guidelines and standards of practice. This approach is more relevant to clinical practice as it reflects the individual and collective equipoise of clinicians than
Primary, Secondary and Additional Outcome
RI PT
strict protocol-driven eligibility criteria.
In the original study design the primary outcome was the composite of CV death, non-fatal MI and non-fatal stroke. Based on in-trial blinded overall observed event rates,
SC
which were slightly lower than expected, the International Steering Committee for the trial decided to amend the trial to include two co-primary outcomes, the original
M AN U
composite of CV death, non-fatal MI and non-fatal stroke and the broader composite of CV death, non-fatal MI, non-fatal stroke, resuscitated cardiac arrest, heart failure and arterial revascularizations. Secondary outcomes are the composite of CV death, non-fatal MI, non-fatal stroke, resuscitated cardiac arrest, heart failure, arterial revascularizations
TE D
and angina with objective evidence of ischemia for both study arms and fatal and nonfatal stroke for the BP lowering arm of the trial. Additional outcomes include total mortality, the components of the co-primary outcomes, new diagnosis of diabetes,
EP
cognitive function in participants 70 years or older and erectile dysfunction in men. Sample Size and Data Analysis
AC C
The CTT meta-analysis of individual patient data from over 176,000 people in 27
statin RCTs, showed that for each 1 mmol/L reduction in LDL cholesterol over 5 years, there was a 21% RRR in major CV events,37 so an expected slightly larger reduction in LDC-C in the trial would reduce the risk for major CV events by about 25%. The BP Lowering Treatment Trialists Collaboration (BPLTTC) meta-analysis of individual patient data from over 100,000 participants in 29 trials showed that lowering systolic BP
ACCEPTED MANUSCRIPT 13
by 5 mmHg over 5 years with most drugs reduced the risk of major CV events by about 25%.25 The trial was originally planned to start in the spring of 2007, to recruit 11,000
RI PT
participants and to complete follow-up by March 2013. Original power calculations
considered the factorial design of the trial, estimated yearly placebo event rates of 1% for the original primary outcome, anticipated recruitment completion by the end of 2009, a
SC
mean follow-up of 5 years, 25% relative risk reduction for each intervention alone
(comparisons at the margins of the factorial design; these are independent comparisons,
M AN U
with no effect on the type I error rate; the effect of a modest, 10%, subadditivity was included in the sample size estimates), cumulative non-adherence rates of 6% in year one,11% by 2 years, 15% by 3 years and 23% by 5 years, drop-in rates of 3% in the first year and 2%/year in subsequent years (11% over 5 years) and rates of lost to follow-up of
TE D
<1%. These original calculations estimated also that the trial had >90% power to detect 40-50% relative reductions in risk for the double active (i.e. rosuvastatin 10 mg/day plus candesartan/HCTZ 16/12.5 mg/day) vs. the double placebo comparison.
EP
Recruitment started in May 2007, lasted 3.66 years and was skewed, with higher enrolment rates during the last year of recruitment. Due to the delay in recruitment and
AC C
the lower than expected in trial observed event rates, additional 1,705 study participants were enrolled for a total sample size of 12,705 and the Steering Committee amended the protocol twice. The first amendment approved on February 29th, 2012 allowed for two co-primary outcomes (see above). The second amendment approved on June 30th, 2013 was for an extension of follow-up of 2.5 years to October 2015 to ensure accrual of at least 500 first co-primary events. This will result in a mean follow-up of 5.8 years. To
ACCEPTED MANUSCRIPT 14
preserve alpha for testing of both co-primary outcomes and for testing at the margins of the factorial and the diagonal comparisons, the first co-primary outcome will be tested at a p value of 0.04 and the second co-primary at 0.02 at the margins and both co-primaries
RI PT
will be tested at a p value of 0.0044 for the diagonal comparisons (calculated via
simulation based on 80% overlap between the co-primary outcomes). We estimate that
the current amended sample size, co-primary study outcomes and revised timelines will
SC
allow the detection of relative risk reductions of at least 22.5% with each intervention
alone vs. its placebo with over 80% power and of at least 35% for the combined effects of
M AN U
cholesterol and BP lowering vs. double placebo with over 90% power. The study is expected to accrue at least 500 events for the first co-primary outcome and at least 600 for the second co-primary outcome.
The main analyses will use an intention to treat approach. Survival curves will be
TE D
estimated for the co-primary and the secondary outcomes using the Kaplan-Meier procedure. The main efficacy analyses will be the comparisons at the margins (i.e. separately for the rosuvastatin vs. rosuvastatin placebo and for candesartan/HCTZ vs. the
EP
candesartan/HCTZ placebo) and for the double active vs. the double placebo cells of the factorial design. The Cox model stratified by the opposite arm of the factorial design will
AC C
be used for treatment effect estimates and to evaluate effects in subgroups. A possible interaction between the two treatments will be assessed by inclusion of an interaction term in the model. In the very unlikely event of a significant interaction between the two treatment arms, the effects of rosuvastatin vs. placebo will be reported separately in those randomized and those not randomized to candesartan/HCTZ, and conversely the effects of candesartan/HCTZ will be reported separately in strata defined by rosuvastatin use.
ACCEPTED MANUSCRIPT 15
The main pre-defined hypothesis testing subgroup analyses will be conducted in subgroups defined by baseline risk, LDL-C and systolic BP. Additional analyses will be conducted to test the consistency of the trial results in subgroups defined by sex, age,
RI PT
additional lipid parameters, diastolic BP, waist to hip ratio, and geographic region.
Study Procedures
SC
Among 15,469 people screened, 14,665 eligible study participants entered an
active single blind run-in phase of 4 weeks, during which they received both active study
M AN U
drugs. A fasting blood sample and a first morning urine sample were obtained before administration of any study drugs for central analyses of lipids and other biomarkers and for local review of eligibility. Adherent participants who tolerated the study drugs were randomized using central concealed randomization, stratified by center (with fixed
TE D
randomization blocks). A total of 505 (3.4%) participants were not randomized after runin due to side effects. The majority of run-in failures were due to participants’ unwillingness to continue, 595 (4.0%) or poor adherence, 860 (5.9%). Individualized
EP
lifestyle advice was provided at randomization and in follow-up. Follow-up visits occurred at 6 weeks post randomization and every 6 months thereafter and assessed
AC C
adherence, side effects, use of concomitant drugs and outcome events. Data on BP, lipids and other biomarkers, lifestyle, cognitive function, erectile dysfunction, health care utilization and quality of life were obtained at baseline and in follow-up. Study Organization
HOPE-3 is an investigator-initiated trial conducted in 228 centers in 21 countries, led by an independent International Steering Committee and sponsored by the Canadian Institutes of Health Research and Astra-Zeneca (online Appendix). Ethics approvals were
ACCEPTED MANUSCRIPT 16
obtained at all centers and all participants signed informed consent. The Coordinating Center is the Population Health Research Institute, Hamilton Health Sciences and McMaster University in Hamilton, Ontario, Canada. A blinded Event Adjudication
RI PT
Committee adjudicates all primary and secondary events using pre-specified criteria. An independent Data and Safety Monitoring Board (DSMB) oversees the trial. Three formal interim efficacy analyses were planned, equally spaced with respect to accumulating
M AN U
Baseline Characteristics
SC
numbers of events.
Key baseline characteristics are shown in Table 3.
Discussion
TE D
Unanswered questions remain regarding possible benefits of cholesterol and BP lowering in people with average levels of both these risk factors and without CVD, which represent a large proportion of the population. The HOPE-3 trial is testing a novel
EP
approach based on the use of a statin and combination BP lowering drugs in a wide range of easily identifiable individuals at intermediate risk. In addition to evaluating each
AC C
intervention alone, the trial is assessing the efficacy and safety of statin plus combination BP lowering drugs and may therefore provide proof of concept for the use of fixed dose combinations (polypills) in primary prevention. The trial enrolled 12,705 participants, will have a long duration of follow-up and will provide robust data on the efficacy of the study interventions and also on their safety and impact on quality of life and health care costs. Drug safety and tolerability are essential in primary prevention, as true and
ACCEPTED MANUSCRIPT 17
perceived side effects adversely affect adherence and persistence and limit the potential benefits of preventive therapies. For example, statins are reported to increase the risk of incident diabetes, based mainly on post-hoc analyses of unadjudicated data.37 Similarly,
RI PT
thiazide diuretics may increase the risk of developing diabetes, but ARBs may have the opposite effect. Concerns have been raised also about the impact of statins and
antihypertensive drugs on cancer, cognitive decline, erectile dysfunction, visual acuity
SC
and overall quality of life,37,38 although it may be hypothesized that improved vascular health associated with cholesterol and BP lowering may actually benefit some of these
M AN U
outcomes. These and other safety outcomes are prospectively and carefully evaluated in the trial. As planned, participants’ mean LDL-C and BP at baseline were at levels for which considerable uncertainty regarding best management exists (3.2 mmol/L and 136.6/81.6 mmHg, respectively). Importantly, the trial randomized a large number of
TE D
women (46%) and has broad geographic and ethnic representation including large numbers of participants from Asia, South America, India and Africa (81% of the study population), regions of the world with increasing CV disease burden but
EP
underrepresented in previous primary prevention trials. HOPE-3 is large, simple, global trial that addresses the next frontier in CVD
AC C
prevention and its findings are expected to have a worldwide impact.
ACCEPTED MANUSCRIPT 18
References: 1.
The top 10 causes of death. Fact sheet N°310. Updated July 2013. http://www.who.int/mediacentre/factsheets/fs310/en/-accessed February 16, 2014 Lloyd-Jones, DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for
RI PT
2.
cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113:791-98.
Rose G. Strategy of prevention: lessons from cardiovascular disease. BMJ
SC
3.
1981;282:1847-51.
Ford ES, Li C, Zhao G, Pearson WS, Capewell S. Trends in the prevalence of low
M AN U
4.
risk factor burden for cardiovascular disease among United States adults. Circulation 2009;120:1181-88. 5.
Yusuf S, Hawken S, Ounpuu S, et al.; INTERHEART Study Investigators. Effect
TE D
of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:93752.
Chow CK, TeoKK, RangarajanS, et al.; PURE Investigators. Prevalence,
EP
6.
awareness, treatment, and control of hypertension in rural and urban communities
7.
AC C
in high-, middle-, and low-income countries. JAMA 2013;310:959-68. Lemstra M, Blackburn D, Crawley A, Fung R. Proportion and risk indicators of nonadherence to statin therapy: a meta-analysis. Can J Cardiol 2012;28:574-80.
8.
Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent cardiovascular disease: meta-analysis on 376,162 patients. Am J Med 2012;125:882-87.
ACCEPTED MANUSCRIPT 19
9.
Chowdhury R, Khan H, Heydon E, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J 2013;34:29408. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple
RI PT
10.
risk factor interventions for primary prevention of coronary heart disease Cochrane Database Syst Rev 2011;1:CD001561.
Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and risk of
SC
11.
cardiovascular disease: the Women's Health Initiative Randomized Controlled
12.
M AN U
Dietary Modification Trial. JAMA 2006;295:655-66.
Wing RR, Bolin P, Brancati FL, et al; Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-54.
Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program
TE D
13.
Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. Sacks FM, Svetkey LP, Vollmer WM, et al.; DASH-Sodium Collaborative
EP
14.
Research Group. Effects on blood pressure of reduced dietary sodium and the
AC C
Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.N Engl J Med 2001;344:3-10.
15.
Miller RR, Sales AE, Kopjar B, Fihn SD, Bryson CL. Adherence to heart-healthy behaviors in a sample of the US population. Prev Chronic Dis 2005;2:A18.
16.
Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
ACCEPTED MANUSCRIPT 20
17.
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419-24.
18.
Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The Polypill in the
and future directions. Circulation 2010;122:2078-88. 19.
RI PT
Prevention of cardiovascular diseases: key concepts, current status, challenges,
Yusuf S, Attaran A, Bosch J, et al.; Working Group on the Summit on
SC
Combination Therapy for CVD. Combination pharmacotherapy to prevent
cardiovascular disease: present status and challenges. Eur Heart J 2014;35:353Lewington S, Whitlock G, Clarke R, et al.; Prospective Studies Collaboration.
M AN U
20.
Blood cholesterol and vascular mortality by age, sex, and blood pressure: a metaanalysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829-39.
Prospective Studies Collaboration. Age-specific relevance of usual blood pressure
TE D
21.
to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-13. Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ
EP
22.
2002;324:1570-77.
Baigent C, Blackwell L, Emberson J, et al.; Cholesterol Treatment Trialists’
AC C
23.
(CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
24.
Turnbull F. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events:
ACCEPTED MANUSCRIPT 21
results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527-35. 25.
Ridker PM, Danielson E, Fonseca FA, et al.; JUPITER Study Group.
reactive protein N Engl J Med 2008;359:2195-207. 26.
RI PT
Rosuvastatin to prevent vascular events in men and women with elevated C-
Shepherd J, Cobbe S, Ford I, et al for the West of Scotland Coronary Prevention
SC
Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995 Nov. 20;333.1301-7.
Downs J, Clearfield M, Weis S, et al for the AFCAPS/TexCAPS Research Group.
M AN U
27.
Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998 May 20;279:1615-22. 28.
Nakamura H, Arakawa K, Itakura H, et al.; MEGA Study Group.Primary
TE D
prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368:1155-63. 29.
Server P, Dahlof B, Poulter N, et al for the ASCOT investigators. Prevention of
EP
coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-
AC C
Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58.
30.
Colhoun H, Betteridge J, Durrington P, et al for the CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet 2004;364: 685-96.
ACCEPTED MANUSCRIPT 22
31.
Knopp R, d’Emden M, Smilde J, Pocock S for the ASPEN Study Group. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes. Diabetes Care 2006;29:1478-85. Shepherd J, Blauw G, Murphy M, et al. Pravastatin in elderly individuals at risk
RI PT
32.
of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study
SC
33.
of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a
34.
M AN U
randomised placebo-controlled trial. Lancet 2002;360:7-22.
Mihaylova B, Emberson J, Blackwell L, et al.; Cholesterol Treatment Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27
35.
TE D
randomised trials. Lancet 2012;380:581-90.
Kjeldsen S, Feldman RD, Lisheng L, et al. Updated national and international hypertension guidelines: a review of current recommendations. Drugs.
36.
EP
2014;74:2033-2051.
Sackett DL. Why randomized controlled trials fail but needn’t: 1. Failure to gain
AC C
“coal-face” commitment and to use the uncertainty principle. CMAJ 2000;162:1311-1314.
37.
Mancini GB, Gosselin G, Chow B et al; Canadian Cardiovascular Society. Can J Cardiol 2014;3:837-849.
38.
Bakris G, Sarafidis P, Agarwal R, Ruilope L. Review of blood pressure control rates and outcomes. J Am Soc Hypertens 2014;8:127-141.
ACCEPTED MANUSCRIPT 24
Funding Sources: The Canadian Institutes of Health Research, Funding Reference Number IR2-91038 and
AC C
EP
TE D
M AN U
SC
RI PT
Astra Zeneca.
ACCEPTED MANUSCRIPT 25
Tables Table 1: The HOPE-3 Factorial Study Design (N=12,705):
Rosuvastatin Active/ Candesartan/HCTZ Placebo n=3,176
Rosuvastatin Placebo/ Candesartan/HCTZ Active n=3,176 Candesartan/HCTZ Active n=6,352
Rosuvastatin Placebo/ Candesartan/HCTZ Placebo n=3,177 Candesartan/HCTZ Placebo n=6,353
Candesartan/HCTZ Margins
AC C
EP
TE D
HCTZ=hydrochlorothiazide
M AN U
Placebo
SC
Rosuvastatin Active/ Candesartan/HCTZ Active n=3,176
Active
Rosuvastatin Margins
RI PT
Candesartan/HCTZ Active Placebo
Rosuvastatin
Rosuvastatin Active n=6,352
Rosuvastatin Placebo n=6,353
ACCEPTED MANUSCRIPT 26
Table 2: HOPE-3 Eligibility Criteria Inclusion Criteria
At least one of the following additional CV risk factors: Waist/hip ratio ≥ 0.85 in women and ≥ 0.90 in men
RI PT
Women aged ≥ 65 years* and men aged ≥ 55 years
History of current or recent smoking (regular tobacco use within 5 years)
SC
Low HDL-C ( HDL-C < 1.0 mmol/L in men and <1.3 mmol/L in women)
diabetes treated with diet only) Early renal dysfunction**
M AN U
Dysglycemia (impaired fasting glucose, impaired glucose tolerance or uncomplicated
Family history of premature coronary heart disease in first degree relatives (age < 55 years in men or <65 years in women)
Exclusion Criteria
TE D
Provision of informed consent
Documented clinically manifest atherothrombotic CVD
EP
Indication for statin and/or ARB, ACE inhibitor or thiazide diuretics
AC C
Contraindications for statin and/or ARB or thiazide diuretics1 Symptomatic hypotension Chronic liver disease (cirrhosis or persistent hepatitis) or abnormal liver function (ALT or
1
Subjects with persistently elevated blood pressure and who are considered by the recruiting /local physician to require antihypertensive therapy can be entered in the trial after BP control is attained with lifestyle interventions or with non-study drugs such as beta-blockers, calcium channel blockers or alpha blockers. Subjects on lipid lowering therapy other than a statin or a fibrate can also be considered for the trial.
ACCEPTED MANUSCRIPT 27
AST > 3 x ULN) Inflammatory muscle disease (such as dermatomyositis or polymyositis) or creatine kinase (CK) > 3 x ULN)
RI PT
Moderate renal dysfunction defined as serum creatinine >180µmol/L (2.0 mg/dL) or eGFR <45ml/min/1.73m² Treatment with cyclosporine or fibrates
SC
Other serious condition(s) likely to interfere with study participation or with the ability to complete the trial
M AN U
Concurrent use of any experimental pharmacological agent
* women ≥ 60 years with at least two additional risk factors were also eligible **microalbuminuria or estimated GFR<60ml/min/1.73m² or creatinine>124µmol/L
AC C
EP
TE D
(1.4mg/dL), unless the participant has proteinuria or blood pressure >130/80mmHg
ACCEPTED MANUSCRIPT 28
Table 3: Key Baseline Characteristics of the 12,705 HOPE-3 Study Participants N (%) Demographic Data 5,873 (46.2)
RI PT
Women Geographic Region South America
3,870 (30.5)
1,156 (9.1)
SC
North America Europe
1,169 (9.2)
3,677 (28.9)
India
1,824 (14.4)
Other Asian countries South Africa
TE D
Australia Race
EP
Chinese Latin
M AN U
China
AC C
European/ Caucasian
753 (5.9) 211 (1.7) 45 (0.4)
3,691 (29.1) 3,496 (27.5) 2,546 (20.0)
South Asian
1,854 (14.6)
Other Asian
696 (5.5)
Black African
225 (1.8)
Other
197 (1.6)
Risk Factors Accounting for Trial Eligibility Elevated waist/hip ratio
11,022 (86.8)
ACCEPTED MANUSCRIPT 29
4,581 (36.1)
Recent or current smoking
3,516 (27.7)
Dysglycemia
2,342 (18.4)
Family history of premature coronary heart disease
3,327 (26.2)
Renal dysfunction
348 (2.7)
Participants with 2 risk factors
5,915 (46.5)
3,063 (24.1)
SC
Participants with > 3 risk factors
Aspirin Beta-Blocker Calcium-Channel Blocker Alpha Blocker
TE D
Niacin
EP
Physical and Laboratory Measures Age
M AN U
Medication Use:
Ezetimibe
RI PT
Low HDL-cholesterol
AC C
Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg)
1,392 (11.0) 1,017 (8.0)
1,884 (14.8) 140 (1.1) 17 (0.1) 11 (0.1) Mean (SD) 65.6 (6.4) 136.6 (14.6) 81.6 (9.3)
Heart Rate (beats/minute)
72.7 (10.4)
Body mass index (kg/m2)(
27.1 (4.7)
Waist/Hip ratio (cm)
0.94 (0.1)
Total cholesterol (mmol/L)
5.2 (1.0)
Triglycerides (mmol/L)
1.6 (0.9)
ACCEPTED MANUSCRIPT 30
3.2 (0.9)
HDL-cholesterol mmol/L (mmol/L)
1.3 (0.4)
Fasting plasma glucose (mmol/L)
5.5 (1.2)
Apolipoprotein B (mg/L)
1.0 (0.3)
RI PT
LDL-cholesterol (mmol/L)
Apolipoprotein A (mg/L)
1.5 (0.3)
hs- CRP (mg/L) – median (IQR)
1.9 (1.0-3.8)
AC C
EP
TE D
M AN U
Reactive Protein; IQR = interquartile range
SC
LDL=low density lipoprotein; HDL=high density lipoprotein; hs-CRP=high sensitivity C
ACCEPTED MANUSCRIPT
Appendix: The HOPE-3 Investigators
RI PT
Steering Committee: S Yusuf (Chair and Principal Investigator), E Lonn (Co-Chair and CoPrincipal Investigator), A Avezum, J Bosch, I Chazova, G. Dagenais, A Dans, R Diaz, G Fodor, C Held, P Jansky, M Keltai, K Khunti, J-H Kim, L Leiter, B Lewis, L Loss, L Liu, P LopezJaramillo, P Pais, A Parkhomenko, R Peters, L Piegas, J Pogue, C Reid, K Sliwa, W Toff, J Varigos, D Xavier, K Yusoff, J Zhu.
SC
Event Adjudication Committee: G Dagenais (Chair), R McKelvie (Co-Chair), N Anderson, A Avezum, P Bogaty, I Chazova, M Corson, G Fodor, D Halon, R Hart, C Held, P Hildebrandt, M Keltai, Y Liang, P Magloire, J Mann, M Naufal, R Peters, Z Punthakee, M Sharma, J Silva, B Tsang, J Wilkinson, N Yakubovich, K Yusoff.
M AN U
Data and Safety Monitoring Board: D Sackett (Chair), D DeMets (Interim Chair), C Baigent, C Hennekens, J Mancini. Study Statisticians: J Pogue, H Jung, G Wong, K Balasubramanian Project Office Study Coordination: J Bosch, J Wilkinson, J Miller, K Brettell, A Rogge, C Choppick, A Kuptsova, S. Owens, S MacRae, A Mead, J Gibson, N Barkhordari.
AC C
EP
TE D
National Leader Office Coordination and Monitoring by Country: Argentina: R Diaz, M Cabezon, B Dellavedova, A Pascual Australia: C Reid, J Varigos, L Shiel Brazil: L Piegas, A Avezum, M Steiner Marroni, D Nova, L Pini Tanabe, Canada: E. Lonn, L Leiter, L Baetz, S Kulkarni, T Newman China: L Liu, J Zhu, Y Liang, L Ma, H Tan, Y Ge Colombia & Ecuador: P Lopez-Jaramillo, M Lopez Czech Republic: P Jansky, J Vanova Hungary: M Keltai, K Keltai India: P Pais, D Xavier, A Sigamani, F Xavier, S G, R Gupta Israel: B Lewis, Y Marmor*, R Yuval Korea: J-H Kim Malaysia: K Yusoff, S Muhamad-Yunus Netherlands: R Peters, N Bruinsma, P Ebbinkhuijsen Philippines: A Dans, J Sanchez, E Villarruz-Sulit Russia: I Chazova, A Aksenova, N Blinova, E Helis Slovakia: G Fodor, S. Africa: K Sliwa-Hahnle Sweden: C Held, G Lindstrom, E Svensson UK: K Khunti, W Toff, E Parker, S Legi, E Wadey Ukraine: A, Parkhomenko, L Parkhomenko, O Skarzhevsky. *deceased Site Principal Investigators and Co-Investigators by Country: Argentina: M Alzogaray, M Aparici, M Berli, M Bevacqua, M Bustamante Labarta, B Bustos, A Caccavo, A Candiello, M Carignano, N Carrillo, N Carro, L Cartasegna, W Casali, A Cassettari, G Ceconi, M Centeno, J Cuello, Sandra Cusimano, C Cuneo, C Damonte, M De Landaluc, E De Martino, R Diez, R Duran, A Fernandez, A Ferrari, L Forti, M Galello, C Garcia, F Giachello, M Garrido, F Guerlloy, R Guerrero, A Hrabar, H Imposti, M Hominal, G Liniado, P Lanchiotti, C Laugle, A Longhi, M-R Litvak, H Luciardi, I Mackinnon, J Marino, R Manzano, B Merlo, R Milesi, C Mulazzi, S Nemi, S Orio, M Pelaggage, S Raimondi, L Rodino, C Rodriguez, L Sago, S Salazar, J Sala, A Sanchez, R Sanchez, D Santos, P Schygiel, V Sernia, T Smith, F Sokn, L Soso, M Toledo, M Trivi, M Vico, O Vilamajo, A Villamil, D Vogel, C Zaidman, Australia: W
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Abhayaratna, J Canalese, P Groenestein, H Krum, A Patel, D Sullivan Brazil: C Amaro, J-C Ayoub, M Blacher, L Bondanese, J Braga, C Brasil, M Costa, O Costa, C De Melo Novelli, M Del Monaco, A Do Valle, L Fabian Restelatto, F Filho, R Franco, M Furtado, M Hernandes, P Leaes, A Leite, L Maia, D Mion, D Mota, F Mothe, G Oliveira, L Oliveira, E Pelloso, C Polanczyk, A Rabelo, L Rabelo, P Raupp Da Rosa, A Rodrigues, C Rodrigues, J Saraiva, A Schmidt, A Sobral Sousa, V Silva Canada: B Abramson, S Anand, J Aw, W Baxter, S Brulotte, J Berlingieri, R Casey, M Crete, J Cha, R Chaulk, T Chetty, G Dagenais, D Dattani, M Degrace, F Delage, D Dion, M Dominguez, R Gallo, K Glendinning, H Goldman, G Grosselin, A Greenspoon, F Grondin, Q Hungly, M Juneau, P Keegan, A Kelly, H Kilby, R Labonte, M Lavoie, P Magloire, P Mehta, A Mente, N Mercante, H Miscescu, G Moran, S Nawaz, A Nigam, W Nisker, P Pang, E Papp, R Petrella, C Poirier, P Poirier, R Rabasa-Lhoret, Q Rizvi, R St-Hilaire, D Saulnier, M Sharma, P Sohal, S Stern, S Tobe, P Walsh, R Ward, W Watson, V Woo, H Yamamoto, J Yellin, P Zuliani China: X Bai, M Baobin, L Dajun, L Dong, P Dong, S Doufei, J-Z Feng, M Feng-Ling, L Fengying, P Fu, P Gao, Y Ge, S Hong, Z Hong, Z Hui, Q Hua, Y Husheng, T Jialun, C Jianguo, A Kaying, N Liu, L Liu, F Lu, T Lv, S Ma, R Man, L Minge, Z Qingtan, G Quing Ling, Z Run Ping, J Shi, K Song, H Tanabe, B Wang, S-Y Wang, J Wang, Q Wang, Y Wang, Y Wei, S Ziandon, Y Ziaohong, L Xiaolin, L Xiumei, N Yang, X Yang, M Yanhua, K Yu, S Yunai, B Zhang, H Zhang, J Zhang, F Zhang, L Zengyan, J Zhao, Y Zhao Colombia: J Accini, G Aroca, E Arcos, N Cabrera Lopez, M Casanova, C Celemin, A Cervantes, B Collante, J Coronel, C Cotes, C Cure, A Duarte, D Escobar, M Figueredo, H Garcia, L Garcia, M Grisales, Z Hernandez, D Ines, K Martinez, B Nino Castellanos, M Olite, N Ospina Rendon, I Posada, A Quintero, F Quiros, G Sanchez, A Sotomayor, M Suarez, M Urina, T Valencia Czech Republic: V Adamkova, R Cifkova, R Ferkl, M Galovcova, J Hartman, M Jozifova, K Linhart, T Linhart, D Moravcikova, B Nussbaumerova, M Plachy, H Rosolova, B Seifert, M Soucek Ecuador: Y Duarte-Vera, M Espinel, M Lopez, J McDermont, E Penaherrera, F Plascencia, F Pow-Chon-Long, D Tettamanti Hungary: L Bajnok, E Baranyior, E Bartfai, K Beck, Z Bedo, E Bod, B Bodis, I Czuriga, H Eleonora, R Janosne, E Mezosi, E Monostori, F Poor, E Somos, Z Tarjanyi, T Tatrai, J Tomcsanyi, A Tumpek, A Vertes, A Zsary India: DK Agarwal, KG Alexander, V Ayyars, B Bosco, N Chidambaram, N Deshpande, HR Devendra, B Ganapathi, S George, D Ghosh Roy, S Gnanasekaran, R Gupta, S Joshi, SP Kalantri, CB Keshavamurthy, A Khan, C Kocherlakaota, S Kulkarni, S Kumar, AR Manjunath, K Mehta, A Modi, V Mohan, S Murthy, A Nambiar, J Narendra, S Paul, A Purshit, MA Qureshi, D Rajasekaran, M Ramu, R Ranjani, RL Ranka, S Roy, MR Satyanarayana, K Selvam, M Shunmugavelu, G Sidhu, R Singh, R Singh Khedar, J Drinivas, B Srinivasulu, S Suresh, R Razyeem Khan, N Thomas, R Tongia, R Umarani, K Varghese, S Varma, S Yelwatkar, B Yerrathota Israel: A Biton, A Goldhaber, S Ivri, R Kaminsky, I Lentsisky, A Lubov, T Pugacsov, B Punchik, T Rozenthal, A Schlesinger, A Seidman, I Shapiro, E Shveydel, N Shveydel, D Tsalihin, N Viliky, S Vinker, A Weinar, C Yosefy Korea: S Kil Kim Malaysia: A Abdullah, D Ambigga, A Ghapar, C Krishnan, H Liew, M Maizatullifah, Y Mazapuspavina, M Mo Aris, U Muthukumaru, L Ramanathan, K Selvaraj, A Shah Mohd Shah Netherlands: JH
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Bonarius, A De Jong, ZDG De Ruiter, R De Vos, HA Dirkse, E Drenth, H Ferguson, R Jansen, H Rol, A Schilder, I Spelt, P Van Leeuwen Philippines: M Abola, H Co, A Loyola, J Mercado, D Morales, N Nicodemus, D Padi, L Padua, L Palileo, A Patanao, G Rogelio, A Roxas, D Sulit, A Tang-Manga, B Tumanan-Mendoza Russia: F Ageev, S. Boytsov, I Chukaeva, J Grinishina, Y Karpov, D Kirakozov, O Kisliak, Z Kobalava, I Kolos, L Krilova, A Ledyacva, T Lobzhanidze, Y Lopatin, M Markova, T Myshlyaeva, S Nedogoda, M Pokichenko, S Postnikova, S Serdyuk, G Soboleva, M Solovieva, I Teupko, Z Tigay, V Tsoma, T Tyurina Slovakia: M Hranai, S Stevikova S. Africa: A Badat Sweden: F Al-Khalili, B Carlberg, A Dotevall, P Nilsson, A Olsson, A Rosengren, S Soderberg UK: W Toff Ukraine: D Artomov, T Babanina, A Bagriy, G Chobotko, S Danyliuk, N Doretska, O Dorovska, N Dovgan, G Dzyak, L Glushko, I Gorbas, T Ilashchuk, P Ivanchuk, K Karapetyan, I Karavanska, L Khimion, A Khorsun, L Kononenko, O Kuryata, S Lazareva, D Loktyev, V Martynyuk, N Miroshnchenko, O Onyschenko, D Palianichko, N Petryk, S Pivovarova, O Polishchuk, I Rakytskay, L Sapozhnychenko, V Serneniaka, T Shandra, I Sichkaruk, I Smymova, O Soya, V Tashchuk, N Turubarova-Leunova, O Vasilkova, L Vasilyeva, N Velichko, O Verbovska, A Yagensky, S Zborovskyy, S Zhurba, A Zhukova, R Zubyk UK: I Loke,