Fewer Mega-Trials and More Clinically Oriented Studies in Hypertension Research? The Case of Blocking the Renin-Angiotensin-Aldosterone System

Abstract

In recent years, medical practice has been influenced substantially by several factors, including the overwhelming development of evidence-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 the effects of drugs or treatments on hard end points that cannot be 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 response or behavior of large populations rather than of individuals, is systematically replacing the former knowledge and reference points of the physician, as a substitute rather than as an aid. Taking into account the case of hypertension and particularly the renin-angiotensin system-blocking agents, this article reviews the issues and limitations of transferring evidence from mega-trials to clinical practice and suggests new strategies to make trials more effective and transferable to the case of individual patients.J Am Soc Nephrol 17: S36 -S43, 2006S36 -S43, . doi: 10.1681 I n the past two decades, medical practice has been influenced and modified substantially by several factors, including the overwhelming development of evidencebased medicine (EBM), which is a consequence of the impressive, growing number of large clinical trials, the socalled "mega-trials." These clinical studies are designed mostly to investigate the effects of drugs or treatments on hard end points, such as overall cardiovascular mortality, myocardial infarction, ischemic stroke, heart failure, ESRD, and, more in general, major prognostic outcomes, all items that cannot be 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 response or behavior of large population samples rather than of individuals, is systematically replacing the former knowledge and reference points of the physician, as a substitute rather than as an aid. Besides and beyond the personal clinical experience and professional skills and a sufficient knowledge of pathophysiologic mechanisms and pharmacologic drug properties, today each individual physician is required to be aware of the results of many trials and to transfer them to her or his clinical activity. Any significant deviation from the strict application of EBM to therapeutic management of the clinical cases may seem not to be justified.In fact, the results of large international trials are more and more perceived not as a valid basis for therapeutic decisions but rather as the only evidence that can validate a treatment or an intervention. As a consequence, doctors are becoming more prone 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 happen...

Calcium Channel Blockers and Hypertension

“…10,11 Results of large, randomized, controlled clinical trials demonstrated that it is possible to reach these BP targets in large proportions of treated patients with hypertension having different cardiovascular risk profiles. [12][13][14] Indeed, the design of these clinical trials systematically included antihypertensive therapies based on drugs inhibiting the renin-angiotensin system (RAS) and calcium channel blockers (CCBs) compared to b-blockers and diuretics. [12][13][14] On the basis of these findings, a preferred use of these antihypertensive drug classes have been pursued by recent hypertension guidelines, in order to bridge the gap between the attained and expected BP control rates, to ensure adequate adherence and persistence to prescribed medications and to improve cardiovascular outcomes in treated patients with hypertension.…”

“…[12][13][14] Indeed, the design of these clinical trials systematically included antihypertensive therapies based on drugs inhibiting the renin-angiotensin system (RAS) and calcium channel blockers (CCBs) compared to b-blockers and diuretics. [12][13][14] On the basis of these findings, a preferred use of these antihypertensive drug classes have been pursued by recent hypertension guidelines, in order to bridge the gap between the attained and expected BP control rates, to ensure adequate adherence and persistence to prescribed medications and to improve cardiovascular outcomes in treated patients with hypertension. 10,11 Being the vast majority of these evidence based on the use of dihydropyridinic CCBs, these drugs are now recommended both as first-line therapy and as an ideal partner for dual or triple combination therapies for the clinical management of hypertension and hypertension-related comorbidities.…”

A Novel Electrocardiographic T‐Wave Measurement (Tp‐Te Interval) as a Predictor of Heart Abnormalities in Hypertension: A New Opportunity for First‐Line Electrocardiographic Evaluation

“…[29][30][31][32] As such, ECG detection, as well as regression of cardiac OD, namely LVH, can be viewed as an intermediate endpoint that may help physicians during the long-term clinical management of hypertension. 33,34 Over the past years, several novel ECG criteria for LVH have been tested for the diagnostic workup of hypertensive outpatients in order to try to overcome some intrinsic limitations of this approach and to ameliorate its relatively low specificity. 35 The applicability of these new diagnostic criteria, however, was at least, in part, limited to frankly hypertensive populations (ie, patients with established diagnosis of hypertension under pharmacologic treatment), and it has not been tested in untreated, recently diagnosed hypertensive patients.…”

Combination Therapy for the Clinical Management of Hypertension

“…The benefi ts of RAS-inhibiting drugs in different clinical conditions have been demonstrated in different clinical settings, from asymptomatic patients with cardiac disease to severe refractory heart failure, end-stage renal disease and cardiovascular death [ 37 ]. In particular, the favourable effects of RAS-blocking agents, including both ACE inhibitors and ARBs, as compared to conventional treatment (mostly including beta-blockers and diuretics) have been extensively tested in a large, representative population and corroborated by the achievement of reduced cardiovascular morbidity and mortality [ 37 ].…”

“…In particular, the favourable effects of RAS-blocking agents, including both ACE inhibitors and ARBs, as compared to conventional treatment (mostly including beta-blockers and diuretics) have been extensively tested in a large, representative population and corroborated by the achievement of reduced cardiovascular morbidity and mortality [ 37 ]. On the basis of the observation that in most cases both ACE inhibitors or ARBs were systematically associated with other classes of antihypertensive drugs, mostly thiazide diuretics or CCBs, it has been suggested that implementing the use of combination therapies based on drugs able to inhibit the deleterious effects of abnormal RAS activation may also improve BP control and tolerability, beyond the favourable effects on cardiovascular protection in the clinical management of hypertension.…”