Blood Pressure Lowering Efficacy of Perindopril/ Indapamide Fixed Dose Combination in Uncontrolled Hypertension

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1 525 Blood Pressure Lowering Efficacy of Perindopril/ Indapamide Fixed Dose Combination in Uncontrolled Hypertension PHIMDA Kriangsak 1* and CHOTNOPARATPAT Paiboon 2 1 Diabetes and Hypertension Clinic, Department of Internal Medicine, Udonthani Hospital, Bangkok, THAILAND. 2 Department of Medicine, Bangkok Metropolitan Administration Medical College Vajira Hospital, Bangkok, THAILAND Corresponding Author: PHIMDA Kriangsak, Diabetes and Hypertension Clinic, Department of Internal Medicine, Udonthani Hospital, Bangkok, THAILAND., kriangsak_kp@hotmail.com ABSTRACT Introduction: The national health examination survey in Thailand determined that T2DM and dyslipidemia were probable risk factors resulting in higher rate of uncontrolled hypertension. This had been reported with controlled rate as low as 15%. The authors investigated if the choice of antihypertensive agents render better blood pressure control in Thai hypertensive patients. Objective: To assess the blood pressure (BP) lowering efficacy of Perindopril/indapamide Fixed Dose Combination (P/I FDC), as an antihypertensive of choice in Thai hypertensive patients with multiple co-morbidities and risk factors. Method: A prospective consecutive open-blind evaluation short-term follow-up was initiated with Perindopril 4 mg/indapamide 1.25 mg Fixed Dose Combination (P/I FDC) among 1,364 Thai hypertensive patients, as newly diagnosed monotherapy, or switched from either inhibitors of angiotensin converting enzyme or angiotensin receptor blocking agents, with addition of either calcium channel blockers of beta-blockers allowed in a multi-center trial hypertensive patients with safety monitoring program demanded by Thai health authority. Result: After 3 months of treatment, the SBP/DBP of patients receiving P/I FDC-based treatment (mean ± SD), [95% CI] was 131.6±9.6 [ ] /78.7 ±7.1 [ ] mmhg resulting from SBP/DBP reduction of 26.6/11.8 mmhg respectively. In the overall cohort, only 9.7% of patients required additional antihypertensive agents. The authors founded that in newly diagnosed stage 2 hypertensive patients, hypertensive patients with diagnosed dyslipidemia, and with diagnosed T2DM, P/I FDC mono-therapy or in combination effectively reduced SBP/DBP by 33.9/16.0 mmhg, 30.7/12.8 mmhg and 23.5/11.0 mmhg respectively. Overall blood pressure normalization with P/I FDC with SBP/DBP<130/80 mmhg and <140/90 mmhg were 48.2% and 91.4% respectively which were above earlier reported in Thai hypertensive patients. P/I FDC was well tolerated by patients, with a reported cough incidence of 5.1 %. Conclusion: The choice of antihypertensive agents is a critical factor for the control of hypertension. P/I FDC is an effective antihypertensive agent in Thai hypertensive patients for

2 526 uncontrolled hypertension. It is effective in both newly diagnosed stage I, stage II hypertension and among patients with diagnosed Type 2 Diabetes and dyslipidemia. In daily clinical practice, P/I FDC should be recommended as the first choice antihypertensive among uncontrolled Thai hypertensive patients. Keywords: Perindopril/Indapamide Fixed Combination, Angiotensin Blocking Agent, Uncontrolled Hypertension, Type 2 Diabetes Mellitus, Blood pressure staging. Introduction Several epidemiologic studies (1-2) have demonstrated that elevated blood pressure both systolic and diastolic may have strong, consistent, graded and etiologically significant positive association with cardiovascular outcomes (3-4). In Thailand, hypertension is one of major health burden with increasing incidence of 5.4%, 11.0% and 22% in 1991, 1996 and A multistage national health examination survey phase III, of the ministry of public health in Thailand conducted among 19,374 individuals aged 60 years and older reported a very high prevalence at 51.1% and 21.9% for hypertension and hypertension with diabetes. The study suggested that diabetes and hypercholesterolemia were major risk factors attributed to uncontrolled hypertension with blood pressure controlled rate lower than 15% (5-6). Failure to control high blood pressure may be linked to the selection of anti-hypertensive agents. We opted for P/I FDC, as blood pressure lowering agent, because it had been proven in several landmark trials as a safe antihypertensive agent for secondary stroke prevention, in Type 2 diabetes mellitus patients and in hypertensive patients with cardiovascular risk profiles (7-9). In addition, P/I FDC had been widely prescribed as antihypertensive agent in general practice clinic in Thailand (10). Moreover, most uncontrolled hypertensive patients were of high risk hypertensive population which should have received various antihypertensive agents earlier. Specifically, should the switching of antihypertensive agents render similar blood pressure control in this population, this had not been investigated elsewhere. As such, prospective plan for switching of antihypertensive agent were of the authors interest. In addition, several antihypertensive intervention trials including antihypertensive switched study, like many randomized control trials, had not been able to guide our current daily practice for the treatment of uncontrolled hypertension in Thailand. The authors believed that although randomized clinical trials provide essentially high-quality evidence about the benefits and harms of medical interventions, many such trials have limited relevance to clinical practice (11). Authors acknowledged the concept of pragmatic trials though they represent less-perfect experiments than efficacy trials, yet they represent a real-world practice and their results are likely to be more applicable in day-to-day clinical practice. Objectives To investigate the blood pressure lowering efficacy of P/I FDC in newly untreated and uncontrolled Thai hypertensive patients switched from other antihypertensive agents, in particular, inhibitor of angiotensin converting enzyme(ace-i) and angiotensin receptor blocking agent (ARB).

3 527 Material and Method A prospective consecutive open-blind evaluation short-term follow-up was initiated with Perindopril 4 mg/indapamide 1.25 mg Fixed Dose Combination (P/I FDC) as antihypertensive agent. It was prescribed in a multi-center trial of 1,500 Thai hypertensive patients integrated within safety monitoring program demanded by Thai health authority. Among these, there were 634 uncontrolled patients switched from either ACE-I or ARB. Eligibility criteria Any hypertensive patients aged above 18 years old with SBP/DBP 130/80 mmhg. Inclusion: i. Any uncontrolled hypertensive patient regardless of patients type (new diagnosis, uncontrolled hypertension from either ACE-I or ARB). ii. Patients with or without history of uncomplicated CHD. iii. Patients with current diagnosis of T2DM. iv. Patients with current diagnosis of dyslipidemia confirmed with laboratory results. Exclusion: i. Secondary hypertension. ii. Complicated hypertensive patients with multiple organic diseases. iii. Hypertensive patients with severe renal disease and are under dialysis procedures. iv. Hypertensive patients with planned cardiac procedures. v. Hypertensive patients previously treated by CCBs, BBs and alpha-1 receptor blockers. vi. Suspected noncompliance hypertensive patients with psychiatric symptoms. Blood pressure measurement and laboratory examination i. Standard digital blood pressure measuring device, routinely standardized as employed in the hypertension/diabetic clinics for its validity. ii. Blood pressure was recorded three times with an average value measurement in sitting position by research assistant nurse. iii. Blood pressure records were taken at baseline, and at follow-up visits after 1 and 3 months. Both systolic and diastolic blood pressure readings were recorded with an average of three readings. iv. Hypercholesterolemia was diagnosed after laboratory examination with total cholesterol 240 mg/dl whereas dyslipidemia with total cholesterol 200 mg/dl. v. Type 2 diabetes mellitus, a current diagnosis based on American Diabetes Association classification with HbA1c >6.5% or FPG>126 mg/dl (7.0mmol/l) or in patients with classic symptoms of hyperglycemia with random plasma glucose 200mg/dl (12). vi. At recruitment entry, subjected to inclusion/exclusion criteria, patients were informed for compulsory follow-up pertaining to requirement of the integrated safety monitoring program prescribed by Thai health authority by research assistant nurse and by virtue of

4 528 vii. viii. physician in charge with consent conform to follow-up regularly at month 1 and month 3 for the entire study period. All patients participating in the study were given advice for their basic life style modifications in particular, as well as general counseling with assistance from pharmacy department. Treatment algorithms as prescribed with newly diagnosis patients started with P/I FDC one tablet at bed time, or switched patients (only from any ACEI/ARB were allowed) due to uncontrolled hypertension; The second line as the third antihypertensive agents maybe prescribed after one month monitoring (SBP/DBP 130/80 mmhg), were either any CCBs or BBs as determined by physician in-charge if needed. Patients treated with diuretics and other antihypertensive agents rather than ACEI or ARB were not allowed to avoid any possible drug interaction with Indapamide. Population, sample and statistical analysis Population: All Thai hypertensive patients Sample: All Thai hypertensive patients visit the ambulatory hypertension and diabetes clinics from major 25 public and private hospitals, nationwide randomly distributed with 40% of patients recruited were from Bangkok and 60% of patients recruited were from upcountry hospitals. The sample size (n) as 95% CI of µ = ±0.5, n = [(Z α//2 SD) / 0.5] (2) for calculation based on efficacy of P/I on mean SBP reduction from Phimda K et al (9), with α = 0.05 and SD = 8.2 and Z α 1/2 =1.96, n= [(1.96 X 8.2) / 0.5] 2 = 1,033, with 30% lost of follow-up of 310 patients, as such n = 1,343 patients. Each centers recruited 60 patients and our total sample was 1,500 hypertensive patients. Statistical Analysis: A descriptive statistics with one sample t-test before and after treatment from baseline to month 1 and month 3; the efficacy for hypertensive at risk for Type 2 diabetes mellitus and dyslipidemia employed ANOVA repeated measure for blood pressure lowering efficacy from baseline to month 3. A blood pressure normalization rate based on level of SBP/DBP (in mmhg) after completion of the study was presented in frequency. Results Thai Hypertensive Population There were 25 hospitals participated in this multicenter trial, a consecutive approach allowed us to recruit 1,500 patients. However, only 1,364 patients were completed and available for analysis. There were 136 (9.0%) incomplete follow-up. Major demographic and clinical characteristics of the hypertensive cohort were given Table1. Overall blood pressure lowering efficacy of P/I FDC was given in Table 2. In the context of presence of Type 2 diabetes mellitus and dyslipidemia, blood pressure lowering efficacy of P/I FDC was sustained and consistent over the 3 months follow-up. However, among patients without Type 2 diabetes mellitus, their blood pressure levels were slightly lower at mean (±SD),

5 529 [95% CI] SBP in mmhg of 132.5±10, [ ], as compared to patients with Type 2 diabetes mellitus of 131.1±10.0 [ ], a significant slightly better systolic blood pressure reduction for patients without Type 2 diabetes mellitus with a reduction of 28.3 mmhg Vs 23.5 mmhg, with 95% confidence interval at p=0.029 was noted. Whereas, there was no significant different systolic blood pressure reduction among hypertensive patients in the presence of dyslipidemia( p=0.111) as given in Table 3. Blood pressure controlled rate and normalization The overall blood pressure normalization after 3 months of the hypertensive cohort based on P/I FDC as monotherapy for newly diagnosis and hypertensive switched (ACE-I/ARB) and then with added CCBs and BBs after 1 month as per intention-to-treat basis were given in Table 4. Discussion The inadequate blood pressure control among Thai hypertensive patients, in particular with the presence of either type 2 diabetes mellitus or dyslipidemia or both (5-6), may probably due to the result of the inappropriate choice of antihypertensive agents, the severity of hypertension, the inadequate adherence to treatment or combination. In spite of higher blood pressure reduction in patients without type 2 diabetes, this could due basically to their higher baseline blood pressure. Thus, this may probably support that P/I FDC is even more effective in patients with higher blood pressure level as compared with lower blood pressure level for same individual. Up to date, no such trial addressed specifically this issue. The authors approach is to address the usefulness of P/I FDC in terms of its clinical efficacy during short-term evaluation regardless of the severity of hypertension (stage 1 or stage 2). It is observed that P/I FDC was highly effective in controlling blood pressure among hypertensive patients, in particular patients with presence of Type 2 diabetes and, or dyslipidemia. The authors found that only 70 patients reported mild cough with incidence of 5.13 %. Landmark trials such as PROGRESS and ADVANCE (8-9) have demonstrated that P/I FDC was able to provide beneficial effects with hard outcomes in terms of reduction of both macrovascular and microvascular events in long-term. The authors evaluation confirmed that short-term efficacy and patient compliance are key to long-term success in blood pressure control. P/I FDC thus should be considered as first-line antihypertensive agent in the management of hypertension. Despite the shortcomings of the study, such as lack of randomization and blinded approach, the authors believe that a pragmatic setting and open selection is more relevant to real clinical settings and thereby better generalization. As such, this study was appropriate by its own right to assess short-term blood pressure control as surrogate outcome. Conclusion Uncontrolled hypertension either untreated or uncontrolled after a switch from Inhibitor of Angiotensin Converting Enzyme (ACE-)I or Angiotensin Receptor Blocking (ARB) agents can be successfully controlled by Perindopril /Indapamide Fixed-Dose Combination (P/I FDC). P/I FDC mono-therapy or combination treatment of hypertension were useful antihypertensive approaches in daily clinical practice. P/I FDC was well tolerated by Thai patients. These results

6 530 suggest that P/I FDC should be prescribed as the first line antihypertensive agent regardless of hypertension severity and patients risk profile. Conflict of Interest: None declared. Acknowledgement The authors would like to thank all the investigators from participating public and private hospitals both in Bangkok and upcountry nationally, each of which had provided the authors data for analysis. Reference 1. Stamler J,Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med 1993, 153(5): Kannel WB. Blood pressure as a cardiovascular risk factor:prevention and treatment. JAMA. 1996, 275(20): 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(8692): Puavilai W, Laorungpongse D, Prompongsa S, et al Prevalence and some important risk factors of hypertension in Ban Paew District, second report. J Med Assoc Thai. 2011, 94(9): Porapakkham Y, Pattaraarchachai J, Aekplakorn W. Prevalence, awareness, treatment and control of hypertension and diabetes mellitus among the elderly: The 2004 National Health Examination Survey III, Thailand. Singapore Med J. 2008, 49(11): Khonputsa P, Veerman JL, Vos T, et al Joint Prevalence and Control of Hypercholesterolemia and Hypertension in Thailand:Third national health Examination Survey. Asia Pac J Public Health. 2011, 23: PROGRESS Collaborative Group, Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001, 358(9287): Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003, 362(9386): MacMahon S, Chalmers J, Neal B. et al Effects of a fixed combination of perindopril and indapamide on macrovascualr and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial):a randomized controlled trial. Lancet. 2007, 370(9590): Phimda K, Limpaiboon R, Sattayasai J. Management of Hypertension in the General Practice Clinic: Post-Marketing Surveillance with a fixed Combination of Perindopril and Indapamide Sringarind Med J. 2005, 24(4):308-13

7 Ware JH, Hamel MB. Pragmatic trials-guides to better patient care. N Engl J Med. 2011, 364(18): American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus, Diabetes Care. 2011, 34(suppl1):S62-S69 Table 1: Demographic and clinical characteristics of Thai hypertensive population Demographic characteristics N (%) Mean (±SD) Gender Age Male 656(48.1%) Female 708(51.9%) >55 years old 925(67.8%) 55 years old 439(32.2%) 61.5 (±11.1) Smoker 154(11.3%) Alcoholic drinker 70(5.1%) Clinical Characteristics Stage 2 HT: SBP/DBP>160/100 mmhg 738(54.1%) Stage 1 HT: SBP/DBP>140/90mmHg 626(45.8%) Type 2 Diabetes Mellitus 511(37.5%) Dyslipidemia 430(31.5%) Left Ventricular Hypertrophy 110(8.1%) Coronary Artery Disease 190(13.9%)

8 532 Table 2: Reduction in BP from baseline to month 3 *P<0.001 SBP (mmhg) Baseline (BP in mmhg) DBP (mmhg) SBP (mm Hg) After 3 Months follow-up DBP (mm Hg) Reduction from baseline Reduction from baseline Overall hypertensive population (n=1364) 158.2± ± ± * 78.7± * Diabetic subpopulation (n=511) 156.0± ± ± * 78.3± * Dyslipidemia subpopulation (n=430) 161.4± ± ± * 77.5± * Stage2 hypertensive subpopulation(n=738) BP>160/100mmHg 168.3± ± ± * 79.3± * Stage1 hypertensive subpopulation (n=626) BP >140/90 mmhg 147.5± ± ± * 78.2± * P/I FDC monotherapy (n=730) 155.2± ± ± * 79.0± * Switched from ACEI/ARB (n=634) 161.6± ± ± * 78.1± * Calcium channel blockers added-(n=97) 161.9± ± ± ±12.7* 79.4± ±10.5* Beta-blockers added(n=35) 159.8± ± ± *± ± ±9.5* Note ACEI=Inhibitor of Angiotensin Converting Enzyme, ARB = Angiotensin Receptor Blocking Agent *p-value by one sample t-test.

9 533 Table 3: Blood pressure reduction, effects of type 2 diabetes mellitus and dyslipidemia *p<0.05 for blood pressure reduction from baseline and effects of risks **p<0.05 SBP- Reduction* Mean SBP(±SD) D0[95% CI] Mean SBP(±SD) M3[95% CI] ** p-value W/ T2DM(n=511) 156.0(±14.6) 132.5(±10.0) 23.5* [ ] [ ] W/O T2DM(n=853) 159.4(±15.3) 131.1(±10.0) 28.3* [ ] [ ] P**= W/ DLP (n=430) 161.4(±14.6) 130.7(±9.7) 30.7* [ ] [ ] W/O DLP(n=934) 156.6(±15.1) 132.1(±9.5) P**= * [ ] [ ] * p-value by one sample t-test **p-value by ANOVA Repeated Measure Table 4: Blood pressure level at the end of Month 3, by P/I FDC based-treatment

10 534 Blood pressure type Numbers Percentage CCBs and BBs added (%) SBP< 130 mmhg 743/ % at the ends of Month 1 DBP< 80 mmhg 1,080/ % SBP/DBP <130/80 mmhg 658/ % SBP/DBP <140/90 mmhg 1,247/ % N= 107 added CCBs N= 35 added BBs Added CCBs or BBs 142(10.4%) Note. CCBs= Calcium Channel Blockers, BBs=Beta-Blcokers