Post on 29-Apr-2023
for the SAVOR-TIMI 53 Steering Committee and InvestigatorsSteg and Deepak L. Bhatt
Boaz Hirshberg, Robert Frederich, Basil S. Lewis, Darren K. McGuire, Jaime Davidson, Ph. GabrielJarolim, Jacob A. Udell, Ofri Mosenzon, KyungAh Im, Amarachi A. Umez-Eronini, Pia S. Pollack,
Benjamin M. Scirica, Eugene Braunwald, Itamar Raz, Matthew A. Cavender, David A. Morrow, PetrRandomized Trial
Heart Failure, Saxagliptin and Diabetes Mellitus: Observations from the SAVOR - TIMI 53
Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2014 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online September 4, 2014;Circulation.
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DOI: 10.1161/CIRCULATIONAHA.114.010389
1
Heart Failure, Saxagliptin and Diabetes Mellitus: Observations from the
SAVOR - TIMI 53 Randomized Trial
Running title: Scirica et al.; Saxagliptin and Heart Failure
Benjamin M. Scirica, MD, MPH1; Eugene Braunwald, MD1; Itamar Raz, MD3; Matthew A. Cavender, MD, MPH1; David A. Morrow, MD, MPH1; Petr Jarolim, MD, PhD2;
Jacob A. Udell, MD, MPH4; Ofri Mosenzon, MD3; KyungAh Im, PhD1; Amarachi A. Umez-Eronini, MPH1; Pia S. Pollack, MD5; Boaz Hirshberg, MD5; Robert Frederich, MD6; Basil S. Lewis, MD7; Darren K. McGuire, MD, MHSc8;
Jaime Davidson, MD9; Ph. Gabriel Steg, MD10; Deepak L. Bhatt, MD, MPH1 for the SAVOR-TIMI 53 Steering Committee and Investigators*
1TIMI Study Group, Cardiovascular Division; 2Department of Pathology, Brigham and Women’s
Hospital and Harvard Medical School, Boston, MA; 3Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel; 4Cardiovascular Division,
Women’s College Hospital and Toronto General Hospital, University of Toronto, Toronto, Canada; 5AstraZeneca Research and Development, Wilmington, DE; 6Bristol-Myers Squibb,
Princeton, NJ; 7Cardiovascular Research Institute, Lady Davis Carmel Medical Center and Ruth and Bruce Rappaport School of Medicine, Technion-IIT, Haifa, Israel; 8Cardiovascular Medicine; 9Division of Endocrinology, Dept of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, TX; 10Département Hospitalo-Universitaire FIRE, INSERM U-1148, Université Paris-Diderot, and Hôpital Bichat, AP-HP, Paris, France, and
NHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom *A complete list of the SAVOR-TIMI 53 Steering Committee and Investigators can be found in
the Online Data Supplement Address for Correspondence:
Benjamin M. Scirica, MD, MPH
TIMI Study Group, Cardiovascular Division
Brigham and Women’s Hospital
75 Francis Street, Boston, MA 02115
Tel: 617-278-0145
Fax: 617-734-7329
E-mail: bscirica@partners.org
Journal Subject Codes: Heart failure:[110] Congestive, Diabetes:[190] Type 2 diabetes
TIMI Study Group, Cardiovascular Division; 2Department of Pathology, Brighhamamam andndnd WWWomomomenen’sHospital and Harvard Medical School, Boston, MA; 3Diabetes Unit, Division fof Internal
Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel; 4Cardiovascular Division,WoWomemem n’n s s s CoCollllllegege e Hospital and Toronto Gennererraaal l Hospital, Univerrsisiitytyty of Toronto, Toronto,
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and Bruce RaRaRapppaaapooort t SScSchhohoololl oooff MeMeMediciinnee, TTeccchniniioonon-I-I-IITTT, HHaHaiiifa, IIsrsraeael;l;; 88CaCardrddioovavascccuulararr Mediciinenn ;; 999DDDivisssiooon ooff f EEnEndod crcrrininolologogyy,, DDDeppttt oofof IIntntnteernrnnall Mededicineee, UUnnnivveversr ityyy oofof TTeeexass
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DOI: 10.1161/CIRCULATIONAHA.114.010389
2
Abstract
Background—Diabetes and heart failure frequently coexist. However, few diabetes trials have
prospectively evaluated and adjudicated heart failure as an endpoint.
Methods and Results—16,492 patients with type 2 diabetes and a history of, or at risk for,
cardiovascular events were randomized to saxagliptin or placebo (mean followup-2.1 years). The
primary endpoint was the composite of cardiovascular death, myocardial infarction, or ischemic
stroke. Hospitalization for heart failure was a predefined component of the secondary endpoint.
Baseline NT-proBNP was measured in 12,301 patients. More patients treated with saxagliptin
(289, 3.5%) were hospitalized for heart failure compared to placebo (228, 2.8%) (HR 1.27;
95%CI 1.07-1.51; p=0.007). Corresponding rates at 12-months were 1.9% vs.1.3% (HR 1.46,
95%CI 1.15-1.88, p=0.002, with no significant difference thereafter (time-varying interaction
p=0.017). Subjects at greatest risk for hospitalization for heart failure had prior heart failure,
eGFR <60 ml/min and/or elevated baseline levels of NT-proBNP. There was no evidence of
heterogeneity between NT-proBNP and saxagliptin (p for interaction=0.46), though the absolute
risk excess for heart failure with saxagliptin was greatest in the highest NT-proBNP quartile
(2.1%). Even in patients at high-risk for hospitalization for heart failure, the risk of the primary
and secondary endpoints were similar between treatment groups.
Conclusions—In the context of balanced primary and secondary endpoints, saxagliptin treatment
was associated with an increased risk for hospitalization for heart failure. This increase in risk
was highest among patients with elevated levels of natriuretic peptides, prior heart failure, or
chronic kidney disease.
Clinical Trial Registration Information— ClinicalTrials.gov. Identifier: NCT01107886.
Key words: heart failure, diabetes mellitus, saxagliptin
, p , g ( y gg
p=0.017). Subjects at greatest risk for hospitalization for heart failure had prior heheeararrtt fafafailililururure,e,e,
eGFR <60 ml/min and/or elevated baseline levels of NT-proBNP. There was no evidence of
heterogeg neity y between NT-proBNP and saxaglipptin (p for interaction=0.46), though the absolute
iisksksk eeexcxcessss fofofor hehearart t faaillurure e wiithth saxxagagliptptin waw ss ggrgreeatestst iinn the hihihighghg esest t NNT-pprooBNB P ququarrtit le
222.111%)% . Even iinn papapatiienenntsss aaattt hihihighggh-r-risisi kk k fofoorr hossppiiitalizzzaattionnn fofor r hheeararttt ffaaililururee, thehee rrriisisk k ofofof ttthehehe pppriririmmamarryry
anannd d seses cocondarararyy y enennddpdpoioinntss wewererer ssiimimiilalalar r bebeetwtweeeennn trtreeaeatmtmenenent t grgrrouupsps.
Concnclulu isionons——InI tthehe contetextt oof f babalal nceded ppririmamaryry andnd sesecocondndaaryy enendpdpoio ntnts,s ssaxaxaga liptptini ttrereatatmemen
was associatattededed wwwititith hh ananan iiincncrerereaaasededd rrrisisskk k fofoforr hohohospsppitittalalalizizzatatatioion n fofof rr r hehehearart fafafailililururureee. TTThihih ss inini crcrc eaeaeassse in risk
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DOI: 10.1161/CIRCULATIONAHA.114.010389
3
Introduction
Diabetes adds incremental risk for the development and subsequent exacerbation of heart failure
even after adjusting for common risk factors such as ischemic heart disease and hypertension. 1
Though incompletely understood, cardiac metabolic dysregulation of glycolysis and fatty acid
oxidation observed in the heart of patients with diabetes probably impairs cardiac function and
causes additional myocardial damage. 2-5 In addition, accelerated coronary atherosclerosis is
likely to play a role. 6 Moreover, the choice of antihyperglycemic agents in those patients with
diabetes with heart failure or at risk of developing it remains challenging. Some agents such as
thiazolidinediones and dual PPAR / agonists increase plasma volume and exacerbate heart
failure7-11 while sulfonylureas12 and insulin potentially exacerbating the dysregulation of
myocardial metabolism and worsening left ventricular function. 13, 14 Metformin, once felt to be
contraindicated in patients with heart failure, is now considered to be one of the safest options,
despite the absence of large randomized comparisons. 15, 16 Despite the observational
relationship between glycemic control and the risk of heart failure, there is no evidence that
improved glycemic control modifies this risk. 17 Therefore, identification of antihyperglycemic
agents that can be used safely in patients with heart failure or at risk of developing heart failure
remains an important unmet clinical need.
Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor.18 The Saxagliptin
Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) –
Thrombolysis in Myocardial Infarction (TIMI) 53 trial was designed to evaluate the long-term
cardiovascular efficacy and safety of saxagliptin in patients with DM at risk for cardiovascular
events.19 Over a median of 2.1 years follow-up, saxagliptin neither increased nor decreased the
risk of the primary or secondary composite endpoints; however, there was an unexpected 27%
failure7-11 while sulfonylureas12 and insulin potentially exacerbating the dysreguulalaatitionono ooof f fr
myocardial metabolism and worsening left ventricular function. 13, 14 Metformin, once felt to be
coontntntrararaininindididicacac tetet d ininin ppatients with heart failure, is nonon www considered ttooo be onononeee of the safest options,
ddedespppite the absesenncncee ofofof laarargegege rrraanandodoommimizezeedd compmpmparisssoonns. 15,15,, 16166 DDeDessppiitte ththhee oobobseseserrvrvatatioioionananalll
eelalalatitiionononshshipipip bbbetetweweweenen ggglyyycecemimimic c cccononontrtrtrolol aandndnd ttthehee rrrisiskk oof hheaeaeartrtrt faaailililururre,e, tttheheherere iis s nnono eeeviviidededencceee tththatat
mproved glylyycececemimimic c c cococontntntrool l l momm dididififif esess thihihiss ririr sksksk.. 171717 TTThehehererefofoforerere,, , ididi enenentitit fiiicacacatititiononon ooof ff ananntititihyhyhypepepergr lycemic
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DOI: 10.1161/CIRCULATIONAHA.114.010389
4
increased relative risk (and 0.7% absolute risk over 2 years) of hospitalization for heart failure in
patients assigned to saxagliptin. 20 This report explores further the observation surrounding
hospitalizations for heart failure by examining baseline risk factors associated with an increased
risk of hospitalizations for heart failure, the timing of hospitalizations and the risk of recurrent
events, and the association between baseline levels of natriuretic peptides and future
hospitalizations for heart failure events.
Methods
Study Design and Oversight
As previously described19, SAVOR-TIMI 53 was a multicenter, randomized, double-blind,
placebo-controlled trial that randomized 16,492 patients at 788 sites in 26 countries between
May 2010 and December 2011 with type 2 diabetes mellitus, HbA1c between 6.5% and <12.0%
within 6 months of randomization, and either a history of established CV disease or multiple risk
factors for vascular disease to receive either saxagliptin 5 mg daily (or 2.5 mg daily in patients
with an estimated glomerular filtration rate (eGFR) of 50 mL/min or less) or matching placebo.
The full eligibility criteria and analysis plan have been reported previously. 19, 20 Written
informed consent was obtained from all patients. The relevant ethics committees at all
participating centers approved the protocol.
Endpoints
A clinical events committee, unaware of the study-group assignments, adjudicated all
components of the primary and secondary composite efficacy endpoints. The primary endpoint
was a composite of cardiovascular death, myocardial infarction (MI), or ischemic stroke. The
secondary endpoint included the primary composite endpoint together with hospitalization for
As previously described19, SAVOR-TIMI 53 was a multicenter, randomized, dououublblble-ee blblblininind,d,d,
placebo-controlled trial that randomized 16,492 patients at 788 sites in 26 countries between
MaMayyy 202020101010 aaandndn DDDecececeember 2011 with type 2 diabebeetttesss mellitus, HbAAA1c bbbetetetwween 6.5% and <12.0%
wwithhhini 6 monththss off rrananndododommimizazazattitiononn,,, aananddd eeeitheeer a hiisttoory y y oofof eeststababliliishshheded CCCVVV didiiseseeasasee ororor mmululu tititi lplpleee rrrisk
faactctctororrss s foforr vavavascscuululaarr ddiisseeaasese ttoo o rereecececeivivivee eieie thththererer saaaxaxax ggglipipiptiiin n 555 mgmgmg dddaaiilyyy (((ororr 2.5.5. mmmg g dadailililyy y inn paatatieiennntsss
with an estimamaateteed d glglglomommeree ulululararar fililltrtrtratatioioion n rararatetete (((eGeGeGFRFRR) )) ofofo 5550 00 mLmLmL/m/m/mff inini ooor rr lelelessssss) ) ) ororo mmmatatatchchchininnggg placebo.
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DOI: 10.1161/CIRCULATIONAHA.114.010389
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heart failure, coronary revascularization, or unstable angina. Heart failure requiring
hospitalization was defined as an event that required hospitalization to an inpatient unit or a visit
to an emergency department that resulted in at least a 12 hour stay with clinical manifestations of
heart failure including at least one of the following signs or symptoms: new or worsening
dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, pulmonary basilar crackles, jugular
venous distension, new or worsening third heart sound or gallop rhythm, or, radiological
evidence of worsening heart failure; together with additional or increased therapy that included:
initiation of intravenous diuretic, inotropic, or vasodilator therapy, uptitration of intravenous
therapy, if already on therapy, initiation of mechanical or surgical support/intervention, or the
use of ultrafiltration, hemofiltration, or dialysis that is specifically directed at treatment of heart
failure. 19, 20 The endpoint definitions were developed to be consistent with the draft Standardized
Definitions for End Point Events in Cardiovascular Trials created by an initiative from the
FDA.21 History of prior heart failure was a pre-defined subgroup based on medical history
obtained at randomization.
NT-proBNP was measured in 12,301 patients (74.6% of the overall trial) at
randomization and in a randomly selected subset of patients at 2 years or the end of treatment,
whichever was earlier. Blood samples were collected in serum separator plastic tubes and then
centrifuged and stored frozen in aliquots at -20° to -80°C at the enrolling site until shipped to the
Biomarker Research/TIMI Clinical Trials Laboratory, Boston, MA, USA where they were
maintained at -80°C. Serum NT-proBNP concentrations were measured at the first thaw using a
sandwich immunoassay (proBNP II, Roche Diagnostics, Indianapolis, IN). The analytic range
extends from 5 to 35,000 pg/mL. The reported within run coefficient of variation was 4.2% at a
level of 44 pg/mL and 2.7% at a level of 33,606 pg/mL. Plasma high-sensitivity TnT (hsTnT)
use of ultrafiltration, hemofiltration, or dialysis that is specifically directed at treeaaatmemm ntntnt ooof ff hehehearart
failure. 19, 20 The endpoint definitions were developed to be consistent with the draft Standardized
DeDefififinininitititiononnsss fofofor EnEnEnddd Point Events in Cardiovascululularar Trials created d byb aan n n iininitiative from the
FDFDAAA.21 Historyry ooof f prrioioior hehehearararttt ffafaililuururee e wwawass a pppreee-deefiinnedd d ssusubbgbgrroroupupp bbbasaseed dd oonon mmmeededicicalala hhhisiistotorryry
obbbtatatainininedede aatt t rararandndomomomizizaaatioioon.n.
NT-p-pprororoBNBNBNPPP wawaw sss mememeasasasururrededed iiin nn 121212,3,33010101 pppatata ieiei ntntntss s (7774.44 6%6%6% ooof f f thtt eee ovovoverereralalall l l trtriaiaial)l)l) aaatt t
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DOI: 10.1161/CIRCULATIONAHA.114.010389
6
was measured with an electrochemiluminescent immunoassay assay (Roche Diagnostics). The
lower limit of detection of the assay is 0.003 g/L. 22
Statistical Analysis
All analyses were conducted on an intention-to-treat basis among patients who underwent
randomization. Categorical variables were compared using chi-squared test and continuous
variable with either a t-test or Wilcoxon rank-sum test, as appropriate. Events rates are presented
as 2-year Kaplan-Meier estimates. The relative risks of hospitalization for heart failure between
saxagliptin and placebo were examined using an unadjusted Cox proportional hazards model
stratified by baseline renal impairment category and baseline cardiovascular risk group and with
treatment as a model term. A post hoc Bonferonni correction was applied for the multiple
comparisons of each composite of the secondary endpoint (n=6), providing a p-value of 0.0083
for the comparison of saxagliptin versus placebo. Recurrent events analyses accounted for
multiple hospitalizations for heart failure under a counting process assumption based on the
method described by Anderson-Gill.23 The risk for rehospitalization for heart failure following
an initial hospitalization for heart failure was examined by Prentice-Williams-Peterson Gap Time
model. 24 Multivariable modeling for the risk of hospitalization for heart failure in the overall
population was developed by first examining univariate associations, and then with backward
elimination method to reduce the pool of covariates base on a p-value of <0.05. It was refined
further to include clinically meaningful covariates in the final model. The hazard ratio and
95%CI were reported from landmark analyses based on subject-level censoring at 6 and 12
months that excluded subjects who did not have enough follow up time or experienced the event
prior to the landmarked time. A time –varying coefficient model was fitted as described by Gray
to evaluate any heterogeneity between saxagliptin and heart failure over time. 25
reatment as a model term. A post hoc Bonferonni correction was applied for the e mumuulttipipiplelele
comparisons of each composite of the secondary endpoint (n=6), providing a p-value of 0.0083
foor r thththee e cocompmpmpaaarissononon oof saxagliptin versus placebooo.. RRRecurrent eventntnts annalalalyyyses accounted for
mmulltltiple hospiitatalill zzzatitiiooonsss fofofor r hehehearart tt fafafaililuururee unnndeeer a cooounnntitingng pprroroceceessss aasssumumumptpttioioion n babaaseses d d d oonon ttthhehe
memeethththododod ddesesscrcrcribibeedd bbby y AnAnAndederssonono -G-G-Gililillll.23 TTThehehe rrrisskk k fofoor rrehhohospspspitititalllizizizatattiooonnn fofoor hheheararart t fafaf ililururureee fofoolllowowiiningg g
an initial hosspipipitatataliliizazazatit ononon fororor hhheaeaartrtr ffaiaiailulurerere wwwasasa eeexaxaxamimim nenen d d bybyby PPPrereentntnticii e-e-e-WiWiWilllllliaiaiamsmsm -P-PPetetetererersososon Gap Timmme
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DOI: 10.1161/CIRCULATIONAHA.114.010389
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Results
There were a total of 741 hospitalizations for heart failure over a median follow-up of 2.1 years
in 517 patients across both treatment groups. A substantial proportion of patients hospitalized for
heart failure, regardless of the treatment assignment, were subsequently re-admitted for recurrent
heart failure episodes (n=137, 26.5%) and/or died (n=135, 26.1%), mostly due to cardiovascular
causes (n=121, 89.6% of deaths).
A comparison of the baseline variables in the patients hospitalized for heart failure
compared with those who were not are shown in Table 1. The former were older, more likely to
be male and have a history of heart failure, chronic kidney disease, established cardiovascular
disease, including prior MI, or coronary revascularization. In addition, they were more likely to
be treated with aspirin, beta-blockers, diuretics, statins, inhibitors of the renin-angiotensin-
system, and insulin, and less likely to be treated with metformin, sulfonylureas or
thiazolidinediones.
Risk Factors for Hospitalization for Heart Failure in the Overall Population
Unadjusted hazard ratios for the risk of hospitalization for heart failure by baseline
characteristics are presented in Table 1. In multivariable analysis, the strongest association with
hospitalization for heart failure (as assessed by chi-squared value) regardless of treatment
assignment, was prior heart failure, and two markers of renal disease, eGFR and
albumin:creatinine ratio. (Table 2) There was a step-wise increase in the risk of hospitalization
for heart failure in patients who had 0, 1, or 2 of the risk factors of history of heart failure or an
eGFR <60 m/min: 1.2% with 0 risk factors (n=10,418, 63.2%) (referent); 5.3% with 1 risk factor
(n=5,188, 31.5%), HR 4.48, 95%CI 3.62-5.54, p<0.001; and 14.3% with 2 risk factors (n=886,
5.4%), HR 13.51, 95%CI 10.55-17.31, p<0.001. When randomization is added to this model, the
disease, including prior MI, or coronary revascularization. In addition, they were e momomoreee lllikikikelelely y y tto
be treated with aspirin, beta-blockers, diuretics, statins, inhibitors of the renin-angiotensin-f
yyststtememem,, anannd d d inininsuulililinn,n, and less likely to be treated d wwiwitth metformin, susus lffononnyylylureas or
hhhiaaazoz lidinediiononesese .
RiRiisksksk FFFacaca tototorsrsrs ffororr HHHososspipiitatalil zazaatitiiononon ffforor HHHeeeararart FFaFailillururre ininn ttthhehe OOOveveeraraallllll PPPopppulullatata ioioion n
Unadjusted hhazazazarara dd d rarar tititiososo fffororo ttthehee rrrisisk k k offf hhososo pipipitatatalilil zazazatitiionono fffororor hhheaeaeartrtrt fffaiiilululurerere bbby yy babab seseselililinenene
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DOI: 10.1161/CIRCULATIONAHA.114.010389
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risk associated with saxagliptin was consistent with the overall trial (HR 1.29, 95%CI 1.08-1.54).
The c-statistic for the model with eGFR and prior heart failure alone was 0.74, which increased
to 0.81 with the addition of all clinical variables in Table 2.
Saxagliptin and Hospitalization for Heart Failure
Over 2 years of follow-up, more patients in the saxagliptin group (289/8280, 3.5%) were
hospitalized for heart failure compared with the placebo group (228/8212, 2.8%) (HR 1.27;
95%CI 1.07 to 1.51 p=0.007). The corresponding rates at 6-months were 1.1% vs. 0.6% (HR
1.80, 95%CI 1.29 to 2.55, p=0.001) and 1.9% vs.1.3% (HR 1.46, 95%CI 1.15 to1.88, p=0.002 at
12 months. The rates for hospitalization for heart failure based on “investigator” reported events
were consistent with the adjudicated results. (Supplemental Table 1)
Based on landmark analysis beginning at 6 months and 12 months, the risk of
hospitalization for heart failure after in patients assigned to saxagliptin was similar to placebo
(2.4% vs. 2.1%, HR 1.11, 95%CI 0.91-1.36, p=0.31 beginning at 6 months and 1.7% vs. 1.5%,
HR 1.09, 95%CI 0.85-1.39, p=0.51 at 12 months). (Figure 1) To examine the attenuating effects
of saxagliptin on the risk of hospitalization due to heart failure over time, a time varying
coefficients model was developed (p-value for a time-time varying interaction term = 0.017).
The lower CI of the log HR crosses 0 at around 314 days, suggesting that the risk of
hospitalization for heart failure with saxagliptin subsided at 10-11 months after randomization. .
(Supplemental Figure 1) When the landmark analyses were restricted to patients taking study
drug, the corresponding risks were similar to the intent-to-treat analysis: from randomization to
12 months (HR1.52, 95%CI 1.17 to 1.96, p=0.0015) and from 12 months onward (HR 1.05,
95%CI 0.81-1.35, p=0.73).
When analyzing both first and recurrent events combined, 413 total events occurred in
were consistent with the adjudicated results. (Supplemental Table 1)
Based on landmark analysis beginning at 6 months and 12 months, the risk of t
hoospspspitititalalalizizizatatatioioion fofoorrr heh art failure after in patients aaasss iigned to saxaggglilil ptininn wwawas similar to placebo
222.444% % vs. 2.1%%, , HHRR 111.1. 1,11, 9995%5%5%CICI 000.9.9. 11-11.366,, ppp=0.3131 beeeggiginnnnninnngg aaat 666 mmooontthhs s ananandd 1.1.7%7%7% vvvs.. 111.55.5%%%,
HRHRR 111 0.0.09,9,9, 9995%5%5%CICII 000.8.855--11..3939, p=p=p=000.515151 aat t 12122 mmmonononththths)s)s). (((FiFiigugugurerere 1))) ToToTo eeexaxaxammminnene ttheheh atata teteenununuatttining g g efefffeectcts
of saxagliptinin ooon n n thththee e riririsksksk ooof f f hohoh spspspititi alallizii atatatioioon nn dududueee totoo hhheaeae rtt fffaiaiailululureree ooovevev rr r titiimememe,,, a a a titimememe vvvarara yiyiy ng
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the saxagliptin group compared with 328 events in placebo (HR 1.26. 95%CI 1.02-1.55, p=0.04).
The risks for re-hospitalizations for heart failure following an initial hospitalization for heart
failure were similar in both groups (hospitalization for heart failure: 80, 27.7% saxagliptin vs. 57,
25.0% for placebo, HR 1.06, 95%CI 0.75-1.50, p=0.73; and mortality 26.3% vs. 25.9% placebo,
HR 1.01, 95%CI 0.72-1.43, p=0.95). The median length of stay for the initial adjudicated
hospitalization for heart failure was 7.0 days in both treatment groups. The most common
treatment was intravenous diuretics (88% in each group). Vasodilator therapy was used in 6.2%
for saxagliptin subjects and in 7.9% for placebo. Ultrafiltration/hemodialysis (2.8% and 2.2%
for saxagliptin and placebo, respectively) and advanced hemodynamic support (1.7% and 0.9%
for saxagliptin and placebo, respectively) were used infrequently.
At 1 year, weights were similar in the overall saxagliptin and placebo groups (87.6 ± 18.4
kg vs. 87.9 ± 19.4 kg, p=0.87) and in patients with a history of heart failure (91.5 ± 19.5 kg vs.
92.8 ± 20.5 kg, p=0.27) or eGFR <60 ml/min (87.1 ± 18.8 kg vs. 87.9 ± 19.7, p=0.47). Treatment
with saxagliptin did not result in clinically detectable fluid overload as reflected by similar rates
of adverse event reports of edema (45, saxagliptin vs. 46, placebo) and peripheral edema (347,
saxagliptin vs. 352, placebo).
While the absolute rate of hospitalization for heart failure varied considerably among the
pre-defined subgroups and in patients with and without prior heart failure, the relative risk in
patients treated with saxagliptin was similar across subgroups (Supplemental Figure 2).
Consequently, the absolute rates of heart failure difference between saxagliptin and placebo
varied according to the overall risk within each subgroup. This pattern was reinforced when
examining the relative and absolute risk differences in patients with the two clinical risk factors
that most greatly increased the risk of hospitalization for heart failure, eGFR <60 ml/min and a
for saxagliptin and placebo, respectively) were used infrequently.
At 1 year, weights were similar in the overall saxagliptin and placebo groups (87.6 ± 18.4
kgkg vvvs.s.. 888777.99 9 ±±± 199.44.4 kkg, p=0.87) and in patients wwititithh aa history of heaeaart ffaiaiailululure (91.5 ± 19.5 kg vs.
9922.888 ± 20.5 kgg, p=p=p=0.0.272727) ororor eeGFGFGFR R <<<66060 mmll/miiin (87..1 ± 181818.8.8 kkkggg vsvs. 88787.999 ±± 119.9..7,7,7, pp=0=00.4447)7)7).. TrTrTreaeatmtmtmen
wiwiiththth sssaxaxa agagaglililiptpptinin ddiidid nnotot rresesulullt t ininin ccclililinniniccacallllllyy y dddetetetectctaabablle ffluuuididid ooveveverlrlloaoaadd d asass reefefleleectctc edede bbby y y simmmillalar r rrrattees s
of adverse eveveentntnt rrrepepepororrtstss of f f edededememma a a (4(445,5, sssaxaxaxagagaglllipipiptitin n n vsvss.. 46466,,, plplplacacacebebebo)o)o aaandndnd ppperereripipipheheerararal l l edededemee a (347,
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prior history of heart failure. (Figure 2) For example, in patients with neither of these risk factors
the absolute risk difference over 2 years between saxagliptin and placebo was 0.3% compared
with 1.7% in patients with both risk factors. The number of excess hospitalizations for heart
failure per year if 1000 patients were treated with saxagliptin ranged from 0 in patients with no
risk factors to 9 in patients with both risk factors.
Baseline NT-proBNP and Heart Failure
The median NT-proBNP in the 12,301 patients in whom it was measured at baseline was 141
pg/mL (IQR 64 - 332) and it was similar in patients assigned to saxagliptin (143 pg/mL, IQR 65
- 336) and placebo (139 pg/mL, IQR 63 - 330). There was a step-wise increased risk of
hospitalization for heart failure with higher quartiles of baseline NT-proBNP. (Figure 3) When
added to the clinical multivariable model, quartile 4 of NT-proBNP level was the factor most
strongly associated with the risk of hospitalization for heart failure (HR 5.51, 95%CI 4.24-7.16,
p<0.001). (Supplemental Table 2) The c-statistic increased from 0.81 to 0.85 (p<0.001) when
NT-proBNP was added to the clinical variables in Table 2. In the cohort with highest quartile of
NT-proBNP, the risk of hospitalization for heart failure in patients treated with saxagliptin was
similar to that observed in the overall trial (HR 1.31, 95%CI 1.04-1.66, p=0.02). While there was
no evidence of heterogeneity between levels of NT-proBNP, treatment with saxagliptin, and
hospitalization for heart failure (p for interaction=0.46), the absolute risk excess for heart failure
with saxagliptin was greatest in the highest NT-proBNP quartile (2.1%) compared with quartiles
1 (0.0%), 2 (0.7%), and 3 (0.2%). (Figure 3) Similar results were seen when evaluating NT-
proBNP according to deciles or an established dichotomous cutpoint. (Supplemental Figure 3)
The addition of the highest quartile of baseline NT-proBNP to the risk factors of history
of heart failure and eGFR further stratified patients according to baseline risk of hospitalization
hospitalization for heart failure with higher quartiles of baseline NT-proBNP. (FiFiiguguurere 333) ) ) WhWhWhenen
added to the clinical multivariable model, quartile 4 of NT-proBNP level was the factor most
ttroroongngnglylyly aaassssssocociaateteteddd wiw th the risk of hospitalizatioioon n ffor heart failurre ee (HHR R R 555.51, 95%CI 4.24-7.16,
p<00.0.000 1). (Suupppppleeemementntalalal TTTababablele 222)) ) ThThhee c-stttatttisticcc iinncrrreaeaasesed d frfromomm 00.888111 tooo 00.88.8555 (p(p<0<0<0.0.0.00010 ))) whwhwhenenn
NTNTT-p-p-prororoBNBNNPPP wawasss aadaddedeed toto thehehe cclililinininiccacal l vavavariririababableeesss ininn TTTabblbleee 222.. Innn tthhhe cccohoho ooortt t wiwiiththt hihih ghghgheeest quququarartitiilele oof
NT-proBNP,P,, ttthehehe rrrisisisk kk ofofof hososospipipitaaalililizzzatattioioi n n n fofoor rr heheheararart t fafafailillururu e e ininin pppatatatieieiennntst tttrerereatatatededed wwwitith hh sasasaxaxaxaglglg iptin was
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for heart failure regardless of treatment assignment (Supplemental Figure 4). The addition of
the NT-proBNP to the two clinical variables increased the c-statistic from 0.74 to 0.82 (p<0.001).
Among the lowest quartiles of NT-proBNP, most patients had none of the aforementioned risk
factors for heart failure (n=6599, 53.6%), a correspondingly low rate of heart failure, and no
treatment difference between saxagliptin or placebo (0.6% v. 0.6%, HR 0.84, 95%CI 0.46-1.52,
p=0.56), whereas patients with NT-proBNP in the top quartile and 2 risk factors, the absolute
risk difference was 1.6% (Supplemental Figure 5). The baseline concentration of NT-proBNP
was a particularly strong risk factor for hospitalization for heart failure. Even among patients
with normal renal function and no reported history of heart failure, a level of NT-proBNP in
quartile 4 (>332 pg/ml) was associated with a higher risk of hospitalization for heart failure
(4.3% vs. 0.6% with lower levels of NT-proBNP) (Supplemental Figure 4), and a
correspondingly higher absolute risk with saxagliptin compared to placebo (5.35% vs. 3.33%,
p=0.083). (Supplemental Figure 5)
Change in NT-proBNP, hsTnT, and C-reactive Protein
In patients with both baseline and two years or end-of-treatment assessments, median NT-
proBNP (n=2026) increased both in patients treated with placebo (107 to 126 pg/ml, p<0.001)
and saxagliptin (107 to 122 pg/ml, p=0.001), with a slightly greater increase in placebo (median
change 10 vs. 4 pg/ml, p=0.001). The pattern of change was similar in patients with prior heart
failure (n=237) in placebo (230 to 287 pg/ml, p=0.149, n=100) and saxagliptin (187 to 214
pg/ml, p=0.238, n=117, median change 15 vs. 4 pg/ml, p=0.70), and patients without prior heart
failure (n=1809) in placebo (99 to 120 pg/ml, p<0.001) and saxagliptin (99 to 117 pg/ml,
p=0.003, median change 10 vs. 4 pg/ml, p<0.001). Similar results were observed after excluding
patients who experienced any of the primary or secondary endpoints (data not shown). In the
quartile 4 (>332 pg/ml) was associated with a higher risk of hospitalization for heheearrrtt fafafailili ururure e e
4.3% vs. 0.6% with lower levels of NT-proBNP) (Supplemental Figure 4), and a
coorrrrresesesppopondndndinininggly y hihihighg er absolute risk with saxaglgllipipi ttiin compared ttooo placaccebebebo (5.35% vs. 3.33%,
p=00.0.080 3). (Suupppppleeemementntalalal FFFigigiguurure e 55)))
ChChhananangegege iinnn NTNTN -p-p-prorooBNBNNPP,P, hhsTsTTnTnTnT, anaand d C-C-C-rerereacacctititivevee PPProooteeeininin
n patients wiwiththth bbototothhh bababasess liliinenene aandndnd ttwoww yyyeaeaarsrss ororo eendndnd-o-oof-f trtrreaeaeatmtmtmenenent t t asassesesessssssmemementntnts,s, mmmededediaiaiann n NT-
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subset of patients with baseline and follow-up biomarkers, there were no differences between
placebo and saxagliptin in the median change in concentrations from baseline to 2-years or end
of treatment of hsTnT (n=1355) (0.71 vs. 0.52 vs. /ml, p=0.067) or C-reactive protein (n=513)
(0.08 vs. 0.15, p=0.75).
Patients with Prior Heart Failure
A total of 2,105 patients (12.8%) reported prior heart failure at baseline. They were older and
more likely to have established cardiovascular disease and renal impairment, though there was
no difference in the duration of DM and only a small difference in baseline HbA1c (7.7% in
prior heart failure vs. 7.6% in no prior heart failure, p=0.08). More patients with prior heart
failure were on aspirin, statins, B-blockers, and insulin, but fewer on metformin or sulfonylureas.
(Supplemental Table 3) Patient with prior heart failure were at increased risk for all
cardiovascular events compared to those without prior heart failure. The relative effect of
saxagliptin versus placebo was similar in patients with and without prior heart failure for the
primary and secondary composite endpoints as well as all-cause mortality. However, the absolute
increase in the rate of hospitalization for heart failure with saxagliptin was 1.5% in patients with
prior heart failure compared to 0.6% in patients without prior heart failure, p for
interaction=0.67. The rates of cardiovascular events as well as hypoglycemia, and adverse events
are presented in the Supplemental Table 4. We further evaluated the risk of hospitalization for
heart failure in patients with prior heart failure by NHYA Functional Classification.
(Supplemental Table 5).
Discussion
In patients with established cardiovascular disease or multiple cardiovascular risk factors, the
failure were on aspirin, statins, B-blockers, and insulin, but fewer on metformin ooor suss lflflfonnonylylylururu eae s
Supplemental Table 3) Patient with prior heart failure were at increased risk for all
caardrddioioiovvavascscculululaaar eevevevennts compared to those withoututut pprrrior heart failururre.e ThThThee e relative effect of
aaxaaaglg iptin veersrsuuus plalacecebobobo wwwasasas ssimimmiililararr inn paaatieeentss wwwithhh aaandnd wwwitithhoouutut ppriirioorr heheeararartt fafailililururree foff r r r hththeee
prprimimimarararyy y ananndd d sesecocoonnddararyy ccocompmpposositititeee eneendpdppoioiointntntsss asasas wwwelell l asass aaallllll-c-c-cauauuseses mmmororortataalitytyty. HoHoHowewew vevever,r, tthehehe aabsbssolollutu e
ncrease in thheee rarar tetete ooof f hohohospsppititi alala izzzatatatioioonnn fofoor r r heheheararartt t fafaf ilili ururureee wiwiwiththth ssaxaxaxagagaglil ptptptininn wawawas s s 1.1.1 5%5%5% iiin n n papapatients withh
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DPP-4 inhibitor saxagliptin, when compared with placebo, increased the risk of hospitalization
for heart failure, in particular during the first 12 months of therapy. Several clinical features
easily identified patients at highest absolute risk of heart failure, regardless of treatment
assignment. While there were no individual pre-defined subgroups in which the relative risk
associated with saxagliptin treatment was particularly high or low, the incremental risk with
saxagliptin was greatest in patients at a high overall risk of heart failure (i.e., history of heart
failure, impaired renal function, or elevated baseline levels of NT-proBNP), and correspondingly
small in patients at lower risk. Therefore, a combination of clinical factors and biomarkers
identify a population of patients with diabetes in whom the excess risk of hospitalization for
heart failure with saxagliptin treatment is greatest, while conversely identifying a larger
population without those features in whom the absolute risk is small.
Based on saxagliptin’s mechanism of action and the accumulated preclinical and clinical
data of DPP IV antagonists, the observation of a higher incidence of hospitalization for heart
failure in patients treated with saxagliptin in SAVOR-TIMI 53 was unexpected and requires
confirmation with several ongoing cardiovascular outcomes trials of DPP-4 inhibitors and
glucagon-like-peptide (GLP)-1 agonists.26, 27 There was no signal of fluid retention, weight gain,
or heart failure with saxagliptin in the Phase 2 and 3 development program. 28 Moreover, prior
preclinical data and small studies with other incretin-based agents suggested potential
improvement of left ventricular function26, though these data are inconsistent. Two preliminary
reports of other studies in patients with DDP-4 inhibitors produced unanticipated findings that
highlight potential mechanisms by which treatment with DPP-4 inhibitors could exacerbate heart
failure. In one study in patients with reduced left ventricular function, after twelve months of
therapy, the DPP-4 inhibitor vildagliptin increased left ventricular end diastolic volumes.27 In
heart failure with saxagliptin treatment is greatest, while conversely identifying aaa llarara ggeer r
population without those features in whom the absolute risk is small. t
BaBaBaseses d dd onnn sssaaxaxagliptin’s mechanism of actititiononn and the accuumumm laatetetedd d preclinical and clinical
ddadataaa of DPP IVV aaannttagagoononisisistststs, , thththe e obobbseseservrvvaattionn ooff a hhhiggheeer r inincicciddeencncce ofof hhhoosospipitataalililizzatatioioion n fofof rr heheheararrt t
faailililururureee inin pppatatatiieientnts ttrtreaeateted d d wiwiththth ssaxaxaxagagaglilipptptininin iiinnn SASASAVOVOVOR-R--TITIIMIMIMI 555333 wwawasss unununexexexpepep cctctededed aandndnd reqeqquuiuireres ss
confirmationn wwwititi h h h seseseveveerarar l ononongogog inining g g cacac rdddioioiovavavascscscululu ararar oooututu cooomememes s trtrriaiaialslsl ooof ffr DPDPDPP-P-P 4 4 4 ininnhihihibibibitototorsrsr and
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another six-week trial, several DPP-4 inhibitors worsened endothelial function as assessed by
flow-mediated dilation, independent of GLP-1 levels or DPP-4 activity.29 Regardless, no clear
mechanism of action to explain the increased risk of hospitalization for heart failure in SAVOR-
TIMI 53 could be identified.
Though unexpected, the incremental risk of heart failure hospitalization observed with
saxagliptin is likely valid, given the large number of events and the pre-specification of heart
failure hospitalizations as a component of the secondary endpoint, together with central blinded
adjudication. The observation of an increased risk of hospitalization for heart failure with
saxagliptin must however be taken in the context of multiple testing and the risk of a “false
positive” result, though there was a statistically significant difference between the two groups
after post hoc adjustment for multiple comparisons. Left ventricular function was not captured at
baseline and therefore the temporal changes, even in patients with prior heart failure, cannot be
evaluated.
The Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in
Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial that
evaluated the DPP-4 inhibitor alogliptin versus placebo also identified a numerically similar
trend for increased risk of hospitalization for heart failure, though the overall number of events
was smaller (106 [3.9%] vs. 89 [3.3%], HR 1.19, 95%CI 0.90-1.58, p=0.22). 30 When the 712
first hospitalization for heart failure events from both studies are combined, the overall odds of
hospitalization for heart failure with DPP-4 inhibition is 1.24 (95% 1.07-1.44, p=0.004)
(Supplemental Figure 6).
An increased risk of heart failure has been observed in some studies of other anti-
hyperglycemic agents, including sulfonylureas13, thiazolidinediones7-9, 11 and dual PPAR /
positive” result, though there was a statistically significant difference between thheee twtwwoo grgrgrouououpspsp
after post hoc adjustment for multiple comparisons. Left ventricular function was not captured at
baaseseelililinnene aaandndnd tttheererereffofore the temporal changes, eveeen nn iinn patients withthh priiororor hhheart failure, cannot be
evvalalluau ted.
ThThee e ExExE amammiinnatatiiionnn ofo CCCarrrdididiovovovasascucuculalalarr r OuOuutctct omomomesess wwwititithh h AlAlAlogogogliiptptptinini veerersusuus s StStS anannddadarddd oof f CaCaareee in
Patients with h TyTyTypepepe 222 DDDiaiai beeetetetesss MeMeMellllitititususs aaandndnd AcAcAcututu e ee CoCoCororonananaryryry SSynynyndrdromomome e e (E(E(EXAXAX MIMIMINENENE) ) ) trt ial that
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15
agonists 10, 31 with divergent results in trials of intensive glucose management.32, 33 The lack of
adequate safety data on antihyperglycemic agents in heart failure is highlighted by the example
of metformin, which for many years was contraindicated in patients with heart failure, until
observational data demonstrated an acceptable safety profile.15, 16 Patients both diabetes and
heart failure are relatively under-represented in clinical trials that either excluded them 34-36 or
enrolled less than 5% of the population.37, 38 The 2105 patients with prior heart failure in
SAVOR-TIMI 53 therefore represent one of the largest cohorts of such patients with diabetes
studied. 1
There are presently no known mechanisms by which DPP-4 inhibition could precipitate
heart failure. The hemodynamic effects of glycemic modulation in myocardium accustomed to
years of hyperglycemia are unknown and could potentially exacerbate cardiac dysfunction as
glycemic changes may unfavorably alter the balance of free fatty acid oxidation and glycolysis.
39 Intensive glycemic control increased the risk of heart failure in one of the large glucose
lowering trials40, but not in two others.36,38 In contrast to the thiazolidinediones, there is no signal
of volume overload observed in SAVOR-TIMI 53 with saxagliptin nor did saxagliptin raise
levels of NT-proBNP. Interestingly though, treatment with the glitazones increases levels of
natriuretic peptides in some41, but not all studies.7 The cardiovascular consequences of DPP-4
inhibition on other peptide substrates such as natriuretic peptides or bradykinins are also
unknown. Nor was there evidence of direct myocardial toxicity with saxagliptin as reflected by
the similar change in concentrations of hsTnT and hsCRP between treatment groups.
With the possible exception of metformin 15, 16 and insulin42, most reported studies to date
evaluating effects on heart failure of specific glucose-lowering medications either increased the
risk of heart failure, or were insufficiently powered and therefore often discordant.33 Moreover,
heart failure. The hemodynamic effects of glycemic modulation in myocardium aaaccucuc ssttomomomededed tto o
years of hyperglycemia are unknown and could potentially exacerbate cardiac dysfunction as
glglycycycememmiicic ccchahahanngeseses mmay unfavorably alter the ballaaancnce of free fatty y acaa idd oooxxixidation and glycolysis. aaa
999 Inntntensive glylycceemmimic c cocoontntntrroroll l ininincrcreaeaeaseseddd ttthe rrrissk offf hhhearrtrt ffaiailulul rrere iinn onone e ofofo thehee llarargegee gglululuccoosesese
oowewweririringngng ttriririalalalss4040,,, bbubut t nonnot tt inin ttwowow ooothththeerers.s.366,6,3838 IIIn cococonntntraraastt tooo thththee thththiaiaazozoolililididinnenedidiononnesess, , , ththhererere iiis nnnoo sssigngnna
of volume ovverererlolol adadad oobsbsbsere veveved d d innn SSSAVAVAVOROROR-T-TTIMIMIMIII 53535 wwwitith h sasasaxaxaxaglglglipipiptitt n n n nononor r r dididid d d sasaxaxaxaglglglipipptititin n raise
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16
the trials of metformin and insulin by design enrolled patients with recently diagnosed diabetes
in whom glycemic modulation may be better tolerated by the myocardium. In this well-powered
study of patients at high cardiovascular risk, we found that saxagliptin did not increase the
overall risk of the primary or secondary cardiovascular composite endpoints, even in those with
prior heart failure. However, patients treated with saxagliptin had an increased risk of
hospitalization for heart failure - an event that itself was associated with a high subsequent
mortality – and in particular in patients at the highest absolute risk of heart failure. The decision
to choose one antihyperglycemic agent versus another must balance the benefit in reducing
microvascular complications via improved glycemic control together with potential adverse
events such as hypoglycemia and heart failure. The results from contemporary large
cardiovascular outcome studies in patients with diabetes across the spectrum of classes of anti-
hyperglycemic agents will greatly improve our evidence-based approach to treatment of these
two commonly coexistent conditions.
Funding Sources: SAVOR-TIMI 53 was funded by AstraZeneca and Bristol-Myers Squibb.
Conflict of Interest Disclosures: Dr. Scirica reports research grants via the TIMI Study and
Brigham and Women’s Hospital from AstraZeneca and Bristol-Myers Squibb, Daichi-Sankyo ,
GlaxoSmithKline, Johnson and Johnson, Bayer Healthcare, Gilead, Eisai, Merck. Consulting fees
from AstraZeneca, Gilead, Lexicon, Arena, Eisai, St. Jude's Medical, Bristol-Myers Squibb, Forest
Pharmaceuticals, Boston Clinical Research Institute, Decision Resources, University of Calgary,
Elsevier Practice Update Cardiology, Forest Pharmaceuticals. Dr. Braunwald reports grants from
Astra Zeneca, grants from Bristol Myers Squibb, during the conduct of the study; grants from
Johnson & Johnson, grants from Merck & Co., grants from Sanofi Aventis, grants from Daiichi
Sankyo, grants from Glaxo Smith Kline, grants from Beckman Coulter, grants from Roche
Diagnostics, grants from Pfizer, grants from Eli Lilly, grants from Duke University, personal fees
from Eli Lilly, personal fees from Merck, personal fees from CVRx, personal fees from CV
events such as hypoglycemia and heart failure. The results from contemporary llararrgeee
cardiovascular outcome studies in patients with diabetes across the spectrum of classes of anti-r
hyhypepepergrgrglylylycececemimimic agaggeenents will greatly improve our evevevidddence-based appppp roacacchh h to treatment of these
wwooo coc mmonlyly cccoeeexixiistsstenennttt cococondndndititioioonnsns.
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Therapeutics, now Gilead, personal fees from Daiichi Sankyo, personal fees from Menarini
International, personal fees from Medscape, personal fees from Bayer, personal fees from
Genzyme, personal fees from Medicines Company, personal fees from Sanofi Aventis, outside the
submitted work. Dr. Raz reports grants from Astra Zeneca, grants from Bristol Myers Squibb,
during the conduct of the study; scientific board membership from Novo Nordisk, MSD, Eli Lilly,
Sanofi, Medscape, Andromeda, Insuline; Payment for lectures including service on speakers
bureaus for lectures from Eli Lilly, Novo Nordisk, Johnson and Johnson, Sanofi, MSD, Novartis;
stock options in Insuline. Dr. Cavender reports no conflicts. Dr. Morrow reports grants from
AstraZeneca during the conduct of the study; consultancy fees from Abbott Laboratories, BG
Medicine, Critical Diagnostics, Daiichi Sankyo, Genetech, Gilead, Instrumentation Laboratories,
Johnson & Johnson, Konica Minolta, Merck, Novartis, Provenchio, Roche Diagnostics, Servier;
grants from Abbott Laboratories, Beckman Coulter, BG Medicine, Critical Diagnostics, Bristol-
Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, , Roche Diagnostics, Sanofi
Aventis, Gilead. Dr. Jarolim reports grants from Abbott, AstraZeneca, Daiichi Sankyo, Merck,
Roche Diagnostics and Waters Technologies; consultancy fees from Biosystems and Quanterix.
Dr. Udell reports no conflicts. Dr. Mosenzon reports grants from AstraZeneca and Bristol-Myers
Squibb, during the conduct of the study; consulting fees from AstraZeneca and Bristol-Myers
Squibb; support for travel to meetings for the study from AstraZeneca and Bristol-Myers Squibb;
scientific advisory board membership from Novo Nordisk, Eli Lilly, sanofi, Norvartis, speakers
bureaus for Novo Nordisk, Eli Lilly, sanofi, Norvartis, Mercj, Sharpe and Dohme. Ms.Umez-
Eronini reports no conflicts. Dr. Pollack reports employment by AstraZeneca and having
stock/stock option in AstraZeneca. Dr. Hirshberg reports employment by AstraZeneca and having
stock/stock option in AstraZeneca. Dr. Frederich reports employment by Bristol-Myers Squibb and
having stock/stock option in Bristol-Myers Squibb. Dr. Lewis reports grants from AstraZeneca
during the conduct of the study; scientific advisory board membership from MSD and
AstraZeneca; grants from Bayer Healthcare, Amylin, Amgen, GDK, MSD, Eli Lilly, Sanofi. Dr.
McGuire reports grants from Brigham and Womens Hospital, personal fees from Brigham and
Womens Hospital, during the conduct of the study; personal fees from Boehringer Ingelheim,
personal fees from Janssen Research and Development LLC, personal fees from Sanofi Aventis
Groupe, personal fees from Genentech, Inc., personal fees from Merck Sharp and Dohme Corp.,
personal fees from Medscape Cardiology, personal fees from Pri-Med Institute, personal fees from
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Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, , Roche Diagngnnossstitit ccss,, SaSaSanononofifi
Aventis, Gilead. Dr. Jarolim reports grants from Abbott, AstraZeneca, Daiichi Sankyo, Merck,
Roche Diagnostics and Waters Technologies; consultancy fees from Biosysystems and Quanterix.
DrDrr. UUdUdele l rerepopoports s nono ccononfllicictst . DrDr. MoM ses nzzon repepoorrrtss granntsts ffrom AsAsA traZaZeneneca annd d Brisstool-MyM ers
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at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from
DOI: 10.1161/CIRCULATIONAHA.114.010389
18
The Brigham and Women's Hospital, Inc, personal fees from Duke Clinical Research Institute,
personal fees from The Cleveland Clinic Coordinating Center for Clinical Research, personal fees
from The University of Oxford, personal fees from Daiichi Sankyo, Inc., personal fees from Lilly
USA, personal fees from Novo Nordisk, personal fees from F. Hoffmann La Roche, non-financial
support from Gilead Sciences, personal fees from Axio Research, personal fees from Premier
Research, personal fees from INC Research LLC, personal fees from Glaxo Smith Kline, personal
fees from Takeda Pharmaceuticals North America, personal fees from Bristol-Myers Squibb,
personal fees from Eisai, personal fees from Omthera, personal fees from Regeneron, outside the
submitted work. Dr. Davidson reports personal fees from TIMI Group during the conduct of the
study. Dr. Steg reports personal fees from AstraZeneca, during the conduct of the study; personal
fees from Amarin, personal fees from Bayer, personal fees from Boehringer-Ingelheim, personal
fees from Bristol-Myers-Squibb, personal fees from Daiichi-Sankyo, personal fees from
GlaxoSmithKline, personal fees from Lilly, personal fees from Merck-Sharpe-Dohme, personal
fees from Novartis, personal fees from Otsuka, personal fees from Pfizer, personal fees from
Roche, personal fees from TheMedicines Company, grants and personal fees from Sanofi, grants
and personal fees from Servier, personal fees from Vivus, outside the submitted work. Dr. Deepak
L. Bhatt discloses the following relationships - Advisory Board: Elsevier Practice Update
Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research
Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The
Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute,
Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria:
American College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir Publications
(Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering
committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP
Communications (Editor in Chief, Journal of Invasive Cardiology), Population Health Research
Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology
Today’s Intervention), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy
Editor), Journal of the American College of Cardiology (Section Editor, Pharmacology); Research
Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi
Aventis, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda.
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GlaxoSmithKline, personal fees from Lilly, personal fees from Merck-Sharpe-Doohmhmhme,ee pppererersososonanan ll m
fees from Novartis, personal fees from Otsuka, personal fees from Pfizer, personal fees from
Roche,, ppersonal fees from TheMedicines Compaanyy, , grants and personal fees from Sanofi, grants
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DOI: 10.1161/CIRCULATIONAHA.114.010389
19
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Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderssononon WWG,G, Huang GD. Glucose control and vascular complications in veterans with type 2 dddiaiabebeb tetetes.s. N N N EnEEnglg J Med. 2009;360:129-139.
39. Dutka DP, Pitt M, Pagano D, Mongillo M, GaG thercole D, Bonser RS,S, Camici PG. Myocardiaglglucuccososseee trtrtrananansppporrt tt aanand utilization in patients with hh tytyt pppe 2 diabetes memm llitittususus, , left ventricular dydyysfsffuunction,n, aaandnd cccororononnarara y yy arara teteryryry dddisiseaeasese. J J AmAm CCoololll Caardrdrdioioioll. 2000060606;4;4; 8:8:222222252 -2-22323231.1.1
40400. GGeG rsteinn HHC, MMMillleerr MEEE, GGGenunuththh SSS, IIsmmaaiill-Beeeigggi i F,F,F, BBBususee JBB, GGGofff DDDC,C, Jrr.r., Proobobststffifieelld JLLL,,CuCuushshshmamam nn WCWCWC,, GGGinnsnsbebeerggg HHN,N,N BBBigigiggegeger r JJTJT, GrGrGrimimmm m m RHRHRH, , JrJrJ .,, BBByiyiyingngn ttoton nn RPRPRP, RRoRoseseenbnbnbererrg g g YDYDYD, Frieededewaldld WWTT. LLonong-g termrm eeffffecectsts of inntetensnsivivee glg ucosose e loloweweriringg oon n cacarddioiovavascsculular ooutu cocomemes. New Engl J MMMededed.. 20202011111;3;336444:8:8818188-8-8828288..
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DOI: 10.1161/CIRCULATIONAHA.114.010389
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Table 1. Baseline Characteristics
Characteristic
Hospitalization for Heart Failure
(n = 517)
No Hospitalization for Heart Failure
(n = 15,975) p-
value Unadjusted HR
(95%CI) Demographic Characteristics Age – years, Median (IQR) 68.0 (62.0 - 75.0) 65.0 (60.0 - 71.0) <0.01 1.05 (1.03 - 1.06)* Age 75 years, n(%) 137 (26.5%) 2,193 (13.7%) <0.01 2.27 (1.87 - 2.76) Male, n(%) 377 (72.9%) 10,660 (66.7%) <0.01 1.36 (1.12 - 1.65) Race <0.01 White, n(%) 424 (82.0%) 11,983 (75.0%) 1.45 (1.16 - 1.82)* Black, n(%) 32 (6.2%) 536 (3.4%) Asian, n(%) 35(6.8%) 1745(10.9%) Multiracial, n(%) 21(4.1%) 1505(9.4%) Other , n(%) 5 (1.0%) 206 (1.3) Hispanic, n(%) 68 (13.2%) 3,473 (21.7%) <0.01 0.55 (0.43 - 0.71) Weight – kg, Median (IQR) 89.9 (75.3 - 106.6) 86.0 (74.5 - 99.5) <0.01 1.01 (1.01 - 1.02)* Weight > 80 kg, n(%) 360 (69.8%) 10,196 (63.9%) 0.01 1.27 (1.05 - 1.54) Body-mass index - kg/m2, Median (IQR) 31.5 (27.6 - 36.3) 30.4 (27.2 - 34.4) <0.01 1.03 (1.01 - 1.04)* Body-mass index 30, n(%) 299 (57.9%) 8,517 (53.4%) 0.04 1.17 (0.98 - 1.40) Duration of diabetes, Median (IQR) 12.7 (7.3 - 20.2) 10.3 (5.2 - 16.6) <0.01 1.03 (1.02 - 1.04)* Established atherosclerotic disease, n(%) 470 (90.9%) 12,489 (78.2%) <0.01 3.29 (2.43 - 4.46) Hypertension, n(%) 421 (81.4%) 13,071 (81.8%) 0.82 0.99 (0.80 - 1.24) Dyslipidemia, n(%) 411 (79.5%) 11,328 (70.9%) <0.01 1.61 (1.30 - 1.99) Prior myocardial infarction, n(%) 282 (54.5%) 5,955 (37.3%) <0.01 2.11 (1.77 - 2.51) Prior heart failure, n(%) 226 (43.7%) 1,879 (11.8%) <0.01 5.77 (4.85 - 6.87) Prior coronary revascularization, n(%) 296 (57.3%) 6,827 (42.7%) <0.01 1.90 (1.60 - 2.26) Glycated hemoglobin, Median (IQR) 7.7 (7.0 - 8.7) 7.6 (6.9 - 8.7) 0.34 1.03 (0.97 - 1.10)* Glycated hemoglobin, n(%) 0.44
<6.5% 33 (6.5%) 1,230 (7.8%) Ref. 6.5 - <7.0% 81 (15.9%) 2,775 (17.7%) 1.09 (0.73 - 1.64) 7.0 - <8.0% 187 (36.7%) 5,229 (33.3%) 1.35 (0.93 - 1.96) 8.0 - <9.0% 98 (19.2%) 3,041 (19.4%) 1.24 (0.83 - 1.83)
9.0% 111 (21.8%) 3,414 (21.8%) 1.26 (0.85 - 1.86) Fasting serum glucose (mg/dl), Median (IQR)
146.0 (115.0 - 186.0) 145.0 (118.0 - 182.0)
0.92 1.005(0.99 - 1.02) †
Estimated glomerular filtration rate – mL/min, Median (IQR)
55.7 (41.3 - 75.0) 72.1 (57.8 - 86.7) <0.01 0.74 (0.71 - 0.77) †
Estimated glomerular filtration rate, n(%) <0.01 < 30 mL/min 44 (8.5%) 288 (1.8%) 7.26 (5.26 - 10.03) 30 - 60 mL/min 248 (48.0%) 4275 (26.8%) 2.98 (2.49 - 3.57 ) > 60 mL/min 225 (43.5%) 11412 (71.4%) Ref.
Albumin/creatinine ratio – mg/mmol, Median (IQR)
7.1 (1.7 - 43.1) 1.8 (0.7 - 7.3) <0.01 1.38 (1.32- 1.44)‡
Albumin/creatinine ratio, n(%) <0.01 < 3.4 mg/mmol 182 (36.9%) 9,514 (62.3%) Ref. 3.4 - 33.9 mg/mmol 177 (35.9%) 4,249 (27.8%) 2.20 (1.79 - 2.71) > 33.9 mg/mmol 134 (27.2%) 1,504 (9.9%) 4.70 (3.76 - 5.87)
Baseline Cardiovascular Medications, n(%)
Aspirin 416 (80.5%) 11,988 (75.0%) 0.01 1.41 (1.14 - 1.75) Beta-Blockers 417 (80.7%) 9,745 (61.0%) <0.01 2.71 (2.18 - 3.38) ACE Inhibitors 303 (58.6%) 8,637 (54.1%) 0.04 1.19 (1.00 - 1.41) Angiotensin Receptor Blockers 142 (27.5%) 4,453 (27.9%) 0.84 0.98 (0.81 - 1.19) Diuretics 386 (74.7%) 6,812 (42.6%) <0.01 3.88 (3.18 - 4.73)
Duration of diabetes, Median (IQR) 12.7 (7.3 - 20.2) 10.3 (5.2 - 16.6) <0.01 1.1..03030 ((1.1.0202 -- 11..04)Established atherosclerotic disease, n(%) 470 (90.9%) 12,489 (78.2%) <0.01 3.3.29299 (((2.2.2 434343 --- 444..46)Hypertension, n(%) 421 (81.4%) 13,071 (81.8%) 0.82 0.0 999999 (((0.00.808080 -- 111 2.2.24)4)4Dyslipidemia, n(%) 411 (79.5%) 11,328 (70.9%) <0.01 1.61 (1.30 - 1.99)Prior myocardial infarction, n(%) 282 (54.5%) 5,955 (37.3%) <0.01 2.11 (1.77 - 2.51)Prior heheart faillurure, nn(%(%( )) 226 (43.7%%) ) 1,879 (11.8%) ) <0.01 5.77 (4.85 - 6.87)Prrioioor rr cocoorroronanaaryryry rreevasasscucuculalarization, n(%) 296 (57.3%3%%) 6,827 (442.2.2 7%) ) <0.01 1.90 (1.60 - 2.26)GlGllycycaatateded hemmogogoglobibin,n, MMedediaian n (I(IQRQR)) 7.7.7 7 (7(7.0.0 -- 88.77) 7.7.6 (66.9.99 -- 88.77)) 0.0 3434 1.1.033 ((0.0.9797 - 11.1.10)GGGlycccata ed hemoglolobbibin,, nn(%(%(%) 0.0.0.444444
<<6<6.5% 33 ((6..5%)) 111,2230 (((7..88%) RRRef.f 6..5 5 5 - <7.0% % 81 ((155.9%))) 2,2,77775 (1177..7%) 1...0909 (00..73 -- 1..64)7.77.0 0 -- <8<8<8 0.0.0% % % 1818187 7 7 ((36.6.6 7%7%7%) 5,5,5,22229 99 (3(333.3 3%3%3%)) ) 11.1.3535 (0.0.9393 --- 1.99.96)68.8.0 0 - <9<9.0.0% % 9898 ((1919.22%)%) 3,3 040411 (19.9.4%4%) ) 1..2424 (0.0.8383 - 1.883)3
99.0%0% 111111 (2(2( 1.1.8%8%) ) 3,3,41414 4 (2(2( 11.8%8%8%) )) 1.1.2626 ((00.8585 - 11 8.86)6Fasting g serum m glgllucucososee (m(mg/g/dldld ),), MMMedediaan n 14146.66 00 (1(1151515 0.0 - 11868686 00.0)) 14144555.000 (1(11888 00.0 - 0.0 92922 1.1.00000 5(5(0.0.9999 - 1.0.02)2)
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Characteristic
Hospitalization for Heart Failure
(n = 517)
No Hospitalization for Heart Failure
(n = 15,975) p-
value Unadjusted HR
(95%CI) Statins 429 (83.0%) 12,488 (78.2%) 0.01 1.39 (1.10 - 1.74) Calcium antagonists 174 (33.7%) 5,204 (32.6%) 0.61 1.04 (0.87 - 1.25)
Baseline Anti-hyperglycemic Medications, n(%)
Metformin 273 (52.8%) 11,200 (70.1%) <0.01 0.47 (0.39 - 0.56) Sulfonylurea 157 (30.4%) 6,476 (40.5%) <0.01 0.64 (0.53 - 0.77) Thiazolidinediones 18 (3.5%) 960 (6.0%) 0.02 0.56 (0.35 - 0.89) Insulin 304 (58.8%) 6,528 (40.9%) <0.01 2.08 (1.74 - 2.47)
Hazard ratio, CI and P-value for risk of event for subjects with characteristic relative to base category. * Per unit of measurement defined in the 1st column; † HR per 10 unit increase for fasting glucose and eGFR; ‡ HR per 1 unit increase for logACR Data on race/ethnicity were entered by study coordinators based on patient self-identification.
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Table 2. Multivariable Analysis Evaluating the Relationship between Baseline Clinical Characteristics and Risk for Hospitalization for Heart Failure in the overall SAVOR-TIMI 53 population.
N Chi-Square Adjusted
Hazard Ratio 95% Confidence
IntervalsP
valuesPrior Heart Failure 1986 231.99 4.18 3.48 5.02 <0.01 Albumin/creatinine ratio > 33.9 mg/mmol 1,638 119.26 3.66 2.90 4.62 <0.01 Albumin/creatinine ratio 3.4 - 33.9 mg/mmol 4,426 35.77 1.89 1.54 2.34 <0.01 eGFR 60 ml/min 4602 49.86 2.00 1.65 2.42 <0.01 Age 75 years 2192 24.92 1.70 1.38 2.09 <0.01 Prior MI 5933 15.62 1.47 1.21 1.78 <0.01 Non-hispanic 12327 10.71 1.56 1.20 2.04 <0.01 Established CV disease 12344 8.81 1.64 1.18 2.28 <0.01 Saxagliptin 7916 7.77 1.29 1.08 1.54 0.01 Female 5205 6.93 0.76 0.62 0.93 0.01 Dyslipidemia 11213 4.63 1.27 1.02 1.59 0.03
R 60 ml/min 4602 49.86 2.00 1.65 22.4.422 <0 75 years 2192 24.92 1.70 1.388 222.00.0999 <0MI 5933 15.62 1.47 1.211 111.77.7888 <0<00hispanic 12327 10.71 1.56 1.20 2.04 <0lished CV disease 12344 8.81 1.64 1.18 2.28 <0
glipptin n 7916 7.77 1.29 1.08 1.54 0.lee 5205 6.93 0.00 76 0.62 0.93 0.ppididi mememiaia 1112121313 4.633 1.1.1 2727 1.1.0202 1.1.5959 0.
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Figure Legends:
Figure 1. Kaplan-Meier (KM) Failure Estimates of Hospitalization for Heart Failure According
to Treatment with Saxagliptin versus Placebo. KM Estimates, and corresponding hazard ratios
(HR) are presented at 6 months, 12 months, and 2 years.
Figure 2. Risk of Hospitalization for Heart Failure with Saxagliptin or Placebo in Patients with
and without Baseline Risk Factors (eGFR < 60 ml/min, or history of prior heart failure). ARD –
Absolute risk difference; HR – hazard ration; # excess events per 1000 pt-years refers to the
number of excess hospitalizations for heart failure in patients treated with saxagliptin versus
placebo per 1000 patients-years.
Figure 3. Risk of Hospitalization for Heart Failure with Saxagliptin or Placebo According to
Baseline Quartile of NT-proBNP (pg/ml).
number of excess hospitalizations for heart failure in patients treated with saxaglglipiiptitiin vevev rsrsrsususus
placebo per 1000 patients-years.
FFiguugure 3. Riskk oof HoHoHospsspitittalalalizizizatatatiioion n fofofor r HeHeHeart FaFaailurrre withthth SSaaxxaagagliliptptinin oorrr PPlacaccebebebo o AAcAcccocordrdrdinnngg tototo
BaBaaseses lililinenen QQQuauauartrtililee oofof NNNTT--prproBoBBNPNPNP (((pgppg/m/mml)l)l). .
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3.5%
2.8%
1.3%
0.6%
1.9%
1.1%
HR 1.80(1.29-2.55)
P=0.001
HR 1.46(1.15-1.88)
P=0.002
HR 1.27(1.07-1.51)
P=0.007
Placebo
Saxagliptin
8036
8064
7856
7867
7389
7375
4959
4978
8212
8280
Figure 1
2.8%
11..33%%
00.66%%
1.9%
11.11%%
HR 1.80(1.29-2.55)
P=0.0010
(1.15-1.88)P=0.002
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4855 2105 10,418 8665,188# of excess HHF events/1000 pt-year 065 4 9
N=11637 1438711
Figure 2 at Malmad Medical Libraries Consortium on September 8, 2014http://circ.ahajournals.org/Downloaded from
Quartiles of NT-proBNP (pg/ml)
(5 - 64) (65 - 141) (1412- 333) (333 - 46,627)
p for interaction=0.46
N=3076 3076 3076 3073
ARD 0.2%HR 0.94
(0.57-1.55)P=0.82
ARD 0%HR 1.04
(0.04-26.30)P=0.98
ARD 0.7%HR 1.82
(0.86-4.09)P=0.12
ARD 2.1%HR 1.31
(1.04-1.66)P=0.02
# of excess HHF events/ 1000 pt-year
1 00 7
Figure 3
p for interaction=0.46
ARD 0.2%HR 0.9.94 4
(00.5.5. 7-1.1.555555)P=P=P 0.0.82282
ARRD D 0%0%0%HR 1 0.044
(0.04-4-4-2622 33. 0)00P=P=P=0.0.989898
ARD 0.7%HRHRHR 111.8.8.82220(0(0 8.86- .4. 90909)
=P=P=0. 211
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Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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SUPPLEMENTAL MATERIAL
Heart Failure, Saxagliptin and Diabetes Mellitus –
Observations from the SAVOR - TIMI 53 Trial
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Supplemental Figure Legends
Supplemental Figure 1
Risk of Hospitalization for Heart Failure Over Time According to Treatment with Saxagliptin.
To test for a differential relationship between saxagliptin and hospitalization for heart failure by time after
randomization, we created a time-varying interaction term (treatment*time) and found the p value for
interaction= 0.017, suggesting heterogeneity. To further examine the attenuating effects of saxagliptin on
the risk of hospitalization due to heart failure, a time varying coefficients model over 10 time intervals
where the number of events are equally distributed was developed. The figure represents this analysis.
The lower confidence interval of the log HR crosses 0 at around 314 days, suggesting that about 10-11
months is when the risk of hospitalization for heart failure with saxagliptin subsided in this trial.
Supplemental Figure 2
The Risk of Hospitalization for Heart Failure according to Treatment with Saxagliptin versus Placebo in
Various Subgroups.
Supplemental Figure 3
The Risk of Hospitalization for Heart Failure by Deciles (top) and Established Cutpoint (bottom). The
risk of hospitalization for heart failure is low in the lower levels of NT-proBNP but the risk associated
with saxagliptin is present at all levels of NT-proBNP. We have repeated our analysis using a cutpoint of
125 pg/mL for patients younger than 75 years and 450 pg/mL for patients 75 years or older which is listed
in the product insert for this assay and is based on data from an elderly cohort with stable coronary artery
disease, where the top quartile of NT-proBNP was > 450 pg/ml.1 In another cohort of patients with
T2DM, in whom the majority did not have established coronary disease, the highest quartile was 200
pg/ml.2
Reference:
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
3
1. Bruno G, Landi A, Barutta F, Ghezzo G, Baldin C, Spadafora L, et al. N-terminal probrain
natriuretic peptide is a stronger predictor of cardiovascular mortality than C-reactive protein and albumin
excretion rate in elderly patients with type 2 diabetes: the Casale Monferrato population-based study.
Diabetes Care. 2013;36(9):2677-82.
2. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type
natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med.
2005;352(7):666-75.
Supplemental Figure 4
Increased Risk of Hospitalization for Heart Failure in patients according to Baseline Quartiles of NT-
proBNP and Number of Baseline Risk Factors (eGFR < 60 mL/min or prior history of heart failure). ARD
– Absolute risk difference; HR – hazard ratio; # excess events per 1000 pt-years refers to the number of
excess hospitalizations for heart failure in patients treated with saxagliptin versus placebo per 1000
patients-years.
Supplemental Figure 5
Risk of Hospitalization for Heart Failure with Saxagliptin or Placebo in Patients with Normal and
Elevated concentrations of NT-proBNP according to Baseline Risk Factors (eGFR < 60 ml/min or prior
history of heart failure). ARD – Absolute risk difference; HR – hazard ratio; # excess events per 1000 pt-
years refers to the number of excess hospitalizations for heart failure in patients treated with saxagliptin
versus placebo per 1000 patient-years.
Supplemental Figure 6
Pooled Analysis of the Risk for Hospitalization for Heart Failure from the SAVOR-TIMI 53 and
EXAMINE Trials in patients treated with a DPP4 inhibitor.
Methods: The measure of effectiveness of DDP-IV inhibitors on hospitalization due to heart failure
(HHF) from individual trial is summarized as odds ratios using observed and expected number of events.
These individual odds ratios were then combined by Peto method (Yusuf et al. 1985) to yield a point
estimate of the pooled effect and 95% confidence interval. The pooled effect describes a weighted average
of the studies, giving more weight to a larger sized trial. Statistical heterogeneity across the two trials
was assessed by Cochran’s Q statistic.
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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This figure presents a meta-analysis of the effects of DDP-IV inhibitors (alogliptin and saxagliptin) on
hospitalization due to heart failure (HHF) endpoint from two recently completed randomized clinical
trials. The number of HHF events is given in the left two columns for treatment and placebo groups,
respectively. The treatment and control group sizes were comparable in each trial (8280 vs 8212 in
SAVOR; 2701 vs 2679 in EXAMINE trial26
). There was no statistical heterogeneity across these two
trials (Cochran’s Q=0.13 with df=1, p-value=0.714). Therefore, results are summarized from the fixed
effects estimates only. The pooled estimate of Peto odds ratios indicates there is a 24% increase in risk of
admission to hospital due to heart failure in DPP IV inhibitor treatment group (odds ratio 1.24; 95% CI
1.07-1.44). Nonetheless, these results should be interpreted with a caution as the combined estimate is
based upon only two trials.
Reference:
Yusuf S. Peto R. Lewis J. Colins R. Sleight P. Beta blockade during and after myocardial infaction. An
overview of randomized trials. Progress in Cardiovascular Disease 1985:27:335-371
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
5
Supplemental Table 1 Investigator reported events based on narrow and broad narrow Standardised MedDRA Query
(SMQ) terms for cardiac failure.
Saxagliptin
N=8280
Placebo
N=8212
Subjects
with events
n (%) 2-yr KM%
Subjects
with events
n (%) 2-yr KM% HR 95% CI
Any SMQ term (Narrow)-
Serious events only
325 (3.93) 3.9% 275 (3.35) 3.3% 1.18 1.01-1.39
Any SMQ term (Broad)-
Serious Events only
333 (4.02) 4.0% 281 (3.42) 3.4% 1.19 1.01-1.39
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Supplemental Table 2
Multivariable Analysis Evaluating the Relationship between Baseline Clinical Characteristics and level of
NT-proBNP and Risk for Hospitalization for Heart Failure
N Chi-
Square
Adjusted
Hazard
Ratio 95% Confidence
Intervals P
values
NT-proBNP > 332 pg/ml (Quartile 4) 2949 161.9 5.47 4.21 7.10 <0.01
Prior Heart Failure 1537 99.0 2.98 2.40 3.69 <0.01
Albumin/creatinine ratio > 33.9 mg/mmol 1211 38.1 2.35 1.79 3.08 <0.01
eGFR ≤60 ml/min 3237 14.5 1.43 1.12 1.83 <0.01
Non-Hispanic 3463 14.0 1.54 1.23 1.92 <0.01
Albumin/creatinine ratio 3.4 - ≤ 33.9
mg/mmol 9129 8.2 1.80 1.32 2.45 <0.01
Saxagliptin 5915 6.4 1.30 1.06 1.60 0.01
Prior MI 4562 4.8 1.28 1.03 1.60 0.03
Female 3949 4.3 0.78 0.62 0.99 0.04
Age ≥ 75 years 1630 2.7 1.23 0.96 1.57 0.10
Dyslipidemia 8403 1.7 1.18 0.92 1.51 0.19
Established CV disease 9210 0.7 1.17 0.82 1.68 0.39
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Supplemental Table 3
Baseline characteristics by history of heart failure
Characteristic
Prior Heart
Failure
(n = 2,105)
No Prior Heart
Failure
(n = 14,387) p-value
Demographic Characteristics
Age – years, Median (IQR) 65.0 (59.0 - 72.0) 65.0 (60.0 - 71.0) <0.01
Age ≥ 75 years, n(%) 391 (18.6%) 1,939 (13.5%) <0.01
Male, n(%) 1,399 (66.5%) 9,638 (67.0%) 0.63
Race <0.01
White, n(%) 1,778 (84.5%) 10,629 (73.9%)
Black, n(%) 82(3.9%) 486(3.4%)
Asian, n(%) 137(6.5%) 1638(11.4%)
Multiracial, n(%) 91(4.3%) 1435(10.0%)
Other , n(%) 17(0.8%) 199(1.4%)
Hispanic, n(%) 278 (13.2%) 3,263 (22.7%) <0.01
Weight – kg, Median (IQR) 90.0 (78.0 - 105.0) 85.5 (74.0 - 98.9) <0.01
Weight > 80 kg, n(%) 1,499 (71.3%) 9,057 (63.0%) <0.01
Body-mass index - kg/m2, Median (IQR) 31.6 (28.1 - 36.2) 30.3 (27.1 - 34.2) <0.01
Body-mass index ≥ 30, n(%) 1,292 (61.5%) 7,524 (52.4%) <0.01
Duration of diabetes, Median (IQR) 10.4 (5.0 - 17.7) 10.3 (5.3 - 16.6) 0.65
Established atherosclerotic disease, n(%) 1,920 (91.2%) 11,039 (76.7%) <0.01
Hypertension, n(%) 1,810 (86.0%) 11,682 (81.2%) <0.01
Dyslipidemia, n(%) 1,544 (73.3%) 10,195 (70.9%) 0.02
Prior myocardial infarction, n(%) 1,208 (57.4%) 5,029 (35.0%) <0.01
Prior coronary revascularization, n(%) 1,117 (53.1%) 6,006 (41.7%) <0.01
Glycated hemoglobin, Median (IQR) 7.7 (7.0 - 8.8) 7.6 (6.9 - 8.7) 0.08
Glycated hemoglobin, n(%) 0.11
<6.5% 170 (8.2%) 1,093 (7.7%)
6.5 - <7.0% 341 (16.5%) 2,515 (17.8%)
7.0 - <8.0% 660 (32.0%) 4,756 (33.6%)
8.0 - <9.0% 403 (19.6%) 2,736 (19.4%)
≥9.0% 487 (23.6%) 3,038 (21.5%)
Fasting serum glucose (mg/dl), Median (IQR) 148.0 (117.0 - 189.0) 145.0 (119.0 - 181.0) 0.12
Estimated glomerular filtration rate – mL/min, Median
(IQR)
64.9 (50.0 - 80.3) 72.7 (58.4 - 87.2) <0.01
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Characteristic
Prior Heart
Failure
(n = 2,105)
No Prior Heart
Failure
(n = 14,387) p-value
Estimated glomerular filtration rate, n(%) <0.01
< 30 mL/min 72 (3.4%) 260 (1.8%)
30 - ≤60 mL/min 814 (38.7%) 3709 (25.8%)
> 60 mL/min 1219 (57.9%) 10418 (72.4%)
Albumin/creatinine ratio – mg/mmol, Median (IQR) 2.1 (0.8 - 9.5) 1.8 (0.7 - 7.5) <0.01
Albumin/creatinine ratio, n(%) <0.01
< 3.4 mg/mmol 1,169 (58.9%) 8,527 (61.9%)
3.4 - ≤ 33.9 mg/mmol 571 (28.8%) 3,855 (28.0%)
> 33.9 mg/mmol 246 (12.4%) 1,392 (10.1%)
Baseline Cardiovascular Medications, n(%)
Aspirin 1,684 (80.0%) 10,720 (74.5%) <0.01
Beta-Blockers 1,676 (79.6%) 8,486 (59.0%) <0.01
ACE Inhibitors 1,187 (56.4%) 7,753 (53.9%) 0.03
Angiotensin Receptor Blockers 615 (29.2%) 3,980 (27.7%) 0.14
Diuretics 1,484 (70.5%) 5,714 (39.7%) <0.01
Statins 1,710 (81.2%) 11,207 (77.9%) <0.01
Calcium antagonists 605 (28.7%) 4,773 (33.2%) <0.01
Baseline Anti-hyperglycemic Medications, n(%)
Metformin 1,138 (54.1%) 10,335 (71.8%) <0.01
Sulfonylurea 797 (37.9%) 5,836 (40.6%) 0.02
Thiazolidinediones 76 (3.6%) 902 (6.3%) <0.01
Insulin 1,029 (48.9%) 5,803 (40.3%) <0.01
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
9
Supplemental Table 4
Clinical endpoints in patients with and without Prior Heart Failure
Prior Heart Failure
(n=2105)
No Prior Heart Failure
(n=14387)
Saxa. (2yr-
KM%)
Plac. (2yr-
KM%) HR
p-
value
Saxa. (2yr-
KM%)
Plac. (2yr-
KM%) HR
p-
value
Interaction
p-value
1° Endpoint 13.9 12.3 1.13 0.32 6.4 6.5 0.97 0.61 0.28
2° Endpoint 23.9 22.9 1.06 0.50 11.2 10.9 1.01 0.87 0.63
CV Death 7.6 7.3 1.03 0.88 2.6 2.3 1.04 0.73 0.94
ytioatroM 4.9 8.8 5..1 ...1 9.4 5.1 5.55 ..59 ...9
Hospitalization for
Heart Failure 11.7 10.2 1.21 0.15 2.3 1.7 1.32 0.02 0.67
yMtiaiaratM
nIiaiiortI 1.5 9.1 5.4. ..49 4.4 5.4 ..8. ..4. ..55
Minor/Major
Hypoglycemia 51.. 59.. 5.4. ..54 51.. 55.5 5.5. ....5 ..85
Major
Hypoglycemia 5.. 4.5 5.9. ..59 5.4 5.. 5.45 ..5. ..1.
Hospitalization for
Hypoglycemia 1.3 0.5 2.55 0.04 0.5 0.5 1.02 0.94 0.09
sareiAeMsreIoAM Saxa. (n/N%)M
Plac. (n/N%)M ORM
p-
valueMSaxa. (n/N%)M
Plac. (n/N%)M ORM
p-
valueM
Interaction
p-valueM
sIMMsareiAeM
sreIoA .9.. .5.5 5..4 ..9. .5.1 .5.. ..44 ..85 ..54
eirtvAMsareiAeM
sreIoA 59.4 59.5 5..9 ...4 49.9 45.4 5..4 ..1. ..84
M Saxa. (%)M
Plac. (%)M M
p-
valueMSaxa.
(%)MPlac. (%)M M
p-
valueMM
A1c Reduction at
2yrs (median)M-0.2%M -0.1%M M 0.15M -0.2%M 0%M M <0.001M M
MMAbs5iM<.M%aoM4M
MeaiA 54.8 44.5 M .0..0> 9..5 5..9 M .0..0> M
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Supplemental Table 5
Risk of hospitalization for heart failure in patients with prior heart failure according baseline New York
Heart Association (NYHA) Functional Classification
NYHA
Classification
Saxagliptin Placebo
N 2yr –
KM%
N 2yr –
KM%
HR 95%CI p-value for
interaction
I 320 8.0% 303 7.6% 1.09 (0.61-1.96) 0.52
II 623 11.4% 625 10.4% 1.12 (0.80-1.57)
III/IV 113 24.3% 121 15.6% 1.75 (1.75-3/36)
NYHA
Class Symptoms
I Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when
walking, climbing stairs etc.
II Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short
distances (20–100 m).
Comfortable only at rest.
IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
11
Supplemental Figure 1
Risk of Hospitalization for Heart Failure Over Time
According to Treatment with Saxagliptin
Days since randomization
Lo
g H
azard
Rati
o f
or
Ho
sp
itali
zati
on
fo
r H
eart
Fail
ure
1 62 116 173 251 314 397 482 550 610 697 1043
-0.5
0.0
0.5
1.0
upper 95% CI
lower 95% CI
log(HR)
Saxagliptin
worse
Saxagliptin
better
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
12
Overall 16492 3.5% 2.8% 1.27 (1.07, 1.51)
0.2 0.5 1 2 5
N Saxagliptin Placebo
1.27 (1.06, 1.51)
1.63 (0.64, 4.44)
No
YesBaseline
Thiazolidinedione 15514
978 2.1%
2.8%
1.5%
3.6%
0.78
1.17 (0.91, 1.51)
1.39 (1.09, 1.77)
No
YesBaseline
Metformin 5019
11473
5.2%
2.8%
4.6%
2.0% 0.35
1.28 (1.04, 1.57)
1.28 (0.93, 1.76)
No
YesBaseline
Sulfonylurea 9859
6633
4.1%
2.6%
3.3%
2.0% 0.99
1.36 (1.04, 1.79)
1.21 (0.96, 1.51)
No
YesBaseline
Insulin 9660
6832
2.5%
4.8%
1.9%
4.1% 0.51
1.03 (0.71, 1.50)
1.78 (1.19, 2.73)
1.06 (0.80, 1.42)
1.70 (1.17, 2.50)
≥9%
8-<9%
7-<8%
<7%Baseline
HbA1c
3525
3139
5416
4119
3.2%
3.8%
3.6%
3.5%
3.1%
2.2%
3.4%
2.1% 0.08
1.12 (0.80, 1.59)
1.58 (1.02, 2.47)
1.17 (0.82, 1.68)
1.05 (0.70, 1.57)
1.73 (1.12, 2.73)
≥20 yrs
15-<20 yrs
10-<15 yrs
5-<10 yrs
<5 yrsDuration of
Diabetes
3025
2111
3500
3925
3916
4.6%
4.9%
3.8%
2.5%
2.6%
4.0%
3.2%
3.3%
2.3%
1.6% 0.30
1.32 (1.04, 1.66)
1.21 (0.93, 1.58)
No
YesPrior Heart Failure
14387
2105
2.3%
11.7%
1.7%
10.2% 0.67
1.51 (1.00, 2.30)
1.22 (1.01, 1.48)
No
YesPrior Hypertension
3000
13492
3.8%
3.4%
2.6%
2.8% 0.31
1.35 (1.04, 1.77)
1.22 (0.97, 1.53)
<30
≥30Body-Mass Index
7647
8816
3.3%
3.7%
2.5%
3.0% 0.57
1.47 (1.05, 2.08)
1.21 (0.99, 1.48)≥ 75 years
< 75 yearsAge
2330
14162
6.8%
3.0%
4.9%
2.4% 0.34
1.29 (1.07, 1.55)
1.17 (0.73, 1.90)Non-Hispanic
HispanicEthnicity
12951
3541
3.9%
2.1%
3.0%
1.8% 0.74
1.12 (0.81, 1.57)
1.34 (1.09, 1.65)
Female
MaleSex
5455
11037
2.6%
3.9%
2.4%
3.0% 0.35
0.83 (0.46, 1.51)
1.46 (1.13, 1.89)
1.17 (0.90, 1.52)
<30
30-60
>60Glomerular
Filtration Rate
332
4523
11637
12.3%
6.4%
2.1%
14.2%
4.6%
1.8% 0.18
1.19 (0.67, 2.15)
1.28 (1.07, 1.53)
Risk Factors
EstablishedDisease
State 3533
12959
1.2%
4.2% 3.3%
0.9%
0.83
1.01 (0.72, 1.42)
1.31 (0.98, 1.77)
1.47 (1.10, 1.99)
≥300
30-300
<30Baseline albumin:
creatinine ratio(μg/mg) 1638
4426
9696
8.6%
4.4%
2.3%
8.1%
3.5%
1.5% 0.29
HR (95%CI)P for
interaction
Hazard Ratio Favors PlaceboFavors Saxagliptin
1.33 (0.94, 1.88)
1.25 (1.03, 1.53)
No
YesBaseline
Diuretic9294
7198
1.6%
6.0%
1.1%
4.9% 0.76
1.39 (1.12, 1.72)
1.08 (0.80, 1.46)
No
YesBaseline Calcium
Antagonist 11114
5378
3.6%
3.2%
2.6%
3.0% 0.17
1.60 (1.08, 2.41)
1.21 (1.00, 1.47)
No
YesBaseline
ACEi/ARB 3497
12995
3.4%
3.5%
2.4%
2.9% 0.28
1.20 (0.79, 1.84)
1.28 (1.06, 1.56)
No
YesBaseline
Statin 3575
12917
2.5%
3.8%
2.2%
2.9% 0.77
1.81 (1.21, 2.76)
1.18 (0.97, 1.43)
No
YesBaseline
Beta-Blocker 6330
10162
2.0%
4.4%
1.0%
3.9% 0.06
Supplemental Figure 2
Scirica BM, et al SAVOR-TIMI 53 Heart Failure Online Material
13
Risk of Hospitalization for Heart Failure
According to Deciles of NT-proBNP
0.0% 0.2% 0.2% 1.2% 1.4% 1.5%
2.5% 3.5%
8.0%
17.8%
0.0% 0.2% 0.3% 0.2% 0.4% 0.6%
3.3% 2.4%
5.9%
15.2%
0%
5%
10%
15%
20%
1 2 3 4 5 6 7 8 9 10
Ho
sp
ita
liza
tio
n f
or
He
art
Fa
ilu
re
(2y
r K
M%
)
Deciles of NT-proBNP
Saxagliptin Placebo
Supplemental Figure 3
Risk of Hospitalization for Heart Failure
According to Established Cutpoint
0.6%
6.8%
0.3%
5.5%
0%
2%
4%
6%
8%
10%
Low High
Ho
sp
. fo
r H
ea
rt F
ailu
re (
%)
Saxagliptin Placebo
NT-proBNP (High > 125 pg/ml if<75 yo, or > 450 pg/ml if >=75 yo)
N=6415 5886
ARD 1.3%
HR 1.25
1.02-1.55)
P=0.04
ARD 0.3%
HR 1.54
(0.78-3.18)
P=0.22
Scirica BM, et al SAVOR-TIMI 53 Heart Failure Online Material
14
Supplemental Figure 4
0.6%1.7%
3.1%4.3%
11.6%
19.2%
0%
5%
10%
15%
20%
25%
0 Risk Factors 1 Risk Factor 2 Risk Factors
Ho
sp
. fo
r H
eart
Fa
ilu
re (
%)
Quartile 1-3 Quartile 4
HR 6.45
(4.25-9.78)
p<0.001
Risk of Heart Failure According to Risk
Factors and NT-proBNP
HR 7.13
(5.06-10.05)
p<0.001
HR 6.06
(3.04-12.06)
p<0.001
N=6599 2385 4391135 1499 244
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
15
Risk of Heart Failure According to Risk
Factors and NT-proBNP
Q1-Q3 NT-proBNP
0.6%2.3%
3.2%
0.6% 1.1%
2.9%
0%
5%
10%
15%
20%
25%
0 Risk Factors 1 Risk Factor 2 Risk Factors
Ho
sp
. fo
r H
eart
Failu
re (
%)
Saxagliptin Placebo
Q4 NT-proBNP
ARD 0.0%
HR 0.84(0.46-1.52)
p=0.56
ARD 1.2%
HR 1.76(0.93-3.33)
p=0.08
ARD 0.3%
HR 1.05(0.28-3.91)
p=0.94
N=6599 2442385
5.4%
12.7%
19.9%
3.3%
10.4%
18.4%
0%
5%
10%
15%
20%
25%
0 Risk Factors 1 Risk Factor 2 Factors
Ho
sp
. fo
r H
eart
Failu
re (
%)
Saxagliptin Placebo
ARD 2.0%
HR 1.700.93-3.11
p=0.08
ARD 2.3%
HR 1.27(0.93-1.73)
p=0.13
ARD 1.6%
HR 1.22(0.79-1.88)
p=0.36
N=1135 4391499# of excess
HHF events/
1000 pt-year2 20 5 8 7
Supplemental Figure 5
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
16
Peto odds ratio plot
0.5 1 2
SAVOR-TIMI 53 1.27 (1.06, 1.51)
EXAMINE 1.19 (0.89, 1.58)
combined 1.24 (1.07, 1.44)
Peto odds ratio (95% confidence interval)
EXAMINE
SAVOR-TIMI 53
Combined
106 89
289 228
DPP4i Placebo
1.19 (0.89-1.58)
1.27 (1.07-1.51)
1.24 (1.07-1.44)395 317
OR (95%CI)
Supplemental Figure 6
Scirica BM, et al SAVOR-TIMI 53 Heart Failure Online Material
17
Executive Committee: Eugene Braunwald (Study Chair), Deepak L. Bhatt (Co-Principal Investigator), Itamar Raz (Co-
Principal Investigator), Jaime A. Davidson, Robert Frederich (non-voting), Boaz Hirshberg (non-
voting), Ph. Gabriel Steg
Trial Organization
TIMI Study Group – Eugene Braunwald (Study Chair), Deepak L. Bhatt (Co-Principal Investigator),
Benjamin M. Scirica, Jacob A. Udell, Matthew A. Cavender, Nihar Desai, Timothy Abrahamsen,
Michelle Grossman, Suzanne Morin, Kyungah Im, Elaine Hoffman, Daniel Gabovitch, Alexandra
Pricken
Hadassah Medical Organization– Itamar Raz (Co-Principal Investigator), Ofri Mosenzon, Alona
Buskila
AstraZeneca – Peter Ohman, Boaz Hirshberg, Christina Stahre, Deborah Price, Solveig Billing-Clason,
Karin Sabel, John Monyak, Mikalea Sjöstrand, Cheryl Wei, Jane Lu, Elinor Miller, Joel Raichlen, Sandy
Fitt
Bristol-Myers Squibb – Robert Frederich, Nayyar Iqbal, Mark Donovan
Steering Committee
Members of the Operations Committee and Ph. Gabriel Steg (Executive Committee member), Jaime A.
Davidson (Executive Committee member) and Carlos Aguilar-Salinas (Mexico), Michael Alvarsson
(Sweden), John Amerena (Australia), Diego Ardissino (Italy), Oleg Averkov (Russia), Angelo Avogaro
(Italy), Anthony Barnett (United Kingdom), Reinhard Bretzel (Germany), Chern-En Chiang (Taiwan),
Verner Codoceo (Chile), Ramon Corbalan (Chile), Anthony Dalby (South Africa), Harald Darius
(Germany), Chaicharn Deerochanawong (Thailand), Mikael Dellborg (Sweden), Freddy Eliaschewitz
(Brazil), Armando Garcia-Castillo (Mexico), Ramon Gomis (Spain), Patrick Henry (France), Joost
Hoekstra (Netherlands), Gyorgy Jermendy (Hungary), John Kastelein (Netherlands), Anthony Keech
(Australia), Robert Kiss (Hungary), Michel Krempf (France), Markku Laakso (Finland), Lawrence
Leiter (Canada), Eran Leitersdorf (Israel), Basil Lewis (Israel), Leon Litwak (Argentina), Jose Lopez-
Sendon (Spain), Ronald Ma (Hong Kong), Darren McGuire (United States), Felix Medina (Peru),
Robert Moses (Australia), Jose C. Nicolau (Brazil), Grzegorz Opolski (Poland), Ton Oude Ophuis
(Netherlands), Ernesto Paolasso (Argentina), Kausik K. Ray (United Kingdom), Mikhail Ruda (Russia),
K.M. Prasanna Kumar (India), Marina Shestakova (Russia), Wayne H-H Sheu (Taiwan), Alena
Smahelova (Czech Republic), B. Soma Raju Bhupathiraju (India), Jindrich Spinar (Czech Republic),
Piyamitr Sritata (Thailand), Krysztof Strojeck (Poland), Jaime E. Villena-Chavez (Peru), Weiping Jia
(China), Young Huo (China)
Clinical Events Committee
TIMI Study Group - Chair: Stephen D. Wiviott; Director: Cheryl Lowe; Cardiovascular Specialists: Eric
Awtry, Clifford Berger, Akshay S. Desai, Eli Gelfand, David Leeman, Mark Link, Frederick Ruberg,
Joseph Vita; Neurology Specialists: Natalia Rost, Scott Silverman; Pancreas Specialists: Norton J.
Greenberger, Markus M. Lerch
Data Monitoring Committee
Chair: Bernard Gersh (USA); Members: Richard Nesto (USA), Stefano Del Prato (Italy), Jaakko
Tuomilehto (Finland), and Sheryl Kelsey (USA)
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Investigators
Argentina
National Lead Investigators: L. Litwak and E. Paolasso
A. Alvarisqueta, Centro de Investigaciones Médicas, Mar del Plata, Buenos Aires; J. Cuadrado,
Framingham, La Plata, Buenos Aires; L. Rista, CEDyN Centro de Diabetes y Nutrición, Rosario, Santa
Fe; S. Hermida, CIAD Consultorio Integral de Atención al Diabético, Moron, Buenos Aires; C. Baccaro,
CIMeL, Lanus, Buenos Aires; C. Luquez, Centro Medico Luquez/Fundacion Luquez, San Vicente,
Cordoba; M. Lagrutta, Instituto de Investigaciones Clínicas de Rosario, Rosario, Santa Fe; L. Maffei,
Consultorios Asociados de Endocrionología, Ciudad Autonoma de Buenos Aires; I. Bartolacci, Instituto
de Investigaciones Clínicas de Córdoba, Cordoba; O. Montaña, DIM Clínica Privada, Ramos Mejia,
Buenos Aires; H. Cutuli, Centro Urológico Ballester SRL, Villa Ballester, Buenos Aires; M. Berli,
CEDIR Centro de Diagnostico y Rehabilitacion, Santa Fe; A. Lorenzatti, Fundación Rusculleda,
Cordoba; G. Frechtel, Hospital Sirio Libanés, Ciudad Autonoma de Buenos Aires; R. La Greca, Hospital
Churruca Visca, Ciudad Autonoma de Buenos Aires; O. Fretes, Saint Deniss Medical Group, Ciudad
Autonoma de Buenos Aires; M. Diaz, MD Investigaciones, Ciudad Autonoma De Buenos Aires; N.
Rodríguez Papini, INSARES, Mendoza; E. Farías, Instituto de Cardiología "Juana F. Cabral",
Corrientes; C. Issa, Sanatorio Güemes, Ciudad Autonoma de Buenos Aires; A. Elbert, CEREHA Centro
de Enfermedades Renales e Hipertensión Arterial, Sarandí, Buenos Aires.
Australia
National Lead Investigators: J. Amerena and R. Moses
R. Lehman, Adelaide Medical Research, Ashford; J. Amerena, Geelong Hospital, Geelong; M. Arya,
Australian Clinical Research Network, Maroubra; B. Singh, Launceston General Hospital, Launceston;
D. Colquhoun, Core Research Group, Milton; R. Jayasinghe, Gold Coast Hospital, Southport; F. de
Looze, AusTrials, Auchenflower; P. Blombery, Avenue Cardiovascular Centre, Windsor; F. de Looze,
AusTrials, Sherwood; G. Ward, St. Vincent's Hospital Melbourne, Fitzroy; G. Szto, Peninsula Heart
Centre, Frankston; W. Abhayaratna, Clinical Trials Unit - Canberra Hospital, Woden.
Brazil
National Lead Investigators: F. Eliaschewitz and J. Nicolau
J. Borges, Centro de Pesquisa Clínica do Brasil, Brasília; L. Russo, CCBR BRASIL Centro de Pesquisas
e Análises Clínicas, Rio De Janeiro; F. Eliaschewitz, CPClin - Centro de Pesquisas Clínicas, São Paulo;
J. Felício, Hospital Universitário João de Barros Barreto, Belém; F. Santos, Loema - Instituto de
Pesquisa Clínica, Campinas; F. Guimarães Filho, Instituto do Coração de Marília, Marília; M. Lazaretti
Castro, IMA Brasil - Instituto Medicina Avançada, São Paulo; P. Rossi, Núcleo de Pesquisa Clínica,
Curitiba; D. Armaganijan, Instituto Dante Pazzanese de Cardiologia, São Paulo; P. Leães, Irm. Santa
Casa de Misericórdia de Porto Alegre, Porto Alegre; F. Bandeira, Centro de Pesquisas Médicas Básica e
Clínica, Recife; M. Franken, Heart Institute (InCor) - University of São Paulo Medical School, São
Paulo; N. Rassi, Hospital Geral de Goiânia Dr Alberto Rassi, Goiânia; R. Réa, Serviço de
Endocrinologia do Hospital de Clínicas da UFPR, Curitiba; M. Zanella, Hospital do Rim e Hipertensão,
São Paulo; C. Amodeo, Instituto Dante Pazzanese de Cardiologia, São Paulo; L. César, Heart Institute
(InCor) - University of São Paulo Medical School, São Paulo; R. Betti, Heart Institute (InCor) -
University of São Paulo Medical School, São Paulo; A. Chacra, Centro de Pesquisa Clínica em Diabetes
- UNIFESP, São Paulo; H. Schmid, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto
Alegre.
Canada
National Lead Investigator: L. Leiter
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
19
A. Bell, Keele Medical Place, Toronto, ON; G. Syan, G.S. Cardiac Lab Medicine Professional Corp.,
Sudbury, ON; R. Zadra, Newmarket Cardiology Group, Newmarket, ON; H. Conter, MSHJ Research
Associates Inc., Halifax, NS; R. Dumas, Centre de Recherche Clinique de Laval, Laval, QC; D. Borts,
Brampton Research Associates, Brampton, ON; I. Dattani, Prairie Clinical Research Group, Saskatoon,
SK; P. Poirier, Institut de cardiologie et de pneumologie de Quebec, Quebec, QC; J. Cha, Dr. James Cha
MD, Oshawa, ON; P. Dzongowski, Milestone Research, London, ON; R. Labonte, Dr. R. Labonte
Professional Medicine Corporation, Sudbury, ON; B. St. Pierre, Centre de Recherche Godin and St.
Pierre, Sherbrooke, QC; D. Gaudet, ECOGENE-21 Clinical Trial Center/Centre de santé et de services
sociaux de Chicoutimi, Chicoutimi, QC; S. Kouz, CSSSNL/CHRDL, St-Charles-Borromee, QC; A.
Lamy, Hamilton Health Sciences, General Site, Hamilton, ON; S. Tishler, Mississauga Clinical
Research Centre Incorporated, Mississauga, ON; R. Chehayeb, Viacar Recherche Clinique Inc.,
Greenfield Park, QU; J. Bedard, Recherche Clinique London, Sherbrooke, QC; I. Hramiak, St. Josephs
Health Care London, London, ON; I. Teitelbaum, JJ DIG Research Ltd., Toronto, ON; C. Fortin,
Neufort Inc., St-Lambert, QC; V. Woo, Health Sciences Centre - Diabetes Research Group, Winnipeg,
MB; J. Conway, Diabetes Clinic, Smiths Falls, ON; P. Mehta, Laxmi Centre, Winnipeg, MB; S.
Robinson, Victoria Heart Institute Foundation, Victoria, BC; B. Sussex, Health Sciences Centre, St.
John's, NL; J. Chiasson, CRCHUM, Montréal, QC; N. Muirhead, London Health Sciences Centre,
London, ON; S. Bose, Dr. S Bose Medical Prof. Corp., Saskatoon, SK; A. Ouellet, ViaCar Recherche
Clinique, Longueuil, QC; J. Yale, MUHC - Royal Victoria, Montreal, QC; R. Bhargava, Heart Care
Research, Oshawa, ON; D. Lau, Clinical Trials Unit, University of Calgary, Calgary, AB; S. Tobe,
Sunnybrook Health Sciences Center, Toronto, ON; P. Perron, Centre Hospitalier Universitaire de
Sherbrooke, Sherbrooke, QC; J. Sigalas, Rouge Valley Metabolic Research Associates, Scarborough,
ON; L. Bilodeau, Centre Medical L'Enjeu/L'Enjeu Medical Center, Montreal, QC; R. Tytus, Hamilton
Medical Research Group, Hamilton, ON; G. Achyuthan, Regina Medical Centre, Regina, SK; M.
Pearce, St. Mary General Hospital, Kitchener, ON; A. Steele, Co-Medica Research Research Network
Inc., Courtice, ON; G. Bailey, The Bailey Clinic, Red Deer, AB; P. Ma, Heart Health Research, Calgary,
AB; F. St-Maurice, ViaCar Recherche Clinique Inc., Brossard, QC; D. Rupka, Fraser Clinical Trials Inc,
New Westminster, BC; R. Houlden, Kingston General Hospital, Kingston, ON; A. Bailey, BioQuest
Research, Spruce Grove, AB; G. Rewa, Toronto East Cardiology Research Associates, Toronto, ON; P.
Sohal, Surrey Medical and Travel Clinic, Surrey, BC; R. Ting, Corporate Medical Centre, Scarborough,
ON.
Chile
National Lead Investigators: V. Codoceo and R. Corbalan
J. Prieto, Hospital Clínico Universidad de Chile, Santiago; M. Rodriguez, Hospital Sótero del Río,
Santiago; G. Godoy, Servicios Medicos Godoy Ltda., Santiago; G. Larenas, Centro Médico Stockins y
Larenas, Temuco; C. Pincetti, Centro de Investigacion Clinica del Sur, Temuco; L. Cobos,
CARDIOCOB, Santiago; V. Saavedra, CECIM, Santiago; P. Varleta, Hospital DIPRECA, Santiago; F.
Lucero, Hospital San Borja Arriaran, Santiago; O. Kuzmanic, Hospital Militar, Santiago; M. Acevedo,
Centro de Investigaciones Clínicas UC, Santiago; M. Aguirre, ADICH, Santiago; F. Florenzano,
Psicomedica, Santiago.
China
National Lead Investigators: W. Jia and Y. Huo
J. Ma, Nanjing First Hospital, Nanjing; Y. Bao, Shanghai the 6th People's Hospital, Shanghai; M. Jiang,
1st Affiliated Hospital of Beijing University, Beijing; W. Xu, Second Affiliated Hospital of Suchow
University, Suzhou; y. Shi, Shanghai Changzheng Hospital, Shanghai; M. Zheng, The 2nd Affiliated
Hospital of Tianjin Medical Un, Tianjin; Y. Li, The First Affiliated Hospital of Sun Yat-sen University,
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Guangzhou; Y. Dong, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou; W. Zhao,
Peking Union Medical Collegue Hospital, Beijing; M. Sun, Tianjin Medical University General
Hospital, Tianjin; M. Lei, Xiangya hospital of Center-South university, Changsha; Y. Li, Shanghai
Huashan Hospital, Shanghai; J. Wang, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University,
Guangzhou.
Czech Republic
National Lead Investigators: A. Smahelova and J. Spinar
Z. Píštěk, Interní a diabetologická ambulance, Uherské Hradiště; I. Řiháček, Centrum pro zdraví s.r.o.,
Brno; D. Kučera, Kardiologická a angiologická ambulance, Ostrava; M. Brada, Privátní diabetologická
ambulance, Břeclav; R. Náplava, Lunacor s.r.o., Centrum pro choroby srdce a cév, Kroměříž; J. Špinar,
Fakultní nemocnice Brno, I. Interní kardiologická klinika, Brno; J. Karasová, Interní a diabetologická
ordinace, Cheb; H. Vlašicová, Diabetologická ambulance, Zlín; J. Skopeček, Interní a diabetologická
ambulance, Hořovice; L. Špinarová, Fakultní nemocnice U sv. Anny, I. Interní kardioangiologická
klinika, Brno; A. Šmahelová, Fakultní nemocnice Hradec Králové, Klinika gerontologická a
metabolická, Hradec Králové; L. Raclavská, Medicentrum Beroun, spol. s r.o., Beroun; R. Šarbochová,
Nemocnice Slaný, Interní oddělení, Slaný; L. Okénka, Diabetologická ambulance, Hodonín; E. Račická,
Poliklinika Mittal Steel, Interní a diabetologická ordinace, Ostrava; K. Urbancová, Diabetologická a
interní ambulance, Ostrava; M. Oznerová, Soukromá diabetologická a interní ambulance, Ostrava; Z.
Lorenc, Kardiologická ordinace, Plzeň; B. Wasserburger, DIKa centrum s.r.o., Havířov; E.
Záhumenský, Interní a diabetologická ordinace, Zlín; H. Grünfeldová, Městská nemocnice Čáslav,
Interní oddělení, Čáslav; J. Hradec, Interní a diabetologická ordinace, Chrudim; M. Lukáč, Nefromed
s.r.o., Praha; Š. Svačina, Všeobecná fakultní nemocnice, 3. Interní klinika - 1. Lékařská fakulta UK
VFN, Praha; J. Podzimek, Diabetologická a interní ordinace, Jablonec Nad Nisou; L. Hemžský,
Přeloučská poliklinika a.s., Ordinace diabetologie, Přelouč; I. Mikulková, Nemocnice Blansko, Interní a
diabetologická ambulance, Blansko; J. Pavlíčková, Diabetologická ambulance, Pardubice; T. Brychta,
Diabetologická a interní ambulance, Olomouc; J. Chochola, Nemocnice milosrdných sester sv. Karla
Boromejského, Interní oddělení, Praha.
France
National Lead Investigators: P. Henry and M. Krempf
P. Henry, Hôpital Lariboisiere, Paris; T. Couffinhal, Hôpital Haut Lévêque, Pessac; M. Krempf, CHU de
Nantes - Hôpital Nord Laennec, Nantes; M. Elbaz, CHU Rangueil, Toulouse; C. Petit, Centre
Hospitalier, Corbeil-Essonnes; B. Faller, Hôpitaux Civils de Colmar, Colmar; R. Marechaud, CHRU la
Milètrie, Poitiers; P. Moulin, Hôpital Louis Pradel, Bron; S. Fendri, Hôpital Sud - CHU Amiens,
Amiens; P. Nazeyrollas, CHR Robert Debré, Reims.
Germany
National Lead Investigators: R. Bretzel and H. Darius
U. Wendisch, Praxis Dr. med. U. Wendisch, Hamburg; K. Busch, Praxis Dr. med. K. Busch, Dortmund;
G. Klausmann, Studienzentrum Haematologie/Onkologie/Diabetologie, Aschaffenburg; H. Duengen,
Campus Virchow Klinikum der Charite Berlin Medizinische Klinik mit Schwerpunkt Kardiologie am
Campus Virchow, Berlin; K. Appel, Ambulantes Herzzentrum Kassel, Kassel; N. Toursarkissian, Praxis
Dr. med. N. Toursarkissian, Berlin; T. Jung, Praxis Dr. med. T. Jung, Deggingen; P. Ott, An der
Teleportalklinik, Dippoldiswalde; I. Schenkenberger, KFB- Klinische Forschung Berlin, Berlin; D.
Kuesters, Praxis Dr. med. D. Kuesters, Eschweiler; B. Landers, Praxis Dr. med. B. Landers, Mayen; R.
Nischik, medamed GmbH, Leipzig; H. Fischer, Zentrum für klinische Prüfungen in der Facharztzentrum
Dresden-Neustadt GbR, Dresden; D. Tschoepe, Herz- & Diabeteszentrum NRW Forschungsleitung
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Diabeteszentrum, Bad Oeynhausen; B. Paschen, Praxis Dr. med. B.Paschen, Hamburg; K. Krause, Gem.
Praxis Drs. Krause und Menke, Goch; K. Derwahl, Institut für klinische Forschung und Entwicklung
Berlin GmbHam St. Hedwig Krankenhaus Elisabeth Haus 2. OG, Berlin; V. Wenzl-Bauer, Praxis Dr.
med. V. Wenzl-Bauer, Rehlingen-Siersburg; A. Hamann, Diabetes-Klinik Bad Nauheim GmbH, Bad
Nauheim; H. Strotmann, Medizin Consult GmbH, Rotenburg; K. Milek, Praxis Dr. med. K. Milek,
Hohenmölsen; S. Mueller, Gem. Praxis Drs. Hamann und Mueller, Gueglingen; R. Bretzel, Praxis Prof.
Dr. med. R.G. Bretzel, Giessen.
Hong Kong
National Lead Investigator: R. Ma
R. Ma, Prince of Wales Hospital, Sha Tin, Hong Kong; D. Chu, Chai Wan Health Centre, Hong Kong;
K. Tan, Queen Mary Hospital, Hong Kong; K. Kung, Lek Yuen General Outpatient Clinic, Hong Kong;
D. Chu, Violet Peel General Outpatient Clinic, Hong Kong; C. Tsang, Alice Ho Miu Ling Nethersole
Hospital, Hong Kong; D. Chu, Sai Wan Ho Health Centre, Hong Kong; B. Tomlinson, Prince of Wales
Hospital, Sha Tin, Hong Kong; K. Kung, Fanling Family Medicine Centre, Sha Tin, Hong Kong.
Hungary
National Lead Investigators: G. Jermendy and R. Kiss
L. Korányi, DRC Gyógyszervizsgáló Központ, Balatonfüred; Z. Kerényi, Csepeli Egészségügyi
Szolgálat Szakorvosi Rendelõ, Budapest; B. Benczúr, Jász-Nagykun-Szolnok Megyei Hetényi Géza
Kórház, Szolnok; L. Illyés, Kardiolódiai Szakrendelés Miskolc, 3530 Miskolc; T. Hidvégi, Petz Aladár
Megyei Kórház, Gyõr; A. Somogyi, Semmelweis Egyetem II. Belgyógyászati Klinika, Budapest; J.
Valcó, Ceglédi Toldy Ferenc Kórház, Cegléd; G. Jermendy, Bajcsy-Zsilinszky Kórház Medical
Department, Budapest; S. Ferenczi, Petz Aladár Megyei Kórház Immunnephrológia, Gyõr; J. Rapi,
Bugát Pál Kórház Belgyógyászat, Gyöngyös; P. Vörös, Fõvárosi Önk. Szent István Kórház, Budapest;
G. Winkler, Szent János Kórház II. Belgyógyászati Osztály, Budapest; T. Sydó, Jeruzsálemhegy
Egészségház, Veszprém; M. Hetey, Markhot Ferenc Kórház Egészségügyi Szolgáltató Non, Eger; K.
Simon, Siófok Városi Kórház-Rendelõintézet, Siófok; J. Pénzes, Konszenzus Plusz Kft., Csongrád; P.
Kempler, Semmelweis Egyetem I. Belgyógyászati Klinika, Budapest; B. Bakó, Borsod-Abaúj-Zemplén
Megyei Kórház, Miskolc; Z. Lengyel, Szent Margit Kórház Belgyógyászat-Nephrologia, Budapest; I.
Witmann, PTE ÁOK II. Belgyógyászati Klinika, Pécs; M. Dudás, Pándy Kálmán Megyei Kórház,
Gyula; G. Vándorfi, Veszprém Megyei Csolnoky Ferenc Kórház, Veszprém; J. Takács, Jahn Ferenc
Dél-Pesti Kórház, Budapest; A. Matoltsy, Kanizsai Dorottya Kórház Begyógyászat Kardiológia,
Nagykanizsa; R. Kiss, Állami Egészségügyi Központ Kardiológiai Osztály, Budapest; E. Ladányi, FMC
Miskolci Nefrológiai Központ, Miskolc; A. Gyimesi, Réthy Pál Kórház II. Belgyógyászati Osztály,
Békéscsaba.
India
National Lead Investigators: B. Somaraju, K. M. P. Kumar, and S. Sadikot
K. Parikh, Care Institute of Medical Sciences, Ahmedabad; S. Jain, Totall Diabetes Hormone Institute,
Indore; C. Yajnik, KEM Hospital, Pune; A. Sosale, DIACON Hospital and Research Centre, Bangalore;
P. Shamanna, Bangalore Clinisearch, Bangalore; S. Srikanta, Jnana Sanjeevini Medical Center,
Bangalore; S. Shah, Diabetes Action Centre, Mumbai; A. Srinivas, Vikram Hospital Private Limited,
Mysore; K. M. P.. Kumar, Bangalore Diabetes Hospital Bengaluru, Bangalore; D. Banker, Bankers
Heart Institute, Vadodara; P. Shah, Gujarat Endocrine Centre, Ahmedabad; A. Sharda, Endocrinology
and Diabetes Centre, Bangalore; B. Makkar, Diabetes and Obesity Centre, New Delhi; N. Desai,
Namana Medical Center, Bangalore; N. Rais, Chowpatty Medical Centre, Mumbai; H. Mardikar,
Spandan Heart Institute, Nagpur; A. Mishra, Fortis Flt. Lt. Rajan Dhall Hospital, New Delhi; S. Bhupati,
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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CARE Hospitals, Hyderabad; J. Menon, Mar Augustine Golden Jubilee Hospital, Ernakulam district; S.
Sathe, Dr Shireesh Sathe Clinic, Pune; R. Gupta, Fortis Escorts Hospital, Jaipur; V. Sharma, N.H.I.A.I.
Heart Foundation, New Delhi.
Israel
National Lead Investigators: B. Lewis and I. Raz
M. Darawsha, Diabetes and Lipid department Linn MC, Haifa; T. Herskovits, Western Galillee Hospital
Diabetes Institue, Nahariya; S. Hamoud, Rambam Medical Center Internal Medicine Haifa, Haifa; E.
Nikolsky, Rambam Health care Campus Department of Cardiology, Haifa; I. Raz, Hadassah Ein Karem
M.C diabetes unit, Jerusalem; F. Adawi, Ziv Medical Center Endocrinology Unit, Zefat; R. Zimlichman,
Tel Aviv Community Center, Tel Aviv; D. Tsalihin, Ben Yair Community Clinic Beer-Sheva, Beer
Sheva; J. Wainstein, Wolfson Medical Center Diabetes unit, Holon; E. Klainman, Gefen Cardiac Health
Center, Givatayim; M. Mosseri, Meir Medical Center Division of Cardiology, Kfar Saba; Y.
Yerushalmi, Clalit Tel Aviv Diabetes clinic, Tel Aviv; E. Karnieli, Rambam Medical Center Institute of
Endocrinology, Haifa; H. Knobler, Kaplan Medical Center Metabolic Unit, Rehovot; R. Zimlichman,
Wolfson Medical Center Medicine and Hypertension, Holon; S. Benchetrit, Meir MC Blood pressure
and Nephrology, Kfar Saba; A. Tsur, Clalit Health Services Diabetes clinic Jerusalem, Jerusalem; Y.
Yagil, Barzilai Medical Center Nephrology, Ashkelon; B. Lewis, Lady Davis Carmel Medical Center,
Haifa; S. Atar, Western Galilee Hospital cardiology, Nahriya; I. Beberashvili, Assaf Harofeh Medical
Center Nephrology, Be'er Ya'akov; S. Fuchs, Beilinson Hospital Department of Internal Medicine,
Petach Tikva; N. Stern, Sourasky Medical Center Metabolic Unit, Tel Aviv; A. Pollak, Hadassah
Medical Organization Heart Institute, Jerusalem; T. Chajek-Shaul, Hadassah Hospital Mount Scopus
Internal Medicine, Jerusalem; Y. Rozenman, Wolfson Medical Center Heart Institute, Holon; A. Biton,
Clalit Clinic Dimona, Dimona.
Italy
National Lead Investigators: D. Ardissino and A. Avogaro
D. Ardissino, A.O.U., Parma; E. Bramucci, O. P. San Matteo, Pavia; A. Fiscella, A.O. Cannizzaro,
Catania; V. Grassia, P.O. S. Maria delle Grazie, Pozzouli; P. Piatti, Istituto di Ricovero e Cura a
Carattere Scientifico e Universitario Ospedale San Raffaele, Milano; S. De Cosmo, Casa Sollievo della
Sofferenza, San Giovanni Rotondo; L. Di Lorenzo, Ospedale San Rocco, Sessa Aurunca; P. Merlini,
Ospedale Niguarda Cà Grande, Milano; E. Mannucci, A.O.U. Careggi, Firenze; S. Frontoni, Ospedale
Fatebenefratelli, Roma; R. Trevisan, Opedali Riuniti di Bergamo, Bergamo; L. Zenari, Ospedale Sacro
Cuore Don Calabria, Negrar; A. Avogaro, A.O. di Padova, Padova; C. Lambiase, Ospedale Amico
Gaetano Fucito, Mercato San Severino; A. Salvioni, Ospedale Cardiologico Monzino, Milano; O.
Silvestri, A.O. Cardarelli, Napoli; G. Ambrosio, Ospedale Santa Maria di Terni, Terni; P. Di Bartolo,
A.U.S.L. di Ravenna, Ravenna; L. Fattore, P.O. San Giuseppe, S. Maria Capua Vetere; P. Presbitero,
Istituo Clinico Humanitas, Rozzano; M. Calabrese, A.U.S.L. 4, Prato; R. Evola, Ospedale San Vincenzo
USL 5, Taormina.
Mexico
National Lead Investigators: C. Aguilar-Salinas and A. Garcia-Castillo
M. Alcocer Gamba, Instituto de Corazón de Queretaro, Querétaro; M. Odin de los Ríos Ibarra, Centro
para el Desarrollo de la Medicina y de Asistencia Médica Especializada S.C., Culiacán; E. Cardona
Muñoz, ICLE S.C., Guadalajara; D. Reyes Sánchez, Cardioprevent S.C., Durango; C. Hernandez
Herrera, Centro para el Desarrollo de la Medicina y de Asistencia Médica Especializada S.C. (CDMAE),
Monclova; J. Pérez Ríos, Oaxaca Site Management Organization, Oaxaca De Juárez; E. Bayram Llamas,
Fundación Cardiovascular de Aguascalientes A.C., Aguascalientes; G. Llamas Esperon, Hospital
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Cardiológica Aguascalientes, Aguascalientes; E. García Cantú, Cardiolink Clin Trials S.C., Monterrey;
J. Nuñez Fragoso, Hospital General de Durango, Durango; J. González González, Hospital Universitario
"Dr. José Eleuterio González", Monterrey; G. Rivera Martinez, Hospital General de Tijuana, Tijuana; F.
Padilla Padilla, Consultorios Tarascos, Guadalajara; G. Meléndez Mier, Centro de Investigación Médica
de México (MENTRIALS S.A. de C.V.), México D.F.; D. Herrera Marmolejo, Torre Médica
Providencia, Guadalajara; J. Garza Ruiz, Internal Medicine Clin Trials, Monterrey; N. Caracas Portilla,
Hospital Ángeles de Lindavista, México D.F.; E. López Rosas, Centro de Especialidades Médicas del
Estado de Veracruz (CEMEV), Xalapa; C. Aguilar Salinas, Instituto Nacional de Ciencias Médicas y
Nutrición "Salvador Zubirán", México D.F.; G. Méndez Machado, Médica del Este, Xalapa; J. Chevaile
Ramos, Hospital Central "Dr. Ignacio Morones Prieto", San Luis Potosí; I. Rodríguez Briones,
Cardioarritmias e Investigación S.C., San Luis Potosí.
Netherlands
National Lead Investigators: J. Hoekstra and T. Oude Ophuis
M.W.J. van Hessen, Groene Hart Ziekenhuis locatie Bleuland, Gouda; S. Strikwerda, Amphia
Ziekenhuis locatie Molengracht, Breda; S.H.K. The, Bethesda Ziekenhuis, Hoogeveen; A. Kooy,
Bethesda Diabetes Research Center, Hoogeveen; E. Ronner, Reinier de Graaf Gasthuis, Delft; P.R.
Nierop, Sint Franciscus Gasthuis, Rotterdam; J.J. Remmen, Canisius-Wilhelmina Ziekenhuis, Nijmegen;
B.E. Groenemeijer, Gelre Ziekenhuizen loc. Lukas Ziekenhuis, Apeldoorn; B.J.B. Hamer, Meander
Medisch Centrum, Amersfoort; D.C.G. Basart, Vasculair Onderzoekscentrum Hoorn BV, Hoorn;
H.W.O. Roeters van Lennep, Admiraal de Ruyterziekenhuis, Goes; M. Nieuwdorp, AMC, Amsterdam;
M.P.M. van Dijk, Julius Centrum UMCU, Utrecht; S. Kentgens, Andromed Eindhoven, Eindhoven;
W.W. van Kempen, Andromed Rotterdam, Rotterdam; J. Hoogendijk, Andromed Oost, Velp; W.
Spiering, UMCU, Utrecht; C. Voors-Pette, Andromed Noord, Groningen; V. Köse, Andromed Breda,
Breda; D.E.P. de Waard, Antonius Ziekenhuis, Sneek; F. Gonkel, Saxenburgh Groep Röpcke Zweers
Ziekenhuis, Hardenberg; H.A.H. Kaasjager, Rijnstate ziekenhuis, Arnhem; G.M. Rojas Lingan,
Andromed Zoetermeer, Eindhoven; I. Agous, Andromed Leiden, Leiderdorp; H.J. Kruik, Ziekenhuis
Groep Twente lokatie Almelo, Almelo; B.P.M. Imholz, Tweesteden Ziekenhuis, Waalwijk; M. Pieterse,
Stichting Cardiologie Amsterdam, Amsterdam.
Peru
National Lead Investigators: F. Medina and J. Villena-Chavez
H. Manrique, Centro de Expertos en Diabetes obesidad y nutricion, Lima; F. Medina, Clinica Medica
Cayetano Heredia, Lima; J. Villena, Hospital Nacional Cayetano Heredia, Lima; L. Leon, Clinica Anglo
Americana, Lima; K. Kundert, Centro de Investigacion Ricardo Palma, Lima; J. Minchola, Clinica San
Gabriel, Lima; M. Pinto, Clínica Oftalmolaser, Lima; J. Heredia, Clinica Anglo Americana, Lima; A.
Rodriguez, Hospital Nacional Alberto Sabogal Sologuren, Callao; C. Guerreros, Clinica Internacional,
Lima; P. Berrospi, Clinica El Golf, Lima; C. Zubiate, METABOLICARE, Lima; A. Allemant, Hospital
Nacional Hipolito Unanue, Lima; H. Arbanil, Hospital Nacional Dos de Mayo, Lima; W. Ponciano,
Clinica San Borja, Lima; J. Calderon, Clínica Novocardio, Lima; R. Lisson, Hospital Nacional Edgardo
Rebagliati Martins, Lima; L. Segura, Instituto Medico Miraflores, Lima.
Poland
National Lead Investigators: G. Opolski and K. Strojek
A. Sidorowicz-Bialynicka, Synexus SCM, Wroclaw; R. Sciborski, Zespol Opieki Zdrowotnej w Olawie
SPZOZ, Olawa; I. Fares, NZOZ Medicus, Naklo Nad Notecia; P. Mader, NZOZ Praktyka Dentystyczno
- Internistyczna, Kamieniec Zabkowicki; J. Skierkowska, NZOZ JUDYTA, Skierniewice; T. Stasinska,
NZOZ Regionalna Poradnia Diabetologiczna, Wroclaw; W. Pomiecko, Samodzielny Niepubliczny ZOZ
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Mazur-Med., Mragowo; M. Skorski, SPZOZ w Lecznej Szpital Powiatowy, Leczna; E. Krzyzagorska,
Praktyka Lekarska Ewa Krzyzagorska, Poznan; M. Polaszewska-Muszynska, Bydgoskie Centrum
Diabetologii i Endokrynologii SPZOZ, Bydgoszcz; D. Sowinski, Wojewodzki Zespol Specjalistycznej
Opieki Zdrowotnej we Wroclawiu SP ZOZ, Wroclaw; K. Strojek, Wojewodzka Przychodnia dla
Chorych na Cukrzyce, Zabrze; J. Rosinska-Migda, NZOZ Mig - Med, Wabrzezno; P. Romanczuk,
NZOZ Gdanska Poradnia Cukrzycowa, Gdansk; G. Golebiowski, Szpital Specjalistyczny sw. Wojciecha
Adalberta SP ZOZ, Gdansk; J. Kubica, NZOZ MEDICUS Jacek Kubica, Bydgoszcz; T. Mazurek, I
Katedra i Klinika Kardiologii Akademii Medycznej, Warszawa; L. Wojnowski, Lecznice Citomed,
Torun; D. Pasternak, NZOZ Centrum Zdrowia i Profilaktyki Dabie, Krakow; P. Stachlewski, NZOZ
Eskulap, Koluszki; E. Trzepla, Centrum Medyczne Warszawskiego Uniwersytetu Medycznego,
Warszawa; G. Bogdanowicz, PS ZOZ Wojewodzkie Centrum Medyczne, Opole; A. Uzunow,
Przychodnia Medycyny Rodzinnej Nowy Fordon, Bydgoszcz; I. Potakowska, Zespol Poradni Zdrowie
NZOZ, Sieradz; Z. Miszczyszyn, Prywatny Specjalistyczny Gabinet Lekarski, Przemysl; T.
Waszyrowski, Wojewodzka Stacja Ratownictwa Medycznego w Lodzi SPZOZ, Lodz.
Russian Federation
National Lead Investigators: O. Averkov, M. Ruda, and M. Shestakova
O. Smolenskaya, Hospital #14 Ural State Med Academy Ekat, Ekaterinburg; Y. Lukyanov, State
Medical University n.a. Pavlov, Saint Petersburg; N. Vorokhobina, Chair of Endocrinology Med
Postgrad Academy, Saint Petersburg; Y. Khalimov, Endocrinology NII Med Postgrad Academy, Saint
Petersburg; O. Orlikova, Research Institute of Cardiology Saratov, Saratov; A. Rebrov, SGMU n.a.
Razumovsky Saratov, Saratov; V. Kukharchuk, Atherosclerosis Problems Department Cardiocomplex,
Moscow; S. Boldueva, Cardiology Clinic Mechnikov Med Acad, Saint Petersburg; M. Arkhipov, MO
Novaya Ural State Med Academy Ekat, Ekaterinburg; T. Zhelninova, Out-patient Dep Almazov Federal
Center, Saint Petersburg; E. Pavlysh, Out-patient department #25, Saint Petersburg; M. Antsiferov,
Moscow Endocrinological Dispensary, Moscow; A. Panov, Cardiology Dep Almazov Federal Center,
Saint Petersburg; M. Pavlova, MMA n.a. Sechenov I.M., Moscow; S. Shustov, Military Medical
Academy n.a. Kirov, Saint Petersburg; E. Demchenko, Rehabilitation Lab Almazov Federal Center,
Saint Petersburg; A. Galyavich, KGMU Kazan, Kazan; E. Malakhina, Center of new medical
technology Novosibirsk, Novosibirsk; O. Semenova, Alexandrovskaya City Hospital, Saint Petersburg;
Z. Kobalava, City Clinical Hospital #64, Moscow; M. Shestakova, Institute of Diabetes Scientific Centre
of Endocri, Moscow; S. Kotova, Chair of Endocrinology Mechnikov Med Acad, Saint Petersburg; I.
Gavrisheva, OOO "AVA-Peter", Saint Petersburg; E. Oschepkova, Arterial Hypertension Department
Cardiocomplex, Moscow; Y. Karpov, Angiology Department Cardiocomplex, Moscow; B. Sidorenko,
Central Clinical Hospital, Moscow; O. Kislyak, City Clinical Hospital #79, Moscow; A. Ametov, Chair
of endocrinology RMAPO, Moscow; A. Dreval, Moscow Research Clinical Institute n.a.Vladimirsky,
Moscow; E. Grineva, Endocrinology Inst Almazov Federal Center, Saint Petersburg; A. Mkrtumyan,
MGMSU, Moscow; T. Tyurina, Leningrad Regional Cardiology Dispensary, Saint Petersburg; O.
Sazonova, Novosibirsk State Medical University, Novosibirsk.
South Africa
National Lead Investigators: F. Bonnici and A. Dalby
N. Ranjith, Dr Nash Ranjith Research Centre, Merebank, Durban; L. Burgess, TREAD Research -
Tygerberg Hospital, Parow; H. Nortje, Unit B1-N1 City Mews, Cape Town; L. Distiller, Centre for
Diabetes and Endocrinology, Johannesburg; I. Mitha, Worthwhile Clinical Trials - Lakeview Hospital,
Benoni; R. Moore, 14 Medigate Medical Centre, Umhlanga Rocks; M. Conradie, Endocrine Unit -
Tygerberg Hospital, Parow; A. Horak, Room 3000 2nd Floor - Vincent Pallotti Hospital, Pinelands; S.
Pillay, Dr SR Pillay Practice, Ottawa, Verulam; H. Wellmann, Helderberg Diabates and Medical Centre,
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
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Somerset West, Cape Town; E. Berg, Dr EC Van den Berg Practice - Zuid Afrikaans Hospital, Pretoria;
P. Pillai, Drs Chetty and Pillai Medical Centre, Phoenix; T. Padayachee, Aliwal Shoal Medical Centre,
Umkomaas; C. Corbett, Panorama Medi-Clinic - Suite H01, Cape Town; H. Makan, Suite 6 - Seva
Sadan, Lenasia; J. Wing, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg; Z. Vawda,
Dr ZFA Vawda's Practice, Durban; I. Ebrahim, Suite 309 - Unitas Hospital, Centurion; A. Dalby, Suite
C Ground Floor - Milpark Hospital, Johannesburg; E. Mitha, Suite 3 - Newgate Centre, Johannesburg;
A. Bhorat, Soweto Clinical Trial Centre, Soweto.
Spain
National Lead Investigators: J. Lopez-Sendon and R. Gomis
J. Cruz Fernández, Hospital Universitario Virgen Macarena, Sevilla; C. Muñoz, Hospital General Jerez
de la Frontera, Jerez De La Frontera-Cádiz; J. Bruguera Cortada, Hospital del Mar, Barcelona; A. Castro
Conde, Hospital de Cantoblanco- La Paz, Madrid; C. Calvo, Hospital Universitario de Santiago,
Santiago De Compostela; B. Gil Extremera, Hospital Clínico San Cecilio, Granada; E. Delgado,
Hospital Universitario Central de Asturias, Oviedo; L. Masmiquel, Hospital Son Llàtzer, Palma De
Mallorca; J. García Puig, Hospital Universitario de La Paz, Madrid; L. de Teresa Parreño, Clínica
Mediterranea de Neurociencias, Alicante; D. Mauricio, Hospital Arnau de Vilanova, Lerida; J. Redón,
Hospital Clínico Universitario de Valencia, Valencia; M. Brito, Hosp. Universitario Puerta de Hierro-
Majadahonda, Majadahonda-Madrid; C. Lopez, Centro de Salud El Cristo, Oviedo; J. Segura de la
Morera, Hospital Universitario Doce de Octubre, Madrid;
Sweden
National Lead Investigators: M. Alvarsson and M. Dellborg
C. Linderfalk, Redeby Eksjö, Eksjö; H. Larnefeldt, Rättvikshälsan, Rättvik; A. Olsson, Sthlm Heart
Center, Stockholm; L. Lönneborg, Söråkers vårdcentral, Söråker; M. Ekelund, Hbg lasarett,
Helsingborg; B. Samad, Danderyd, Stockholm; B. Borgencrantz, Capio Läkargruppen AB Örebro,
Örebro; J. Nilsson, Skånes Universitetssjukhus Malmö, Malmö; O. Berglund, Ålidhem Umeå, Umeå; M.
Svensson, SU SS Gbg, Göteborg; T. Mooe, Östersunds sjukhus, Östersund; M. Alvarsson, KS Solna,
Stockholm; D. Curiac, Me3and Gbg, Göteborg; J. Albin, Söråkers vårdcentral, Söråker; E. Angesjö,
Brämhults VC, Brämhult; O. Lannemyr, Länssjukhuset Ryhov, Jönköping; M. Dellborg, SU Östra Gbg,
Göteborg.
Taiwan
National Lead Investigators: C. Chiang and W. Sheu
C. Chiang, Taipei Veterans General Hospital, Taipei; W. Sheu, Taichung Veterans General Hospital,
Taichung; J. Chen, Chang Gung Medical Foundation Kaohsiung Branch, Kaohsiung; K. Tien, Chi Mei
Medical Center, Tainan; K. Ueng, Chung Shan Medical University Hospital, Taichung; W. Lai,
Kaohsiung Medical University Hospital, Kaohsiung; W. Yin, Cheng Hsin General Hospital, Taipei; Y.
Hung, Tri-Service General Hospital, Taipei; K. Shyu, Shin Kong Wu Ho-Su Memorial Hospital, Taipei;
J. Hou, Mackay Memorial Hospital, Taipei; H. Lam, Kaohsiung Veterans General Hospital, Kaohsiung.
Thailand
National Lead Investigators: C. Deerochanawong and P. Sritara
P. Laothavorn, Phramongkutklao Hospital, Bangkok; P. Sritara, Ramathibodi Hospital, Bangkok; S.
Kuanprasert, MaharajNakornChiangMai Hospital, Chiangmai; C. Deerochanawong, Rajavithi Hospital,
Bangkok; W. Khovidhunkit, King Chulalongkorn Memorial Hospital, Bangkok; Y. Benjasuratwong,
Phramongkutklao Hospital, Bangkok; C. Chotinaiwattarakul, Siriraj Hospital, Bangkok; S. Mamanasiri,
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
26
Ratchaburi Hospital, Ratchaburi; S. Suraamornkul, Vajira Hospital, Bangkok; T. Pratipanawatr,
Srinagarind Hospital, Khon Kaen; W. Nitiyanant, Siriraj Hospital, Bangkok.
United Kingdom
National Lead Investigators: S. Heller, A. Barnett, and K. Ray
R. Pieters, Estuary View Medical Centre, Whitstable; C. Strang, Mortimer Surgery, Mortimer - Reading;
B. Bodalia, The Gables Medical Centre, Coventry; A. Middleton, Fowey River Practice, Fowey; T. Hall,
Knowle House Surgery, Plymouth; G. Chapman, Sunbury Health Centre, Sunbury On Thames; J.
Calvert, Waterloo Medical Centre, Blackpool; R. Reed, Westongrove Research Centre Aston Clinton
Surgery, Aston Clinton - Aylesbury; D. Tam, The Circle Practice, Kenton; G. Butcher, Ecclesfield
Group Practice, Ecclesfield, Sheffield; N. Jones, St Chad's Surgery, Midsomer Norton, Bath; A. Takhar,
Wansford and Kings Cliffe Practice, Wansford - Peterborough; W. Turner, Burbage Surgery, Burbage -
Leicester; D. McNally, Ormeau Health Centre, Belfast; O. Corey, The Avenue Surgery, Warminister; J.
Chapman, Widcombe Surgery, Bath; S. Mohr, The Porch Surgery, Corsham, Bath; S. Edwards, Elm
Tree Surgery, Shrivenham, Swindon.
United states of america
National Lead Investigators: D. Bhatt and J. Davidson
A. Ocampo, Future Care Solution, LLC, Miami, FL; D. Kandath, Saratoga Clinical Research, LLC,
Saratoga Springs, NY; Y. Aude, Valley Heart Consultants, McAllen, TX; W. Ervin, InterMed, PA,
Portland, ME; V. Savin, Kansas City VA Medical Center, Kansas City, MO; R. Anderson, VA
Nebraska-Western Iowa Healthcare System, Omaha, NE; R. Littlefield, Palmetto Research Center, LLC,
Spartanburg, SC; M. Oberoi, Central Jersey Medical Research Center, Elizabeth, NJ; G. Platt, George E.
Platt, MD, Green Cove Springs, FL; S. Yazdani, Virginia Cardiovascular Associates, Manassas, VA; R.
Mangoo-Karim, Gamma Clinical Research Institute, Mission, TX; J. Walder, Black Hills Cardiovascular
Research, Rapid City, SD; H. Gogia, Cardiology Consultants of Orange County Medical Group Inc.,
Anaheim, CA; Y. Chandrashekhar, VA Medical Center, Minneapolis, MN; F. Boccalandro, Permian
Research Foundation, Odessa, TX; W. Rogers Jr., University of Alabama Medical Center, Birmingham,
AL; S. Bilazarian, Pentucket Medical Associates, Haverhill, MA; F. Zieve, McGuire VA Medical
Center, Richmond, VA; Y. Siage, Deaconess Clinic, Inc., Evansville, IN; T. O'Connor, American Health
Network of Indiana, LLC, Greenfield, IN; S. Mudaliar, VA San Diego Healthcare System, San Diego,
CA; A. Nikas, Health Texas Research Institute, San Antonio, TX; R. Giusti, Clinical Research of
Central Florida, Winter Haven, FL; R. Glover, Heartland Research Associates, LLC, Newton, KS; S.
Chilka, Midland Clinical Research Center, Midland, TX; W. French, Los Angeles Biomedical Research
Institute at Harbor-UCLA Medical Center, Torrance, CA; E. Roth, Sterling Research Group, Ltd.,
Cincinnati, OH; N. Singh, Atlanta Heart Specialists, LLC, Cumming, GA; R. Christofferson, North
Ohio Research Ltd., Elyria, OH; M. Stich, Westside Center for Clinical Research, Jacksonville, FL; S.
Dagogo-Jack, University of Tennessee Health Sciences Center, Memphis, TN; J. Allison III, Three
Rivers Medical Associates, Columbia, SC; G. Arroyo Zengotita, Georgina Arroyo Zengotita - Medicina
de Familia, Jardines de Loiza, Loiza, PR; R. Ison, Community Health Care, Inc., Canal Fulton, OH; B.
Iteld, Louisiana Heart Center, Slidell, LA; M. Sulistio, University of Texas Southwestern Medical
Center, Dallas, TX; E. Gonzalez, Eastside Clinical Research Associates, Inc., Los Angeles, CA; T.
Gorman, Great Lakes Medical Research, Westfield, NY; E. Hage-Korban, Kore CV Research, Jackson,
TN; R. Reddy, T& R Clinic, PA, Fort Worth, TX; W. Byars, Mountain View Clinical Research, Greer,
SC; M. Antonishen, Northern Michigan Regional Hospital, Petoskey, MI; S. Benjamin, Universal
Research Group, Tacoma, WA; B. First, Ritchken & First MD's, San Diego, CA; J. Rosado, Florida
Heart and Vascular Center, Leesburg, FL; H. Bruschetta, Humberto Rafael Bruschetta, MD, Kingsville,
TX; P. Mehta, Heartland Research Associates, LLC, Wichita, KS; T. Poling, Heartland Research
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
27
Associates, LLC, Wichita, KS; C. Rosendorff, James J. Peters VA Medical Center, Bronx, NY; H.
Kerstein, Howard J. Kerstein, MD, Denver, CO; F. Saba, Professional Health Care of Pinellas, Inc., St.
Petersburg, FL; J. Willis, San Gabriel Clinical Research, Georgetown, TX; K. Adams, Baptist Heart
Specialists, Jacksonville, FL; E. Camilo Vazquez, Central Research Clinic of Puerto Rico, Aguas
Buenas, PR; H. Ellison, Rockdale Medical Research Associates, Conyers, GA; B. Kahn, Overlea
Personal Physicians, Baltimore, MD; D. Kereiakes, The Carl & Edyth Lindner Center for Research &
Education at The Christ Hospital, Cincinnati, OH; S. Powell, PMG Research of Bristol, Bristol, TN; P.
Raskin, University of Texas Southwestern Medical Center, Dallas, TX; K. Smith, Burke Primary Care,
Morganton, NC; S. Varma, Boice-Willis Clinic, P.A., Rocky Mount, NC; F. Whittier, Clinical Research
Limited, Canton, OH; R. Casanova, South East Medical Centre, Oakland Park, FL; S. Isserman, Clinical
Trials of America, Inc., Hickory, NC; W. Kaye, Metabolic Research Institute, Inc., West Palm Beach,
FL; W. McGuinn II, North Ohio Research Ltd., Sandusky, OH; A. Bartkowiak Jr., Blair Medical
Associates P.A., Altoona, PA; L. Dworkin, Rhode Island Hospital, Providence, RI; C. Labrador, Carlos
A Labrador, MD, St. Petersburg, FL; D. Podlecki, Longmont Medical Research Network, Longmont,
CO; M. Popovtzer, Southern Arizona VA Healthcare System, Tucson, AZ; S. Aronoff, Research
Institute of Dallas, P.A., Dallas, TX; C. Ballantyne, Baylor College of Medicine, Houston, TX; E.
Gonzalez Ortiz, Elena Gonzalez-Ortiz, M.D., Cidra, PR; A. Mora III, Southwest Clinic, San Antonio,
TX; T. Pitts, Diverse Clinical Research Center of Chicago, LLC, Chicago, IL; S. Reinhardt, Central
Bucks Cardiology, Doylestown, PA; G. Soucie, Blackfoot Medical Center, Blackfoot, ID; W.
Wainwright, Baptist Heart Specialists, Jacksonville Beach, FL; B. Henson, Essentia Institue of Rural
Health, Duluth, MN; N. Sklaver, Medical Specialists Associated, Dallas, TX; R. Arakaki, University of
Hawaii Diabetes and Endocrinology, Honolulu, HI; J. Brown, Internal Medical Associates of Grand
Island, PC, Grand Island, NE; G. Chalavarya, Florida Cardiology Group, Hudson, FL; R. Chochinov,
Ronald H. Chochinov, MD, Ventura, CA; T. Dixon, Northport Veteran Affairs Medical Center,
Northport, NY; M. Kutner, Suncoast Research Group LLC, Miami, FL; R. Perlman, Associated
Cardiovascular Consultants, Voorhess, NJ; A. Raisinghani, University of California San Diego Medical
Center, San Diego, CA; A. Salacata, Endeavor Medical Research, Alpena, MI; V. Awasty, Harrison
Community Research Center, Cadiz, OH; V. Elinoff, Regional Clinical Research, Inc., Endwell, NY; W.
George, Cadillac Clinical Research, LLC, Cadillac, MI; A. LaRochelle-Gryseels, Sharon Regional
Physician Services, Hermitage, PA; A. Mercado, Stewart Medical Group, Alhambra, CA; G. Miller,
Clinical Research Works, Bristol, CT; M. Qureshi, Michigan Heart, PC, Ypsilanti, MI; A. Steljes,
Steljes Cardiology, PC, Henderson, NV; F. Wefald, Clinical Trials of America, Inc., Smithfield, NC; J.
Wilson, PMG Research of Winston-Salem, Winston-Salem, NC; J. Chinn, VA Southern Nevada Health
Care System, North Las Vegas, NV; R. Chuang, Clinical Research Advantage, Inc/Rita B. Chuang,
M.D., Henderson, NV; A. Comulada-Rivera, Instituto de Endocrinologia, Diabetes & Metabolismo,
Bayamon, PR; I. Hartman, Discovery Clinical Trials, Arlington, TX; P. Narayan, Clinical Research
Institute of Northern Virginia, Burke, VA; T. Pacheco, North Ohio Research, Ltd., Lorain, OH; R.
Weiss, Central Maine Medical Center, Lewiston, ME; J. Beavins, American Health Network of Indiana,
LLC, Franklin, IN; J. Creevy, Intercoastal Medical Group, Sarasota, FL; G. Hamroff, NYU Hudson
Valley Cardiology, Cortlandt Manor, NY; R. Hodson, Providence Heart Clinic at The Oregon Clinic
Gateway, Portland, OR; E. Kosinski, Connecticut Clinical Research, LLC, Bridgeport, CT; P. Krichmar,
Research Physicians Network Alliance, Pembroke Pines, FL; R. Patel, Lycoming Internal Medicine,
Inc., Jersey Shore, PA; R. Schneider, Holy Cross Medical Group, Coral Springs, FL; J. Shapiro,
Philadelphia Health Associates - Adult Medicine, P.C., Philadelphia, PA; D. Sharp, Clinincal Research
Advantage, Inc/Internal Medicine Physicians, PC, Omaha, NE; J. Speer, Clinical Research
Advantage/Colorado Springs Health Partners, Colorado Springs, CO; R. Stegemoller, American Health
Network of Indiana, LLC, Avon, IN; F. Waxman, GSA Medical Research, Deerfield Beach, FL; F.
Young Chang, Pasco Cardiology Center, Hudson, FL; E. Braun, Midtown Medical Center, Tampa, FL;
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
28
F. Eder, United Medical Associates, Binghamton, NY; S. Minor, Austin Heart PLLC, San Marcos, TX;
M. Albert, Acadia Clinical Research, LLC, Bangor, ME; K. Carr, Kenneth W. Carr, M.D., Oceanside,
CA; B. Diaczok, St. Joseph Mercy Oakland, Pontiac, MI; I. Gastman, Waterford Medical Associates PC,
Waterford, MI; V. Gupta, Borgess Research Institute/Borgess Cardiovascular Research, Kalamazoo, MI;
K. Longshaw, Texas Health Physicians Group, Dallas, TX; J. M. Gonzalez-Campoy, MNCOME
Foundation, Eagan, MN; M. Raikhel, Torrance Clinical Research, Lomita, CA; J. Thomas, Medical
University of South Carolina, Charleston, SC; K. Wood, Belleville Family Medical Associates, Ltd.,
Belleville, IL; I. Diab, Paramount Medical Research & Consulting, LLC, Middleburg Hts., OH; J.
Furda, Minneapolis Heart Institute, Baxter, MN; M. Gelernt, Cardiovascular Associates of the Delaware
Valley, PA, Elmer, NJ; M. Halter, Ilumina Clinical Associates, Tyrone, PA; B. House, American Health
Network of Indiana, LLC, Fishers, IN; S. Kaster, Wenatchee Valley Medical Center, Wenatchee, WA;
G. Raad, PMG Research of Charlotte, Charlotte, NC; R. Stamatin, Remedica LLC, Rochester, MI; B.
Barker, Delaware Smith Clinic, Delaware, OH; R. Blonder, Colorado Health Medical Group, Colorado
Springs, CO; R. Bloomberg, Robert J. Bloomberg, MD, PC, Tempe, AZ; R. Burgos Calderon, RCMI-
Clinical Research Center, Rio Piedras, PR; A. Carrol, Center for Thyroid Diseases and Endocrinology,
Beachwood, OH; A. Comerota, Jobst Vascular Center, Toledo, OH; M. Feinglos, Duke University
Medical Center, Durham, NC; D. Henderson, Cardiology Research Associates, Daytona Beach, FL; R.
Kastelic, Ilumina Clinical Associates, Johnstown, PA; L. Stonesifer, Larry D Stonesifer, MD, Federal
Way, WA; J. Talano, Southwest Florida Research, LLC, Naples, FL; P. Ver Lee, EMMC Northeast
Cardiology Associates, Bangor, ME; J. Brosseau, Altru Health System, Grand Forks, ND; W. Clark,
Oregon Health and Sciences University (Oregon Stroke Center), Portland, OR; E. Cohen, Metabolic
Research Institute, Boynton Beach, FL; J. Fialkow, Cardiovascular Research Center of South Florida,
Miami, FL; K. Horton, IMED Healthcare Associated, PLLC, San Antonio, TX; H. Kozman, SUNY
Upstate Medical University, Syracuse, NY; J. McGill, Washington University, St. Louis, MO; C.
Mihills, Southlake Clinical Trials, Southlake, TX; R. Poonawala, Family Practice Centre South, Austin,
TX; K. Shore, Medical Clinic of North Texas, Plano, TX; L. Tejada, St. Luke's Hospital and Health
Network, Bethlehem, PA; R. Torres, Caribbean Clinical Trials, Corp, San Juan, PR; W. Wright, Esse
Health Cardiology Consultants, St. Louis, MO; G. Calatayud, Del Rosario Medical Center, Inc.,
Huntington Park, CA; H. Chandna, Victoria Heart and Vascular Center, Victoria, TX; R. Drozdiak,
Ilumina Clinical Associates, Clymer, PA; R. Fink, Diabetes and Endocrine Associates, La Mesa, CA; R.
Gill, Virginia Commonwealth University, Richmond, VA; M. Glandt, Bronx-Lebanon Hospital Center,
Bronx, NY; D. Gottlieb, Daniel W. Gottlieb, MD, PS, Burien, WA; T. Hack, Primary Care Cardiology
Research, Inc., Ayer, MA; J. Kay, Clinical Research Advantage, Inc/Ridge Family Practice, Council
Bluffs, IA; V. Mansouri, Saint Thomas Research Institute, Nashville, TN; T. McKnight, Prairie Fields
Family Medicine, P.C., Fremont, NE; E. Mostel, Palm Beach Gardens Research Center, LLC, Palm
Beach Gardens, FL; L. Schmidt, Genova Clinical Research, Tucson, AZ; H. Seide, Daytona Heart
Group, Daytona, FL; E. Sonel, VA Pittsburgh Healthcare System, Pittsburgh, PA; R. Taylor, North
Memorial Heart and Vascular Institute, Robbinsdale, MN; M. Velasquez, The George Washington
University (Medical Faculty Associates), Washington, DC; E. Bretton, Albuquerque Clinical Trials,
Inc., Albuquerque, NM; R. Feldman, MediQuest Research Group Inc. at Munroe Regional Medical
Center, Ocala, FL; A. Hartman, Virginia Research Center, LLC, Midlothian, VA; K. Hershon, North
Shore Diabetes and Endocrine Associates, New Hyde Park, NY; C. Leach, Charles R. Leach, MD,
Arlington, TX; E. Martin, Martin Diagnostic Clinic, Tomball, TX; F. Mohiuddin, Apollo Medical
Research, LTD, Niles, IL; Y. Naygandhi, Northwest Med Care P.A., Houston, TX; T. Riske, Hayden
Lake Family Physicians, Hayden Lake, ID; S. Schima, The Cardiac Center of Creighton University,
Omaha, NE; E. R. Uzoaga, Oxford Clinical Research, LLC, Houston, TX; H. Ward, Clinical Research
Works, LLC, Southington, CT; R. Weinstock, SUNY Upstate Medical University, Syracuse, NY; T.
Williams, Texas Health Physicians Group, Irving, TX; A. Altschuller, Hawthorn Medical Associates,
Scirica BM, et al SAVOR-TIMI 53 Heart Failure
29
North Dartmouth, MA; T. Aoki, Aoki Diabetes Research Institute, Sacramento, CA; S. Blumenthal,
Zablocki VAMC, Milwaukee, WI; A. Cash, Ilumina Clinical Associates, Indiana, PA; G. Eisner, Gilbert
Eisner, M.D. Research, Washington, DC; J. Gutmann, Deaconess Clinic, Inc., Evansville, IN; M. Hagan,
Montana Health Research Institute, Inc., Billings, MT; A. Kabour, Cardiovascular Research Center,
LLC, Toledo, OH; T. Markus, The Dayton Heart Center, Dayton, OH; W. McKenzie, M & O Clinical
Research, LLC, Ft. Lauderdale, FL; M. Moursi, Central Arkansas Veteran's Healthcare System, Little
Rock, AR; P. Mystkowski, The Hope Heart Institute, Bellevue, WA; F. Ovalle, University of Alabama
at Birmingham, Birmingham, AL; R. Perkins, Texas Health Physicians Group, Grapevine, TX; L.
Popeil, Magnolia Research Group, Inc., Ocala, FL; R. Saniuk, Clinical Research Advantage,
Inc/Bellevue Family Practice, P.C., Bellevue, NE; Y. Sierra, Dra. Yolanda Sierra Quiñones, Medicina
Interna, Toa Baja, PR; O. Alvarado, Medical Group of Texas, Fort Worth, TX; J. Anderson, Integris
Cardiovascular Physicians LLC, Oklahoma City, OK; M. Bajaj, Baylor College of Medicine, Houston,
TX; R. Blank, Southern Peidmont Primary Care, Presbyterian Novant Heart & Wellness, Monroe, NC;
A. Chu, Amarillo Heart Clinical Research Institute Inc., Amarillo, TX; L. Levinsky, CPL Associates,
LLC, Buffalo, NY; P. Levy, Phoenix Endocrinology Clinic, Ltd., Phoenix, AZ; J. Osborne, State of the
Heart Cardiology, Grapevine, TX; H. Pavon, Internal Medicine, Kidney & Hypertension Center,
Norfolk, VA; D. Sanderlin, Lone Star Clinical Research, Houston, TX; G. Schaer, Rush University
Medical Center, Chicago, IL; S. Zarich, Bridgeport Hospital, Bridgeport, CT; K. Atassi, Northwest
Indiana Cardiovascular Physicians, P.C., Valparaiso, IN; C. Bayron, Interventional Cardiac Consultants,
PLC, Trinity, FL; M. Casagrande, West Houston Area Clinical Trial Consultants LLC, Houston, TX; D.
Das, St. Vincent Heart Clinic Arkansas, Little Rock, AR; M. Gimness, Clinical Research of Central
Florida, Plant City, FL; F. Handel, Schuster Cardiology Associates Inc., Kettering, OH; T. Kinstrey,
Family Medical Clinic, Shreveport, LA; S. Leu, Baptist Heart Specialists, Jacksonville, FL; K. Osei, The
Ohio State University Medical Center, Columbus, OH; J. Soba Nouel, Jose M. Soba Medicina General,
Juncos, PR; Z. Soltani, LSU Health Sciences Center, Department of Internal Medicine, Section of
Nephrology and Hypertension, Kenner, LA; H. Sussman, Iconic Clinical Trials, Pembroke Pines, FL; K.
Chiu, City of Hope National Medical Center, Duarte, CA; R. Duda Jr., Oklahoma Heart Institute, Tulsa,
OK; K. Farnsworth, Northern Indiana Research Alliance, Fort Wayne, IN; M. Lano, Ridgeview
Research, Chaska, MN; F. Lee, Guthrie Clinic Ltd. & Robert Packer Hospital, Sayre, PA; P. Levin,
MODEL Clinical Research, Baltimore, MD; S. Pratt, West Coast Research LLC, San Ramon, CA; R.
Richwine, Texas Health Physicians Group, Fort Worth, TX; L. Ruiz-Rivera, Endocrine Lipid Diabetes
Research Institute, Ponce, PR; J. Turner, Cardiac Wellness Consultants SC (Division of Diverse Clinical
Research Center of Chicago, LLC), Chicago, IL; J. Wood, Texas Health Physicians Group, Richardson,
TX; W. Zigrang, William D. Zigrang MD, Burlingame, CA; H. Baquerizo, Hernan R. Baquerizo, M.D.,
Miami, FL; C. Benitez-Colon, Dr. Carlos Benitez Colon-Medicinia Interna, San Juan, PR; J. Demattia,
JVC Family Medicine, Houston, TX; V. Desai, Charles River Medical Associates, Natick, MA; D. Fitz-
Patrick, East-West Medical Research Institute, Honolulu, HI; S. Goral, University of Pennsylvania,
Philadelphia, PA; A. Odhav, West Houston Area Clinical Trial Consultants LLC, Houston, TX; A.
Prentiss, Prentiss Family Medicine, Colleyville, TX; C. Ruff, Brigham and Women's Hospital, Boston,
MA; W. Wu, Central Cardiovascular Research Foundation, San Antonio, TX; K. Wyne, The Methodist
Hospital Research Institute, Houston, TX; L. Abbott, Lisa G. Abbott, MD, Reno, NV; R. Applegate,
Wake Forest University Baptist Medical Center, Winston-Salem, NC; J. Cabral, Cleveland Clinic
Florida, Weston, FL; P. Kotha, Purushotham and Akther Kotha MD, Inc., La Mesa, CA; P. Ortega,
Central Florida Primary Care, Winter Park, FL; D. Simmons, Central Arkansas Veteran's Healthcare
System, Little Rock, AR.