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Nature of Control & Design HT

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  • 1. 13Indian Journal of Pharmacology | February 2011 | Vol 43 | Issue 1 | 13-17Clinical trials of antihypertensives: Nature of control and designBhaswat S. ChakrabortyEducational ForumCadila Pharmaceuticals,Ahmedabad, Gujarat - 387 810,IndiaReceived: 19-05-2010Revised: 21-08-2010Accepted: 21-10-2010Correspondence to:Dr. Bhaswat S. Chakraborty,E-mail: drb.chakraborty@cadilapharma.co.inIntroductionThe global burden of hypertension (HT) and comorbidcardiovascular diseases (CVD) is becoming heavier than everbefore with each passing year. It is estimated that by 2025,up to 1.58 billion adults worldwide will suffer from somecomplications of or from HT.[1]That makes one out of eachthree adults, on an average, will develop clinical HT or itsco-morbidities or both. Currently, the prevalence of HT variesaround the world, with the lowest prevalence in rural India(3.4% in men and 6.8% in women)[2]and the highest prevalencein Poland (68.9% in men and 72.5% in women).[2]However, infact, the low-prevalence rates, e.g. as those cited for India, donot necessarily mean a really low occurrence of the diseasein this population. Even in those who are diagnosed with HT,treatment is frequently inadequate. In any case, regardless ofthe prevalence rate, large or small, HT and related diseasesmust be intervened for prevention, diagnosis and control.According to the latest JNC, i.e. JNC7, in patients olderABSTRACTThis paper reviews the critical issues in the control and design of antihypertension (anti-HT)clinical trials. The international guidelines and current clinical and biostatistical practiceswere reviewed for relevant clinical, design, end-point assessments and regulatory issues.The results are grouped mainly into ethical, protocol and assessment issues. Ethical issuesarise as placebo-controlled trials (PCTs) for HT-lowering agents in patients with moderateto severe HT are undertaken. Patients with organ damage due to HT should not beincluded in long-term PCT. Active-control trials, however, are suitable for all randomizedsubsets of patients, including men and women, and different ethnic and age groups.Severity subgroups must be studied separately with consideration to specific study design.Mortality and morbidity outcome studies are not required in anti-HT trials except whensignificant mortality and cardiovascular morbidity are suspected. Generally, changes inboth systolic and diastolic blood pressures (BP) at the end of the dosing interval from thebaseline are compared between the active and the control arms as the primary endpointof anti-HT effect. Onset of the anti-HT effect can be studied as the secondary endpoint.For maintenance of efficacy, long-term studies of ≥6 months need to be undertaken. Error-free measurement of BP is a serious issue as spontaneous changes in BP are large andactive drug effect on diastolic BP is often small. Placebo-controlled short-term studies (of~12 weeks) for dose-response and titration are very useful. Safety studies must be veryvigilant on hypotension, orthostatic hypotension and effects on heart. In dose-responsestudies, at least three doses in addition to placebo should be used to well characterizethe benefits and side-effects.KEY WORDS: Blood pressure, endpoints, good clinical practices, hypertension,randomized clinical trialsthan 50 years of age, systolic blood pressure (SBP) of >140mmHg is a more important CVD risk factor than diastolic BP(DBP).[3]However, beginning at 115/75 mmHg, the CVD riskdoubles for each increment of 20/10 mmHg. In addition,those who are normotensive will have a 90% lifetime risk ofdeveloping HT at the age of 55 years.[3-5]Obesity, dyslipidemia(lower high-density lipoprotein levels), insulin resistanceand diabetes mellitus (DM) are the disease conditions thatoften coexist with HT. Perhaps, physical inactivity and geneticcofactors are involved in these comorbidities. Reduced physicalactivity is also a risk factor in coronary heart disease (CHD).Other heart conditions such as congestive heart failure (CHF)and fatal or nonfatal myocardial infarctions (MI) and ventricularhypertrophy (VH) also cause elevated BP, and BP-loweringdrugs have been found efficacious to different extents in suchconditions.[6,7]The direction of discovery of new and appropriateanti-HT interventions ought to be inclusive of those that mayeven replace the first line of treatment, with superior safetyand efficacy profiles. This paper is an attempt to review theAccess this article onlineWebsite: www.ijp-online.comQuick Response Code:DOI: 10.4103/0253-7613.75659[Downloaded free from http://www.ijp-online.com on Wednesday, August 22, 2012, IP: 182.19.80.161]  ||  Click here to download free Android application for this journ
  • 2. 14 Indian Journal of Pharmacology | February 2011 | Vol 43 | Issue 1 | 13-17important control and design issues involving the higher-phaseclinical research of the discovery of new HT drugs.Early and Current HT TrialsRandomized clinical trials (RCTs) of anti-HT drugs arementioned in the literature that date back to the late 1960s toearly 1970s. These early trials were carried out in rather selectpopulations (both high- and low-risk elderly patients), and weremainly interested in efficacy measurement of the anti-HT drugsin lowering BP relative to placebo or no treatment. The trialsof the 1980s focused on middle-aged hypertensive individualsand later on the elderly. These trials mainly investigated theefficacy of β-blockers and diuretics in reducing the systolic BPin these patients and, subsequently, the DBP.These early efficacy trials did not address the effect of anti-HT agents in controlling serious comorbidities like MI, CHD andCHF. Their compliance with Good Clinical Practices (GCP) wasalso rather poor.[8]During the 90s, large randomized trials ina much broader patient population came in vogue and a greatportion of these trials elucidated whether and whom to treatwith different classes of anti-HT drugs. Continuing to date,these trials of angiotensin converting enzyme inhibitors (ACEIs),β-blockers, angiotensin receptor blockers (ARBs) and calciumchannel blockers (CCBs) investigated the exact end-point goals,such as reduction of a certain percent of risk of MIs in GradeII HT patients over 1 year of treatment. The trials evaluated,often, the superiority of the end-point reduction by one agentover another as opposed to the overall efficacy of one agent orthe other. Reduction in the relative risk of mortality from theprimary and secondary outcome measures is one of the mainobjectives of the RCTs over the last 5–7 years.[8,9]The reason for the outcome measurement shifting fromlowering of BP to other parameters is that for some drugs,the BP lowering is an inadequate marker (surrogate) of healthbenefits in HT. Anti-HT drugs can have other important actionsthat may alter the benefit of lowering of BP. For example, manyanti-HT drugs have shown consistent beneficial effects onlong-term mortality and morbidity, most clearly on stroke andless consistently on cardiovascular events, such as, low- andhigh-dose diuretics, reserpine and β-blockers, usually as partof combination therapy (FDA guideline).[10]Ethical ConsiderationsThe ethical considerations in HT trials arise mainly on twoaccounts. Firstly, is it really ethical to put a hypertensive patienton a placebo arm in a RCT or there has to be an active controlof some sort in all these trials? Very special populations whoare either fragile or cannot make their own decision representthe other main concern for the HT trials.Placebo-controlled HT trialsEthical considerations in HT trials arise mainly on twoaccounts. Firstly, is it really ethical to put a BP patient on aplacebo arm in a RCT or there has to be an active control ofsome sort in all these trials? Very special populations who areeither fragile or cannot make their own decision representthe other main concern for the HT trials. Placebo-controlledHT clinical trials have been found to be very useful especiallywhen the efficacy of BP lowering is to be measured in an RCT.They have also been found to be useful in the determinationof the end points as a direct effect of therapeutic intervention.Despite the availability of a standard and efficacious treatment,the use of placebo-controls in CTs can be considered ethicalwhen withholding the effective treatment leads to no seriousadverse events (SAEs) and patients are fully informed aboutthe available therapies and the consequences of delayedtreatment.[11]As mentioned above, in case of the HT trials,placebo-controlled efficacy studies are particularly helpful inthoroughly quantifying the effect of treatment. The hazard topatients can be minimized by exposing them to placebo forthe least possible time and obtaining proper informed consentfrom them. In addition, particular attention should be paid toreducing the probability of CV events by excluding subjects withsevere HT or major concomitant risk factors.There are several good reasons why placebo-controls,when appropriate, are preferred to active controls. Firstly,placebo-controlled trials (PCTs) are sensitive in distinguishingan estimate of pure effectiveness of the treatment without anyexternal reference. This kind of estimation, however, is notuseful for equivalence, noninferiority and superiority trials.In these later trails, either a clinically meaningful effect of thecontrol has to be preserved or exceeded. In addition, PCTsrequire a smaller sample size to attain statistical significancethan comparing the experimental therapy to another treatment.As a result, these trials are faster and less expensive than activecontrol ones, exposing fewer subjects to the potential risks ofthe experimental treatment.[12]Use of active controls in HT trialsMany major trials for anti-HT drugs that have beenconducted in the last 10 years; ALLHAT,[13,14]INVEST,[15]LIFE,[16]LIFE-ISH[17]and RENAAL[18]belong to the category of activecontrol RCTs. Basically, two types of studies have successfullyused an active control. The first groups of studies are thosein which preservation of a clinically meaningful efficacy andsafety margin is essential (equivalence and noninferioritytrials, respectively). Examples are INVEST,[15]LIFE[16]andLIFE-ISH[17]studies. In the second group of studies using anactive control, the margin of clinically meaningful effect is tobe exceeded, as seen in superiority trials. The ALLHAT trialused chlorthalidone, a diuretic, as an active control standardtreatment in order to determine the superiority of amlodipine,lisinopril or doxazosin.[13,14]Usually, active control RCTs are designed in anticipation ofCV events in patients at high risk and where long-term effectsof the new or experimental interventions are to be observed.These trials, consequently, require, relatively, a higher numberof patients in order to achieve the required number of end pointsrapidly or at the earliest possible time for statistical analysis.Because the effect of experimental treatment separated bothfrom those of active control and natural history with data oftenrequiring appropriate baseline correction, data from thesestudies are rather complex to analyze.[10]Both safety and logistical problems can arise from theuse of an active control, especially in long-term trials. Sucha control can sometimes be very expensive. The long-termtrials also require careful term monitoring of SAEs, includingirreversible toxicities and deaths in participating patient-Chakraborty: Critical issues of hypertension trials[Downloaded free from http://www.ijp-online.com on Wednesday, August 22, 2012, IP: 182.19.80.161]  ||  Click here to download free Android application for this journ
  • 3. 15Indian Journal of Pharmacology | February 2011 | Vol 43 | Issue 1 | 13-17subjects. In addition, active control trials, because of theirlong duration of experimentation, can show cumulative CVtoxicities. Such problems must be overcome either through thestudy design (e.g., dose titration) or through the interventionof an appropriate, but not interfering with experimentation,treatment. If these problems with active controls cannotbe overcome at all, development of new products must beabandoned.[10,12]Protocol ConsiderationsThe trial patient populationFor participation in RCTs for HT or its comorbidities,any patient with a BP >120/80 mmHg, especially with oneadditional risk factor such as body mass index >25, is at riskof developing clinical HT and may qualify for the trial. Forexample, BP values between 130 and 139/85 and 89 mmHg areassociated with a more than two-fold increase in the relativerisk from CVD as compared with those with a BP of 120/80mmHg or below.[3]Patients who are of 55 years of age or moreand are also obese or diabetic are particularly risk-prone.A complete list of cardiovascular risk factors is provided inJNC-7.[3]Currently, the patient population studied with a newanti-HT includes a broad range of patients with HT and itscomorbidities. For mild to moderate HT, however, only BP canbe studied in a CT by measuring both DBP and SBP over thestudy period. More severe HT is usually studied with relevantconcomitant illness, e.g. CHD and DM. Care should be taken thatthe drugs they need would not interfere with the observationsof the effects of the study drug. For example, for patients withCHF, standard treatment requires use of one to several agents(ACE inhibitors) affecting BP, which could have pharmacologicalactions similar to those of the study drug.[10]Grading of HT together with target organ damage (TOD)secondary to HT needs to be established accurately. Patients,e.g. with BP >160/110 mmHg and DM, cannot be includedin PCTs. Such patients, however, can be included in active-controlled trials with proper safety monitoring. Patients fromrelevant demographic subsets should be studied, includingboth men and women, racial/ethnic groups pertinent to theregion and both young and older patients. The very old or"fragile elderly," i.e.. patients >75 years old, should be included.In general, all population subsets should be included in thesame studies rather than conducting studies in subgroups.This facilitates comparisons across subsets in the sameenvironment. An exception would be severity of the subgroups,where study designs could be different for different severities.Patients with secondary HT, isolated systolic HT, HT duringpregnancy and children with HT should be studied separatelyif specific indications for use in those populations are beingsought.[10]RCTs of antihypertensive agentsAll recent trials, since the 1990s, for the assessment ofefficacy and safety of anti-HT drugs have been designed andconducted as randomized, blinded trials.[18-22]Such trials arenot only free of experimental bias but they are also balancedin all important aspects of the study and differ only in theintervention that the experimental and the control groupsreceive. As discussed further in the following section, manybig trials, such as INVEST and ALLHAT, are designed asprospective, randomized, open, blinded-end point evaluation(PROBE) investigations in thousands of patients in multiplecountries. In some studies, there is also an emphasis on thedetermination of the reduction of mortality and/or CV morbidityby the experimental treatments rather than measuring just theBP-lowering effects.[19,20]Well-designed and well-conducted RCTshave been able to estimate such complex end-points with agreat deal of success.Study design and randomizationMost long-term HT trials are designed today as PROBEstudies. Such studies are aimed at comparing a treatmentregimen of newer anti-HT drugs (e.g., a CCB) with a traditionalregimen (β-blocker and/or a diuretic), like prevention of CHD.The study basically consists of two arms, i.e. the control andthe experimental arms, in which appropriate number of patientsare entered following a randomization scheme. Because thecontrol arm in such studies consists of receiving an active drug,which is often one of the standard first-line treatments, thetrial is often dubbed as an “active control trial,” as mentionedabove several times. A schematic representation of a two-armrandomized trial is presented in Figure 1. The total number ofpatients (sample size) and those in each arm are calculatedcarefully such that a clinically meaningful effect size can bedifferentiated between the average outcome measurementsfor the two arms with adequate statistical power (usually 80%)and significance (usually two-sided 5%). Both the power and thelevel of significance are prospectively defined and finalized inthe detailed protocol before the trial begins. The final samplesize includes considerations of drop out patients and all interimanalyses (IA)[21]The RCTs for HT and comorbidities are usually large(few thousand patients) multicentric studies.[19,20]Open labelrefers to a nonconcealment of both the active control and theexperimental drugs to the patients and investigators, in thatthey can figure out the difference in physical and organolepticproperties between the two. Sometimes, there could alsobe a difference in the route of the two administrations. Theinvestigator or the expert who measures the endpoint, however,is blinded to the randomization codes and allocations to allpatients, such that no bias is introduced in the assessmentof the endpoint. If dosage titration for the experimental armis required, the same principle of endpoint blinding should beapplied.[10]Although there may be many subvarieties, essentially, thereare three basic ways to generate a randomization scheme for anRCT. The first approach can be called “simple randomization,”which is equivalent to tossing a coin for each subject thatenters a trial. The heads get the experimental treatment whilethe tails receive the placebo. A computerized or tabulatedFigure 1: Schematic representation of a two-arm randomized clinicaltrial of new and existing antihypertension (anti-HT) treatments in HTpatients with one or more additional risk factorsBaseline of HT patientswith/without additionalrisk factors RandomizationExperimental ArmControl ArmInformed Consent Follow UpChakraborty: Critical issues of hypertension trials[Downloaded free from http://www.ijp-online.com on Wednesday, August 22, 2012, IP: 182.19.80.161]  ||  Click here to download free Android application for this journ
  • 4. 16 Indian Journal of Pharmacology | February 2011 | Vol 43 | Issue 1 | 13-17random number generator is generally used. It is simple andeasy to implement and treatment assignment is completelyunpredictable. The second approach to randomization, calledthe “block randomization,” is very popular and balancedwithin each block. For a trial of n treatments, the total numberpatients are divided into m blocks of size 2n. Then, each ofthe m blocks is randomized such that n patients are allocatedto each of the treatments. One can then choose the blocksrandomly. The INVEST[15]study followed this scheme of blockrandomization. Yet, a third approach to randomization involves“stratified blocks.” Because a trial may not be consideredvalid if it is not well balanced across the prognostic factors,stratification of patients is done to produce comparable groupswith regard to certain characteristics (e.g., gender, age, race,disease severity). This approach produces valid statisticaltests in all stratified subgroups (e.g., high-risk subgroups inthe ALLHAT trial).[13,14]Whatever the mode of randomization is, it is ensured thatthe pattern of assignment of control or experimental drugwithin a group of patients cannot be guessed at any point.It is recommended that the statistician who generated therandomization codes does not get involved in the IA or the finalanalysis of the experimental data.Other study designs can be used in HT trials as long asthey are scientifically valid and manageable. Placebo controlshave been described elsewhere in this article. True double-blinding of patients as well as the investigators is very difficultto achieve as the regimens in the two arms differ on a numberof noticeable properties.[10]Usually, studies are designed for observation and analysisof the primary outcome on which the sample size calculation isalso based. Secondary outcomes, however, can also be validlyanalyzed if the primary outcome difference is not statisticallysignificant provided that they were declared a priori and areclinically important. Another condition for the valid use ofsecondary outcomes in the efficacy or endpoint estimation isthat the method to capture outcomes was the same in eachtreatment group and the data are unbiased (randomized). Inaddition, if the outcomes for secondary endpoints such as heartfailure (HF) and CVD are still compelling even after consideringthe number of comparisons made, then the conclusion basedon these outcomes is valid.Inclusion–exclusion criteria for entry into the studyFollowing any standard inclusion and exclusion criteria mayprove too restrictive or too liberal in a HT clinical study. Inclusionshould be based on three basic scientific questions, viz. (a)what is the primary objective of the study?, (b) which clinicalsymptoms, tests and physical parameters would represent thetrue patient population? and (c) which clinical symptoms, testsand physical parameters will distinguish the outcome frombaseline as well as from control with sensitivity and accuracy?Similarly, the exclusion of all those patients who are likelyeither refractory to the experimental regimen or marginallymeet the true and desirable patient criteria is based on havingan experimental sample that will provide for the estimation ofa clear and sharp effect size.The rationale of the inclusion and exclusion criteria for alarge, long-term RCT for a new anti-HT agent [Table 1] canbe exemplified as follows. Say, the primary endpoint for thistrial (comparing a new ARB with an existing combination ofβ-blocker and diuretic) is reduction of fatal CHD and nonfatalMI. Both men and women of age 55 years or more with SBPand/or DBP ≥140/90 mmHg but ≤180/110 mmHg (treatedbefore or untreated) at two visits with no washout periodleading to randomization can be recruited.[3]Addition of one ormore risk factors will give a representative sample of patientswho are most likely to be benefited from the treatments andalso a sensitive and accurate baseline to which the poststudyprimary outcome between the two arms can be compared andcontrasted. Therefore, patients with at least one additional riskfactor should be recruited for this trial and randomly assignedto one of the arms.Analysis of the StudyEvaluation of efficacyA detailed discussion of the statistical methods employedin analyzing HT trial data is beyond the scope of this paper.However, in general, in efficacy trials, comparison of themean blood BP lowering can be done by conventional tests ofhypothesis, e.g. t-test to compare the relative efficacy of the twotreatments. On the other hand, in more complex, long-term end-point trials aiming to examine efficacy as well as reduction ofmorbidity and mortality, comparison of relative risks or hazardsof two treatments is made. In these latter studies, analyses oftime to event data and Cox regression are often employed toestimate the relative benefits of treatments.[20]Table 1:Usual inclusion/exclusion criteria for hypertension randomizedclinical trialSr.no.Inclusion criteria Exclusion criteriaa. Age/sex: men and women aged > 55yearsAge/sex: men andwomen aged ≤ 55yearsb. BP eligibility:Untreated systolic and/or diastolichypertension (≥ 140/90 mmHg but ≤180/110 mm Hg at two visits)No washout periodMI, stroke or anginawithin 6 monthsc. At least one of the following risk factors:Type 2 diabetes mellitus (DM)HDL cholesterol < 35 mg/dl on any two ormore determinations in the past 5 yearsLeft ventricular hypertrophy (past 2years)ECG or echo (septum + posterior wallthickness ≥ 25 mm)Current cigarette smokingSymptomatic CHF orejection fraction <35%d. Known renalinsufficiency –creatinine ≥ 2 mg/dle. Requiring diuretics,CCB,ACEI or -blockersfor reasons other thanhypertensionChakraborty: Critical issues of hypertension trials[Downloaded free from http://www.ijp-online.com on Wednesday, August 22, 2012, IP: 182.19.80.161]  ||  Click here to download free Android application for this journ
  • 5. 17Indian Journal of Pharmacology | February 2011 | Vol 43 | Issue 1 | 13-17Evaluation of safetyAll anti-HT agents have adverse effects on various organsand systems and can also exacerbate a preexisting damagewhen used chronically. Because a tremendous volume of safetydata is generated in the HT-RCTs, maintenance of a databaseand proper evaluation of the safety profile is required not onlyduring the trial but also at regular intervals post approval. ICHE1 guidance suggests that a database of about 1500 patients(300–600 for 6 months, 100 for 1 year) is usually sufficient forchronically administered drugs. Even larger databases may berequired for large trials with commitments of long follow-upperiods before and after the approval of the trial drug.[3,20,22]Attention must be given to the BP-related adverse eventsin all HT trials, such as excessive hypotension, orthostatichypotension and rebound phenomena. Depending on theparticular drug and other observations, studies of effects onheart rhythm or cardiac conduction, coronary steal effects,effects on risk factors for cardiovascular disease (e.g., bloodglucose, lipids) and further deteriorating effects on TOD canalso be carried out.[10]SummaryThis article deals with control and design principles thatguide the conduct and conclusion of a meaningful HT trial. Byno means can this replace the blue print of medical documents,standard operating procedures, expertise and organization thatare required for a successful trial. Each trial is as meaningfulas the number of scientific questions it answers and pavesthe direction of future trials in that field. Compliance to GCPopens up the data for correct interpretation. Any neglect towardthis end of abiding by the GCP principles can raise a slew ofcritical questions, eventually rendering the entire data to beuninteresting or suspect. Principles of study design and analysismentioned in this article can give the trialists an advantage ofa well-designed study, providing the crucial evidence of safetyand efficacy of the agent under testing.AcknowledgmentThe author gratefully acknowledges the helpful discussion withDrs. N. Patel and V. Vaishnavi and assistance in manuscript preparationby Dhriti Chakraborty, Arpan Mukherjee and Diptiman Roy. He is alsothankful to the reviewers of this manuscript.References1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Globalburden of hypertension: Analysis of worldwide data. Lancet 2005;365:217-23.2. Kearney PM, Whelton M, Reynolds K, Whelton PK, He J. Worldwide prevalenceof hypertension: A systematic review. J Hypertens 2004;22:11-9.3. JNC-7. The Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure U.S. Departmentof Health And Human Services, NIH Publication No. 04-5230; 2004. p. 1-104.4. Reference Card for JNC-7. The Seventh Report of the Joint National Committeeon Prevention, Detection, Evaluation, and Treatment of High Blood PressureU.S. Department of Health And Human Services, NIH Publication No. 04-5230;2004. p. 1-2.5. Scott WA. Haemodynamic monitoring: Measurement of systemic blood pressure.Can Anaesth Soc J 1985;32:294-8.6. Pater C. Beyond the Evidence of the New Hypertension Guidelines. Bloodpressure measurement - Is it good enough for accurate diagnosis of hypertension?Time might be in, for a paradigm shift (I). Curr Control Trials Cardiovasc Med2005;6:1-147. Wiysonge CS, Bradley H, Mayosi BM, Maroney R, Mbewu A, Opie LH, et al.Beta-blockers for hypertension. Cochrane Database Syst Rev 2007;1:CD002003.8. Gavras I,Gavras H.Benefits andsideeffectsofbloodpressureloweringtreatment:What was wrong with doxazosin in the ALLHAT? Curr Control Trials CardiovascMed 2001;2:257-9.9. Rahn KH. Recent intervention studies with antihypertensive drugs and theirinfluence on guidelines. Med Klin 2003;98:771-5.10. Centre for Drug Evaluation and Research, USA Food and Drug Administration.Guidance for industry - E12A: Principles for Clinical Evaluation of NewAntihypertensive Drugs. 2002Available form: http://www.fda.gov/cder/guidance/index.htm [last accessed on 2000]11. Weber MA. The ethics of using placebo in hypertension clinical trials. J Hypertens1999;17:5-8.12. Wright JT Jr, Douglas JG, Rahman M. Prevention of cardiovascular disease inhypertensive patients with normal renal function.Am J Kidney Dis 1998;32:S66-9.13. Davis BR, Furberg CD, Wright JT Jr, Cutler JA, Whelton P. ALLHAT: Setting therecord straight. Ann Intern Med 2004;141:39-46.14. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, et al.Success and predictors of blood pressure control in diverse North Americansettings: The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393-405.15. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH,et al. INVEST Investigators. A calcium antagonist vs a non-calcium antagonisthypertension treatment strategy for patients with coronary artery disease. TheInternational Verapamil-Trandolapril Study (INVEST): A randomized controlledtrial. JAMA 2003;390:2859-61.16. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et al.Cardiovascular morbidity and mortality in the Losartan Intervention For Endpointreduction in hypertension study (LIFE):Arandomised trial against atenolol. Lancet2002;359:995-1003.17. Kjeldsen SE, Dahlof B, Devereux RB, Julius S,Aurup P, Edelman J, et al. Effectsof losartan on cardiovascular morbidity and mortality in patients with isolatedsystolic hypertension and left ventricular hypertrophy:ALosartan Intervention forEndpoint Reduction sub-study. (LIFE-ISH). JAMA 2002;288:1491-8.18. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2diabetes and nephropathy. (RENAAL). N Engl J Med 2001;345:861-9.19. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, etal. Prevention of cardiovascular events with an antihypertensive regimenof amlodipine adding perindopril as required versus atenolol addingbendroflumethiazide as required, in the Anglo-Scandinavian Cardiac OutcomesTrial-Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre randomisedcontrolled trial. Lancet 2005;366:895-906.20. Pocock SJ. Clinical Trials - A Practical Approach. West Sussex, England: JohnWiley and Sons; 2006.21. Centre for Drug Evaluation and Research, USA Food and Drug Administration.Guidance for Clinical Trial Sponsors: Establishment and Operations of ClinicalTrials Data Monitoring Committees. 2006Available form: http://www.fda.gov/cber/gdlns/clintrialdmc.htm [last accessed on 2006]22. Grossman E, Messerli FH. Long-term safety of antihypertensive therapy. ProgCardiovasc Dis 2006;49:16-25.Chakraborty: Critical issues of hypertension trials[Downloaded free from http://www.ijp-online.com on Wednesday, August 22, 2012, IP: 182.19.80.161]  ||  Click here to download free Android application for this journ

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