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Treating high blood pressure: Is reaching the target more important than the means? Yes, the target is more important
European Journal of Internal Medicine 21 (2010) 473–477
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Debate
Treating high blood pressure: Is reaching the target more important than the means? Yes, the target is more important Ettore Bartoli ⁎, Gian Piero Carnevale Schianca, Pier Paolo Sainaghi Internal Medicine, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi del Piemonte Orientale “A. Avogadro”, Via Solaroli, 17, 28100 Novara, Italy
a r t i c l e
i n f o
Article history: Received 22 September 2010 Accepted 24 September 2010 Available online 27 October 2010 Keywords: Arterial hypertension Treatment Target
a b s t r a c t The effectiveness of hypertension treatments is attributed either to the change in blood pressure, independent of the means used, or to an important contribution of appropriate drug selection: this debate probably stems from an inappropriate comparison. Treating essential hypertension in relatively healthy patients without advanced vascular disease and comorbidities affords cardio-vascular protection by the lowering of the mechanical shear stress determined by blood pressure per se: thus, lowering blood pressure is the critical step, while the methods used can only differ through side effects. This treatment is, in fact, a lifetime prophylaxis, as hypertension, rather than a disease, is a symptom affecting one tail of the Gaussian distribution of blood pressure across the normal population. Treating hypertension in the context of diseases, like diabetes mellitus, congestive heart failure, left ventricular hypertrophy, and advanced atherosclerosis, would be improper if focused on just one symptom, while the appropriate treatment must include options which exhibit a more extended profile to include effectiveness on cardiac hypertrophy, insulin resistance, cardiac output, and systemic hemodynamics: thus, drugs may be different in their effectiveness and in the cardio-vascular protection afforded, even though the trials quoted in favour of this thesis were designed to compare drugs in their ability to lower blood pressure rather than in improving the overall complex clinical derangements. In conclusion, while the answer to the question is a sharp YES when dealing with primary prevention, it might be a NO, still clouded by contradictory and inconclusive evidence when dealing with secondary prevention and/or treatment of complex disease conditions and co-morbidities. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
It is well known that treating hypertension is clinically indicated and useful for patients [1]. This evidence was initially based on observations made on normal subjects, where the cardio-vascular risk is a monotonous function of the absolute value of blood pressure [2]. Studies performed on cohorts affected by hypertension demonstrated that cardio-vascular risk regresses to that observed in untreated subjects exhibiting spontaneously the same blood pressure reached by patients on treatment. However, this is not entirely true, since subjects with hypertension, when treated, still retain some degree of the cardio-vascular risk despite the absence of cardio-vascular complications, suggesting the existence of a “residual risk”; in other words, it is possible that the organ damage is already irreversible or only partially reversible when treatment is started [3]. These established data [4] were implemented with more recent evidence, constituting the background justifying the European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines, issued by Mancia et al. [5].
⁎ Corresponding author. Tel.: + 39 0321 3733361; fax: + 39 0321 3733841. E-mail address: [email protected] (E. Bartoli).
This debate stems from the fact that these and other similar guidelines are not shared by the entire scientific community dedicated to hypertension, such that many authors contend that different protective effects can be attained when resorting to different means of abating hypertension. The major point on which the discussion hinges is represented by the “J” curve: reducing blood pressure is attended by a monotonous fall in cardio-vascular mortality and complications till certain absolute values of blood pressure are reached, beyond which the end points observed rise again by an inverse proportion to any further drop in blood pressure [6,7]. Even this finding is debated, since it has been pointed out that the ascending arm of the J curve at low blood pressure values is observed in smokers, diabetics with associated chronic renal failure, and, more generally, in patients with advanced vascular disease [8]. Thus, this controversy on the J curve is probably the cause of the argument, and, as we shall see in the ongoing discussion, its possible solution. In fact, there is not such a thing as “the” treatment of a disease named hypertension, as blood pressure is distributed across the normal population as a single statistical value: there are not 2 or more Gaussian curves describing the distribution of blood pressure values,
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.09.016
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E. Bartoli et al. / European Journal of Internal Medicine 21 (2010) 473–477
one characterizing normal subjects, the other patients with hypertension: as shown in Fig. 1, one Gaussian profile includes all normal subjects [9]. It follows from this phenomenon that treating hypertension is not equivalent to diagnosing a disease state and trying to re-establish normality: rather, it is the prophylaxis of future cardio-vascular events which are more likely to occur in subjects with a higher blood pressure within the same normal population. Thus, treating hypertension is not analogous to treating a disease, while it obeys to the principles of prevention, a hygienic modification of inherent blood pressure towards healthier values spontaneously occurring in the normal population (Fig. 1). Primary prevention is enforced on normal subjects, to reduce or correct the likelihood of adverse events: this is different from secondary prevention, for any disease and/or risk factor, whether this is hypercholesterolemia, thrombosis, or hypertension. We believe that this constitutes the essential point of the controversy: the objectives and the means of treatment are different in primary prevention, which concerns healthy people, from those required by secondary prevention, which concerns subjects who already suffered adverse events, or are affected by an established disease condition. In the presence of an already established, presumably irreversible vascular disease, we are unavoidably faced with complexity, complications, and with a difficult assessment of the risk/benefit ratio. We believe that these are real patients, and that the physician would behave inappropriately if he tackled only one problem, for instance hypertension, as if he were dealing with prophylaxis, rather than considering the clinical picture as a whole. In other words, there cannot be such a thing as an isolated preventive aspect, distinct from the overall treatment of a complex disease state. On the contrary, the correct approach to any such patient would be to treat him according to priorities and to a correct diagnostic evaluation, trying to include the maximum of his problems with the simplest therapeutic regimen available. Viewed in this context, prophylaxis cannot be separated by the overall treatment plan, because, in fact, it must be included in the plan. Let us consider, for example, a patient with type 2 diabetes mellitus, moderate nephropathy (plasma creatinine N 1 b 2 mg/dL), incipient congestive heart failure with exercise dyspnoea, hypertension with echocardiographic evidence of left ventricular hypertrophy, and episodes of exercise angina lasting b1 minute which regress spontaneously during rest: we are convinced that it would not be an optimal medical practice if the physician addressed only the hypertension, choosing a drug combination, and followed this patient
Fig. 1. Schematic representation of the consequences of anti-hypertensive treatment on the cardio-vascular risk. Since blood pressure values are positively correlated with the cardio-vascular risk, a hypertensive patient with blood pressure in the higher tertile (A), has a high cardio-vascular risk. A correct treatment reducing blood pressure values to the middle tertile (B), can confer a reduction of the cardio-vascular risk to normal, or near normal, values. Further decrements of blood pressure values to the lower tertile (C), will confer a lower cardio-vascular risk. Blood pressure values are distributed as a Gaussian curve (continuous line), while cardio-vascular events are a monotonous function of blood pressure (dashed ordinate on the right, and dashed line). The scales are arbitrary, as they are meant to portray a schematic view of phenomena, for illustrative purposes.
as if he were just hypertensive and only in need of normalizing his blood pressure. No doctor would behave this way. The treatment of the symptom hypertension must be inserted into the treatment of this complexity, and it is, then, the complexity per se that dictates the correct choice of anti-hypertensive drugs: if angina were considered a major concern, a β-blocker would be preferred for hypertension, while if congestive heart failure were bothering the patient to a major extent, a diuretic would be mandatory, their association if both problems were considered priorities. In other words, medicine does not treat any disease entity by addressing each symptom separately: the treatment of a disease is not the adding up of symptomatic interventions. Simple as it is, all trials include a number of these subjects, while none selected the drug treatment of hypertension based on objective data concerning the patients: all trials obey to the necessity of comparing commercial drugs, never do they obey to the principle of the correct practice of medicine, which wants to cure patients. The unescapable conclusion is that these large trials do not give applicable and sound information on how to treat patients, neither do they tell us much on the drugs compared except for the difference in reducing blood pressure, as if this were a magic symbol inextricably connected to the risk of death. To the contrary, in such a context, blood pressure is one of the symptoms of the complexity. Nobody familiar with research would be surprised if similar trials differed in their conclusions, contradicted each other, and created more confusion and doubts than reliable information: they were designed to test drugs on a symptom isolated from a complex context, and they tell us just and simply how much that drug reduced blood pressure. Any drug, to be valuable, must act favourably at least on two sides, hypertension and side effects. For instance, nifedipine does normalize blood pressure, but it can trigger angina, congestive heart failure and atrial fibrillation in patients with asymptomatic coronary heart disease and increased end-diastolic left ventricular pressure. Therefore, the goal “reduce blood pressure” must be enforced per se in the prophylaxis concerning healthy subjects, as an aggregate objective in patients, mainly those affected by complex clinical problems. Reducing blood pressure by reducing cardiac output will gratify the sphygmomanometer, but it could kill the patient: hypertension is much better than low output cardiac failure. Therefore, it is easily understood that drugs with an extended pharmacologic profile could be more effective in reducing cardiovascular end points in trials including diseases and complications. In this context, angiotensin converting enzyme and angiotensin receptor inhibitors fare better than other anti-hypertension medications for the same degree of reduction in blood pressure. They decrease intraglomerular pressure, limiting the shear stress which represents the major factor leading to chronic renal failure in hypertension and diabetes mellitus [10]. They act as peripheral vasodilators, improving cardiac output without increasing blood pressure, while reducing the cardiac post-load [11]. They are effective in correctly remodelling cardiac hypertrophy [12]. They antagonize the cellular effects of the renin–angiotensin–aldosterone system, a powerful compounder of the cardio-vascular risk, while acting as mild diuretics at the same time [13]. Within this extended mechanism of action, it seems arbitrary to attribute the reduction of cardio-vascular end points to the fall in blood pressure: these are due to the complex interaction of risk factors, and, presumably, the key to better survival is the improvement in this interaction. For instance, peripheral vasodilation and a negative Na balance improve left ventricular function, to the point that cardiac output could rise: this may be attended by a rise in blood pressure, or by an unchanged mean blood pressure due to a fall in diastolic, and a rise in systolic blood pressure. These changes, which are simply the improvement or disappearance of congestive heart failure, can cause an important reduction of cardio-vascular end points, while the fall in blood pressure would be minor: in the average data, this could create a drop in the likelihood of cardio-vascular
E. Bartoli et al. / European Journal of Internal Medicine 21 (2010) 473–477
events disproportionate to the change in blood pressure: the “trialists” would claim a greater protection afforded by the drug, which is true, although caused by the improvement of the patient and of his major derangement, represented by congestive heart failure, while it is attributed to a better drug profile in affecting hypertension [14]. We can go back now to the initial rationalization of the debate: for hypertension treatment as a goal per se we should focus on the treatment of essential hypertension affecting a large size of the normal population. For these subjects, treatment is a misnomer, as it is an indefinite prophylaxis of adverse events. Focusing on this population, all the evidence points to a protective effect afforded by the fall in blood pressure, proportional to the entity of the change, independent from the means used to reach the goal [8]. Although the main objective is to normalize blood pressure, reaching subnormal values accrues the protection, with no “J curve” [15]. This goal can be reached by lifestyle modifications, without drugs. Although there are no trials where most risk factors were controlled by lifestyle modifications, there is abundance of studies where one risk factor was controlled without drugs. Each of them managed to reduce, although minimally, blood pressure, and adding up the single effects could reproduce a lifestyle modification of complexity: if this procedure is at least roughly acceptable, lifestyle modification alone could be equivalent to drug treatment, while single initiatives, like physical exercise, would be more beneficial than the advantage expected from the drop in blood pressure alone [16]. At any rate, lifestyle changes, as specified by ESH/ESC guidelines [5], are widely recognized to lower blood pressure and should be considered in hypertension management (Table 1). Drug treatment is also effective, independent from the chemical nature of the drug, proportional to the fall in blood pressure. This does not mean that the choice of anti-hypertensive agents could be done by sorting them out causally, as the choice should be guided by the side effects and by guidelines and common sense rules according to the presumed cause of hypertension, age, lifestyle and occupational problem, compliance. While a proper selection will improve management and compliance, the reduction of the cardio-vascular risk is independent from the drugs chosen. Any empirical agent or combination is equivalent, for the same degree of side effect, to any other for the same degree of blood pressure reached [17–20]. This is presumably due to the fact that, in healthy subjects, the prevention is due to reducing the shear stress on the arterial walls, the factor that determines vascular disease in the long run: as the mechanism “shear stress” is related to blood pressure, the protection afforded is exclusively due to the value of blood pressure attained rather than the drug used [21]. Thus, we answer YES to the question we were asked: reaching the target is more important than the means, with the reservation that this “yes” is acknowledged when restricted to the context of essential hypertension in healthy subjects or patients with no complex derangements and/or advanced vascular disease.
Table 1 Well recognized lifestyle measures to lower blood pressure (modified from 5). Lifestyle modification
Variation expected in systolic blood pressure
Smoking cessation
No effect (recommended for cardio-vascular risk management) Up to 20 mm Hg
Weight reduction (and weight stabilization) Reduction of excessive alcohol intake Physical exercise Reduction of salt intake Increase in fruit and vegetable intake and decrease in saturated and total fat intake
Up to Up to Up to Up to
4 mm 9 mm 8 mm 9 mm
Hg Hg Hg Hg
475
We cannot answer YES with the same confidence in populations where the treatment of hypertension appears to be interconnected with other risk factors and with significant disease states: in this case data are inconclusive, contradictory, and must be taken with caution. Often, side effects of treatment improving a laboratory variable, like proteinuria, are interpreted as demonstrating protection. In fact, reducing blood pressure with any drug improves proteinuria [22–26]. However, this does not necessarily mean that the glomerular disease is improving, as a fall in glomerular pressure must reduce the solvent drag for proteins [27]. Moreover, the fact that the reduced proteinuria correlates with the reduction of the cardio-vascular end points can simply mean that both are linked to the fall in blood pressure, while the reasoning that less proteinuria indicates regression of capillary dysfunction, and that the latter has reduced the cardio-vascular risk is an unjustified inference. Incidentally, the claim that proteinuria decreases during chronic treatment with angiotensin converting enzyme inhibitors and angiotensin receptor inhibitors [22,26] has been disclaimed by Mann in a well designed study involving a large number of patients: the angiotensin receptor inhibitors did not reduce proteinuria, which progressed slightly less during treatment. In addition, patients who received both inhibitors exhibited an important worsening of renal function [28]. To quote a trial which claims that either diuretics [29], or β-blockers [30], or Ca-antagonists [31] are the best, is far from difficult. It is reasonable to think that the necessity of examining a drug effect can deviate the focus of an experimental design where complexity, congestive heart failure, angina, diabetes mellitus and other aspects can cause, in a large cohort, effects that favour one drug over the other and cloud the picture, reducing the level of the information obtained. Thus, the debate about the choice of drug-therapy seems to us a distracter. In fact, the analysis of 29 trials, demonstrated that there were no significant differences in total major cardio-vascular events between regimens based on ACE inhibitors, calcium antagonists, or diuretics or beta blockers, although ACE-inhibitor-based regimens reduced blood pressure less [17]. Clearly it is evident, as cited by ESH/ESC guidelines, “… that main benefits of anti-hypertensive treatment are due to the lowering of blood pressure per se and are largely independent on the specific classes of anti-hypertensive drugs employed” [5]. Moreover, these benefits, as evidenced in recent interventional trials [32–34], should be extended also to the high-risk individuals with “normal or high–normal” blood pressure values. Moreover, the hypothesis that different drugs have specific protective properties derives from clinical trials which display several evident methodological problems first of all, patients from different treatment groups do not always reach equal blood pressure targets, making it impossible to rule out with confidence that a better protection attributed to a specific drug was not in turn determined by a greater anti-hypertensive effect. In addition, clinical blood pressure was the principal variable considered in clinical trials while it is well known that other parameters like ambulatory blood pressure, 24 h blood pressure variability, and night blood pressure drop, do correlate better with cardio-vascular events. Finally, it is possible that the proportion of patients with complicated hypertension enrolled in clinical trials was too high to address specific drug effect since in advanced organ damage due to hypertension blood pressure lowering is probably the only way to protect from further damages [3,35,36]. Perhaps, smaller trials, performed on selected and homogeneous patients, having one clinical derangement besides hypertension, like congestive heart failure, angina, oedema, uncomplicated diabetes mellitus, would be more informative, as they could better separate the two conditions, hypertension and the disease, and examine the improvement of each separately. At any rate, the widespread belief that drugs acting on the renin–angiotensin–system may be endowed with a better profile seems credible [12,32,37–40] even though there are studies reaching this same conclusion for many of the drugs available for chronic treatment of hypertension.
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In any case, several meta-analyses, notwithstanding the limitation expressed above, evidenced specific effects of different dugs in preventing or reducing organ damages. In conclusion, a true, alternative contradiction between the two positions, a sharp YES or NO answer, is probably artificial. Probably, both answers are correct in their proper context: YES in primary prevention, NO in secondary prevention and complex patients with multiple risk factors. While the YES in the former situation seems rather established, the NO in the latter conditions requires more detailed investigations with improved experimental designs, made flexible to the point of more convincingly isolating the reduction in blood pressure from the unavoidable effects on related variables and diseases. Learning points What is known: • Lowering blood pressure with any means reduces the occurrence of cardio-vascular events. • Lowering blood pressure beyond certain low values is attended by a rise in cardio-vascular adverse events, except stroke, mainly in smokers, diabetics and patients with advanced cardio-vascular disease and associated co-morbidities. • In complex clinical conditions where hypertension is associated to important diseases (diabetes mellitus, chronic renal failure, congestive heart failure, and coronary artery disease) and co-morbidities, cardio-vascular end points might be influenced by the choice of anti-hypertensive medications. What this article adds: • The life lasting prophylaxis of future cardio-vascular adverse events in healthy subjects depends upon the blood pressure value attained, independent from the means used to reach the goal. • Any empirical treatment is equally effective when blood pressure is lowered to any given value in primary prevention. • Drug choice in lowering blood pressure is important when the physician chooses to treat the patient and his complex comorbid clinical condition rather than hypertension as an isolated symptom. • The trials magnifying the protective and anti-hypertensive effect of any drug or association compared to others in complex clinical situations, including advanced cardio-vascular disease and co-morbidities, are flawed, contradictory and inconclusive as they address the symptom hypertension, isolated from a complex condition, rather than the patient and/or his disease. They do not reproduce the necessary correct medical treatment, while they enforce a rigid scheme which is not transferable to common clinical practice. References [1] Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease: part 2. Short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 1990;335:827–38. [2] MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765–74. [3] Zanchetti A. Evidence-based medicine in hypertension: what type of evidence? J Hypertens 2005;23:1113–20. [4] Thürmer HL, Lund-Larsen PG, Teverdal A. Is blood pressure treatment as effective in a population setting as in controlled trials? Results from a prospective study. J Hypertens 1994;12:481–90. [5] Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and for the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87. [6] Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane Database Syst Rev 2009;3:CD004349. [7] Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85.
[8] Zanchetti A, Mancia G, Black HR, et al. Facts and fallacies of blood pressure control in recent trials: implications in the management of patients with hypertension. J Hypertens 2009;27:673–9. [9] Hypertension Detection and Follow-up Program Cooperative Group. The Hypertension Detection and Follow-up Program. A progress report. Circ Res 1977;40 (Suppl I):I106–9. [10] Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450–6. [11] Giannattasio C, Cattaneo BM, Omboni S, et al. Sympathomoderating influence of benazepril in essential hypertension. J Hypertens 1992;10:373–8. [12] Lindholm LH, Ibsen H, Dahlof B, et al, 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 2002;359:1004–10. [13] Levy BI, Benessiano J, Henrion D, et al. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest 1996;98:418–25. [14] Borghi C, Ambrosioni E. Evidence-based medicine and ACE inhibition. J Cardiovasc Pharmacol 1998;32:S24–35. [15] D'Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham study. BMJ 1991;303:385–9. [16] Trials of Hypertension Prevention Collaborative Research Group. The effects of nonpharmacologic intervention on blood pressure of persons with high normal levels. Results of the Trials of Hypertension Prevention, Phase I. JAMA 1992;267:1213–20. [17] Turnbull F, Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527–35. [18] Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomized trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665, doi:10.1136/bmj.b1665. [19] Blood Pressure Lowering Treatment Trialists' CollaborationTurnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ 2008;336:1121–3. [20] Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003;21:1055–76. [21] Malek AM, Izumo S. Molecular aspects of signal transduction of shear stress in the endothelial cell. J Hypertens 1994;12:989–99. [22] Weidmann P, Schneider M, Böhlen L. Therapeutic efficacy of different antihypertensive drugs in human diabetic nephropathy: an updated meta-analysis. Nephrol Dial Transplant 1995;10(Suppl 9):39–45. [23] Molyneaux LM, Willey KA, Yue DK. Indapamide is as effective as captopril in the control of microalbuminuria in diabetes. J Cardiovasc Pharmacol 1996;27:424–7. [24] Nielsen FS, Rossing P, Gall MA, et al. Long term impact of lisinopril and atenolol on kidney function in NIDdiabetes mellitus patients with diabetic nephropathy (Abstract). J Am Soc Nephrol 1996;7:1363. [25] Bakris GL, Smith A. Effects of sodium intake on albumin excretion in patients with diabetic nephropathy treated with long-acting calcium antagonists. Ann Intern Med 1996;125:201–4. [26] Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACEinhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999;354:359–64. [27] Lambert PP, Verniory A, Gassée JP, Ficheroulle P. Sieving equations and effective glomerular filtration pressure. Kidney Int 1972;2:131–46. [28] Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-bind, controlled trial. Lancet 2008;372:547–53. [29] Appel LJ. The verdict from ALLHAT-thiazide diuretics are the preferred initial therapy for hypertension. JAMA 2002;288:3039–42. [30] Kennedy HL. Current utilization trends for beta-blockers in cardiovascular disease. Am J Med 2001;110(Suppl 5A):2S–6S. [31] Neal B, MacMahon S, Chapman N, Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of Ace inhibitors, calcium antagonists, and other bloodpressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;356:1955–64. [32] Yusuf S, Sleight P, Pogue J, et al. 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 2000;342:145–53. [33] PROGRESS Collaborative Group. Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6, 105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–41. [34] Schrier RW, Estacio RO, Esler A, et al. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and stroke. Kidney Int 2002;61:1086–97. [35] Mancia G. Role of outcome trials in providing information on antihypertensive treatment: importance and limitations. Am J Hypertens 2006;19(1):1–7. [36] Mancia G. Effects of intensive blood pressure control in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation 2010;122:847–9. 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Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Debate
Treating high blood pressure: Is reaching the target more important than the means? Yes, the target is more important Ettore Bartoli ⁎, Gian Piero Carnevale Schianca, Pier Paolo Sainaghi Internal Medicine, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi del Piemonte Orientale “A. Avogadro”, Via Solaroli, 17, 28100 Novara, Italy
a r t i c l e
i n f o
Article history: Received 22 September 2010 Accepted 24 September 2010 Available online 27 October 2010 Keywords: Arterial hypertension Treatment Target
a b s t r a c t The effectiveness of hypertension treatments is attributed either to the change in blood pressure, independent of the means used, or to an important contribution of appropriate drug selection: this debate probably stems from an inappropriate comparison. Treating essential hypertension in relatively healthy patients without advanced vascular disease and comorbidities affords cardio-vascular protection by the lowering of the mechanical shear stress determined by blood pressure per se: thus, lowering blood pressure is the critical step, while the methods used can only differ through side effects. This treatment is, in fact, a lifetime prophylaxis, as hypertension, rather than a disease, is a symptom affecting one tail of the Gaussian distribution of blood pressure across the normal population. Treating hypertension in the context of diseases, like diabetes mellitus, congestive heart failure, left ventricular hypertrophy, and advanced atherosclerosis, would be improper if focused on just one symptom, while the appropriate treatment must include options which exhibit a more extended profile to include effectiveness on cardiac hypertrophy, insulin resistance, cardiac output, and systemic hemodynamics: thus, drugs may be different in their effectiveness and in the cardio-vascular protection afforded, even though the trials quoted in favour of this thesis were designed to compare drugs in their ability to lower blood pressure rather than in improving the overall complex clinical derangements. In conclusion, while the answer to the question is a sharp YES when dealing with primary prevention, it might be a NO, still clouded by contradictory and inconclusive evidence when dealing with secondary prevention and/or treatment of complex disease conditions and co-morbidities. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
It is well known that treating hypertension is clinically indicated and useful for patients [1]. This evidence was initially based on observations made on normal subjects, where the cardio-vascular risk is a monotonous function of the absolute value of blood pressure [2]. Studies performed on cohorts affected by hypertension demonstrated that cardio-vascular risk regresses to that observed in untreated subjects exhibiting spontaneously the same blood pressure reached by patients on treatment. However, this is not entirely true, since subjects with hypertension, when treated, still retain some degree of the cardio-vascular risk despite the absence of cardio-vascular complications, suggesting the existence of a “residual risk”; in other words, it is possible that the organ damage is already irreversible or only partially reversible when treatment is started [3]. These established data [4] were implemented with more recent evidence, constituting the background justifying the European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines, issued by Mancia et al. [5].
⁎ Corresponding author. Tel.: + 39 0321 3733361; fax: + 39 0321 3733841. E-mail address: [email protected] (E. Bartoli).
This debate stems from the fact that these and other similar guidelines are not shared by the entire scientific community dedicated to hypertension, such that many authors contend that different protective effects can be attained when resorting to different means of abating hypertension. The major point on which the discussion hinges is represented by the “J” curve: reducing blood pressure is attended by a monotonous fall in cardio-vascular mortality and complications till certain absolute values of blood pressure are reached, beyond which the end points observed rise again by an inverse proportion to any further drop in blood pressure [6,7]. Even this finding is debated, since it has been pointed out that the ascending arm of the J curve at low blood pressure values is observed in smokers, diabetics with associated chronic renal failure, and, more generally, in patients with advanced vascular disease [8]. Thus, this controversy on the J curve is probably the cause of the argument, and, as we shall see in the ongoing discussion, its possible solution. In fact, there is not such a thing as “the” treatment of a disease named hypertension, as blood pressure is distributed across the normal population as a single statistical value: there are not 2 or more Gaussian curves describing the distribution of blood pressure values,
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.09.016
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E. Bartoli et al. / European Journal of Internal Medicine 21 (2010) 473–477
one characterizing normal subjects, the other patients with hypertension: as shown in Fig. 1, one Gaussian profile includes all normal subjects [9]. It follows from this phenomenon that treating hypertension is not equivalent to diagnosing a disease state and trying to re-establish normality: rather, it is the prophylaxis of future cardio-vascular events which are more likely to occur in subjects with a higher blood pressure within the same normal population. Thus, treating hypertension is not analogous to treating a disease, while it obeys to the principles of prevention, a hygienic modification of inherent blood pressure towards healthier values spontaneously occurring in the normal population (Fig. 1). Primary prevention is enforced on normal subjects, to reduce or correct the likelihood of adverse events: this is different from secondary prevention, for any disease and/or risk factor, whether this is hypercholesterolemia, thrombosis, or hypertension. We believe that this constitutes the essential point of the controversy: the objectives and the means of treatment are different in primary prevention, which concerns healthy people, from those required by secondary prevention, which concerns subjects who already suffered adverse events, or are affected by an established disease condition. In the presence of an already established, presumably irreversible vascular disease, we are unavoidably faced with complexity, complications, and with a difficult assessment of the risk/benefit ratio. We believe that these are real patients, and that the physician would behave inappropriately if he tackled only one problem, for instance hypertension, as if he were dealing with prophylaxis, rather than considering the clinical picture as a whole. In other words, there cannot be such a thing as an isolated preventive aspect, distinct from the overall treatment of a complex disease state. On the contrary, the correct approach to any such patient would be to treat him according to priorities and to a correct diagnostic evaluation, trying to include the maximum of his problems with the simplest therapeutic regimen available. Viewed in this context, prophylaxis cannot be separated by the overall treatment plan, because, in fact, it must be included in the plan. Let us consider, for example, a patient with type 2 diabetes mellitus, moderate nephropathy (plasma creatinine N 1 b 2 mg/dL), incipient congestive heart failure with exercise dyspnoea, hypertension with echocardiographic evidence of left ventricular hypertrophy, and episodes of exercise angina lasting b1 minute which regress spontaneously during rest: we are convinced that it would not be an optimal medical practice if the physician addressed only the hypertension, choosing a drug combination, and followed this patient
Fig. 1. Schematic representation of the consequences of anti-hypertensive treatment on the cardio-vascular risk. Since blood pressure values are positively correlated with the cardio-vascular risk, a hypertensive patient with blood pressure in the higher tertile (A), has a high cardio-vascular risk. A correct treatment reducing blood pressure values to the middle tertile (B), can confer a reduction of the cardio-vascular risk to normal, or near normal, values. Further decrements of blood pressure values to the lower tertile (C), will confer a lower cardio-vascular risk. Blood pressure values are distributed as a Gaussian curve (continuous line), while cardio-vascular events are a monotonous function of blood pressure (dashed ordinate on the right, and dashed line). The scales are arbitrary, as they are meant to portray a schematic view of phenomena, for illustrative purposes.
as if he were just hypertensive and only in need of normalizing his blood pressure. No doctor would behave this way. The treatment of the symptom hypertension must be inserted into the treatment of this complexity, and it is, then, the complexity per se that dictates the correct choice of anti-hypertensive drugs: if angina were considered a major concern, a β-blocker would be preferred for hypertension, while if congestive heart failure were bothering the patient to a major extent, a diuretic would be mandatory, their association if both problems were considered priorities. In other words, medicine does not treat any disease entity by addressing each symptom separately: the treatment of a disease is not the adding up of symptomatic interventions. Simple as it is, all trials include a number of these subjects, while none selected the drug treatment of hypertension based on objective data concerning the patients: all trials obey to the necessity of comparing commercial drugs, never do they obey to the principle of the correct practice of medicine, which wants to cure patients. The unescapable conclusion is that these large trials do not give applicable and sound information on how to treat patients, neither do they tell us much on the drugs compared except for the difference in reducing blood pressure, as if this were a magic symbol inextricably connected to the risk of death. To the contrary, in such a context, blood pressure is one of the symptoms of the complexity. Nobody familiar with research would be surprised if similar trials differed in their conclusions, contradicted each other, and created more confusion and doubts than reliable information: they were designed to test drugs on a symptom isolated from a complex context, and they tell us just and simply how much that drug reduced blood pressure. Any drug, to be valuable, must act favourably at least on two sides, hypertension and side effects. For instance, nifedipine does normalize blood pressure, but it can trigger angina, congestive heart failure and atrial fibrillation in patients with asymptomatic coronary heart disease and increased end-diastolic left ventricular pressure. Therefore, the goal “reduce blood pressure” must be enforced per se in the prophylaxis concerning healthy subjects, as an aggregate objective in patients, mainly those affected by complex clinical problems. Reducing blood pressure by reducing cardiac output will gratify the sphygmomanometer, but it could kill the patient: hypertension is much better than low output cardiac failure. Therefore, it is easily understood that drugs with an extended pharmacologic profile could be more effective in reducing cardiovascular end points in trials including diseases and complications. In this context, angiotensin converting enzyme and angiotensin receptor inhibitors fare better than other anti-hypertension medications for the same degree of reduction in blood pressure. They decrease intraglomerular pressure, limiting the shear stress which represents the major factor leading to chronic renal failure in hypertension and diabetes mellitus [10]. They act as peripheral vasodilators, improving cardiac output without increasing blood pressure, while reducing the cardiac post-load [11]. They are effective in correctly remodelling cardiac hypertrophy [12]. They antagonize the cellular effects of the renin–angiotensin–aldosterone system, a powerful compounder of the cardio-vascular risk, while acting as mild diuretics at the same time [13]. Within this extended mechanism of action, it seems arbitrary to attribute the reduction of cardio-vascular end points to the fall in blood pressure: these are due to the complex interaction of risk factors, and, presumably, the key to better survival is the improvement in this interaction. For instance, peripheral vasodilation and a negative Na balance improve left ventricular function, to the point that cardiac output could rise: this may be attended by a rise in blood pressure, or by an unchanged mean blood pressure due to a fall in diastolic, and a rise in systolic blood pressure. These changes, which are simply the improvement or disappearance of congestive heart failure, can cause an important reduction of cardio-vascular end points, while the fall in blood pressure would be minor: in the average data, this could create a drop in the likelihood of cardio-vascular
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events disproportionate to the change in blood pressure: the “trialists” would claim a greater protection afforded by the drug, which is true, although caused by the improvement of the patient and of his major derangement, represented by congestive heart failure, while it is attributed to a better drug profile in affecting hypertension [14]. We can go back now to the initial rationalization of the debate: for hypertension treatment as a goal per se we should focus on the treatment of essential hypertension affecting a large size of the normal population. For these subjects, treatment is a misnomer, as it is an indefinite prophylaxis of adverse events. Focusing on this population, all the evidence points to a protective effect afforded by the fall in blood pressure, proportional to the entity of the change, independent from the means used to reach the goal [8]. Although the main objective is to normalize blood pressure, reaching subnormal values accrues the protection, with no “J curve” [15]. This goal can be reached by lifestyle modifications, without drugs. Although there are no trials where most risk factors were controlled by lifestyle modifications, there is abundance of studies where one risk factor was controlled without drugs. Each of them managed to reduce, although minimally, blood pressure, and adding up the single effects could reproduce a lifestyle modification of complexity: if this procedure is at least roughly acceptable, lifestyle modification alone could be equivalent to drug treatment, while single initiatives, like physical exercise, would be more beneficial than the advantage expected from the drop in blood pressure alone [16]. At any rate, lifestyle changes, as specified by ESH/ESC guidelines [5], are widely recognized to lower blood pressure and should be considered in hypertension management (Table 1). Drug treatment is also effective, independent from the chemical nature of the drug, proportional to the fall in blood pressure. This does not mean that the choice of anti-hypertensive agents could be done by sorting them out causally, as the choice should be guided by the side effects and by guidelines and common sense rules according to the presumed cause of hypertension, age, lifestyle and occupational problem, compliance. While a proper selection will improve management and compliance, the reduction of the cardio-vascular risk is independent from the drugs chosen. Any empirical agent or combination is equivalent, for the same degree of side effect, to any other for the same degree of blood pressure reached [17–20]. This is presumably due to the fact that, in healthy subjects, the prevention is due to reducing the shear stress on the arterial walls, the factor that determines vascular disease in the long run: as the mechanism “shear stress” is related to blood pressure, the protection afforded is exclusively due to the value of blood pressure attained rather than the drug used [21]. Thus, we answer YES to the question we were asked: reaching the target is more important than the means, with the reservation that this “yes” is acknowledged when restricted to the context of essential hypertension in healthy subjects or patients with no complex derangements and/or advanced vascular disease.
Table 1 Well recognized lifestyle measures to lower blood pressure (modified from 5). Lifestyle modification
Variation expected in systolic blood pressure
Smoking cessation
No effect (recommended for cardio-vascular risk management) Up to 20 mm Hg
Weight reduction (and weight stabilization) Reduction of excessive alcohol intake Physical exercise Reduction of salt intake Increase in fruit and vegetable intake and decrease in saturated and total fat intake
Up to Up to Up to Up to
4 mm 9 mm 8 mm 9 mm
Hg Hg Hg Hg
475
We cannot answer YES with the same confidence in populations where the treatment of hypertension appears to be interconnected with other risk factors and with significant disease states: in this case data are inconclusive, contradictory, and must be taken with caution. Often, side effects of treatment improving a laboratory variable, like proteinuria, are interpreted as demonstrating protection. In fact, reducing blood pressure with any drug improves proteinuria [22–26]. However, this does not necessarily mean that the glomerular disease is improving, as a fall in glomerular pressure must reduce the solvent drag for proteins [27]. Moreover, the fact that the reduced proteinuria correlates with the reduction of the cardio-vascular end points can simply mean that both are linked to the fall in blood pressure, while the reasoning that less proteinuria indicates regression of capillary dysfunction, and that the latter has reduced the cardio-vascular risk is an unjustified inference. Incidentally, the claim that proteinuria decreases during chronic treatment with angiotensin converting enzyme inhibitors and angiotensin receptor inhibitors [22,26] has been disclaimed by Mann in a well designed study involving a large number of patients: the angiotensin receptor inhibitors did not reduce proteinuria, which progressed slightly less during treatment. In addition, patients who received both inhibitors exhibited an important worsening of renal function [28]. To quote a trial which claims that either diuretics [29], or β-blockers [30], or Ca-antagonists [31] are the best, is far from difficult. It is reasonable to think that the necessity of examining a drug effect can deviate the focus of an experimental design where complexity, congestive heart failure, angina, diabetes mellitus and other aspects can cause, in a large cohort, effects that favour one drug over the other and cloud the picture, reducing the level of the information obtained. Thus, the debate about the choice of drug-therapy seems to us a distracter. In fact, the analysis of 29 trials, demonstrated that there were no significant differences in total major cardio-vascular events between regimens based on ACE inhibitors, calcium antagonists, or diuretics or beta blockers, although ACE-inhibitor-based regimens reduced blood pressure less [17]. Clearly it is evident, as cited by ESH/ESC guidelines, “… that main benefits of anti-hypertensive treatment are due to the lowering of blood pressure per se and are largely independent on the specific classes of anti-hypertensive drugs employed” [5]. Moreover, these benefits, as evidenced in recent interventional trials [32–34], should be extended also to the high-risk individuals with “normal or high–normal” blood pressure values. Moreover, the hypothesis that different drugs have specific protective properties derives from clinical trials which display several evident methodological problems first of all, patients from different treatment groups do not always reach equal blood pressure targets, making it impossible to rule out with confidence that a better protection attributed to a specific drug was not in turn determined by a greater anti-hypertensive effect. In addition, clinical blood pressure was the principal variable considered in clinical trials while it is well known that other parameters like ambulatory blood pressure, 24 h blood pressure variability, and night blood pressure drop, do correlate better with cardio-vascular events. Finally, it is possible that the proportion of patients with complicated hypertension enrolled in clinical trials was too high to address specific drug effect since in advanced organ damage due to hypertension blood pressure lowering is probably the only way to protect from further damages [3,35,36]. Perhaps, smaller trials, performed on selected and homogeneous patients, having one clinical derangement besides hypertension, like congestive heart failure, angina, oedema, uncomplicated diabetes mellitus, would be more informative, as they could better separate the two conditions, hypertension and the disease, and examine the improvement of each separately. At any rate, the widespread belief that drugs acting on the renin–angiotensin–system may be endowed with a better profile seems credible [12,32,37–40] even though there are studies reaching this same conclusion for many of the drugs available for chronic treatment of hypertension.
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In any case, several meta-analyses, notwithstanding the limitation expressed above, evidenced specific effects of different dugs in preventing or reducing organ damages. In conclusion, a true, alternative contradiction between the two positions, a sharp YES or NO answer, is probably artificial. Probably, both answers are correct in their proper context: YES in primary prevention, NO in secondary prevention and complex patients with multiple risk factors. While the YES in the former situation seems rather established, the NO in the latter conditions requires more detailed investigations with improved experimental designs, made flexible to the point of more convincingly isolating the reduction in blood pressure from the unavoidable effects on related variables and diseases. Learning points What is known: • Lowering blood pressure with any means reduces the occurrence of cardio-vascular events. • Lowering blood pressure beyond certain low values is attended by a rise in cardio-vascular adverse events, except stroke, mainly in smokers, diabetics and patients with advanced cardio-vascular disease and associated co-morbidities. • In complex clinical conditions where hypertension is associated to important diseases (diabetes mellitus, chronic renal failure, congestive heart failure, and coronary artery disease) and co-morbidities, cardio-vascular end points might be influenced by the choice of anti-hypertensive medications. What this article adds: • The life lasting prophylaxis of future cardio-vascular adverse events in healthy subjects depends upon the blood pressure value attained, independent from the means used to reach the goal. • Any empirical treatment is equally effective when blood pressure is lowered to any given value in primary prevention. • Drug choice in lowering blood pressure is important when the physician chooses to treat the patient and his complex comorbid clinical condition rather than hypertension as an isolated symptom. • The trials magnifying the protective and anti-hypertensive effect of any drug or association compared to others in complex clinical situations, including advanced cardio-vascular disease and co-morbidities, are flawed, contradictory and inconclusive as they address the symptom hypertension, isolated from a complex condition, rather than the patient and/or his disease. They do not reproduce the necessary correct medical treatment, while they enforce a rigid scheme which is not transferable to common clinical practice. References [1] Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease: part 2. Short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 1990;335:827–38. [2] MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765–74. [3] Zanchetti A. Evidence-based medicine in hypertension: what type of evidence? J Hypertens 2005;23:1113–20. [4] Thürmer HL, Lund-Larsen PG, Teverdal A. Is blood pressure treatment as effective in a population setting as in controlled trials? Results from a prospective study. J Hypertens 1994;12:481–90. [5] Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and for the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87. [6] Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane Database Syst Rev 2009;3:CD004349. [7] Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85.
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