Dr. Luis Ruilope
For better blood pressure control in clinical practice, we advise
It is amply recognised that blood pressure (BP) control does not achieve the goals recommended by Guidelines (1,2).
For a goal inferior to 140/90 mmHg :
In the last two cases, when, according to Guidelines, a goal below 130/80 mm Hg had been considered - e.g. when associated clinical conditions, diabetes and Chronic Kidney Disease (CKD), are present- adequate BP control is less than 20% in hypertension units (4) as probably the case in most clinical trials.
Attaining adequate BP goal is very difficult, particularly when it comes to systolic BP. What guidelines consider as adequate BP control could be a non-realistic target in daily clinical practice (6).
Both the level of BP and its consequences rise continuously if arterial hypertension is not adequately treated. Progression from prehypertension to established hypertension is a well known fact (7). If hypertension is not controlled, it progresses with time to more advanced stages and causes the well known increase in cardiovascular (CV) damage and renal damage (8). Defining the most adequate threshold BP to start pharmacological intervention would impede the evolution of arterial hypertension and thus avoid the progression of CV disease.
In daily clinical practice intervention frequently takes place when BP levels are clearly above the levels recommended by Guidelines. Furthermore, once pharmacological therapy is started, clinical inertia (9) greatly contributes to facilitate the absence of a good BP control due to the acceptance by doctors of elevated BP levels as adequate for the patient.
The possibility of preventing the development of arterial hypertension through adequate lifestyle, in particular if obesity is corrected, has been demonstrated (10).
Pharmacological intervention directed at preventing the development of arterial hypertension (BP > 140/90 mmHg) has been recently suggested (11). The TROPHY study tested the hypothesis that pharmacologic treatment of prehypertension prevents or postpones stage 1 hypertension. The study contemplated a follow-up of four years;
Active therapy decreased the risk of developing stage 1 hypertension by 66.3% (p < 0.001) during the first two years. At the end of the study the risk was still reduced by 15.6% (p < 0.007) in those patients who had received the active medication.
The transition from prehypertension to established hypertension reflects, in part, ongoing changes such as arteriolar hypertrophy (12) and endothelial dysfunction (13). In this sense, prehypertension is characterised by the existence of elevations in plasma norepinephrine and plasma renin concentrations (14,15) that could promote growth and endothelial dysfunction. Regression of arteriolar hypertrophy has been shown to occur when treatment with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) are given (16,17). This does not occur in the presence of a beta blocker.
These data stress the consideration that an earlier intervention with drugs in daily clinical practice could facilitate the attainment of a much better BP control facilitated by the regression of the vascular changes accompanying the increase in BP from the initial stages of the process.
Furthermore, it has been demonstrated that BP, within the range of prehypertension, is associated with an elevated risk of cardiovascular disease (18,19) beyond that attributable to accompanying situations such as diabetes, TOD or established CV disease and partly attributable to the association of prehypertension with other CV risk factors (20,21). Early pharmacological intervention in arterial hypertension must then be contemplated in order to diminish the early development of CV disease.
An apparent discrepancy in the choice of the first drug exists between JNC-7 (1) and ESH-ESC (2) guidelines.
- JNC-7 defends the use of diuretics in most patients as a first step therapy to get a significant decrease in the high risk that accompanies elevated BP and thus achieving it at the lowest cost.
- On the contrary, the ESH-ESC guideline defends the need for individual therapy in each patient admitting that any drug available can be considered as adequate for first step therapy.
The demonstration that arterial hypertension is the number one risk factor in promoting death in developed as well as in developing countries (22) fits well with the concept of JNC-7.
However, the fact that, prehypertension today, correlates particularly well with insulin resistance (23) forces the consideration that the benefit of simply lowering BP could not suffice to correct the medium-term risk of elevated BP. In fact, the idea of targeting prediabetes in hypertensive patients has been recently brought forward (24) because it is a situation frequently seen in clinical practice, the one where the choice of the antihypertensive drug is relevant to promote, prevent or delay the development of diabetes.
It is also true that the discussion regarding which monotherapy is most adequate seems inapropriate if we consider the elevated percentage of patients requiring combination therapy to obtain adequate BP control. Only 22-24% of people in clinical trials actually achieve blood pressure goals with monotherapy. In fact, unwanted metabolic effects of certain antihypertensive drugs are attenuated when used in combination with members of other classes of antihypertensive agents particularly, with drugs that suppress the renin-angiotensin system (25). The possibility of using a combination, either free or fixed, since the beginning of pharmacological therapy in hypertensive patients is contemplated in both guidelines (1,2). Implementing this possibility probably will contribute to improve BP control due to the higher capacity of the combination to lower BP.
Recently a new version of the British Society of Hypertension Guideline (26) has been published. The recommended choice of the first antihypertensive drug is based on the fact that hypertensives can be broadly classified as “high renin” and “low renin”. Drugs can be divided according to their effects on the renin-angiotensin system (RAS) into those:
As can be seen in figure 1, patients under the age of 55, with the highest activity of the RAS, deserve, as first drug, one included in group A or B, while those above the age of 55 would receive one of group C or D. The need for a combination should be covered by adding a drug from the other group (C or D for A or B and vice versa).
If three drugs are required A+ C+ D should be the ideal combination. This algorithm of treatment is based on the previous experience of the authors which indicates that BP control is more adequate following the recommendation of the British Guideline (27).
For comparison, an algorithm put forth for patients with kidney disease and /or diabetes that integrates both the JNC 7 and ESC/ESH guidelines is noted in figure 2. In contrast to the British guidelines which focus on the general hypertensive patient, this algorithm focuses on the most prevalent concomitant diseases in the older hypertensive patient with a focus on achieving goal blood pressure (28).
Several factors have been identified as potential impediments for the attainment of adequate BP control. They are generally related to an inadequate lifestyle in particular diet containing an excessive amount of salt, an excessive number of calories facilitating an increase in body weight, an excess in alcohol intake, or a low intake of fruit and vegetables, Table 1.
Other factors are related to inadequate doses of antihypertensive drugs, inadequate combinations or to accompanying therapies interfering with antihypertensive therapy.
However, there is an important predictor of the need for multiple antihypertensive therapy, the degree of CV and renal involvement as a consequence of the increase in BP. The presence of Associated clinical conditions or advanced target organ damage renders control of BP more difficult and the need for more medication to acheive it (29). An aggressive attitude is required for the treatment of these patients because the adequate level of control is inferior to 130/80 mmHg.
Many patients do not take their prescribed medications. In most surveys one fourth to one half of patients had abandoned their antihypertensive drugs one year after starting therapy (30). It is also true that many physicians do not prescribe all the required medications required to control BP in their patients (9). The reasons for a low compliance and for such poor long-term adherence are diverse but in particular poor tolerability has been claimed as one of the most important. Table 2 summarises Guidelines directed to improve maintenance of antihypertensive therapy according to Norman Kaplan (31).
Cardiovascular and renal disease have been described as a continuum (32) starting with the detection of CV and renal risk factors, followed by the detection of target organ damage (TOD) and finally by ACC and eventually death. It is clear that lifestyle interventions can clearly delay the development of hypertension as well as reduce CV risk, Table 1. It is inadequate for only physicians and health care professionals to discuss such issues. Public health authorities need to intervene and set up an economic system that reinforces health behaviour. As a paradigm this has occurred in Finland with a dramatic reduction in the CV events within the last decade.
Table 1 Lifestyle Modifications and Effects on Blood Pressure From Chobanian A et.al. (1).
Figure 1 Recommendations for combining blood pressure lowering drugs (AB/CD rule) (From reference 26, Williams et al)
Legend Exercise caution over the use of high doses of diuretics. If a beta blocker is prescribed then it should be combined with a DHP CCB. ** Carvedilol has been shown to be beneficial in renal impairment and outcome studies. Other beta blockers are not excluded, however, there are no renal outcome data to support the use of atenolol in such patients and only limited data to support metoprolol (AASK trial, Toprol XL). Additionally, other alpha/beta blockers such as labetolol, may be useful but have not been studied in this population. eGFR = estimated glomerular filtration rate (most currently accepted method for Stages 2 through 4-modified MDRD formula(GFR calculator can be found-www.kidney.org; http://www.nephron.com/ and multiple other websites); BP = blood pressure; ARB = angiotensin II receptor blocker; ACEI = angiotensin-converting-enzyme inhibitor; CCB = calcium channel blocker; DHP CCB = dihydropyridine calcium channel blocker; RAAS = renin-angiotensin-aldosterone system.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1- Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7 Report. JAMA 2003; 289: 2560-2571. 2- Guidelines Committee. 2003 European Society of Hypertension- European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21:1011-1053. 3- Borghi C, Dormi A, D'Addato S, Gaddi A, Ambrosioni E; Brisighella Heart Study Working Party.Trends in blood pressure control and antihypertensive treatment in clinical practice: the Brisighella Heart Study. J Hypertens 2004; 22: 1707-1716. 4- Banegas JR, Segura J, Ruilope LM, Luque M, García-Robles R, Campo C, Rodríguez-Artalejo F, Tamargo J, on behalf of the CLUE Study Group Investigators. Blood pressure control and physician management of hypertension in hospital hypertension units in Spain. Hypertension 2004; 43: 1338-1344. 5- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 2002; 288: 2981-2997. 6- O'Rorke JE, Richardson WS. Evidence based management of hypertension: What to do when blood pressure is difficult to control. BMJ 2001; 322: 1229-1232. 7- Vasan RS, Larson MG, Leip EP, et al. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001; 358: 1682-1686. 8- Perera GA. Hypertensive vascular disease. J Chronic Dis 1955; 1: 33-42. 9- Phillips LS, Branch WT, Cook CB, Doyle JP, El-Kebbi IM, Gallina DL, Miller CD, Ziemer DC, Barnes CS. Clinical inertia. Ann Intern Med 2001; 135: 825-834. 10- He J, Whelton PK, Appel LJ, et al. Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension 2000; 35: 544-549. 11- Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Eng J Med 2006; 354: 1685-1697. 12- Folkow B. Physiological aspects of primary hypertension. Physiol Rev 1982;62: 347-504. 13- Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endotheliumdependent vascular relaxation of patients with essential hypertension. Circulation 1993;87:1468-1474. 14- Esler M, Julius S, Zweifler A, et al. Mild high-renin essential hypertension: neurogenic human hypertension? N Engl J Med 1977;296:405-411. 1- Julius S, Krause L, Schork NJ, et al. Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens 1991;9: 77-84. 2- Schiffrin EL, Deng LY, Larochelle P. Progressive improvement in the structure of resistance arteries of hypertensive patients after 2 years of treatment with an angiotensin I-converting enzyme inhibitor: comparison with effects of a betablocker. Am J Hypertens 1995;8:229-236. 3- Schiffrin EL, Deng LY. Comparison of effects of angiotensin I-converting enzyme inhibition and β-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension 1995; 25:699-703. 4- Vasan RS, Larson MG, Leip BP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Eng J Med 2001; 345: 1291-1297. 5- Kshirsagar AV, Carpenter M, Bang H, et al. Blood pressure usually considered as normal is associated with an elevated risk of cardiovascular disease. Am J Med 2006; 119: 133-141. 6- Julius S, Jamerson K, Mejia A, Krause L, Schork N, Jones K. The association of borderline hypertension with target organ changes and higher coronary risk: Tecumseh Blood Pressure study. JAMA 1990; 264: 354-358. 7- Nesbitt SD, Julius S, Leonard D, Egan BM, Grozinski M. Is low-risk hypertension fact or fiction? Cardiovascular risk profile in the TROPHY study. Am J Hypertens 2005;18:980-985. 8- Ezzati M, Lopez AD, Rodgers A, Hoorn SV, Murray CJL, and the Comparative Risk Assessment Collaborating Group Selected major risk factors and global and regional burden of disease. Lancet 2002; 360: 1346-1360. 9- Cordero A, Laclaustra M, Leon M, Grima A, Casasnovas JA, Luengo E, del Rio A, Ferreira I, Alegria E. Prehypertension is associated with insulin resistance state and not with an initial renal function impairment. A Metabolic Syndrome in Active Subjects in Spain (MESYAS) Registry substudy. Am J Hypertens 2006; 19:189-196. 10- Segura J, Campo C, Ruilope LM, Rodicio JL. Do we need to target “prediabetic” hypertensive patients? J Hypertens 2005; 23: 2119-2125. 11- Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006; 24: 3-10. 12- Williams B, Poulter NR, Brown MJ, Davis M, McInnes G, Potter JF, Sever P, Thorn SMcG, the BHS guidelines working party, for the British Hypertension Society. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ 2004; 328: 634-640. 13- Brown MJ, Cruickshank JK, Dominiczak A, et al. Better blood pressure control: how to combine drugs. J Hum Hypertens 2003; 17: 81-86. 14- Kjeldsen, SE, Bakris GL, Giles TD, Mancia G, Ruggenenti P, Ruilope L, Stergiou, GS Consensus Statement: The kidney and cardiovascular risk factors – implications for management J Hypertension, submitted 15- Pepine CJ, Kowey PR, Kupfer S, Kolloch RE, Benetos A, Mancia G, Coca A, Cooper-DeHoff RM, Handberg E, Gaxiola E, Sleight P, Conti CR, Hewkin AC, Tavazzi L; INVEST Investigators. Predictors of adverse outcome among patients with hypertension and coronary artery disease. J Am Coll Cardiol 2006; 47: 547-551. 16- McInnes GT. Integrated approaches to management of hypertension. Am Heart J 1999; 138: S252-S255. 17- Kaplan N. In Kaplan´s Clinical Hypertension. Edited by Lippincott Williams & Wilkins, Philadelphia. 2002 18- Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991; 121(4 Pt 1):1244-1263.
Address for correspondence: Luis M Ruilope Hypertension Unit, Hospital 12 de Octubre Madrid, Spain Email: Ruilope@ad-hocbox.com
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