Managing hypertension: a question of STRATHE

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1 (2005) 19, S3 S7 & 2005 Nature Publishing Group All rights reserved /05 $ ORIGINAL ARTICLE Managing hypertension: a question of STRATHE Department of Cardiovascular Disease, Clinical Investigation Center INSERM CHU, University Henri Poincaré, Nancy, France Current international guidelines recommend the use of therapeutic strategies with proven efficacy in the management of hypertension to achieve a target blood pressure of o140/90 mmhg. After lifestyle intervention, they endorse three different management strategies: (i) first-line use of a low-dose combination of two agents from different antihypertensive classes, with the option of doubling the dose of the combination; (ii) use of a sequential monotherapy strategy, initiating with one antihypertensive to be replaced by another one from a different class, if necessary; and (iii) a stepped care strategy, initiating with one antihypertensive, and increasing the dose or adding another agent from a different class, if necessary. The objective of the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study was to compare the efficacy and tolerability of these three treatment strategies in patients with uncomplicated essential hypertension (n ¼ 533). In all, 62% of the patients in the low-dose combination group were normalised (o140/90 mmhg), compared with 49% of the sequential monotherapy group (P ¼ 0.01) and 47% of the stepped-care group (P ¼ 0.005). The percentage of patients achieving normalisation without experiencing drug-related adverse events was also significantly higher in the low-dose combination group (56%) than in the sequential monotherapy (42%, P ¼ 0.001) and stepped-care groups (42%, P ¼ 0.004), consistent with the observation that the reduced dosage of the antihypertensive agents in such preparations translates into improved acceptability. The results of STRATHE provide further support for an antihypertensive management strategy involving the low-dose combination of perindopril (2 mg) and indapamide (0.625 mg). (2005) 19, S3 S7. doi: /sj.jhh Keywords: low-dose combination; management strategy; perindopril; indapamide; STRATHE Introduction Blood pressure control remains very poor worldwide, despite the medical evidence that treating hypertension can be beneficial for preventing end-organ damage and the current ease of access to health care, particularly in industrialised countries. 1 3 Indeed, more than 50% of treated hypertensive patients do not achieve the target blood pressure of o140/90 mmhg, as recommended by most current international guidelines. 1,4 A good reason for this is that effective therapy of hypertension requires intensive and lifelong treatment. Other reasons include the heterogeneity of hypertension, poor patient compliance associated with the long-term treatment of an asymptomatic disease, and reluctance of physicians to titrate to higher doses of antihypertensive med- Correspondence: Professor, Department of Cardiovascular Disease, Clinical Investigation Center INSERM CHU, University Henri Poincaré, Nancy, France. f.zannad@chu-nancy.fr ication due to concerns about adverse events or negative metabolic consequences. 5,6 Fortunately, this alarming situation has been addressed by the recent appearance of guidelines from three international medical bodies, the European Society of Hypertension (ESH) European Society for Cardiology (ESC), 1 the US Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), 2 and the World Health Organization (WHO). 3 These guidelines emphasise the importance of using therapeutic strategies that have proven efficacy in the management of high blood pressure to achieve a target blood pressure of o140/90 mmhg. The ESH/ESC guidelines, for example, recommend starting with lifestyle modification and, if necessary, initiation of pharmacological treatment in one of two ways: With monotherapy, using a low dose of a diuretic, a b-blocker, an angiotensin-converting enzyme (ACE) inhibitor, a calcium antagonist, or an angiotensin II receptor blocker (ARB). With a low-dose combination of two drugs from different antihypertensive classes.

2 S4 If the monotherapy strategy does not lower blood pressure sufficiently, then the physician has the choice of switching to monotherapy with a drug from a different class (ie, sequential monotherapy), or increasing the dose of the first drug or using a two- or three-drug combination (ie, stepped care). If the first-line low-dose combination does not reduce blood pressure sufficiently, then the dose of the combination can be doubled or a third drug can be added, again at a low dose. Rationale for use of low-dose combinations first-line The guidelines also clearly state that, depending on the baseline diastolic blood pressure (DBP) and systolic blood pressure (SBP) and the presence or absence of complications, it is reasonable to initiate with either low-dose monotherapy or a low-dose combination. 1 A common finding is that most patients require some form of combination therapy to achieve the recommended blood pressure targets. For example, in the Antihypertensive and Lipid- Lowering treatment to prevent Heart Attack Trial (ALLHAT) 7 over hypertensive patients were randomised to receive a diuretic (chlorthalidone, mg/day), a calcium antagonist (amlodipine mg/day), or an ACE inhibitor (lisinopril mg/day) for a mean follow-up of 4.6 years. The treating physicians had the option of adjusting the dosage or adding another drug from a different class in order to achieve a target blood pressure of o140/90 mmhg. The results were clear: 66% of patients had normalised blood pressure at completion of the trial, and 63% were receiving more than two drugs, and 27% more than three. These observations are confirmed by the results of the Losartan Intervention for Endpoint reduction in hypertension (LIFE) trial 8 in over 9000 hypertensive patients, who were randomised to either an ARB (losartan mg/day) or a b-blocker (atenolol mg/day). To achieve the target blood pressure of o140/90 mmhg, a diuretic (hydrochlorothiazide (HCTZ) mg/day) or any other antihypertensive drug class (excluding ARB, b- blocker, or ACE inhibitor) could be added. At the end of this 4.9-year study, 49% of patients in the losartan group had achieved the target blood pressure levels, compared with 46% in the b-blocker group. Interestingly, less than 10% of the patients were still on monotherapy with the initiating drugs. A third example of a study that led to similar conclusions regarding the necessity of combination therapy to achieve normotension was the International Verapamil-Trandolapril Study (INVEST), 9 which included more than hypertensive patients. The patients were initiated on a calcium antagonist (a modified-release formulation of verapamil, mg/day) or b-blocker (atenolol mg/day). The patients then followed a predefined treatment strategy involving sequential addition of an ACE inhibitor (trandolapril 2 4 mg/day), a diuretic (HCTZ, 25 mg/day), and a nonstudy medication. The order of introduction of the second-line treatments varied between the two groups. At the end of the 2-year study, 72% of the calcium antagonist group had achieved the target blood pressure of o140/90 mmhg compared with 71% of the patients in the b-blocker group. Notably, only 17 and 18% of patients in the two groups, respectively, were still on monotherapy. There are, of course, advantages and disadvantages of initiating with low-dose combination therapy vs initiating with monotherapy. 1 The advantage of initiating with low-dose monotherapy is that, if the initial compound is not well tolerated, then the doctor will be able to modify treatment and find the best drug for the individual patient (in terms of both efficacy and acceptability). However, this procedure can be laborious and demotivating, for doctors and patients alike, and may have consequences on compliance. One advantage of the low-dose combination strategy is that, by starting with two drugs with differing mechanisms of action, we dramatically increase the likelihood that the target blood pressure will be achieved. Second, the lower doses of the individual agents reduce the occurrence of the individual side effects of the separate agents. Both of these effects improve compliance, as does the opportunity of taking the two drugs in a single tablet, which is possible in many countries. One objection to low-dose combinations is the unnecessary exposure of patients to drugs, but we should bear in mind that this might apply to most patients in monotherapy in the long term, since they are highly likely to require a second antihypertensive treatment at some point. The STRATHE study Thus, the evidence is clear: to achieve the targets recommended by the international guidelines most patients require combination treatment or at the very least a rigorous treatment strategy to optimise both blood pressure and acceptability. The guidelines clearly set out three management strategies, as outlined above: stepped-care; sequential monotherapy; or low-dose combination. However, which is the most appropriate? It was with this question in mind that the first trial to compare three therapeutic strategies recommended by the international guidelines the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study was designed. 10 The objective of the STRATHE trial was to compare the efficacy and the tolerability of the three different treatment strategies in patients with uncomplicated essential hypertension presenting in

3 private practice. STRATHE is a randomised, doubleblind, parallel-group study in patients with a mean sitting SBPX160 mmhg and/or a mean sitting DBPX95 mmhg. At the end of a 4-week, singleblind placebo period, the patients (n ¼ 533) were randomised to one of three groups, corresponding to the three treatment strategies: A fixed low-dose combination strategy (n ¼ 180) initiating with perindopril (2 mg) and indapamide (0.625 mg), with the possibility of adjusting the doses in two steps (3 mg/0.937 mg and then 4 mg/ 1.25 mg). A sequential monotherapy strategy (n ¼ 176) initiating with atenolol (50 mg), replaced if necessary by losartan (50 mg), and then replaced by amlodipine (5 mg). A stepped-care strategy (n ¼ 177) initiating with valsartan (40 mg), with the possibility of increasing the dose of valsartan (80 mg dose), and then adding hydrochlorothiazide (12.5 mg) if necessary. The first primary end point was blood pressure normalisation (defined as o140/90 mmhg). In each of the three groups, treatment could be adjusted twice, at 3 and 6 months, with a final visit at 9 months, or at 6 months if blood pressure was already normalised. The decision to adjust treatment was entirely in the hands of the doctor. It was mandatory in the case of SBP4160 mmhg and/or DBP495 mmhg, and was recommended for SBP between 140 and 160 mmhg and/or DBP between 90 and 95 mmhg. However, regardless of the blood pressure achieved, the doctor could choose to maintain treatment at the previous level if there were concerns over upgrading for safety reasons. The second study end point was the percentage of patients having normalised their blood pressure without experiencing drug-related adverse events. The baseline demographic characteristics are presented in Table There were no significant differences between the three groups in terms of age, sex, body mass index, or baseline blood pressure. The proportion of patients with a personal or family history of hypertension was similar in the three groups. At the final visit in the intention-to-treat population, the reduction in SBP in the low-dose combination strategy group ( mmhg) was significantly greater than the reduction in SBP in the sequential monotherapy group ( mmhg; P ¼ 0.047) and in the stepped-care strategy group ( mmhg; P ¼ ). 10 The reduction in DBP was comparable in the three groups ( mmhg, mmhg, and mmhg, respectively). Figure 1 shows the percentage of patients who had achieved the target blood pressure of o140/ 90 mmhg at their final visit. 10 In all, 62% of the patients in the low-dose combination group were normalised, which was significantly greater than the patients in the other two groups (49% of the sequential monotherapy group (P ¼ 0.01) and 47% of the stepped-care group (P ¼ 0.005)). Moreover, 59% of the patients randomised to the low-dose combination were still on the lowest dosage (perindopril 2 mg/indapamide mg) at the last visit, compared with 55 and 50%, respectively, for the sequential and the stepped-care strategy. The percentage of patients who normalised their blood pressure without experiencing drug-related adverse events was also significantly higher in the low-dose combination group (56%) than in the % of patients with BP <140/90 mmhg % 49% 47% Low-dose combination (n=180) P=0.01 Sequential monotherapy (n=176) P=0.005 Stepped-care (n=177) Figure 1 Percentage of patients with their blood pressure (BP) normalised (o140/90 mmhg) at the last visit in the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study. (Reproduced from Mourad et al 10 with permission.) S5 Table 1 Baseline characteristics of the patients (mean7s.d.) in the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study 10 Therapeutic strategy Low-dose combination (n ¼ 180) Sequential monotherapy (n ¼ 176) Stepped-care (n ¼ 177) Age (years) Sex (M/F) 118/62 108/68 104/73 Body mass index (kg/m 2 ) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Family history of hypertension (%) Previous treatment (%) Reproduced from Mourad et al 10 with permission.

4 S6 % of patients with BP <140/90 mmhg and no AE sequential monotherapy (42%, P ¼ 0.001) and the stepped-care group (42%, P ¼ 0.004) (Figure 2). 10 There was no significant difference between the three strategies in terms of dropouts for adverse events or the number of patients completing the study. Discussion 56% 42% 42% Low-dose combination (n=180) P=0.001 Sequential monotherapy (n=176) P=0.004 Stepped-care (n=177) Figure 2 Percentage of patients who normalised their blood pressure (BP) (o140/90 mmhg) in the STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) study without developing any adverse event. (Reproduced from Mourad et al 10 with permission.) Among the three therapeutic strategies assessed in this randomised, double-blind study, the strategy of administering a low-dose combination of perindopril 2 mg and indapamide mg has a significantly greater SBP-lowering effect than sequential monotherapy strategy, based on b-blocker, ARB, and calcium antagonist, and the stepped-care strategy, based on an ARB and a diuretic. We might wonder if the same result would have been found if larger doses of the agents had been used in the sequential monotherapy and stepped-care strategies, particularly for the steps involving losartan 50 mg and valsartan 40 mg, which are generally considered as low doses. These dosages were based on the standard recommended dosages in France in 1998 when the STRATHE study was designed. However, the study design did leave ample room for dosage adjustment if the blood pressure was not normalised. Moreover, the ESH/ESC guidelines emphasise the importance of using agents at the lowest dosages possible, and clearly state that it is preferable to combine low doses of two agents from different classes when monotherapy fails. 3 The STRATHE study is therefore truly representative of what doctors can expect in clinical practice if they strictly adhere to the latest ESH/ESC guidelines. In practice, blood pressure control can be improved by addition of the antihypertensive effect of two agents from different classes with different mode of actions. All of the fixed combinations currently available share one important feature: they produce a greater normalisation of blood pressure than the individual drugs given separately. The combination used in STRATHE of the ACE inhibitor perindopril and the diuretic indapamide is particularly justified according to theoretical and experimental evidence. 11 The diuretic stimulates the activity of the renin angiotensin aldosterone system (which may induce hypokalaemia), while the ACE inhibitor blocks this system. This means that the antihypertensive effect of the diuretic is enhanced by the action of the ACE inhibitor, and that lower doses of the two drugs are required to normalise blood pressure. 12 Indeed, the initiating doses of perindopril (2 mg) and indapamide (0.625 mg) in STRATHE correspond to one-half and one-quarter of the standard starting doses, respectively, and as we saw above this dosage normalised 60% of the patients in that group. The STRATHE study also underlines another advantage of the low-dose combination strategy, that is, the reduction in the incidence of adverse events. The perindopril (2 mg)/indapamide (0.625 mg) preparation has been shown to have a tolerability profile (kalaemia, glycaemia, and cholesterolaemia) similar to that of placebo. 13 Together with the possibility of administering the low-dose combination as a single tablet, which simplifies the treatment, this improves quality of life and patient compliance. Conclusion The results of STRATHE provide further support for a management strategy involving a low-dose combination of perindopril (2 mg) and indapamide (0.625 mg) in patients with uncomplicated essential hypertension. Several large, randomised, doubleblind studies comparing this particular combination with first-line antihypertensive monotherapies, such as ARBs, b-blockers or ACE inhibitors have also confirmed the advantage of this low-dose combination, offering superior blood pressure control and higher normalisation rates in essential hypertension, in patients with diabetes 18 or left ventricular hypertrophy, 16 as well as in the elderly. 19,20 STRATHE demonstrates that a low-dose combination strategy normalises blood pressure in significantly more hypertensive patients than a sequential monotherapy or a stepped-care strategy. The better blood pressure results with the low-dose combination strategy were obtained with remarkable tolerance. These advantages fulfil the recommendations of international guidelines 1 3 and confirm the rationale of initiating antihypertensive treatment with a low-dose combination. References 1 Guidelines Committee European Society of Hypertension European Society of Cardiology guide-

5 lines for the management of arterial hypertension. J Hypertens 2003; 21: Chobanian AV, et al, the National High Blood Pressure Education Program Coordinating Committee (2003). Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: World Health Organization (2003) World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21: Vivki L et al. Trends in prevalence, awareness, treatment, and control of hypertension in the adult US population. Hypertension 1995; 26: Dusing R, Weisser B, Mengden T, Vetter H. Changes in antihypertensive therapy the role of adverse effects and compliance. Blood Press 1998; 7: Berlowitz DR et al. Inadequate management of blood pressure in a hypertensive population. N Engl J Med 1998; 339: Cushman WC et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trials (ALLHAT). J Clin Hypertens 2002; 4: Dahlöf B et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in hypertension study (LIFE): a randomised trial against atenonol. Lancet 2002; 359: Pepine CJ et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003; 290: Mourad J, et al, on behalf of the investigators of the STRATHE trial (2004). Comparison of different therapeutic strategies in hypertension: a low-dose combination on perindopril/indapamide versus a sequential monotherapy or a stepped-care approach. J Hypertens 2004; 22: Waeber B. Very-low-dose combination: a first-line choice for the treatment of hypertension. J Hypertens 2003; 21(Suppl 3): S3 S Myers MG et al. Fixed low-dose combination therapy in hypertension a dose response study of perindopril and indapamide. J Hypertens 2000; 18: Laurent S. Very-low-dose combination of perindopril and indapamide: efficacy on blood pressure and targetorgan damage. J Hypertens 2003; 21(Suppl 3): S11 S Neutel JM, Smith DHG, Weber MA. Low-dose combination therapy: an important first-line treatment in the management of hypertension. Am J Hypertens 2001; 14: Chanudet W, De Champvallins M. Antihypertensive efficacy and tolerability of low-dose perindopril/ indapamide combination compared with losartan in the treatment of essential hypertension. Int J Clin Pract 2001; 55: Asmar RG, London GM, O Rourke ME, Safar ME, for the REASON Project coordinators and investigators. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient, a comparison with atenolol. Hypertension 2001; 38: Morgan T, Anderson A. Low-dose combination therapy with perindopril and indapamide compared with irbesartan. Clin Drug Invest 2002; 22: Mogensen CE et al. Effect of low-dose perindopril/ indapamide on albuminuria in diabetes, Preterax in Albuminuria Regression: PREMIER. Hypertension 2003; 41: Mourad JJ, Balcher J, Blin P, Warzocha U, on behalf of the investigators of the PHASTE study. Conventional antihypertensive drug therapy does not prevent the increase of pulse pressure with age. Hypertension 2001; 38: Chalmers J, Castaigne A, Morgan T, Chastang C. Longterm efficacy of a new, fixed, very-low-dose angiotensin-converting enzyme-inhibitor/diuretic combination as first-line therapy in elderly hypertensive patients. J Hypertens 2000; 18: S7

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