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Journal of Human Hypertension (2005) 19, S9–S14& 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 Further evidence for low-dosecombinations in patients with leftventricular hypertrophy B Dahlo¨fDepartment of Medicine, Sahlgrenska University Hospital/O¨stra, Go¨teborg, Sweden Left ventricular hypertrophy (LVH) is a powerful inde- nation produced a significantly greater change in left pendent risk predictor for cardiovascular disease and ventricular mass after 1 year than the b-blocker, despite reversal of LVH has become a primary goal of anti- inducing a similar change in mean blood pressure.
hypertensive management. Recent evidence has con- Additionally, perindopril/indapamide reduced central firmed that most hypertensive patients will benefit from (carotid) and peripheral (brachial) systolic blood pres- a low-dose combination strategy to manage their sure (SBP) and pulse pressure (PP) to a significantly hypertension, and two trials have recently examined greater extent than b-blocker, and these benefits were the effect of this strategy on left ventricular mass. The more pronounced for the central values; LVH is affected REASON study (pREterax in regression of Arterial more by central rather than peripheral haemodynamic Stiffness in a contrOlled double-bliNd study) compared changes. Results of the analysis of the PICXEL study the low-dose combination of an angiotensin-converting showed a significantly greater decrease in LVH para- enzyme (ACE) inhibitor and a diuretic with b-blocker meters and blood pressure over 1 year in favour of the monotherapy in hypertensive patients with LVH, and the low-dose combination. This reduction cannot be entirely PICXEL study (Preterax In a double-blind Controlled explained by the better efficacy of the low-dose study versus Enalapril in LVH) compared the same low- combination on blood pressure reduction.
dose combination with ACE inhibitor monotherapy in Journal of Human Hypertension (2005) 19, S9–S14.
hypertensive patients with echocardiographic LVH. The REASON study demonstrated that the low-dose combi- Keywords: left ventricular hypertrophy; antihypertensive drug treatment; fixed low-dose combination Clinical trials conducted in the past few years indicate that various antihypertensive agents pro- It is now well recognised that it is essential to duce regression of LVH, and thereby improve the manage and prevent cardiovascular target-organ prognosis.7,8 A meta-analysis showed that, for the damage in the treatment of hypertension in order same reduction in blood pressure (BP), left ventri- to avoid the emergence of cardiovascular complica- cular mass (LVM) regression is more pronounced tions.1–3 Left ventricular hypertrophy (LVH) is a with blocking of the renin–angiotensin system than powerful independent risk predictor for cardiovas- with other antihypertensive therapeutic princi- cular disease. Hence, LVH has strong links with ples.9,10 Furthermore, much evidence has been cardiovascular morbidity and mortality in patients accumulated to warrant greater attention being paid to the importance of increased systolic blood More importantly, regression of LVH has been pressure (SBP) as a major risk factor for increased demonstrated to substantially reduce the risk for LVM, increased pulse pressure (PP), and arterial cardiovascular events.4–7 Thus, targeting LVH has become an important goal of antihypertensive Unfortunately, normalisation of BP rarely occurs management, and all current guidelines are con- when the treatment involves administration of gruent in that the presence of LVH should lead to monotherapy. Recent evidence has shown that most patients will benefit from combination of drugs fromdifferent antihypertensive classes, rather than titra-tion of monotherapy.1 Moreover, there are physio- Correspondence: Professor B Dahlo¨f, Department of Medicine, logical reasons for the better performance of a combination strategy.11 Indeed, the first-line, low- dose combination of the ACE inhibitor perindopril (2 mg) and indapamide (0.625 mg) was shown to have a favourable efficacy/safety ratio12 and better antihypertensive efficacy than monotherapy with enalapril,13 losartan,14 and irbesartan.15 Perindopril /
This therapeutic strategy of a fixed-dose combina- indapamide
Atenolol
tion was assessed in hypertensive patients in the REASON study (pREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study) com-pared with b-blocker monotherapy16–20 and, more recently, in the PICXEL study (Preterax In a double- blind Controlled study versus Enalapril in LVH) in hypertensive patients with LVH compared with ACE-inhibitor monotherapy.21 After the echocardio- Figure 1 The study population in REASON. Per/Ind, low-dose graphic substudy of LIFE (Losartan Intervention For combination of perindopril (2 mg) and indapamide (0.625 mg); End point reduction in hypertension),7 PICXEL is the largest study on regression of LVH, and the firstto compare a combination regimen with monother-apy using an antihypertensive class generallyconsidered to be one of the most effective in the In the whole population, after 12 months of treatment, the low-dose combination of perindopril(2 mg) and indapamide (0.625 mg) induced signifi-cantly (À6.271.5 mmHg) and brachial PP (À5.571.0 mmHg) (Table 1).17 This finding, which is more significant in the central than in the brachial artery, wasconfirmed in both the intention-to-treat (ITT) and The REASON trial is an international, multicentre, randomised, double-blind investigation with twoparallel groups.16–20 This trial compared the anti-hypertensive effects of the low-dose combination ofperindopril (2 mg) and indapamide (0.625 mg) with the b-blocker atenolol (50 mg). It was conducted in patients aged 18–84 years with sustained mild-to-moderate essential hypertension, defined as SBP A substudy of the REASON trial18 was conducted to determine whether LVM changes were significantly blood pressure (DBP) X95 mmHg and o110 mmHg.
related to treatment with the low-dose combination of perindopril/indapamide or atenolol, and whether determine whether the low-dose perindopril/inda- the changes in LVM were linked to brachial or pamide combination decreased SBP and PP more than atenolol and, if so, whether this decrease was To address these questions, only data from predominantly caused by reducing aortic pulse patients not withdrawn from the global therapeutic wave velocity (PWV) (measured automatically) and protocol (n ¼ 469) and having complete haemody- wave reflections (determined on the basis of pulse namic measures at both baseline and 12 months wave analysis and applanation tonometry).
Following the wash-out placebo period, 469 The results of this study have shown that the low- patients were randomised to receive a 1-year period dose combination of perindopril/indapamide pro- of treatment with either the low-dose combination duces a significantly greater change in LVM than the of perindopril (2 mg) and indapamide (0.625 mg) standard comparator atenolol, despite inducing a (n ¼ 235) or atenolol (50 mg) (n ¼ 234). The dosage similar change in mean BP (Tables 2 and 3).18 After could be doubled after 3 months if SBP and/or DBP 12 months, LVM and left ventricular mass index continued to exceed 160 mmHg and 90 mmHg, (LVMI) were significantly lower in the patients respectively. In all, 78% of patients completed the receiving perindopril/indapamide than in the pa- 12-month period of treatment. Cardiac output and tients receiving atenolol (P ¼ 0.0125 and 0.0121, total peripheral resistance were also measured at respectively). The consistent differential effect on M0 and M12 using standard echocardiographic LVH is associated with an improvement in large artery function involving central wave reflections, The key results of the REASON trial have already been published, as have the results of several change in central SBP and PP. In summary, the ancillary studies.16–20 Figure 1 displays the various REASON study demonstrated that LVM lowering was more significant with the low-dose combination Table 1 REASON: changes in brachial BP, carotid BP and augmentation index17 Values are mean7s.d. Per/Ind, perindopril–indapamide combination; CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic bloodpressure; PP, pulse pressure; M0, M12, months 0 and 12 (end) of study; D(End-M0), change from baseline.
aAdjusted for age, sex and baseline. yFisher’s test (ANCOVA).
Table 2 REASON: baseline (M0) parameters (mean7s.d.) and dose adjustment during the study in the LVM-only and LVM+tonometrypopulations18 LVM, left ventricular mass; Per/Ind, perindopril and indapamide; M/F, male/female; anti-HT, antihypertensive; BMI, body mass index; SBP,systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; PP, pulse pressure.
with atenolol, and that the intergroup difference in LVM was statistically linked to central, notbrachial PP.
The PICXEL study was a multicentre, randomised, The mechanisms of SBP reduction with atenolol double-blind, controlled study in hypertensive differ substantially from those of the perindopril/ patients with echocardiographically determined indapamide combination. Atenolol reduction is LVMI4100 g/m2 in women and LVMI4120 g/m2 in essentially based on mean BP reduction, while men in nine different countries.22 Its main objective perindopril/indapamide induces changes in arterial was to specifically compare LVH reduction in stiffness of conduit arteries and wave reflections.19 hypertensive patients treated with either a fixed Table 3 REASON: LVM and LVMI (adjusted mean7s.e.) in the LVM-only population (n ¼ 146) at M0 and M12 (adjustments include ageand previous antihypertensive therapy)18 BMI, body mass index; Per/Ind, perindopril and indapamide; d, change between M0 (baseline) and M12 (end of follow-up) (%); LVMI, leftventricular mass index.
*Significant.
Table 4 The PICXEL study: changes in BP and LVH, comparison between the two treatments21 Within group difference: *Po0.01, **Po0.001.
LVM, left ventricular mass; Per/Ind, perindopril and indapamide; SBP, systolic blood pressure; DBP, diastolic blood pressure; PWTd, posteriorwall thickness; IVSTd, interventricular septum thickness; LVID, left ventricular internal dimension.
combination strategy or monotherapy with an pared with enalapril was demonstrated as shown in established antihypertensive agent. Following a 4- Table 4. This reduction cannot be entirely explained week placebo period, patients received either the by the better efficacy of the low-dose combination combination of perindopril (2 mg) and indapamide on BP reduction alone. After adjustment for the (0.625 mg) or enalapril (10 mg) for 52 weeks, with greater BP reduction, age, gender and baseline value, the possibility of doubling the dose twice (to the LVMI reduction with perindopril/indapamide perindopril 8 mg and indapamide 2.5 mg or enala- remained significantly superior. The full results of pril 40 mg) to achieve BP control of 140/90 mmHg. A the PICXEL study will be available in 2005.
Central Echocardiography Committee, blinded tovisit sequence, patient, and treatment, assessed theLVM in a final reading.
The choice of an ACE inhibitor as a comparator was supported by the results of the meta-analysis The REASON study compared the antihypertensive of double-blind trials measuring the effects of effect of two antihypertensive first-line treatment antihypertensive therapy on LVM.10 This analysis strategies, the fixed combination of perindopril and demonstrated a significant difference among the indapamide vs monotherapy with atenolol. After main medication classes (P ¼ 0.004). A À10% mass 1 year’s treatment, the two regimens resulted in decrease in LVMI was recorded with ACE inhibitor.
similar reductions in mean BP and SBP. However, In all, 556 hypertensive patients (47% men), with perindopril/indapamide reduced central (carotid) a mean age of 55 years, with SBP 164.4714.5 mmHg and peripheral (brachial) SBP and PP to a signifi- and DBP 98.678.5 mmHg as well as confirmed LVH cantly greater extent than atenolol, and these at the central reading (LVMI ¼ 143.5728.7 g/m2) benefits were expressed for central SBP and PP. It were evaluated. Both treatment groups were com- is well-known that LVM is affected more by central rather than peripheral haemodynamic changes, and According to the intention-to-treat analysis, a the more pronounced effects of perindopril/indapa- significantly higher decrease in LVH parameters mide on central SBP and PP lowering could explain and BP over 1 year in favour of the low-dose the greater effect of the combination on LVM combination of perindopril and indapamide com- The results of this study are particularly impor- 4 Verdecchia P et al. Prevalent influence of systolic over tant as the study design complies with criteria for pulse pressure on left ventricular mass in essential informative trials on LVM reduction, that is, REA- hypertension. Eur Heart J 2002; 23: 658–665.
SON has a sufficient number of patients, a repre- 5 Levy D et al. Prognostic implications of echocardio- sentative population, a long duration (12 months), graphically determined left ventricular mass in theFramingham Heart Study. N Engl J Med 1990; 322: double-blind randomisation, and blinded central 6 Devereux RB et al. Regression of left ventricular The PICXEL study further substantiates the results hypertrophy as a surrogate end-point for morbid events of REASON by demonstrating that, over 1 year of in hypertension treatment trials. J Hypertens Suppl treatment, the clinical benefits of the fixed combina- tion of perindopril/indapamide occur via significant 7 Devereux RB et al. Prognostic significance of left reductions in BP and LVH, compared with enalapril ventricular mass change during treatment of hyperten- There are physiological reasons for the better 8 Gosse P et al. Regression of left ventricular hypertro- performance of a combination strategy. The ideal phy in hypertensive patients treated with indapamideSR 1.5 mg versus enalapril 20 mg: The LIVE study.
combination therapy should address counter-regu- latory mechanisms, which can limit the efficacy of 9 Klingbeil AU et al. A meta-analysis of the effects of antihypertensive therapy. Thus, the key combina- treatment on left ventricular mass in essential hyper- tion for better control of LVH should use agents with tension. Am J Med 2003; 115: 41–46.
complementary modes of action to reduce the 10 Dahlo¨f B, Pennert K, Hansson L. Reversal of left volume and resistance components of BP and left ventricular hypertrophy in hypertensive patients. A ventricular overload, or — ideally — drugs with meta-analysis of 109 treatment studies. Am J Hyper- similarly efficacies on the two haemodynamic components. The combination of a diuretic and an 11 Ganau A et al. Patterns of left ventricular hypertrophy ACE inhibitor appears to be particularly appropriate and geometric remodelling in essential hypertension.
J Am Coll Cardiol 1992; 19: 1550–1558.
12 Laurent S et al. Clinical benefits of perindopril/ indapamide very-low-dose combination for hyperten-  It combines control of both the volume and sive patients. J Hypertens 2001; 19(Suppl 4): S9–S14.
13 Mogensen CE et al. Effect of low-dose perindopril/  It minimises the activation of the renin–angioten- indapamide on albuminuria in diabetes, Preterax in Albuminuria Regression: PREMIER. Hypertension  It includes the non-BP-related effect of angioten- sin II as a growth factor on the left ventricle and 14 Chanudet W, De Champvallins M. Antihypertensive efficacy and tolerability of low-dose perindopril/indapamide combination compared with losartan in In conclusion, the fixed low-dose of perindopril the treatment of essential hypertension. Int J Clin Pract (2 mg)/indapamide (0.625 mg) is a potential first-line therapeutic approach in essential hypertension that 15 Morgan T, Anderson A. Low-dose combination therapy causes a better improvement in central BP (aortic, with perindopril and indapamide compared with carotid) than in brachial BP. This combination irbesartan. Clin Drug Invest 2002; 22: 553–560.
achieves significantly greater changes in LVM than 16 Asmar RG et al on behalf of the REASON Project the standard comparators atenolol or enalapril and investigators. Amelioration of arterial properties with aperindopril–indapamide very-low-dose combination.
confirms the effectiveness of a fixed combination J Hypertens 2001; 19(Suppl 4): S15–S20.
approach compared with the monotherapy approach 17 Asmar RG et al for the REASON Project coordinators in hypertensive patients with or without LVM.
and investigators. Improvement in blood pressure,arterial stiffness and wave reflections with a very-low-dose hypertensive patient, a comparison with atenolol.
18 De Luca N et al on behalf of the REASON Project 1 Guidelines Committee 2003. European Society of investigators. Selective reduction of cardiac mass and Hypertension–European Society of Cardiology Guide- central blood pressure on low-dose combination lines for the Management of Arterial Hypertension.
2 Chobanian AV et al the National High Blood Pressure 19 London GM et al on behalf of the REASON Project Education Program Coordinating Committee. Seventh investigators. Mechanism(s) of selective systolic blood Report of the Joint National Committee on Prevention, pressure reduction after a low-dose combination of Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–1252.
comparison with atenolol. J Am Coll Cardiol 2004; 3 World Health Organization. 2003 World Health Orga- nization (WHO)/International Society of Hypertension 20 De Luca N et al on behalf of the REASON Project.
(ISH) statement on management of hypertension.
Regression of left ventricular mass in hypertensive patients treated with perindopril/indapamide as a first-line combination. Am J Hypertens 2004; 17: 22 Gosse P et al. Efficacy of very low dose perindopril 2 mg/indapamide 0.625 mg combination on left ven- 21 Dahlo¨f B et al. The PICXEL study: benefit of perindo- tricular hypertrophy in hypertensive patients: the pril/indapamide on LVH reduction. J Hypertens 2004; PICXEL study rationale and design. J Hum Hypertens

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