Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Fewer Mega-Trials and More Clinically Oriented Studies in Hypertension Research? The Case of Blocking the Renin-Angiotensin-Aldosterone System
Massimo Volpe*,,
Giuliano Tocci* and
Erika Pagannone*
* Cardiology, II Faculty of Medicine, University of Rome "La Sapienza," Sant’Andrea Hospital, Rome, and IRCCS Neuromed, Pozzilli, Italy
Address correspondence to: Dr. Massimo Volpe, Division of Cardiology, II Faculty of Medicine, University of Rome "La Sapienza," Sant’Andrea Hospital, Via di Grottarossa 1035-9, 00189 Rome, Italy. Phone: +39-06-8034-5654; Fax: +39-06-8034-55061; E-mail: volpema{at}uniroma1.it
In recent years, medical practice has been influenced substantiallyby several factors, including the overwhelming development ofevidence-based medicine, which is a consequence of the impressive,growing number of large clinical trials, the so-called "mega-trials."These clinical studies are designed mostly to investigate theeffects of drugs or treatments on hard end points that cannotbe tested by individual physicians in their daily clinical practice.The growing role of this epidemiologic approach to medicine,which is based mostly on the assessment of the average responseor behavior of large populations rather than of individuals,is systematically replacing the former knowledge and referencepoints of the physician, as a substitute rather than as an aid.Taking into account the case of hypertension and particularlythe renin-angiotensin system–blocking agents, this articlereviews the issues and limitations of transferring evidencefrom mega-trials to clinical practice and suggests new strategiesto make trials more effective and transferable to the case ofindividual patients.
In the past two decades, medical practice has been influencedand modified substantially by several factors, including theoverwhelming development of evidence-based medicine (EBM), whichis a consequence of the impressive, growing number of largeclinical trials, the so-called "mega-trials." These clinicalstudies are designed mostly to investigate the effects of drugsor treatments on hard end points, such as overall cardiovascularmortality, myocardial infarction, ischemic stroke, heart failure,ESRD, and, more in general, major prognostic outcomes, all itemsthat cannot be tested by individual physicians in their dailyclinical practice. The growing role of this epidemiologic approachto medicine, which is based mostly on the assessment of theaverage response or behavior of large population samples ratherthan of individuals, is systematically replacing the formerknowledge and reference points of the physician, as a substituterather than as an aid. Besides and beyond the personal clinicalexperience and professional skills and a sufficient knowledgeof pathophysiologic mechanisms and pharmacologic drug properties,today each individual physician is required to be aware of theresults of many trials and to transfer them to her or his clinicalactivity. Any significant deviation from the strict applicationof EBM to therapeutic management of the clinical cases may seemnot to be justified.
In fact, the results of large international trials are moreand more perceived not as a valid basis for therapeutic decisionsbut rather as the only evidence that can validate a treatmentor an intervention. As a consequence, doctors are becoming moreprone to accept acritically the conclusions of a mega-trial(and sometimes also the results of a small, "well-published"trial) and to choose a specific and often life-long treatment,as the results suggest. This phenomenon often happens becausepracticing physicians may feel intimidated by their own lackof statistical training or limited skills in data analysis andinterpretation. Therefore, this process, which is dictated bya relatively restricted number of individuals or key opinionleaders and in most is cases financed by industries, has a heavyinfluence on individual physician behavior and on health caresystems. However, the mechanistic application of EBM to clinicalpractice presents several misleading aspects. As an example,for reasons that are intrinsic to the scientific basis of themega-trials, group-averaged data are transferred to individualcare often with weak demographic, ethnic, and clinical associations.In fact, a key feature that makes a trial influential is thesize of the study population. Important trials need to be large,but the size is not a "liberal" choice, because it is dictatedby the need of a large sample to demonstrate an effect or adifference that is expected to be small. In fact, the largestis the sample size, the smallest difference expected. In addition,the price to pay to achieve a large population sample oftenis represented by heterogeneity of clinical characteristics,presence of comorbidities, and associated therapies in the studypopulation, as well as by limited and less rigorous controlof hard end points.
In this view, in designing a trial that will have enough powerto detect statistically significant differences between twoor more antihypertensive treatments in terms of cardiovascularmortality and morbidity, thousands of hypertensive individualswith different pathophysiologic, demographic, and clinical profileswill be put together, randomly assigned, and analyzed with theassumption (or, in the best case, the misled interpretation)that any eventual difference then could be applied to any ofthem. However, the promise of such a conclusion would be thatall hypertensive individuals are alike or share the same pathophysiologicmechanism, thereby allowing trialists to assign the patientsrandomly and indiscriminately to any experimental drug. Suchan assumption definitely would be wrong. In fact, within thepopulation of the trial, the risk for cardiovascular or renalevents is distributed unevenly among individuals, even if theyfall within the same category of BP or cholesterol or creatininelevels. The reason that we accept EBM as a scientific disciplineto be integrated with pathophysiology is that despite theseand other limitations, it may provide helpful information witha rigorous approach based on a properly dimensioned and randomlyassigned population sample, which is analyzed prospectivelyand blindly.
In other words, there is no question that the systematic useof EBM in the scientific process has brought significant progressin common clinical conditions, such as cardiovascular disease,renal disease, or neoplastic disease, often generating severeevents or death. Physicians would not be able to predict effectsof treatments on hard end points on the basis of their clinicalpractice or anecdotal experience. Therefore, they need to relyon large, controlled studies to define whether a treatment iseffective not only in preventing death, myocardial infarction,stroke, or ESRD (hard endpoints) but also in reducing left ventricularhypertrophy, peripheral atherosclerosis, and microalbuminuria(intermediate or surrogate end points).
However, scientific and medical communities need to attributethe real value to the "mega-trials" approach. This area of clinicalscience should add to rather than substitute for the accumulatedbiochemical, physiologic, or pharmacologic knowledge. Indeed,it becomes a valuable tool with the potential to improve careand patient outcomes, when applied rationally to all of thoseclinical conditions for which science is incomplete and multipletherapies are available with uncertainty existing. Much caution,however, must be used in the correct reading of a mega-trial,taking into consideration results rather than conclusions, primaryend points rather than the secondary or the tertiary ones. Finally,effort should be put in the process of education of physiciansin learning how to read and to interpret a mega-trial, besidesthe suggestions of the authors.
The beginning of the history of clinical trials dates back tomore than 2 centuries ago, when a small group of sailors wererandomly assigned to receive limes to prevent scurvy on CaptainCook’s ship while traveling the oceans (1). In the past40 yr, the clinical trial has become the leading method to guideobjectively medical practice. In fact, this scientific methodsurpasses and implements individual clinical experience or uncontrolledobservations. This approach, mostly based on the prospectivestudy of subjects who are randomly assigned to either placeboor active therapy and the blinding of both participants andinvestigators, provides a reliable and helpful tool for testingtherapeutic efficacy and, to a lesser extent, safety. Developmentof clinical trials for specific categories of drugs or treatmentsoften has required very small samples of a population to testthe efficacy of treatment with clear-cut, unequivocal effects,as in the case of penicillin or other antibacterial compounds(1).
Much more complex is the case of conditions, such as hypertension,diabetes, and associated cardiovascular diseases, for whichmultiple factors play a pathophysiologic role and the causeis unclear. In fact, when testing antihypertensive or lipid-loweringagents, we do not expect full prevention of cardiovascular eventsbut rather small changes in the probabilities of developingthese events. Therefore, large sample size, rigorous methods,and strict analytic criteria are needed to get scientific andsignificant answers. A sort of "think big" rule indeed has becomethe scientific manner to answer every question.
The initial trials on antihypertensive therapy were designedto assess whether BP reduction in patients with hypertensionwould be effective in reducing cardiovascular outcomes and besafe at the same time (2–11). The availability of tolerableand effective oral antihypertensive agents, such as blockersand angiotensin-converting enzyme inhibitors (ACE-I), had transformedmalignant hypertension from a rapid and often fatal multisystemdisease into a chronic, although still harmful, condition (2–11).After these first experiences, in the past 2 decades, especiallyduring the past 10 yr, an impressive number of clinical trialshave been designed and undertaken to investigate whether differentantihypertensive agents provide different cardiovascular protectionbenefits independent of substantially comparable BP-loweringproperties (2–31). To achieve significant informationon hard end points, these studies involved and observed forseveral years large cohorts of hypertensive patients rangingfrom a few hundred to several thousand individuals. The mostcommon population profile was represented by individuals withmild to moderate hypertension with the purpose to define whetherthe benefit of BP could be extrapolated to the general populationof individuals whose BP was elevated.
A further, consistent development of the scientific disciplinebased on large, controlled studies coincided with the experiencesof antihypertensive treatment and, mostly, with the developmentof ACE-I in the early 1980s. These compounds were made availablefor the clinical use at a time in which multicenter studieswere planned to be multinational for a number of reasons, includingpatients’ recruitment to achieve the needed numbers, regulatoryand ethical issues, and marketing strategies (2–15). Infact, this was a lucky coincidence because ACE-I were foundto be effective compared with placebo in heart failure (2–5,9,10,19,26),ischemic heart disease (6–8,22,23,25,29,30), diabeticnephropathies (14–18,25,29,30), and other clinical settings,as shown in Table 1. A positive study meant that the net effectof the intervention was favorable in comparison with placeboin terms of outcomes. This approach was used widely also totest the superiority of an active treatment versus another activetreatment in the same condition and was extended throughoutthe spectrum of medicines, and more than 1 million patientswith hypertension have been enrolled in this type of study (32).These studies obviously showed that strokes and heart attackswere not eliminated but rather that there was a change in theprobability of their occurrence (33).
In hypertension, major head-to-head studies, which had the hypothesisto test the superiority of one antihypertensive drug over another,mostly failed to match the primary end point and actually tendedto corroborate the ancestral and debated concept that all thatmatters in the treatment of hypertension is to lower BP, becausecomparisons of end points mostly showed no difference. Certainly,some of the most important recent mega-trials suggested thatthe failure to achieve the postulated end points could be attributedlargely to the experimental design or to unfortunate choicesin the dosage of the drugs or in the study population. In theAntihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) (20), despite the generous effort of theagency that supported the study and of the investigators todemonstrate differences among treatment groups (receiving therapiesbased on chlorthalidone, amlodipine, or lisinopril; the doxazosinarm was interrupted prematurely), no statistical differencein the composite primary cardiovascular end point was found,and differences in specific components of the primary end pointscould be explained with the ethnic influence; for example, onlyin the black subgroup was the chlorthalidone arm superior tothe lisinopril arm. Overall, the results of the study, whichwas performed with approximately 40,000 patients and cost $160million, were negative. The conclusions of the authors, however,sounded very positive, heralding a victory of one treatment(diuretics) over the others. Even though the conclusion thatthe comparable effectiveness of a cheaper drug to a modern andmore expensive therapy may seem to be sufficiently rewardingfor doing the study, this would be attractive only in the hypothesisthat all or most hypertensive patients could be treated effectivelywith a diuretic monotherapy for a long time. This hypothesisobviously is denied by reality, because (1) only a small percentageof hypertensive patients can achieve the target BP levels witha diuretic monotherapy; (2) a certain amount of hypertensivepatients could be treated effectively with a renin-angiotensinsystem (RAS)-inhibiting drug or a calcium antagonist in monotherapy;(3) most hypertensive patients will need a combination therapy;(4) global risk profile, comorbidities, side effects, and mostlypathophysiologic mechanisms underlying hypertension will differin various patients; and (5) in the ALLHAT (20), the vast percentageof black individuals (approximately one third) precluded largelythe effectiveness of ACE-I. Nonetheless, the ALLHAT mega-trial(20) has heavily affected North American Joint National CommitteeVII recommendations (34) for treating hypertension, severalnational health care systems, media reports, and physicians’behavior. Physicians, in fact, often have perceived the ALLHATresults (20) as a superiority of the cheapest diuretic treatmentthat could be extended to all hypertensive individuals.
In the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)mega-trial (27), performed with more than 15,000 hypertensivepatients with a very heterogeneous high-risk profile, the postulatedsuperiority of the valsartan-based treatment over the amlodipine-basedtherapy in the cardiovascular end point could not be demonstrated.However, because the patients were simply and directly "rolledover" from their prestudy treatment as in the ALLHAT mega-trial(20) and because of the relatively low initial dosage of valsartan,which was up-titrated slowly for at least 6 mo, the two armsof the study largely and consistently were unbalanced in termsof BP reductions across the study but especially in the first6 mo. The larger BP reduction that was observed in the amlodipinegroup heavily affected the outcome, as discussed and demonstratedextensively by the authors in a vast post hoc analysis (35).In conclusion, he hypothesis of the study could not be testedbecause of the pitfalls in the design, and to acknowledge thata better control of BP may generate better outcomes probablydid not need such a study.
Some aspects of these two mega-trials also clarify why it sometimesis difficult to translate EBM to clinicians. For instance, the"intention-to-treat" analysis, which is more than acceptablefrom the scientific standpoint and represents an essential requirementof objectivity in a trial, is unacceptable and impossible tounderstand from a clinical standpoint. For instance, in theALLHAT (20) and VALUE (27) mega-trials, almost 25% of the patientscross-switched to other drugs, often including the comparator,but they still were considered as belonging to the originaltreatment group. Another example is that in ALLHAT (20), becauseof the experimental design and protocol, the rational combinationswere denied to the patients, and the combinations that wereused to achieve BP targets were not rational and often wereobsolete. This is hardly transferable to the clinical practice,and, in the end, the results achieved represent almost a theoreticalexercise.
In addition, the results of a trial should be applied only forthe time frame of the observations (usually approximately 5yr). In contrast, they often are extrapolated to a life-longtreatment. In this regard, the case of new-onset diabetes clearlyshows that this extrapolation is unwarranted. In fact, boththe ALLHAT (20) and VALUE (27) trials clearly showed a highernew onset of diabetes (e.g., chlorthalidone in the ALLHAT [20])versus the drug blocking the RAS. This may suggest an expected,projected risk of a specific treatment beyond the time bordersof the study. With regard to the issue of combination therapy,the most frequent approach to hypertension, it also is evidentthat all of the head-to-head studies mostly were designed toshow superiority of one drug to the other in a combination modeland contributed very little to learning about which is the bestapproach to combination.
It is of interest that other studies that included hypertensivepatients but used more homogeneous populations, from the pointof view of the natural history of the disease, as reflectedby the presence of a certain target organ disease (e.g., leftventricular hypertrophy, microalbuminuria) (14–18,28,29,36,37)or risk profile (12,21,27), originated more positive and meaningfulresults on primary end points (Figure 1). As a consequence,the focus of interventional trials probably should change andshift toward more clinically oriented targets. In this regard,the use of intermediate informative end points, such as leftventricular structure or (systolic/diastolic) function, atrialfibrillation, microalbuminuria and renal function, vascularstructural and functional abnormalities, metabolic disorders,or new-onset diabetes, may prove to be more fruitful and moreeconomic at the same time (36,38–43) (Figure 1).
Figure 1. Central role of intermediate end points in the cardiovascular and renal continuum and new targets of therapy. LVH, left ventricular hypertrophy; LVD, left ventricular dysfunction; CHF, congestive heart failure; AMI, acute myocardial infarction; IGT, impaired glucose tolerance.
There is little question that this approach may yield resultsthat are closer to clinical reality and be more easily verifiable.In fact, the results of a single trial can be applied to a specificpatient profile. In addition, the prevention or the regressionof a certain clinical marker (e.g., left ventricular hypertrophy,peripheral vascular atherosclerosis, microalbuminuria) (14–18,28,29,36,37)can be checked by the physician in her or his clinical practice,something that could not be done with hard end points. In thisregard, some recent trials that were performed with drugs thatact on the RAS (ACE-I and angiotensin II receptor blockers [ARB])demonstrated a better efficacy and tolerability in hypertensivepatients in different settings among the cardiovascular continuum,as reported in Table 1.
The Case of RAS in Clinical Trials: Benefits beyond BP Control?
In interpreting the results of a mega-trial in hypertensionand transferring the conclusions to daily practice, it mustbe considered that the potential benefit on outcomes dependslargely on individual absolute cardiovascular risk. In addition,unrecognized pathophysiologic features of the patients may affectthe response to various drugs, especially when comparing mechanisticallydifferent compounds that may exert different effects on BP andoutcomes. In this view, despite comparable effects on BP, differentantihypertensive agents may have different effects on targetorgan damage or outcomes. For instance, the individual reninprofile (high or low) may affect the response to the antihypertensiveagents (larger benefit for a drug’s counteracting theRAS in a high-renin patient). The case of RAS-blocking agents(ACE-I and ARB) indeed is very intriguing and debated, and itprobably is for this reason that it is investigated extensivelyalso in mega-trials. After the "ACE-I age," now it is the timefor ARB to be the most investigated class of drugs in cardiovascularand renal disorders.
In this regard, a large body of evidence has been provided insupport of a role for drugs that interact with the RAS in thetreatment of hypertensive patients with different comorbidities.Blocking the RAS with an ACE-I or an ARB has been shown to reducecardiovascular end points in a variety of conditions, includingisolated systolic hypertension (40), left ventricular hypertrophy(36), atrial fibrillation (41,42), ischemic stroke (43), acutemyocardial infarction and coronary artery disease (23,25,30),heart failure with left ventricular dysfunction (10,11,19,26),microalbuminuria, and type 2 diabetes (14–18,28,29,37).
In this view, the most selective way of blocking the RAS isto use an ARB, because of the specific action, e.g., blockadeof the interaction between angiotensin II and the AT1 receptor(44). This selectivity also may be important because the interactionbetween residual, unbound angiotensin II and the AT2 subtypereceptors may result in an amplification of the beneficial effectsof AT1 blockade and may favor vasorelaxation and reduce developmentof hypertrophy and cardiovascular remodeling (44). This complexpathophysiologic structure of the RAS can hardly be faced wheninterpreting a mega-trial, although this attempt has been madefrequently (9,45). Recently, a growing number of mega-trialshave supported a role for ARB in primary and secondary preventionof cardiovascular and renal disease.
The Losartan Intervention for Endpoint Reduction in Hypertension(LIFE) Study (21) has strongly suggested benefits that go beyondBP reduction in hypertensive patients with left ventricularhypertrophy. In the presence of comparable BP reductions witha treatment regimen that is based on the ARB losartan versusa treatment regimen that is based on the blocker atenolol,the losartan-based treatment significantly reduced the riskfor the primary combined endpoint of cardiovascular death, stroke,and acute myocardial infarction by 13% and the incidence offatal and nonfatal stroke by 25% compared with atenolol in >9000patients who were selected on the basis of the presence of essentialhypertension and left ventricular hypertrophy. Further substudieson the population of the LIFE Study have demonstrated beneficialeffects of losartan on intermediate end points that could notbe ascribed to simple BP reductions, in particular in patientswith isolated systolic hypertension (40), left ventricular hypertrophy(36), new onset of atrial fibrillation (41,42), microalbuminuriaand renal disease (38,39), and diabetes (37).
As mentioned above, an important clinical effect of RAS-blockingtreatments, in particular those that are based on an ARB regimen,is the lower incidence of new-onset diabetes compared with diuretic-, blocker–, or calcium channel blocker–based regimens.This has been shown in a number of trials, including the ALLHAT(20), the LIFE study (37), the Captopril Prevention Project(CAPPP) (46) and, more recently, a convincing analysis of theVALUE Study (27). In fact, recent studies (47,48) show thatnew-onset diabetes during long-term antihypertensive treatmentis associated with poor prognosis. In addition, it is widelyknown that development of diabetes in hypertension acceleratesrenal impairment and evolution toward ESRD. This favorable impactof the drugs’ inhibiting the RAS, particularly ARB, ondevelopment of diabetes is attributable to specific mechanisms(49) associated with angiotensin II blockade (50) and cannotbe accounted for only by the detrimental metabolic effects ofthe comparators (diuretics and blockers). Renal protectionis another important goal of therapy in diabetes, hypertension,and atherosclerotic diseases and has a significant influenceon the overall prognosis of patients. Blocking the RAS representsa successful strategy to slow the progression of renal impairmentin these diseases, and this has been confirmed in three largeclinical trials with ARB in diabetic nephropathy (16–18,29).In fact, ARB have been demonstrated to delay the progressionfrom microalbuminuria to macroalbuminuria in the IrbesartanMicroalbuminuria type 2 Diabetes Mellitus in Hypertensive Patients(IRMA 2) trial (17) and even to delay the further progressionfrom macroalbuminuria to ESRD in the Irbesartan Diabetic NephropathyTrial (IDNT) (16) and in the Reduction of Endpoints in Non-Insulin-DependentDiabetes Mellitus with the Angiotensin II Antagonist Losartan(RENAAL) study (18). In addition, the MicroAlbuminuria Reductionwith VALsartan (MARVAL) study (15) showed that in presence ofstrictly similar BP reduction, a treatment that is based onthe ARB valsartan significantly reduces microalbuminuria excretionmore than a regimen that is based on calcium-channel blockeramlodipine. Recently, in the Diabetics Exposed to TelmisArtanand EnalaprIL (DETAIL) Study (29), the ARB telmisartan was shownnot to be inferior to the ACE-I enalapril in providing renoprotectionin patients with type 2 diabetes and early nephropathy. On thebasis of this clinical evidence, the most recent managementguidelines (34,51) recommend the early inhibition of RAS, particularlyin patients with nephropathy, and the use of a therapeutic regimenthat is based on ARB as the first choice in patients with type2 diabetes.
The epidemiologic "trialist" community needs to alter its approach,namely by seeking to add to rather than to substitute for theaccumulated biochemical, physiologic, and pharmacologic knowledgeabout hypertension and cardiovascular disease. The powerfultools that are offered by an epidemiologic approach to hypertensionneed to be integrated more properly into the overall networkof pathophysiology and clinical science to create the best medicalpractice and should not be used to dismantle it.
Reasonable changes and alternative strategies in designing clinicaltrials will be required to address the large and growing numberof key epidemiologic and clinical issues that still need answers.After the impressive and, sometimes, unreasonable rush to challengedrugs by comparisons on major hard end points, which often hasbeen generated for marketing reasons, rather than from genuinescientific needs, it is time now to move toward more pragmaticmodels. The new studies in hypertension should be of smallersize, be less expensive, be more independent, involve more homogeneouspopulations (from this point of view, the more selected populationsample, used in recent studies, provides an excellent example),and address end points that are relevant to practice and verifiableby physicians.
Alderman MH: The limitations of transferring evidence from clinical trials to the care of individual patients.
High Blood Press Cardiovasc Prevent 12
: 5
–7, 2005[CrossRef]
The CONSENSUS Trial Study Group: Effect of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).
N Engl J Med 316
: 1429
–1435, 1987[Abstract]
Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H: Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II).
N Engl J Med 327
: 678
–684, 1992[Abstract]
The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.
N Engl J Med 327
: 685
–691, 1992[Abstract]
The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
N Engl J Med 325
: 293
–302, 1991[Abstract]
Vantrimpont P, Rouleau JL, Wun CC, Ciampi A, Klein M, Sussex B, Arnold JM, Moye L, Pfeffer M: Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators.
J Am Coll Cardiol 29
: 229
–236, 1997[Abstract]
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
Lancet 342
: 821
–828, 1993[Medline]
Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC: A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
N Engl J Med 333
: 1670
–1676, 1995[Abstract/Free Full Text]
Ryden L, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Packer M, Poole-Wilson PA: Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial.
Eur Heart J 21
: 1967
–1978, 2000[Abstract/Free Full Text]
Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI: Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE).
Lancet 349
: 747
–752, 1997[CrossRef][Medline]
Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B: Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial—The Losartan Heart Failure Survival Study ELITE II.
Lancet 355
: 1582
–1587, 2000[CrossRef][Medline]
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
N Engl J Med 342
: 145
–153, 2000[Abstract/Free Full Text]
PROGRESS Collaborative Group: Randomized trial of perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack.
Lancet 358
: 1033
–1041, 2001[CrossRef][Medline]
The Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN) Study Group: A long-term, randomised clinical trial to evaluate the effects of ramipril on the evolution of renal function in chronic nephropathies. The Ramipril Efficacy In Nephropathy (REIN) Study.
J Nephrol 3
: 193
–202, 1991
Viberti G, Wheeldon NM; MicroAlbuminuria Reduction with VALsartan (MARVAL) Study Investigators: Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: A blood pressure-independent effect.
Circulation 106
: 672
–678, 2002[Abstract/Free Full Text]
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
N Engl J Med 345
: 851
–860, 2001[Abstract/Free Full Text]
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
N Engl J Med 345
: 870
–878, 2001[Abstract/Free Full Text]
Herman WH, Shahinfar S, Carides GW, Dasbach EJ, Gerth WC, Alexander CM, Cook JR, Keane WF, Brenner BM: Losartan reduces the costs associated with diabetic end-stage renal disease: The RENAAL study economic evaluation.
Diabetes Care 26
: 683
–687, 2003[Abstract/Free Full Text]
Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
N Engl J Med 345
: 1667
–1675, 2001[Abstract/Free Full Text]
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA 288
: 2981
–2997, 2002[Abstract/Free Full Text]
Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol.
Lancet 359
: 995
–1003, 2002[CrossRef][Medline]
Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the OPTIMAAL Study Group: Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan.
Lancet 360
: 752
–760, 2002[CrossRef][Medline]
Fox KM: EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators: Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet 362
: 782
–788, 2003[CrossRef][Medline]
Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ; Second Australian National Blood Pressure Study Group: A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly.
N Engl J Med 348
: 583
–592, 2003[Abstract/Free Full Text]
Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM; Valsartan in Acute Myocardial Infarction Trial Investigators: Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
N Engl J Med 349
: 1893
–1906, 2003[Abstract/Free Full Text]
Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators and Committees: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme.
Lancet 362
: 759
–766, 2003[CrossRef][Medline]
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A; VALUE trial group: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial.
Lancet 363
: 2022
–2031, 2004[CrossRef][Medline]
Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators: Preventing microalbuminuria in type 2 diabetes.
N Engl J Med 351
: 1941
–1951, 2004[Abstract/Free Full Text]
Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J; Diabetics Exposed to Telmisartan and Enalapril Study Group: Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.
N Engl J Med 351
: 1952
–1961, 2004[Abstract/Free Full Text]
Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL; PEACE Trial Investigators: Angiotensin-converting-enzyme inhibition in stable coronary artery disease.
N Engl J Med 351
: 2058
–2068, 2004[Abstract/Free Full Text]
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; ASCOT investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial.
Lancet 361
: 1149
–1158, 2003[CrossRef][Medline]
Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists’ Collaboration: Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: Results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration.
Lancet 356
: 1955
–1964, 2000[CrossRef][Medline]
Andersson OK, Almgren T, Persson B, Samuelsson O, Hedner T, Wilhelmsen L: Survival in treated hypertension: Follow-up study after two decades.
BMJ 317
: 167
–171, 1998[Abstract/Free Full Text]
Chobanian A, Bakris G, Black H, Cushman W, Green L, Izzo J, Jones D, Materson B, Oparil S, Wright J, Roccella E: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report.
JAMA 289
: 2560
–2571, 2003[Abstract/Free Full Text]
Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L, Hua T, Laragh JH, McInnes GT, Mitchell L, Plat F, Schork MA, Smith B, Zanchetti A: Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.
Lancet 363
: 2049
–2051, 2004[CrossRef][Medline]
Devereux RB, Dahlof B, Gerdts E, Boman K, Nieminen MS, Papademetriou V, Rokkedal J, Harris KE, Edelman JM, Wachtell K: Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint reduction in hypertension (LIFE) trial.
Circulation 110
: 1456
–1462, 2004[Abstract/Free Full Text]
Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S; LIFE Study Group: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol.
Lancet 359
: 1004
–1010, 2002[CrossRef][Medline]
Ibsen H, Wachtell K, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlof B, Devereux RB, De Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wan Y: Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A Losartan Intervention for Endpoint reduction in hypertension (LIFE) substudy.
J Hypertens 22
: 1805
–1811, 2004[CrossRef][Medline]
Olsen MH, Wachtell K, Bella JN, Calmieri V, Gerdts E, Smith G, Nieminen MS, Dahlof B, Ibsen H, Devereux RB: Albuminuria predicts cardiovascular events independently of left ventricular mass in hypertension: A Losartan Intervention for Endpoint reduction in hypertension (LIFE substudy).
J Hum Hypertens 18
: 453
–459, 2004[CrossRef][Medline]
Kjeldsen SE, Dahlof B, Devereux RB, Julius S, Aurup P, Edelman J, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Snapinn S, Wedel H: Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: A Losartan Intervention for Endpoint reduction in hypertension (LIFE) substudy.
JAMA 288
: 1491
–1498, 2002[Abstract/Free Full Text]
Wachtell K, Hornestam B, Lehto M, Slotwiner DJ, Gerdts E, Olsen MH, Aurup P, Dahlof B, Ibsen H, Julius S, Kjeldsen SE, Lindholm LH, Nieminen MS, Rokkedal J, Devereux RB: Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study.
J Am Coll Cardiol 45
: 705
–711, 2005[Abstract/Free Full Text]
Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlof B, Ibsen H, Julius S, Kjeldsen SE, Lindholm LH, Nieminen MS, Devereux RB: Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study.
J Am Coll Cardiol 45
: 712
–719, 2005[Abstract/Free Full Text]
Kizer JR, Dahlof B, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel S, Wachtell K, Edelman JM, Snapinn SM, Harris KE, Devereux RB: Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study.
Hypertension 45
: 46
–52, 2005[Abstract/Free Full Text]
Volpe M, Musumeci B, De Paolis P, Savoia C, Morganti A: Angiotensin II AT2 receptor subtype: An uprising frontier in cardiovascular disease?
J Hypertens 21
: 1429
–1443, 2003[CrossRef][Medline]
Verma S, Strauss M: Angiotensin receptor blockers and myocardial infarction.
BMJ 329
: 1248
–1249, 2004[Free Full Text]
Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial.
Lancet 353
: 611
–616, 1999[CrossRef][Medline]
Alderman MH, Cohen HW, Sealey JE, Laragh JH: Plasma renin activity levels in hypertensive persons: Their wide range and lack of suppression in diabetic and in most elderly patients.
Am J Hypertens 17
: 1
–7, 2004[CrossRef][Medline]
Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C: Adverse prognostic significance of new diabetes in treated hypertensive subjects.
Hypertension 43
: 963
–969, 2004[Abstract/Free Full Text]
Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC: Angiotensin blockade prevents type 2 diabetes by formation of fat cells.
Hypertension 40
: 609
–611, 2002[Abstract/Free Full Text]
Sowers JR: Insulin resistance and hypertension.
Am J Physiol Heart Circ Physiol 286
: H1597
–H602, 2004[Abstract/Free Full Text]
European Society of Hypertension-European Society of Cardiology Guidelines Committee: 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.
J Hypertension 21
: 1011
–1053, 2003[CrossRef][Medline]
Top
Abstract
Introduction
blockers and angiotensin-converting enzyme inhibitors (ACE-I), had transformed malignant hypertension from a rapid and often fatal multisystem disease into a chronic, although still harmful, condition (2–11). After these first experiences, in the past 2 decades, especially during the past 10 yr, an impressive number of clinical trials have been designed and undertaken to investigate whether different antihypertensive agents provide different cardiovascular protection benefits independent of substantially comparable BP-lowering properties (2–31). To achieve significant information on hard end points, these studies involved and observed for several years large cohorts of hypertensive patients ranging from a few hundred to several thousand individuals. The most common population profile was represented by individuals with mild to moderate hypertension with the purpose to define whether the benefit of BP could be extrapolated to the general population of individuals whose BP was elevated. 
