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ckground Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, myocardial infarction, stroke, heartlure, need for revascularization, nephropathy, and diabetes and its complications. Although angiotensin-II receptorckers (ARBs) have been less extensively evaluated, theoretically they may have protective effects similar to those ofE inhibitors, but with better tolerability. Currently, there is uncertainty about the role of ARBs when used alone or in

mbination with an ACE inhibitor in high-risk populations with controlled hypertension.

bjectives Primary objectives of the ONgoing Telmisartan Alone and in Combination with Ramipril Global End-int Trial (ONTARGET) are to determine if the combination of the ARB telmisartan and the ACE inhibitor ramipril is moreective than ramipril alone, and if telmisartan is at least as effective as ramipril. The Telmisartan Randomized Assess-Nt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND) will determine if telmisartan is superiorplacebo in patients who are intolerant of ACE inhibitors. The primary outcome for both trials is the composite of cardio-scular death, myocardial infarction, stroke, or hospitalization for heart failure.

ethod High-risk patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damagebeing recruited and followed for 3.5 to 5.5 years in 2 parallel, randomized, double-blind clinical trials.

ogress Recruitment from 730 centers in 40 countries for ONTARGET (n 25,620) was completed in July 2003.r TRANSCEND, 5776 patients (out of a projected total of 6000) have been recruited (by May 10, 2004). Baselinetient characteristics are comparable to the Heart Outcomes Prevention Evaluation (HOPE) trial, the basis of the designthe current study, confirming that patients are at high-risk. (Am Heart J 2004;148:5261.)

ardiovascular disease (CVD) is a major and growingbal public and social healthcare problem, account-for 40% to 50% of all deaths in industrialized coun-s and about 25% in other countries.1 Preventive

measures to reduce traditional risk factors, includinghypertension, diabetes mellitus (DM), smoking, andblood cholesterol, can help substantially.2,3 Angioten-sin-converting enzyme (ACE) inhibitors lower angioten-sin II (A-II), elevate levels of bradykinin, and reduceCVD risk in high-risk individuals, resulting in increasedsurvival and prevention of myocardial infarction (MI),strokes, revascularization procedures, heart failure, andnephropathy.46 Recent data suggest ACE inhibitorsmay also prevent DM, dementia, and atrial fibrilla-tion.68

A-II receptor blockers (ARBs) are well-tolerated andeffective blood pressure (BP)-lowering agents,911 and

e Appendix for Writing Group.hringer-Ingelheim GmbH is the main sponsor and GlaxoSmithKline a cosponsor ofONTARGET/TRANSCEND Trials.mitted October 7, 2003; accepted March 26, 2004.rint requests: Koon K. Teo, MD, Room 3U4, McMaster University Medical Centre,0 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.il: [email protected]/$ - see front matter004, Elsevier Inc. All rights reserved.ationale, design, and barge, simple, randomizedlmisartan, ramipril, andigh-risk patients: The Onnd in Combination with Rrial/Telmisartan Randomma10.1016/j.ahj.2004.03.020ine characteristics of 2ials evaluatingeir combination ining Telmisartan Alone

ipril Global Endpointd Assessment Study iny have many of the benefits of ACE inhibitors, with

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American Heart JournalVolume 148, Number 1

The ONTARGET/TRANSCEND Investigators 53rhaps fewer side effects.11,12 The combination of anB with an ACE inhibitor may lead to additive ef-ts.1316 While producing BP reduction similar toer agents, ARBs reduce strokes in high-risk individu-with severe hypertension and left ventricular hyper-phy and increase renal protection in patients withbetic nephropathy.1720 They also reduce cardiovas-lar (CV) death and hospitalization for congestiveart failure in patients with previous heart fail-.14,21,22

erein, we describe the rationale, design, and pa-nt baseline characteristics in 2 randomized trials todress the above concepts: the ONgoing Telmisartanne and in Combination with Ramipril Global End-

int Trial (ONTARGET) and the Telmisartan Random-d AssessmeNt Study in aCE iNtolerant subjects withdiovascular Disease (TRANSCEND).

tionale for telmisartan and ramipril-II, a powerful vasoconstrictor, increases BP, pro-tes vascular and cardiac hypertrophy, and increases

k of CVD events by means of its effects on endothe-l function and atherosclerosis.4,911 Additionally, A-IIreases the inflammatory processes in vessels andcipitates acute coronary syndromes.23,24 ACE inhibi-s reduce A-II but increase levels of bradykinin, al-ugh the clinical importance of the latter is unclear.lockade of angiotensin-receptor subtype 1 (AT1) byBs may also reduce the deleterious effects of A-II,t with a reflex increase in A-II levels and activationother A-II receptors subtypes; the latter may lead toportant antigrowth and antitissue proliferation ac-ns.4,9,25 ACE inhibitors do not completely block thein-angiotensin system (RAS), because A-II is pro-

ced via other nonACE-mediated pathways. ARBso suppress various inflammatory and atherogenesisrkers, such as vascular cell adhesion molecules, tu-r necrosis factor-, and superoxide.24 A combina-n of the 2 agents may be more effective clinicallyn either one alone; recent trials show promisingults.1316,21,22

he recent European Trial on the Reduction of Car-c Events with Perindopril in Patients with Stableronary Artery Disease (EUROPA)26 included patientsth baseline characteristics comparable to those in

Heart Outcomes Prevention Evaluation (HOPE)l.6 Treatment with perindopril was associated witheduction in the composite primary outcome of CVath, MI, or cardiac arrest;26 as in HOPE, these effects

not appear to be explained by BP reductionne.27 The Second Australian Blood Pressure Lower-Trial (ANBP2)28 showed that, in hypertensive pa-

nts, treatment with an ACE inhibitor was associatedth a significant reduction in CVD events compared

a diuretic-based regimen for the same BP reduction. wiE inhibitors can potentially reduce the risk of atrialrillation, cognitive decline, and dementia.7,8

RBs may have similar protective clinical effects asE inhibitors, but may be better tolerated.12,29 Sev-l studies indicate lower rates of cough with ARBs

mpared to ACE inhibitors; however, recent studiesgest that the rates of elevated creatinine and potas-m levels, or angioedema, may be consider-le.13,14,21,22,30 Despite these concerns, in 3 trials onpertensive patients with DM and various degrees ofal impairment, ARBs (irbesartan or losartan) signifi-tly reduced serum creatinine and/or development

end-stage renal failure, compared to placebo or am-ipine, again with similar levels of BP control.17,19,20

e Losartan Intervention For Endpoint reductionFE) trial18 compared losartan with atenolol in indi-uals with severe hypertension and electrocardio-phic evidence of left ventricular hypertrophy; losar-significantly reduced the primary composite end

int of CV mortality, stroke, or MI, although bothnts produced substantial and comparable BP reduc-

ns. Losartan significantly reduced the incidence ofw-onset DM.18

he Candesartan in Heart Failure Assessment in Re-ction of Mortality (CHARM) program13,14,21,22 con-ts of 3 separate trials evaluating the effects of a com-ation of ACE inhibitor and an ARB, candesartan

HARM-Added), candesartan alone in ACE-intoleranttients (CHARM-Alternative) and candesartan in pa-nts with preserved LV function (CHARM-Preserved).ese further confirm the benefits of candesartan inart failure patients, and show clearly that candesar-

(1) is highly efficacious when used alone on ackground of other proven therapy in heart failuretients with LV systolic dysfunction, and (2) addi-nal benefits can be obtained when added to an ACEibitor in these patients, but (3) in CHARM-Pre-ved, the effect of added candesartan on the primarytcome of CV death and heart failure hospitalizationless clear.he Valsartan in Acute Myocardial Infarction Trial

ALIANT),30 which enrolled patients with heart fail-or left ventricular dysfunction during the immedi-postinfarction period, compared the effects of cap-ril and valsartan. Valsartan alone was similar totopril alone. The combination of captopril and val-

tan was not superior to captopril alone but hadre drug-related adverse effects, particularly hypoten-n, renal dysfunction, and hyperkalemia. In the un-ble situation after MI, the combination may haveered BP too aggressively.he inconsistency between the results of CHARM

d VALIANT and uncertainty concerning the protec-e effects of ARBs when used alone or in combina-n with an ACE inhibitor in less high-risk populations

th controlled hypertension form the basis for the

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American Heart JournalJuly 2004

54 The ONTARGET/TRANSCEND Investigatorssent study, which will also explore the impact ofBs on DM, atrial fibrillation, and dementia. The ON-RGET and TRANSCEND trials address these issues inh-risk individuals with baseline BP considered to bethe normal range.

udy designjectiveshe ONTARGET and TRANSCEND trials compare anE inhibitor versus ARB versus a combination of bothhigh-risk individuals. The patients enrolled alreadyeive a number of proven therapies. The primaryjectives of ONTARGET are to determine if (1) thembination of telmisartan 80 mg daily and ramipril 10

daily is more effective in reducing the compositetcome of CV death, MI, stroke, or hospitalization forF than ramipril 10 mg alone; and (2) whether telm-

igure 1

dy design and outcomes. DM, Diabetes mellitus; BP, bloodssure; Tel, telmisastan; Ram, ramipril; Pla, placebo; CV, cardio-cular; MI, myocardial infarction; TIAs, transient ischemic at-ks; LVH, left ventricular hypertrophy.rtan 80 mg daily alone is at least as effective as (ie, ramot inferior to) ramipril 10 mg alone daily. The pri-ry objective of TRANSCEND is to determine if treat-nt with telmisartan 80 mg daily is superior to pla-

bo in patients who are intolerant of ACE inhibitors.umber of secondary and other objectives (Figure 1)

d 7 embedded substudies (Table I) are included.

mple size and data analysis issuesample size calculations are based on the event ratesthe ramipril group of HOPE, in which the hazarde was 0.0397 per year. The 2 objectives of ONTAR-T are being addressed by showing that the hazardio of the combination versus ramipril is 1 (superi-ty) and that the hazard ratio of telmisartan versusipril is less than a predefined margin , a value

suring that most of ramiprils effect versus placeboretained by telmisartan (noninferiority).

etermination of was based on the results of thePE trial.6 In HOPE, the hazard ratio for ramipril 10versus placebo with respect to the same composite

d point was 0.775. Risk reductions of the same mag-ude have been observed in other studies comparingE inhibitors with placebo,5,31 thus assuring consis-cy with the HOPE results. Taking a conservative

proach, the 40th percentile (0.794) rather than theserved hazard ratio is chosen as a more robust refer-ce to describe the ramipril effect. The risk reductionramipril versus placebo is translated into an excess

k of placebo versus ramipril of 1.26. Thus, a of3 assures that telmisartan retains at least half of the

able I. Summary of substudies

e of substudy Objectives

logical samplesollection for centralaboratory analysis

Collection and storage of blood samples atbaseline for analysis of novel risk factorsand markers for cardiovascular disease.

l glucose toleranceest (OGTT)

OGTT carried out in all TRANSCEND patientswho are not known to have DM atbaseline, 2 years follow-up and close-out.In a subsample, insulin sensitivity will bedetermined.

lth economics To determine resources used and directmedical costs associated with clinicalevents; to evaluate the impact of treatmentprogram on patient preference.

bulatory bloodressure monitoring

To determine prognostic value of ambulatoryblood pressure monitoring; to determinethe effects of study medications.

rdiac MRI To examine effects of treatment on cardiacstructure and function.

erial Stiffness To determine efficacy of telmisartan onarterial stiffness, estimated by pulse wavevelocity.

ctile dysfunction To examine the effects of treatment on erectiledysfunction.ipril effect if the upper limit of the 95% CI of the

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The ONTARGET/TRANSCEND Investigators 55zard ratio of telmisartan vs ramipril is less than this2 Once noninferiority has been confirmed, it is thenssible to evaluate if telmisartan is superior toipril.oth hypotheses will be tested using group sequen-

l tests at a 1-sided level of 0.025, with 3nned interim analyses. With the original plannedple size of 7800 patients per group, to be recruited

thin 2 years, and an average observation period ofyears, a power of 93% will be achieved in the su-

riority setting, if the respective hazard ratio is 0.87;the noninferiority setting, the power will be 89% if

respective hazard ratio is 1.00. For TRANSCEND,ilar assumptions apply as for ONTARGET. With

00 patients per group, a 94% power will beieved for the alternative that the hazard ratio for

misartan versus placebo is 0.81.ll analyses will be intention to treat and include alldomized patients. The primary analysis will be timeevent, counting the first occurrence of any compo-nt of the composite outcome.33 Secondary outcomesll be explored in a similar manner. Analyses for con-tency of treatment effects in prespecified subgroupsll be explored with respect to the primary and sec-dary outcomes by the Cox regression model, utiliz-

tests for interaction in order to examine the consis-cy of the results.34 The prespecified subgroups are, age (65 vs 65 years), presence or absence ofdisease, DM, hypertension or microalbuminuria,

d history of coronary artery disease, MI, cerebrovas-lar disease, or peripheral vascular disease.

tient eligibility criteriancluded are patients with coronary artery, periph-l vascular, or cerebrovascular disease or high-risk

with end-organ damage. Patients with known in-erance to ACE inhibitors are randomized to telmisar-

or placebo in the TRANSCEND trial. Eligibility cri-ia are listed in Table II. Therefore, in general,ysicians should be willing to randomize most pa-nts to the ACE inhibitor ramipril, the ARB telmisar-, or their combination, and in TRANSCEND to tel-sartan or placebo.

n-in and randomizationatients who fulfill the initial eligibility criteria enter

ter written informed consent) a single blind run-inriod (Table III); those who remain eligible are ran-mized via a 24-hour service computerized voice-acti-ed telephone call to a central office in Hamilton,tario, Canada. After randomization, follow-up visitsmade at 6 weeks, 6 months later, and then every 6

nths until closeout. Figure 1 and Table III summa-

e the study schedule.usion criteriandividuals 55 years of age with 1 of the followingoronary artery disease Previous myocardial infraction (2 days

post uncomplicated MI)Stable angina or unstable angina 30

days before informed consent and withdocumented evidence of multivesselcoronary artery disease

Multi-vessel PTCA 30 days beforeinformed consent

Multi-vessel CABG surgery 4 yearsbefore informed consent, or withrecurrent angina following surgery

eripheral artery disease Previous limb bypass surgery orangioplasty

Previous limb or foot amputationIntermittent claudication, with ankle:arm

BP ratio 0.80 on at least 1 sideSignificant peripheral artery stenosis

(50%) documented by angiographyor non-invasive testing

erebrovascular disease Previous strokeTransient ischemic attacks 7 days and1 year before informed consent

iabetes mellitus High-risk diabetics with evidence of end-organ damage

lusion criteriaedication use Inability to discontinue ACE inhibitors or

ARBKnown hypersensitivity or intolerance to

ACE inhibitors or ARB (patientintolerant of ACE inhibitor can beenrolled in TRANSCEND)

ardiovascular disease Symptomatic congestive heart failureHemodynamically significant primary

valvular or outflow tract obstructionConstrictive pericarditisComplex congenital heart diseaseSyncopal episodes of unknown etiology3 months before informed consent

Planned cardiac surgery or PTCA 3months of informed consent

Uncontrolled hypertension on treatment(eg, BP 160/100 mm Hg)

Heart transplant recipientStroke due to subarachnoid hemorrhage

ther conditions Significant renal artery diseaseProteinuria (TRANSCEND only)Hepatic dysfunctionUncorrected volume or sodium depletionPrimary hyperaldosteronismHereditary fructose intoleranceOther major noncardiac illness expected

to reduce life expectancy or interferewith study participation

Simultaneously taking anotherexperimental drug

Significant disability precluding regularfollow-up visits

Unable or unwilling to provide writteninformed consent

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56 The ONTARGET/TRANSCEND Investigatorsdy organizationn order to randomize 28,400 patients rapidly, thedy network includes over 700 centers from 40untries, with leadership provided through nationalordinators. The trials are coordinated by the Popula-n Health Research Institute (PHRI), McMaster Uni-rsity, Hamilton, Canada; Oxford University, Unitedgdom; and University of Auckland, New Zealand.

e overall responsibility for the conduct of the trialss with the Steering Committee (see Appendix). Anerations Committee, with representatives from theRI Project Office, the Regional Coordinating Cen-s, and the sponsor, meets regularly.

ndardization and monitoring of data qualitytudy staff underwent training sessions and site visitsensure uniform procedures. A 24-hour toll-free tele-

able III. Study summary

ntification and invitationIdentify eligib

ibility and run-in visit (week 3) Check patient eligObtain informed cConduct physicalCheck urine usingCollect blood and

serum potassiumComplete Run-in CDispense run-in mONTARGETRamipril 2.5 mg Ramipril 2.5 mg Ramipril 5 mg TRANSCENDTelmisartan placeb

domization visit (week 0) Check complianceObtain ECG andArrange for bloodArrange for a ser

randomizationPhone AreS for paONTARGETFirst 2 weeks: telm

placebo 80 mgRemainder of trial

telmisartan placTRANSCENDTelmisartan 80 mgComplete and datMake follow-up a

low-up (at 6 weeks, 6 months, and then everymonths until planned close-out in July 2007)

Check for all cardArrange for ECG,Dispense study meArrange for next fComplete follow-u

OfficeMail discharge su

in the ONTARGone number is available to address any questions adated to study procedures. A manual of operationsvides a detailed outline of the protocol. The caseort forms (CRFs) are simple and easy to follow,

th instructions printed on the reverse sides.ata forms are optically read by DataFax system

linical DataFax Systems, Hamilton, Ontario, Canada)th accuracy and speed sufficient to allow routinenitoring of recruitment rates, patient schedules,

d medication reordering. The original forms areed to the project office on toll-free numbersthin 3 days of patient visits. Project Office staffrify the computer-read data. Queries and qualityntrol reports are faxed to the investigator within

eeks.

ntral event adjudicationrimary study outcomes are adjudicated by a central

ients and invite patient to participate and send patientinformation pamphlet if needed

ee Table II)

tion(exclude from TRANSCEND if proteinuria 1)

amples for local and central laboratory testing and arrange for areatinine measurement during final week of run-in

ns (single blind) as follows:

ing telmisartan placebo 40 mg for 3 days, thenartan 40 mg for 7 days, thentan 40 mg for 11 to 18 days

g for 1 week, followed by telmisartan 80 mg daily for 2 to 3 weeksn-in drugs and confirm eligibilityMMSE and other assessment as required

ion for local and central laboratory testing where requiredssium and creatinine measurement during fifth week of

ndomization and dispense allocated study medication from study kit

80 mg ramipril placebo 5 mg OR ramipril 5 mg telmisartanmisartan 80 mg ramipril 5 mgrtan 80 mg ramipril placebo 10 mg OR ramipril 10 mg mg OR temisartan 80 mg ramipril 10 mg

acebo 80 mg for duration of trialF for randomization visitent for 6 weeks ( 1 week)lar events and all hospitalizationsssessments, local and central blood and urine tests as required

ns and encourage compliancep visit ( 1 month)and, as needed any hospitalization and events reports to Project

s, laboratory results/reports, chest X-ray reports, ECG, CT scans etcNSCEND envelope when requestedrelprorepwi

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The ONTARGET/TRANSCEND Investigators 57tion supporting the diagnoses (eg, electrocardio-phic and cardiac enzyme results for MI or com-ted tomography scans for strokes). Additionalormation may be requested. If there is full agree-nt between the central adjudicator and the clinical

nter, the event will be confirmed. If there is still dis-eement, the events will be reviewed by the Eventsjudication Committee. A random 10% of the eventsnfirmed by the central adjudicator will be reviewedthe Events Adjudication Committee. All unrefuted

ents will be included in the analysis.

rious adverse events and unblindingll serious events, including primary, secondary, ander study outcomes in the randomized period, areorted to the Project Office. Those judged to be seri-

s, related to the study medications, and unexpectedexpeditiously reported to the study sponsor fororting to the regulatory authorities, where required.serious adverse events are tabulated and reviewed

riodically by the independent Data and Safety Moni-ing Board. Central emergency unblinding is avail-le when necessary by a telephone call to the Projectfice.

ics and patient confidentialityhe protocol has been approved by regulatory au-rities and the ethics review committees of local

rticipating institutions in all countries. All patientsvide written informed consent. Their confidentiality

protected.

erim analysis and data monitoringhe independent Data Safety and Monitoring Boardets twice yearly; 3 formal interim analyses arenned, when 25%, 50%, and 75% of the events haveen collected. A modification of the Haybittle-Petoproach35 will be used to guide in decisions regard-

early termination. This modification utilizes aundary of 4 SD in the first half of the trials and 3 SDthe second half as a guide to efficacy. For safety, thepective boundaries are at 3 and 2 SD. Additionally,boundary should remain crossed on 2 consecutive

ks, 4 to 6 months apart.

ial progress and baselinearacteristicsatients have been recruited from 730 centers in 40

untries. Recruitment into ONTARGET closed in July03. As of May 10, 2004, 25,620 patients have beendomized into ONTARGET and 5776 into TRAN-

END; recruitment will be completed by May 2004.ble IV shows the key patient baseline characteristics

each of the trials compared to the HOPE trial. In ofneral, patient characteristics are generally similar toPE except that the current trials have greater eth-diversity (as a result of inclusion of Asian coun-s), individuals are slightly older, and the proportion

able IV. Key baseline characteristics (as of May 10, 2004)

riable ONTARGET TRANSCEND HOPE

. 25,620 5776 9,541e (y) 66.4 66.9 65.9le (%) 73.3 57.1 73.3tory (%)I 48.7 46.2 52.8

table angina 34.8 36.9 55.8nstable angina 14.8 14.9 25.7ABG 22.1 18.9 26.0TCA/PCI 28.9 26.0 18.0troke/TIA 20.7 22.1 10.8arotid endarterectomy 2.8 1.8 2.7eripheral artery surgery 5.8 4.2 6.2ntermittent claudication 11.8 10.1 15.9

factors (%)ypertension 68.3 75.9 46.5M 37.3 35.4 38.3mokingCurrent 12.5 9.8 14.1Former 51.9 43.4 57.1

dications (%)CE inhibitors 57.5 58.1 11.6ngiotensin II blockers 8.6 29.9 -Blockers 56.9 57.9 39.5iuretics 27.9 32.9 15.1itrates 29.2 33.9 31.1iltiazem/verapamil 9.7 9.9 27.1ther calcium-channelblockers

23.8 31.2 20.5

SA 75.6 74.7 73.6iclopidine 2.5 2.6 4.8lopidogrel 8.5 8.1 ral anticoagulants 7.6 7.1 3.8

tatins 60.7 54.5 28.9nsulin 10.4 7.2 11.7

ral hypoglycemics 25.0 23.8 21.8strogen (in females) 8.2 7.2 10.8strogen progesterone(in females)

2.2 2.1 2.6

sical exameart rate (beats/min) 67.9 68.8 68.6P at run-in (mm Hg) 143/82 142/82 139/79P at randomization (mmHg)

134/77 135/78

MI 28.2 28.3 27.7aist-hip ratio 0.9 0.9 0.9

oratory resultsreatinine (mol/L) 94.3 92.6 96.9otassium (mmol/L) 4.4 4.4 4.4otal cholesterol (mmol/L) 4.9 5.1 DL-cholesterol (mmol/L) 1.3 1.3

DL-cholesterol (mmol/L) 2.9 3.0 riglycerides (mmol/L) 1.7 1.8 patients with cerebrovascular disease is higher com-

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58 The ONTARGET/TRANSCEND Investigatorsred to HOPE. In TRANSCEND, the proportion ofmen is higher than in ONTARGET or HOPE. Theof antiplatelet agents is similar, but the use of ther-

ies known to reduce mortality/morbidity such aslockers or lipid-lowering therapy is higher in the

rrent trials. The mean BP at run-in was 143/82 mmand at randomization was 134/77 mm Hg in ON-

RGET; in TRANSCEND, it was 142/82 and 135/78,pectively (note that in a proportion of patients, anE inhibitor or ARB was stopped at the beginning of-in). These values are similar to the entry BP of

9/79 mmHg in HOPE.

scussionhe use of 2 parallel trials in this program will reli-

ly assess the comparative effects of an ARB, telmisar-, under a number of different circumstances. Theects of an ARB can be assessed in 2 ways. One wayto compare telmisartan versus ramipril in patientsth proven indications for an ACE inhibitor, as ituld be unethical to withhold an ACE inhibitor (or atentially similar agent). This is an indirect assess-nt of efficacy and depends on the assumptions thatthe circumstances of the current trial are similar tovious trials that documented the value of ACE in-itors (constancy), and (2) the design of the study

able to detect differences (sensitivity). There arevantages in using a noninferiority design, but whenng such a design to compare telmisartan withipril, their relative efficacy can only be assessed to

imited extent (because of the width of the CI) un-s extremely large trials are carried out (or telmisar-is found to be superior). Even with this trial,

ich is designed to ensure that at least 50% of thenefits of ramipril versus placebo are preserved as-

ing that both treatments are identical, a samplee of 7800 per group (or 15,600 for a 2-arm trial) iseded. This is nearly 1.5 times the size of a trial com-ring ramipril versus placebo or telmisartan versuscebo to detect a relative risk reduction of about%. If 80% of the benefits of ramipril versus placebod to be guaranteed (which would translate into aninferiority margin of 1.052), then the group sizeuld have to be around 46,000 patients. Such studiescurrently not practicable.n alternative method of evaluating whether telmis-

an is better then placebo is to test this question inividuals in whom ACE inhibitors cannot be usedt who are otherwise similar. Thus, by conducting arallel trial with an identical design on those patientso are ACE-inhibitor intolerant, a direct evaluation of

misartan versus placebo is possible. A positive out-me of this trial would also confirm the sensitivity of

design, thereby confirming a potential noninferior-

claim of telmisartan versus ramipril. However, weve to assume that ACE-inhibitor intolerance is unre-ed to responsiveness to ARBs, an assumption that

only be validated at the end of the study. There-e, by conducting the 2 parallel studies, a range ofmplementary information on the relative efficacyd safety of each of 2 drugs and their combination

be obtained.s designed, the baseline characteristics of patients

the trials are comparable to those in the HOPEdy,6 with patients who are at high risk and have ain the normal range. A high proportion of the

tients are receiving other drugs that could lower BP,hough a significant proportion of these are for sec-dary prevention rather than BP control. Therefore,will be evaluating the effects of telmisartan over

d above good BP control and in addition to otheratments. Additionally, 76% patients receive aspirind 60% lipid-lowering medications (statin), a relativelyh rate of use of therapies with proven efficacy.n addition to evaluating the effects of telmisartand ramipril on the CVD outcomes, there are a num-r of other outcomes that are novel, including effectsatrial fibrillation and cognitive decline. The 7 sub-dies embedded in the main trials are designed totain insights into mechanisms of the effects of thegs, and additional benefit of treatments (eg, onctile dysfunction). The stored blood samples canvide unique material for the study of cardiovascular

idemiology and the impact of a range of biologicalrkers on CVD. Since the trials are being conducted40 countries involving all the inhabited continentsthe world, they will provide a unique opportunityexamine the practice patterns and the epidemiologychronic diseases in a large diverse group of individ-ls.

ferencesMurray CJL, Lopez AD. Alternative projections of mortality anddisability by cause 1990-2020: Global Burden of Disease Study.Lancet 1997;349:1498504.Martin MJ, Hulley SB, Browner WS, et al. Serum cholesterol, bloodpressure and mortality: implications from a cohort of 361,662men. Lancet 1986;ii:93346.Yusuf S. Two decades of progress in preventing vascular disease.Lancet 2002;360:23.Lonn E, Yusuf S, Jha P, et al. Emerging role of angiotensin-convert-ing enzyme inhibitors in cardiac and vascular protection. Circula-tion 1994;90:205669.Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor ther-apy in patients with heart failure or left-ventricular dysfunction: asystematic overview of data from individual patients. Lancet 2000;355:157581.The HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on CV events in high-risk patients.

N Engl J Med 2000;342:14553.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

ApW

KFarPo

OpS

I. CT.

SteS

chaardT.Schnat

DaJ


The ONTARGET/TRANSCEND Investigators 59Pedersen OD, Bagger H, Kolber L, et al. Trandolapril reduces theincidence of atrial fibrillation after acute MI in patients with leftventricular dysfunction. Circulation 1999;100:37680.The PROGRESS Collaborative Group. Effects of blood pressurelowering with perindopril and indapamide on dementia and cog-nitive decline in patients with cerebrovascular disease. Arch InternMed 2003;163:106975.Hollenberg NK, Sever PS. The past, present and future of hyper-tension management: a potential role for AT1-receptor blockers. JRenin Angiotensin Aldosterone Syst 2000;1:510.Strawn WB, Dean RH, Ferrario CM. Novel mechanisms linkingangiotensin II and early atherogenesis. J Renin Angiotensin Aldo-sterone Syst 2000;1:1117.Bunier M, Brunner HR. Angiotensin II receptor antagonists. Lancet2000;355:63745.Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan comparedwith captopril on mortality in patients with symptomatic heart fail-ure: randomised trialthe Losartan Heart Failure Survival StudyELITE II. Lancet 2000;355:15827.Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartanon mortality and morbidity in patients with chronic heart disease:the CHARM-Overall programme. Lancet 2003;362:75966.McMurray JJV, Ostergren J, Swedberg K, et al. Effects of cande-sartan in patients with chronic heart failure and reduced left-ven-tricular systolic function taking angiotensin-converting-enzyme in-hibitors: the CHARM-Added Trial. Lancet 2003;362:76771.McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesar-tan, enalapril, and their combination in congestive heart failure:Randomized Evaluation of Strategies for Left Ventricular Dysfunc-tion (RESOLVD) Pilot Study. Circulation 1999;100:105664.Cohn JN, Tognoni G, for the Valsartan Heart Failure TrialInvestigators. A randomized trial of the angiotensin-receptorblocker valsartan in chronic heart failure (Val-HeFT). N Engl J Med2001;345:166775.Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan onrenal and cardiovascular outcomes in patients with type 2 DM andnephropathy. N Engl J Med 2001;345:8619.Dahlof B, Devereux R, Kjeldsen SE, et al. Cardiovascular morbidityand mortality in the Losartan Intervention For Endpoint reduction inhypertension study (LIFE): a randomised trial against atenolol. Lan-cet 2002;359:9951003.Parving H-H, Lehnert H, Brochner-Mortensen J, et al. The effect ofirbesartan on the development of diabetic nephropathy in patientswith type 2 diabetes. N Engl J Med 2001;345:8708.Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of theangiotensin-receptor antagonist irbesartan in patients with nephropa-thy due to type 2 diabetes. N Engl J Med 2001;345:85160.Granger CB, McMurray JJV, Yusuf S, et al. Effects of candesartanin patients with chronic heart failure and reduced left-ventricularsystolic function intolerant to angiotensin-converting-enzyme inhibi-tors: the CHARM-Added Trial. Lancet 2003;362:7726.Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan inpatients with chronic heart failure and preserved left-ventricularejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:77781.Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al. Expression of an-giotensin II and interleukin 6 in human coronary atheroscleroticplaques: potential implications for inflammation and plaque insta-bility. Circulation 2000;101:13727.Navalkar S, Parthasarathy S, Santanam N, et al. Irbesartan, an

angiotensin type I receptor inhibitor, regulates markers of inflam- Wimation in patients with premature atherosclerosis. J Am Coll Car-diol 2001;37:4404.Stoll M, Steckelings UM, Paul M, et al. The angiotensin AT2-recep-tor mediates inhibition of cell proliferation in coronary endothelialcells. J Clin Invest 1995;95:6517.The European Trial on Reduction of Cardiac Events with Perindo-pril in Stable Coronary Artery Disease Investigators. Efficacy ofperindopril in reduction of cardiovascular events among patientswith stable coronary artery disease: randomized, double-blind,placebo-controlled, multicentre trial (the EUROPA study). Lancet2003;362:7828.Sleight P, Yusuf S, Pogue J, et al. Blood-pressure reduction andcardiovascular risk in the HOPE study. Lancet 2001;358:21301.Wing L, Reid C, Ryan P, et al. A comparison of outcomes withangiotensin-converting-enzyme inhibitors and diuretics for hyper-tension in the elderly. N Engl J Med 2003;348:58392.Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartanversus captopril in patients over 65 with heart failure (Evaluationof Losartan in the Elderly Study, ELITE). Lancet 1997;349:74752.Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, capto-pril, or both in myocardial infarction complicated by heart failure,left ventricular dysfunction, or both. N Engl J Med 2003;349:1893906.Teo KK, Yusuf S, Pfeffer M, et al. Effects of long-term treatmentwith angiotensin-converting-enzyme inhibitors in the presence orabsence of aspirin: a systematic review. Lancet 2002;360:103743.Hasselblad V, Kong DF. Statistical methods for comparison to pla-cebo in active-control trials. Drug Inf J 2001;35:43549.Kaplan EL, Meier P. Nonparametric estimation from incompleteobservations. J Am Stat Assoc 1958;53:45781.Cox DR. Regression models and life-tables. J R Stat Soc 1972;34:187220.Peto R, Pike MC, Armitage P, et al. Design and analysis of ran-domized clinical trials requiring prolonged observation of eachpatient, II: analysis and examples. Br J Cancer 1977;35:139.

pendixriting Groupoon Teo, Salim Yusuf, Peter Sleight, Craig Anderson,

ouk Mookadam, Barbara Ramos, Lutz Hilbrich, Janicegue, Helmut Schumacher

erations Committee. Yusuf (Chair), P. Sleight, C. Anderson, K. Teo, B. Ramos,opland, L. Richardson, J. Murphy, L. Hilbrich, M. Haehl,

Meinicke, G. Schmidt, K. Martin, H. Schumacher

ering Committee. Yusuf (Chair and Principal Investigator), P. Sleight (Co-ir), Craig Anderson (Co-chair), K. Teo, B. Ramos, L. Rich-son, J. Murphy, L. Hilbrich, A. Riedel, M. Haehl, K. Martin,Meinicke, G. Schmidt, H. Schumacher, F. Zhao, R.mieder, T. Unger, G. Mancia, R. Asmar, National Coordi-ors as listed below

ta and Safety Monitoring Board. Cairns (Chair), J. Chalmers, M. Gent, C.H. Hennekens, L.

lhelmsen, J. Wittes

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60 The ONTARGET/TRANSCEND Investigatorsjudication Committee. Dagenais (Chair), I. Anand, N. Anderson, P. Auger, A.

ezum, J.T. Bigger, V. Bernstein, P. Linz, E. Lonn, A. Mag-ni, J. Mann, A. Panju, K. Yusoff, all national coordinators

bstudies and Publication Subcommittee. Sleight (Chair), A. Dans, L. Hilbrich, J. Probstfield, K.

o, T. Unger

ordinating Centersamilton (S. Yusuf, K. Teo, B. Ramos, I. Copland); OxfordSleight, L. Richardson); Auckland (C. Anderson, J. Mur-

y)

ncipal Investigators by CountryC National Coordinator; NL National Leaderrgentina: R. Diaz (NC), E. Paolasso (NL), R.A. Ahuad Guer-

o, M. Amuchastegui, M. Bendersky, J. Bono, A. Caccavo,. Cartasegna, C.R. Castellanos, C.A. Cuneo, J. Fuselli, E.sbani, M.A. Hominal, J. Humphreys, F. Inserra, C. Killinger,Kuschnir, C. Majul, E.M. Marzetti, R. Nordaby, A.D. Orlan-i, J.C. Pomposiello, M. Rodrguez, R. Sanchez, C.M.J. Serra,

L. Vicoustralia: G. Jennings (NC), J. Amerena, L. Arnolda, C.ney, G. Aroney, P. Aylward, C. Bladin, B. Chambers, A.

rbett, D. Crimmins, D. Cross, S. Davis, J. Frayne, R. Hen-ks, G. Herkes, A. Hill, L. Howes, B. Jackson, I. Jeffery, J.rrasch, T, Marwick, K. Narayan, D. Owensby, D. Rees, A.ssell, R. Schwartz, B. Singh, S. Thambar, P. Thompson, J.ites, W. Walsh, J. Watson, R. Wattsustria: B. Eber (NL), J. Bonelli, J. Hohenecker, G. Steurer,WeihselgiumR. Fagard (NC), I. Bekaert, P. Chaumont, P.

eron, A. Clement, V. Crasset, J. Degaute, P. Dendale, S.hot, S. Hellemans, M. Herssens, G. Heyndrickx, P. Laloux,. Lesseliers, M. Quinonez-Venegas, W. Van Mieghem, J.

n Overschelde, G. Vanhooren, G. Vervoort, B. Wollaertrazil: L. Piegas (NC), A. Avezum (NL), J.A. Abrantes, D.aganijan, L.C. Bodanese, A.C. Carvalho, M. Coutinho, J.P.

eves, M.Z Fichino, R.J. Franco, V. Jardim, P.E. Leaes, L.N.ia, J.A. Marin-Neto, R.L. Marino, T.L. Martinez, D. Mion Jr.,Oigman, R.C. Pedrosa, E.A. Pelloso, C.A. Polanczyk, A.elo Jr., G. Reis, A.B. Ribeiro, J.M. Ribeiro, J.C. Rocha, P.R.

ssi, J.F. Saraivaanada: G. Dagenais (NC), K. Teo (NC), B. Abramson, M.old, T. Ashton, P. Auger, I. Bata, K. Bayly, J. Beauchef, A.

langer, A. Berdnikoff, V. Bernstein, R. Bhargava, W. E.oth, S. Bose, M. Boulianne, M. Cameron, Y. Chan, J.B.oy, C. Constance, P. Costi, W.E. DeCoteau, J.D. Douketis,Fell, J.P. Giannoccaro, A. Glanz, G. Gosselin, D. Gould, S.ulet, M. Gupta, J.W Heath, J.G. Hiscock, G. Hoag, G. Ho-s, J. Imrie, R. Kuritzky, K. Kwok, C. Lai, A.V. Lalani, A.

y, P. LeBouthillier, H.N. Lee (deceased), E. Lonn, B.elsky, A. Mackey, M. Meunier, A. Milot, L.B. Mitchell, S.

waz, M. Omichinski, A. Panju, C. Pilon, D. Pilon, P. Po-ek, G. Proulx, T. Rebane, A.J. Ricci, E. Sabbah, D. Savard,

. Sharma, D. Shu, R.J. Sigal, R. St. Hilaire, F. St. Maurice,Stakiw, R. Starra, B. Sussex, T. Szaky, P. Talbot, K. Tan, S.

be, R.H. Tytus, R. Vexler, P. Whitsitt, V. Woo Mihina: L. Liu (NC), X. Bai, X. Chen, J. Feng, S. Fu, L. Gong,He, J. Huang, Y. Jiang, L. Li, Y. Liao, Z. Lu, Z. Lu, S. Ma, C., F. Qian, X. Shi, G. Sun, N. Sun, G. Sun, S. Wang, Z. Wu,

Yan, X. Yang, H. Yang, S. Yuan, T. Zhang, C. Zhang, F.ang, S. Zhang, D. Zhao, B. Zheng, S. Zhou, J. Zhuzech Republic: P. Jansky (NC), V. Dedek, J. Dvorak, R.

laj, J. Kotous, E. Pederzoliova, M. Polak, J. Povolny, K.etana, J. Spacenmark: T.L. Svendsen (NC), E. Agner, L. Gtzsche, P.

debrandt, H. Juhl, K. Klendorf, F. Pedersen, T. Pindborg,. Rasmussen, S.L. Rasmussen, M. Scheibel, K. Thygeseninland: K. Metsarinne (NL), R. Antikainen, M. Jaaskivi, I.

ntola, M. Kastarinen, P. Kohonen-Jalonen, A. Koistinen, E.mus, R. Nuuttila, J. Tuomilehto, M. Tuominenrance: J. Mallion (NC), N. Abenhaim, J. Allix, L. Boucher,Bourgoin, A. Boye, N. Breton, D. Cadinot, A. Campagne,Chagnoux, J. Churet, E. De Sainte Lorette, A. El Sawy, G.hegarray, S. Farhat, F. Lacoin, T. Latte, C. Magnani, D.eau-Valenciennes, M. Pithon, A. Queguiner, J. Sicard, G.be, D. Taminau, H. Vilarem, J.Y. Vogelermany: M. Bohm (NC), J. Mann (NC), B. Brado, G. Claus,

Dietz, S. Gehlhar, R. Griebenow, T. Haak, K. Hahn, R.mpel, T. Horacek, C. Klein, R.E. Kolloch, S. Lindemann, S.ewig, W. Motz, T. Munzel, H. Nast, M. Nauck, H. Nebel-

ck, K. Rybak, H. Samer, T. Schafer, R. Schmieder, J.olze, B. Schulze-Schleppinghoff, B. Schwaab, U. Sechtem,Sehnert, A. Sharma, E. Steinhagen-Thiessen, G. Stenzel, P.nkwalder, B. Wedler, J. Zippelreece: N. Karatzas (NC), E. Diamantopoulos, A. Efstrato-

ulos, M. Elisaf, G. Louridas, D. Mentzikof, T. Moun-alakis, Z. Orfanidis, D. Papadogiannis, V. Pyrgakis, P. Tout-

zas, A. Tyrologos, I. Vogiatzis, S. Voyaki, C. Zamboulisong Kong: J. E. Sanderson (NC), C.K. Chan, W.K. Chan,. Lau, Y.K. Lauungary: M. Keltai (NC), I. Czuriga, I. Edes, C. Farsang, K.

rlocai, K. Keltai, Z. Laszlo, V. Nagy, A. Papp, G. Polak, I.da, A. Ronaszeki, G. Sallai, M. Sereg, K. Simon, S. Sonkodi,

Szaboki, J. Szegedi, S. Timar, K. Toth, G. Vandorfireland: J. Feely, V. Maher, A. Stanton, P. Sullivantaly: B. Trimaro (NC), P. Verdecchia (NC), A. MaggioniL), E. Agabiti Rosei, G.B. Ambrosio, A. Battaglia, G. Ben-io, M. Bentivoglio, A. Branzi, P. Cavallo-Perin, V. Ceci, M.iariello, G. Corsini, G. Di Pasquale, R. Ferrari, E. Giovan-i, D. Giuliano, R. Lauro, G. Lembo, L. Moretti, S. Pede, G.tinati, G. Pinelli, C. Porcellati, G. Reboldi, G. Rosiello, E.V.bbia, L. Tavazzi, P. Terrosu, A. Venco, M. Volpe, G. Zilioalaysia: (Rotating NC) A.R. Abdul Rahman, W.A. Ahmad,

Shah, M. Singaraveloo, K. Yusoff, R. Zambahariexico: E. Cardona (NC), G. De La Pena Topete, L.A. Daz

reiro, L.A. Elizondo Sifuentes, H.R. Hernandez Garca,A. Macas Islas, J. Navarro Robles, J.A. Noriega Arellano, R.era Ruiz, J.Z. Parra Carrillo, G. Velasco Sanchez, M. Vidrio

lazquezetherlands: F. W. A. Verheugt (NC), N.J. Holwerda (NL),

.M. Boermans, K.P. Bouter, C.P. Buiks, M.J.M. Cramer,A. De Backer, J. J. De Graaf, J.H.M. Deppenbroek, J.C. Ehr-, F.C.N.M., Gunneweg, H.R. Michels, D. Poldermans, G.rijver, M.I. Sedney, T. Slagboom, J.G. Smilde, P. Van Ber-, G.J.M. Van Doesburg, L.H.J. Van Kempen, H.F.C.M. Vanerlo, A. Veerman, F.A.A.M. Vermetten, A. Wester

New Zealand: R. Doughty, D. Friedlander, R. Luke, L.Nairn, M. Richards, J. Singh, H. White, S. Wong

Norway: K. Dickstein (NL), J.O. Lier, J.E. Ottestad, P.K.Rnnevik, S. Skeie, P. Walle

Philippines: A. L. Dans (NC), M.T.B. Abola, M. Jaro, V.Mendoza, E. Paz-Pacheco, B.A. Tumanan-Mendoza

Poland: L. Ceremuzynski (NC), A. Budaj (NC), Z. Binio, M.Bronisz, P. Burduk, P. Buszman, T. Czerski, M. Dalkowski, H.Danielewicz, J. Gessek, A. Gieroba, K. Janik, M. Janion, T.Kawka-Urbanek, R. Klabisz, M. Krauze-Wielicka, S. Mali-nowski, P. Miekus, J. Mormul, M. Ogorek, G. Opolski, M.Skura, M. Szpajer, M. Tendera, T. Waszyrowski, M. Wierz-chowiecki

Portugal: R. Ferreira (NC), R. Capucho, M. Carrageta, C.Correia, L. Cunha, P.M. Da Silva, M.E. Prazeres De Sa, J.M.Ferro, V. Gama Ribeiro, R.S. Gomes, V. Gomes

Russia: I. Chazova (NC), F. Ageev, Y. Belenkov, A. Ivleva,Y. Karpov, M. Shestakova, E. Shlyakhto, S. Shustov, B. Si-dorenko

SS

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Taiwan: J. Chen (NC), C. Chen, J. Cheng, H. Chiou, M. Fu,W. Lai, C. Tsai, J. Wang, P. Yeh

Thailand: S. Chaithiraphan (NC), K. Jirasirirojanakorn, R.Krittayaphong, P. Laothavorn, N. Mahanonda, S. Sitthisook, S.Tanomsup, S. Tansuphaswadikul, P. Tatsanavivat

Turkey: A. Oto (NC), M. Akin, Y. Aral, N. Caglar, A. Ergin,H. Muderrisoglu, A. Oguz, Z. Ongen, V. Sansoy, T. Tetiker, A.Uysal

UAE: A. S. Binbrek (NC), A.A.R. Al Hajiri, A.A.S. Al-SousiUK: P. Sleight (NC), J. Adgey, R. Andrews, S.G. Ball, D.H.

Barer, A. Barnett, A. Bridges, A. Cowie, A. De Belder, R. Don-nelly, C.M. Francis, A.M. Heagerty, P. Jackson, S. Jackson, D.McEneaney, D.L. Murdoch, P. OHare, W.J. Penny, C. Reid, J.Vora, J. Webster, B, Williams

Ukraine: A. Parkhomenko (NC), E. Amosova, Y. Dykun, G.Dzyak, O. Grishyna, L. Kononenko, V. Kovalenko, V. Ne-tyazhenko, T. Pertseva, Y. Sirenko

USA: J. Probstfield (NC), M. Weber (NC), J. Young (NC), I.AnilayBraN.RS. DJ.VS. GGrHasonD.M.LiadoMcNaPriReH.SStrJ.AWi


The ONTARGET/TRANSCEND Investigators 61ingapore: C. Chen, B.W. Kwoklovakia: G. Fodor (NC), A. Dukat, J. Gonsorck, M. Hranai,Pella, L. Ruffiniouth Africa: P. Commerford (NC), F. Bonnici, B. Brown,. Dalby, G. J. Gibson, L. Herbst, J. King, E. Klug, F.J.ritz, M. Middle, D. P. Naidoo, G. Podgorski, N. Ranjith, K.

a-Hahnle, H. Theronouth Korea: J. H. Kim (NC), S.C. Chae, N.S. Chung, K.P.ng, M.J. Jeong, J.J. Kim, M.H. Kim, M.M. Lee, H.S. Seo,. Shinpain: J. Redon (NC), J. Abellan, P. Aranda, V. Barrios, C.

lvo, R. Carmena, M. De La Figuera, E. De Teresa, R. Dura,Escobar, J. Garcia-Puig, R. Garcia-Robles, B. Gil-Extremera,Gomis, J.R. Gonzalez-Juanatey, A. Llacer, L. Lopez-Bescos,Luque-Otero, J. Ma Pou, F. Malpartida, J. Olivan, A. Pico,Pose, A. Roca-Cusachs, L.M. Ruilope, J. Soler-Solerweden: L. Ryden (NC), P. . Bostrom, M. Dellborg, U.B.csson, J. Herlitz, P. Lofdahl, A. Spjuth, B. Strang-Olander,Sundqvist, B. Tengmark, G. Ulvenstam, B. Westerdahl, R.llenheimerwitzerland: T. R. Luscher (NC), W. Angehrn, P. Dubach,Gallino, F. Mahler, B. Martina, T. Moccetti, G. Noll, H.lapfer, K. Weberand, J.L. Anderson, J.S. Aponte Pagan, R.M. Ashar, J. Barz-, J.N. Basile, A. Bastien, S.S. Blumenthal, W.J. Bommer, D.utigam, C. Brown, N. Brown, A.A. Carr, J. Chinn, D. Chiu,. Cho, J.O. Ciocon, P.J. Colon-Ortz, J.B. Cruz, G. Dolson,orfman, W. Drummond, C. East, F. Eelani, H.S. Ellison,

. Felicetta, R. Force, J.K. Ghali, S.J. Giddings, M. Goldberg,oldman, R. Gomez-Adrover, S.L. Goss, S.P. Graham, C.

anger, M. Greenspan, R. Grimm, G.B. Habib, P. Hart, T.J.rtney, M.A. Henriquez, J. Holland, B. Hoogwerf, A. Jacob-, S.M. Jafri, S.Z.A. Jafri, M.J. Jelley, T. Jones, R.A. Kaplan,Karalis, L. Katz, D.J. Kereiakes, M. Khan, R.M. Kipperman,J. Kozinn, E. Lader, C. Landau, J. Landzberg, S.J. Lewis, C.ng, M. Limacher, P.E. Linz, F. Lopez-Arostegui, R.R. Mad-x, P. Mahrer, D. Mann-Johnson, M. Maurer, J. McBride, D.Guire, A. Mercando, J.H. Mersey, J. Moloo, A. Mooss, P.rayan, R.C. Noel, B. Omar, S. Oparil, A.L. Phillips, M.sant, N. Qureshi, M. Raghuwanshi, R.R. Randall, T.M.tta, R.E. Ringrose, M.G. Saklayen, S. Sastrasinh, A. Schlau,. Schultz, M.J. Schweiger, R. Smith, M. Sosa-Padilla, D.

eja, L. Stuver, D.C. Subich, W.A. Swagler III, M. Taitano,. Tavarez-Valle, E.M. Taylor, M. Tuck, W.B. White, W.ckemeyer, T.B. Wiegmann, X. Zhao, R. Zusman

Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination inRationale for telmisartan and ramiprilStudy designObjectivesSample size and data analysis issuesPatient eligibility criteriaRun-in and randomizationStudy organizationStandardization and monitoring of data qualityCentral event adjudicationSerious adverse events and unblindingEthics and patient confidentialityInterim analysis and data monitoring

Trial progress and baseline characteristicsDiscussionReferencesWriting GroupOperations CommitteeSteering CommitteeData and Safety Monitoring BoardAdjudication CommitteeSubstudies and Publication SubcommitteeCoordinating CentersPrincipal Investigators by Country

study protocol (extra article only)

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