Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Università di Milano and Istituto Auxologico Italiano, Milan, Italy
Correspondence to Professor Alberto Zanchetti, Centro di Fisiologia Clinica e Ipertensione, via F. Sforza 35, 20122 Milan, Italy E-mail: email@example.com, firstname.lastname@example.org
The issue of how strictly evidence-based management of hypertension should be often returns to be discussed. These reflections have been stimulated by the interesting reading of a recent volume  published with the meritorious intention to help doctors manage high blood pressure with decisions based on solid scientific evidence. Hypertension is an area of cardiovascular medicine in which evidence in favour of therapeutic intervention was searched for by randomized controlled intervention trials long before the same methodology was applied to the treatment of other cardiovascular illnesses, such as myocardial infarction and heart failure . Despite this pioneering approach, readers of this recent volume may be surprised to discover how scanty is the real evidence available on many issues of practical importance. Although I do not share the enthusiasm of many theorists of evidence-based medicine for a Linnean-like classification of levels and grades of evidence (why post-hoc analyses when called meta-analyses should bring forth a higher level of evidence than correctly conducted randomized trials?), the use of these symbols throughout this volume  allows the readers to realize quickly how rarely the top evidence symbols Ia/A or Ib/B could be used.
This does not mean that antihypertensive therapy is not founded on evidence. On the contrary, the evidence that high blood pressure is one of the most important and widely prevalent risk factor for cardiovascular disease is very solid and incontrovertible . Likewise, substantial reduction of cardiovascular morbidity and mortality by lowering blood pressure has been established beyond any doubt by a host of placebo-controlled trials in the last 30 years of the past century  that have placed antihypertensive therapy in the forefront of evidence-based medicine .
However, most of the practical questions worth being investigated once the benefit of lowering blood pressure had been established have remained substantially unexplored. Not that there have been few trials of antihypertensive treatment in the last 20 years or so, but too many of them have focused on comparing the benefits of different antihypertensive regimens, with the intent to show specific benefits of new agents or, vice versa, the superiority of the older ones. This is not to deny that these comparative trials have led to useful information, but 46 trials and more than 230 000 patients  have probably been too many to end up with the current conclusion that what really matters is lowering blood pressure whatever the agents administered [5–8].
Some of the everyday questions raised by the management of hypertension have remained unanswered. Whom should we treat? Should we also treat uncomplicated hypertensive patients and individuals with high normal blood pressure if complicated by metabolic disturbances, diabetes or concurrent cardiovascular disease? How far should blood pressure be reduced? Is goal blood pressure different in complicated or uncomplicated hypertension, in the elderly and in the young hypertensive patients?
The reappraisal document of the European guidelines prepared by a European Society of Hypertension Task Force  1 year ago, based as it was on a critical review of available trial evidence , clearly made the point that most of these practical issues have not been, or have not sufficiently been, investigated by randomized trials, and there is no direct evidence for recommending antihypertensive treatment to be given to a high normal blood pressure individual even if with previous cardiovascular events. Likewise, no direct evidence is available either in favour of lower blood pressure targets for high-risk patients, or vice versa, against too aggressive blood pressure lowering because of a raised threshold for cardiac or cerebral autoregulation in these patients (J-shaped curve) . This critical reappraisal of European guidelines has been very warmly received in the United States . Although not citing these previous papers, the opening chapter of the recent volume on Evidence-based management of hypertension  correctly shares all these conclusions, and must be commended for the neatness of its positions.
The strength of opinion over evidence, however, is sometimes creeping through even in a volume explicitly focused on evidence. For example, a statement in favour of lowering blood pressure below 130/80 mmHg in diabetic patients or in patients with chronic kidney disease, which is correctly refuted in chapter 1, is given class Ia/A or Ib/B rank in other chapters. The statement that blood pressure lowering can reduce cardiovascular outcomes in patients with coronary heart disease and ‘normal’ blood pressure is given Ib/A status because of the results of the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial , which for the same blood pressure decrease showed benefit from amlodipine and no benefit from enalapril, and, therefore, may be used, at best, to support superiority of an agent versus another, rather than efficacy of blood pressure reduction. The results of Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE)  and A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system (ACTION) trials  are not cited, nor are the opposite ones of the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) trial , otherwise the same high rank (Ib/A) should have been given to two opposite statements.
This is not a specific criticism to any particular publication, as this approach is common even to guidelines in which opinions and often compromise between opinions dominate. This is only to show that even a rigid taxonomic classification of evidence by levels and grades does not help much, if Ia/A rank can be attributed to a statement like the following: ‘…… tend to provide possible benefits ……’.
The conclusion of these reflections is not that management of hypertension should only rely on evidence provided by randomized trials. Randomized trials provide strong evidence, but their results are sometimes contradictory and meta-analyses – as all post-hoc analyses – are not proofs but hypotheses generating instruments. Other sources of evidence should be used to support reasonable opinions, but the strength of opinions is not the same as that of a large well designed and efficiently conducted randomized trial. Differences in opinion are legitimate and proficuous, but averaging different opinions in a consensus document does not make the average opinion necessarily right. This does not mean guidelines are not useful. On the contrary, they are certainly useful and important, provided they are not conceived as prescriptive documents but rather as a source of critical information. This has always been the wise position taken in the preparation of the European hypertension guidelines [7,8], and probably this is the main reason why they have been so widely accepted even outside Europe.
At a time when a new US Joint National Committee (JNC) report is to be announced soon, and the procedure for the third edition of the European guidelines is being started, a humble suggestion is to keep clearly distinct, on one side, the firm recommendations that can be given about a few but fundamental issues on the basis of solid, coherent information from randomized trials, and, on the other side, those recommendations concerning issues that have insufficiently been explored by trials, or for which only indirect evidence is available and recourse has to be made to reasonable opinions or experts' wisdom. This clear distinction (which we have seen can hardly be achieved by ranking or labelling recommendations by numbers and letters) will greatly help the authority of guidelines: it will show that guidelines prepared by various bodies or committees in different parts of the world do not really differ in those issues for which evidence is available, but rather in those recommendations still based on opinions (which can often differ) or on ‘wisdom’ (which is not always equally wise).
Nonetheless, now and in the foreseeable future, management of hypertension will be based not only on evidence but also on wisdom. What is important, however, is that wisdom is not taken as solid evidence: taking wisdom for evidence has been a powerful obstacle to clarification of some relevant issues of hypertension management by discouraging the design of adequate randomized trials. Among these orphan issues, probably the most important is investigating the optimal blood pressure target for antihypertensive treatment, particularly in high-risk patients, in whom a few mmHg lower blood pressure may markedly increase the benefit or the risk.
1 Weir MR (ed). Evidence-based management of hypertension
. Harley, UK: Tmf Publishing Ltd; 2010. pp. X-232.
2 Zanchetti A. Evidence-based medicine in hypertension: what type of evidence? J Hypertens 2005; 23:1113–1120.
3 Lewington S, Clarke R, Qizilbash N, Peto N, Collins R, Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903–1913.
4 Collins R, Peto R, MacMahon S, Herbert P, Fieback NH, Eberlein KA, et al
. Blood pressure, stroke, and coronary heart disease. Part 2: Short-term reductions in blood pressure – overview of randomised drug trials in their epidemiological context. Lancet 1990; 335:827–838.
5 Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338:1665–1683.
6 Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et al
, Blood Pressure Treatment Trialists' Collaboration. Effects of different blood pressure lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus. Results of prospectively designed overviews of randomized trials. Arch Intern Med 2005; 165:1410–1419.
7 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 Hypertens
8 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al
. 2007 guidelines for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology. J Hypertens 2007; 25:1105–1187.
9 Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al
. Reappraisal of the European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27:2121–2158.
10 Zanchetti A, Grassi G, Mancia G. When should antihypertensive drug treatment be initiated and to what level should systolic blood pressure be lowered? A critical reappraisal. J Hypertens 2009; 27:923–934.
11 Zanchetti A. Blood pressure targets of antihypertensive treatment: up and down the J-shaped curve. Eur Heart J
2010. [Epub ahead of print]
12 Weber MA, Materson BJ. Hypertension guidelines: a major reappraisal critically examines the available evidence. J Clin Hypertens 2010; 12:229–236.
13 Nissen SE, Tzcu EM, Libby P, Thomson PD, Ghali M, Garza D, et al
. Effects of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT Study – a randomized controlled trial. JAMA 2004; 292:2217–2225.
14 Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, et al
, The PEACE trial investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351:2058–2068.
15 Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, et al
, A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system investigators. Effects of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): a randomised controlled trial. Lancet 2004; 364:849–857.
16 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 2003; 362:782–788.
© 2011 Lippincott Williams & Wilkins, Inc.