Η συνδυασμένη αγωγή στην αντιμετώπιση της υπέρτασης σήμερα

Η συνδυασμένη αγωγή στην αντιμετώπιση της υπέρτασης σήμερα Παντελής Α. Σαραφίδης, MD, MSc, PhD Επίκουρος Καθηγητής Νεφρολογίας, Νεφρολογική Κλινική Α.Π.Θ., Ιπποκράτειο Νοσοκομείο Θεσσαλονίκης

Mortality due to Leading Global Risk Factors (WHO 2010) Lim et al. Lancet 2012;380:2224-2260.

Αρτηριακή Πίεση και Θνητότητα από Στεφανιαία Νόσο ανά Ηλικιακή Δεκαετία IHD mortality (floating absolute risk and 95% CI) 256 128 64 32 16 8 4 2 SBP 256 128 64 32 16 8 4 2 DBP Age at risk: 80-89 y 70-79 y 60-69 y 50-59 y 40-49 y 1 1 120 140 160 180 Usual SBP (mm Hg) 70 80 90 100 110 Usual DBP (mm Hg) IHD, ischemic heart disease. Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

Adjusted Relative Risk of ESRD in 332,544 men in MRFIT study Adjusted Relative Risk 25,0 22.1* 20,0 15,0 11.2* 10,0 6* 5,0 3.1* 1,0 1,2 1.9* 0,0 * p<0.001 Optimal Normal High Normal Men with optimal blood pressure was the reference category. Stage 1 Stage 2 Stage 3 Stage 4 Blood Pressure Category Hypertension Klag MJ, et al. NEJM 1996;334:13-18.

Μικρές μειώσεις της αρτηριακής πίεσης μπορούν να μειώσουν τον καρδιαγγειακό κίνδυνο Lewington S et al. Lancet. 2002;360:1903-13.

Wright JT et al, N Engl J Med 2015 The SPRINT Study

Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 Average : 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

The SPRINT and ACCORD together Overall, these data call for careful reassessment of the target of <140 mm Hg in DM until, and if, a properly designed trial comparing <130 to <140 mmhg thresholds is conducted. Sarafidis P, et al. Nature Reviews Endocrinol 2017 Perkovic & Rodgers, N Engl J Med 2015

Θεραπεία Αρτηριακής Υπέρτασης Φαρμακευτικά μέτρα

Προτάσεις για συνδυασμένη θεραπεία ΑΥ από τις οδηγίες JNC-VI και 1999 WHO-ISH With any single drug, not more than 25 50% of hypertensives achieve adequate blood pressure control J Hum. Hypertens 1995; 9:S33 S36 For patients not responding adequately to low doses of monotherapy Increase the dose of drug. This, however, may lead to increased side effects Substitute with another drug from a different class Add a second drug from a different class (Combination therapy) If inadequate response obtained Add second drug from different class (Combination therapy)

JNC VII : Αλγόριθμος Θεραπείας ΑΥ Initial Drug Choices Without Compelling Indications With Compelling Indications Stage 1 Hypertension (SBP 140 159 or DBP 90 99 mmhg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Stage 2 Hypertension (SBP >160 or DBP >100 mmhg) 2-drug combination for most (usually thiazidetype diuretic and ACEI or ARB or BB or CCB) Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed Not at Goal BP Optimize dosages or add additional drugs until goal BP is achieved. Consider consultation with hypertension specialist.

2013 ESH/ESC Hypertension Guidelines Monotherapy vs. drug combination strategies to achieve target BP Mild BP elevation Low/moderate CV risk Choose between Marked BP elevation High/very high CV risk (IIbC) Single agent Two-drug combination Switch to different agent Previous agent at full dose Previous combination Add a third drug at full dose Full dose monotherapy Two drug combination at full doses Switch to different twodrug combination Three drug combination at full doses Moving from a less intensive to a more intensive therapeutic strategy should be done whenever BP target is not achieved.

Θεραπεία Αρτηριακής Υπέρτασης H θέση της περινδοπρίλης

ESC/ESH 2013: Επιλογή αντιυπερτασικών φαρμάκων

New onset diabetes: Network meta-analysis Elliott WJ and Meyer P, Lancet 2007

Αναστολή της εξέλιξης της διαβητικής νεφροπάθειας μέσω του αποκλεισμού του RAS Angiotensin Receptor blocker LIFE VALUE TRENDY ValEndo ROADMAP LIFE-Diabetes TRANSCEND MARVAL IRMA-2 AMADEO IDNT DROP RENAAL VIVALDI Prehypertension Typ-2- Prediabetes Diabetes Metabol. S. Hypertension Endothelial Dysfunction Microalbuminuria Albuminuria Reduced renal function ALLHAT CAPPP TRENDY BENEDICT DETAIL MICRO HOPE ACE-Inhibitor Time frame: up to 25 years 2098 Franklin #53

Effects of major antihypertensive classes on CV Events and mortality ACE inhibitors ARBs CCBs ACE: angiotensin converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; CHD: coronary heart disease; CI: confidential interval; CV: cardiovascular; HF: heart failure; RR: risk ratio; SBP: systolic blood pressure; DBP: diastolic blood pressure. 1- Zanchetti et al. Circ Res. 2015;116:1058-1073.

24h blood pressure reduction Perindopril has a long duration of action Perindopril 1 1 COVERSYL 75-100% Lisinopril 38-60% Enalapril Captopril 1 1 38% 55-70% Quinapril Ramipril Losartan Valsartan Candesartan 1 1 2 2 2 45-63% 50-60% 58-78% 69-76% 80% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Maximum blood pressure effect remaining 24 hours post dose (%) T/P ratio (%) 1- Morgan T et al. ibr J Cardol. 1995;(suppl 1):7-9. 2- Song JC et al. Formulary. 2001;36:487-499.

24h blood pressure reduction Perindopril provides sustained BP reduction 0 Losartan 100 mg Telmisartan 80 mg Perindopril 10 mg -5-10 -15-20 -12 mm Hg* -15 mm Hg* -22 mm Hg -25 *P<0.05 vs Perindopril BP: blood pressure -30 Mean 24-hour systolic BP (mm Hg) 1- Nedogoda SV et al. Clin Drug Investig. 2013;33:553-561.

Θεραπεία Αρτηριακής Υπέρτασης Συνδυασμένη Θεραπεία

Η ΛΟΓΙΚΗ ΤΗΣ ΣΥΝΔΥΑΣΜΕΝΗΣ ΑΝΤΙΥΠΕΡΤΑΣΙΚΗΣ ΘΕΡΑΠΕΙΑΣ 1. Ανεπαρκής έλεγχος της ΑΠ στην πλειονότητα των υπερτασικών ασθενών υπό θεραπεία (μεγαλύτερη αποτελεσματικότητα συνδυασμένης αγωγής) 2. Πολυπαραγοντική παθοφυσιολογία της ιδιοπαθούς ΑΥ αποκλεισμός περισσότερων μηχανισμών (συμπληρωματική δράση ή/και αποκλεισμός «αντιροπιστικών» μηχανισμών) 3. Μείωση παρενεργειών των αντιυπερτασικών φαρμάκων (χαμηλότερες δόσεις ή/και αποκλεισμός παρενεργειών άλλης κατηγορίας) 4. Βελτίωση της συμμόρφωσης των ασθενών με χρήση δισκίων σταθερών συνδυασμών 5. Υψηλότερος δείκτης κόστους-αποτελεσματικότητας (μείωση επισκέψεων για τιτλοποίηση και κόστους σκευασμάτων)

2 out 3 treated hypertensive patients have uncontrolled BP (17 countries) International, multicentre, cross-sectional study of 153 996 adults, 35-70 years old 110 Chow CK et al. JAMA. 2013;310(9):959-968.

Έλεγχος της ΑΠ σε ασθενείς με ΣΔ στη Σουηδία % 60 50 40 30 33 39 39 49 47 44 42 56 52 20 10 8 10 10 10 11 13 13 14 16 0 BP <130/80 mm Hg BP 140/85 mm Hg 1996 1997 1998 1999 2001 2002 2003 2004 2005

Multiple Interactions among the Mechanisms Controlling BP Stress Central factors Carotid sinus Hypertension Baroreflex defects β CO Sustained PVR Adrenergic drive 1 2 High renin α All 4 PVR Diet Na+ kept Low renin 3 K + Na+ Ca 2+ Age Na + Ca 2+ Kaplan and Opie. Lancet 2006;367:168 76

Απάντηση της ΑΠ στη Μονοθεραπεία Thiazides 50 55% Beta blockers 45 50% ACE inhibitors 50 60% Calcium Antagonists 40 60% Alpha blockers 35 40% Central agonists 30 35% 0 10 20 30 40 50 60 70 % Responders Adapted from Neutel et al. Hosp Med. 1998;34:35 38, 41 43.

ESH-ESC Guidelines 2013: Recommendations for Drug Combination Five major classes of antihypertensive agents thiazide diuretics, calcium antagonists, ACE inhibitors, angiotensin receptor antagonists and b-blockers are suitable for the initiation and maintenance of antihypertensive treatment, alone or in combination. Diuretics β-blockers ARBs CCB ACEi Mancia et al. J Hypertens 2013:31:1281-1357

Λογική του συνδυασμού αμεα ή ARB με διουρητικό Diuretic Effects JG Cells Renin Angiotensin I Volume Depletion Renin Release Angiotensin II Less Na + Reabsorbed Distal Tubule ARB Na + Diuresis AT 1 Receptor Vasoconstriction

Περινδοπρίλη Ινδαπαμίδη: 24ωρη δράση Flack JM et al. Vasc Health Risk Manag. 2011;7:777-787, Song JC et al. Formulary. 2001;36:487-4991, Mallion JM et al, Journal of Cardiovascular Pharmacology 1998;32:673-678, Lacourcière Y et al. Am J Hypertens. 1995;8:1154-1159.

Indapamide vs HCTZ: a meta-analysis 14 randomized trials with 883 patients comparing HCTZ with INDAP and chlorthalidone on antihypertensive potency or metabolic effects. Roush GC, et al. Hypertension 2015

Preferred thiazide-like diuretics National Clinical Guideline Centre UK. Hypertension the clinical management of primary hypertension in adults. August 2011. http://guidance.nice.org.uk/cg127. 142

ADVANCE: αυστηρότερη ρύθμιση ΑΠ από UKPDS = περαιτέρω CV κινδύνου συγχορήγηση α-μεα (Per/Ind), στατίνες Μείωση σχετικού κινδύνου Θνησιμότητα κάθε αιτιολογίας - 14% p=0.03 Καρδιαγγειακός θάνατος - 18% p=0.03 Σύνολο στεφανιαίων συμβαμάτων - 14% p=0.02 Σύνολο νεφρικών συμβαμάτων - 21% p<0.0001 AD V UKP DS Πρωτεύον τελικό σημείο (Συνδυασμός Μακρο+ Μικρο αγγειακών επιπλοκών) - 9% p=0.04 n= 11140, 5.5 έτη, ΑΠ 135/75 vs 140/77 mmhg Effects of fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus Lancet 2007; 370: 829-40

Zoungas S et al, N Engl J Med 2014 Mortality (Overall follow-up: median of 9.9 years)

The Trial: International, multi-centre, randomised double-blind placebo controlled Inclusion Criteria: Exclusion Criteria: Aged 80 or more, Standing SBP < 140mmHg Systolic BP; 160-199mmHg Stroke in last 6 months + diastolic BP; <110 mmhg, Dementia Informed consent Need daily nursing care Primary Endpoint: All strokes (fatal and non-fatal) + Perindopril 2 mg Indapamide SR 1.5 mg + Perindopril 4 mg Placebo Placebo Target blood pressure 150/80 mmhg + Placebo + Placebo M-2 M-1 M0 M3 M6 M9 M12 M18 M24 M60

ITT Summary of events HR 95% CI All Stroke Stroke Death All cause mortality NCV/Unknown death CV Death Cardiac Death Heart Failure CV events 0.70 (0.49, 1.01) 0.61 (0.38, 0.99) 0.79 (0.65, 0.95) 0.81 (0.62, 1.06) 0.77 (0.60, 1.01) 0.71 (0.42, 1.19) 0.36 (0.22, 0.58) 0.66 (0.53, 0.82) 0.1 0.2 0.5 0 2

Λογική του συνδυασμού ανταγωνιστή Ca με αμεα ή ARB CCB Arteriodilation Peripheral edema Effective in low-renin patients Reduces cardiac ischemia BP ACE/ARB RAS blockade CHF and renal benefits ACE/ARB Venodilation Attenuates peripheral edema Effective in high-renin patients No effect on cardiac ischemia Synergistic BP reduction Complementary clinical benefits CCB RAS activation No renal or CHF benefits

Mean BP change from baseline (mm Hg) STRONG study: Rapid and strong blood pressure-lowering efficacy 1250 patients with newly diagnosed grade 2 hypertension, or uncontrolled by monotherapy or inadequately managed with any other two-drug therapy Whole population Severe HT SBP >180 15 days 30 days 60 days 60 days 0 10 20 30 21* 11* 29* 16 23 29 40 50 41* 60 70 63* n=1250 Baseline BP: 167/101 mm Hg 170 *P<0.0001 SBP DBP Bahl et al. Am J Cardiovasc Drugs. 2009;9:135-142.

Blood pressure (mm Hg) COVERAM provides full 24-hour blood pressure control 150 140 130 120 110 100 90 Baseline SBP САД исходно 3-month SBP САД через 3 мес. Baseline DBP ДАД исходно 3-month DBP ДАД через 3 мес. 80 P<0.0001 vs baseline 70 60 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 Time (h) 176 1. Karpov YA et al. High Blood Press Cardiovasc Prev. 2015 Sep 9. [Epub ahead of print]. PUBLISHED SEP

The ASCOT-BPLA study (%) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Cardiovascular mortality Atenolol ± thiazide (No of events patients: 342) Amlodipine ± perindopril (No of events patients: 263) HR = 0.76 (0.65-0.90) - P=0.0010 0.0 1.0 2.0 3.0 4.0 5.0 years (mmhg) 180 160 140 120 100 80 60 Systolic and diastolic blood pressure 164.1 163.9 94.8 94.5 SBP DBP Mean difference 2.7 Mean difference 1.9 Atenolol ± thiazide Amlodipine ± perindopril 137.7 136.1 Baseline 0.5 1.0 1.5 2.0 2.5 3.0 3.5 41.0 4.5 5.0 5.5 Last visit 79.2 77.4 Number at risk Amlodipine ± Perindopril 9639 9544 9441 9322 9167 8078 Atenolol ± Thiazide 9618 9632 9415 9261 9085 7975 Adjustment for the mean difference in SBP (2.7 mmhg) explains only half of event reduction in ASCOT 178 Dahlöf et al. Lancet. 2005;366:895-906.

The ASCOT-BPLA study 181 Dahlöf et al. Lancet. 2005;366:895-906.

Cumulative event rate Kaplan Meier for Primary Endpoint Time to 1 st CV morbidity/mortality HR (95% CI): 0.80 (0.72, 0.90) 20% Risk Reduction p = 0.0002 Mean Follow-up 36 months Days Jamerson K, et al. N Engl J Med 2008;359:2417-2428

Kaplan-Meier curves for progression of chronic kidney disease for the intention-to-treat population Bakris GL, Sarafidis PA, Weir M, et al. Lancet 2010;375:1173-81

Systolic blood pressure (mm Hg) Better reduction in central blood pressure with amlodipine/perindopril 140 135 130 Brachial blood pressure 125 120 Central aortic pressure 0 1 2 3 4 5 6 Time (years) Amlodipine/Perindopril Atenolol/bendrofluazide N=2199 193 Williams et al. Circulation. 2006;113(9):1213-1225.

COVERAM reduces blood pressure variability more effectively in the long-term n=1 372 n=2 319 Visit-to-visit variability of systolic blood pressure (SBP) in ASCOT-BPLA patients treated exclusively with either amlodipine/perindopril or β-blocker/thiazide for at least 6 months. Difference in baseline SBP (mm Hg, 95% CI) = -1.6 (-2.7 to -0.0056) Difference in final SBP (mm Hg, 95% CI) = -0.6 (-1.6 to 0.4), P=0.2216 198 Watson et al. J Hypertens. 2014;32(e-suppl 1):e125.9C.06.

ACEi/ARB - Hydrochlorothiazide Combination: Safety Advantages ACEi/ARB RAAS Aldosterone Serum Potassium + Thiazide Diuretic Plasma volume and natriuresis RAAS Aldosterone Serum Potassium Serum potassium levels remain within normal limits

Tolerability and Risk Factor Modification: CCBinduced Peripheral Edema Minimized by the ARB CCB dilates arteries Veins remain constricted ARB dilates arteries and veins Capillary overload forces fluid into surrounding tissue Reduces CCB-induced peripheral edema Single mode of action of the CCB Dual mode of action of the CCB ARB Illustration modified from www.lotrel.com Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42 73 White et al. Clin Pharmacol Ther 1986;39:43 8; Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl. 1):S121 31; Messerli et al. Am J Cardiol 2000;86:1182 7

% of patients Compliance and Persistence with Anti-HTN Therapy Typically Falls to <50% in One Year Study of hypertensive patients in clinical studies 4783 patients in 21 Phase IV trials Evaluated by medication event monitoring system 100 90 80 70 60 50 Vrijens et al. BMJ 2008;336:1114-7. 0 Fall in adherence because of poor execution of dosing regimen Persistence Adherence/compliance Perfect adherence Fall in persistence because of discontinuation of treatment 0 50 100 150 200 250 300 350 Time (days) No of patients 3108 980 828 618 474 400 331 remaining in study

Regimen Complexity: A Major Reason for Failure to Adhere with Medication As the number of pre-existing prescription medications increased, the likelihood of adequately refilling antihypertensive therapy and LLT decreased Number of pre-existing Rx medications 0 1 2 3 5 6 Unadjusted odds ratio for adherence (>80%) to both antihypertensive therapy and LLT (95% CI; p value) 1.73 (1.56 1.90; p<0.001) 1.25 (1.13 1.39; p<0.001) 0.96 (0.86 1.06; p=0.41) 0.87 (0.79 0.94; p<0.001) 0.65 (0.59 0.71; p<0.001) 0.5 1 1.5 2 2.5 Decreased compliance Increased compliance Chapman RH, et al. Arch Intern Med 2005;165:1147 52

Fixed versus Free Combinations: Impact of an Increase in the Number of Concomitant Drugs Medication-possession ratio (MPR) 100% 90% 85,9% 87,3% 86,5% 88,8% 87,7% 89,6% 90,2% 80% 70% * * 73,7% 73,6% * 72,1% * * 70,1% 69,7% * 67,2% * 65,6% 60% 50% 1 2 3 4 5 6 >6 Number of concomitant drugs *p<0.0001 Fixed-dose combination (n=2,839) Free combination (n=3,367) Wanovich et al. Am J Hypertens 2004;17:223A (poster)

Patients with BP control* (%) High Compliance with Anti-hypertensive Therapy Significantly Improves BP Control 50 40 30 43 Odds ratio = 1.45 p=0.026 (controlling for age, gender and comorbidities) 34 33 20 10 0 High ( 80%) Medium (50 79%) Level of compliance Low (<50%) BP goal: <140/90 mmhg (or <130/85 mmhg in patients with diabetes) Bramley et al. J Manag Care Pharm 2006;12:239 45.

Risk of first acute CV event (hazard ratio) Good Compliance is Associated with a Reduced Risk of CV events in Europe 1.0 0.8 p<0.001 1.00* >18,800 newly 0.87 diagnosed and (0.73 1.03) treated hypertensive patients free from CVD 0.6 0.4 0.50 (0.35 0.69) Mean follow-up: 4.6 yrs *reference 0.2 0.0 Low (<40%) Medium 1 (40 79%) High ( 80%) Compliance within 6 months after diagnosis Mazzaglia et al. Circulation 2009;120:1598-605.

SYMBIO: Benefit from switching from free combinations to fixed-dose combinations BP measurement Systolic BP (mean ± SD) Diastolic BP (mean ± SD) n=694 Baseline on free perindopril + amlodipine combination 155 ± 16 mm Hg 92 ± 10 mm Hg 1 month on COVERAM 139 ± 12 mm Hg 84 ± 7 mm Hg -24 mm Hg (P<0.0001) 3 months on COVERAM 131 ± 9 mm Hg 81 ± 6 mm Hg 252 Hatalová et al. J Hypertens. 2014;32(e-Suppl 1):e590.PP.36.33.

Θεραπεία Αρτηριακής Υπέρτασης Τριπλοί Συνδυασμοί

3 φάρμακα 1 φάρμακο 2 φάρμακα 18.652 ασθενείς Northern Europe (Belgium, Germany, Sweden, Switzerland), Southern Europe (Greece, Italy, Spain, Turkey), North America (Canada), Latin America (Columbia, Mexico, Peru), Middle East (Kuwait, Lebanon, Qatar, Saudi Arabia, UAE), Asia (Hong Kong, Indonesia, Korea, Singapore, Taiwan, Thailand, Vietnam, Australia) Thoenes M et al. J Hum Hypertens. 2010;24:336-344.

Ποσοστό ρύθμισης της αρτηριακής πίεσης (%) P<0,05 για τη διαφορά των 2 φύλων 65-70% αρρύθμιστοι Άνδρες Γυναίκες 18.652 ασθενείς Northern Europe (Belgium, Germany, Sweden, Switzerland), Southern Europe (Greece, Italy, Spain, Turkey), North America (Canada), Latin America (Columbia, Mexico, Peru), Middle East (Kuwait, Lebanon, Qatar, Saudi Arabia, UAE), Asia (Hong Kong, Indonesia, Korea, Singapore, Taiwan, Thailand, Vietnam, Australia) Thoenes M et al. J Hum Hypertens. 2010;24:336-344.

Μέσος αριθμός αντιυπερτασικών φαρμάκων και αντίστοιχες τιμές ΣΑΠ σε μεγάλες μελέτες Studies in non-ckd patients HOT (138 mmhg) UKPDS (144 mmhg) ALLHAT (138 mmhg) INVEST (136 mmhg) Studies in patients with CKD MDRD (132 mmhg) ABCD (132 mmhg) AASK (128 mmhg) IDNT (138 mmhg) RENAAL (141 mmhg) 1 2 3 4 Number of BP medications Sarafidis PA & Bakris GL, J Clin Hypertens 2008

Effective regardless of the previous two-drug therapy 4731 hypertensive patients with uncontrolled hypertension Tòth K et al; PIANIST Investigators. Am J Cardiovasc Drugs. 2014;14:137 145.

Tòth K et al; PIANIST Investigators. Am J Cardiovasc Drugs. 2014;14:137 145. TRIPLIXAM s efficacy meets the needs of a large range of patients 4731 hypertensive patients with uncontrolled hypertension

TRIPLIXAM s efficacy is maintained over 24 hours P<0.0001 P<0.0001 P<0.0001 24 hours Daytime Nighttime Tòth K et al; PIANIST Investigators. Am J Cardiovasc Drugs. 2014;14:137 145.

Evolution of guidelines on fixed-dose combinations 285 1999 WHO/ISH 2003 WHO/ISH 2003 JNC 7 2003 ESH/ESC 2007 ESH/ESC 2009 ESH/ESC 2013 ESH/ESC The use of fixed-dose combinations may be advantageous Where they are no more expensive, such formulations may be preferable since they have advantages in terms of compliance When BP is more than 20/10 mm Hg above goal, consideration should be given to initiating therapy with two drugs, either in separate prescriptions or in fixed-dose combinations Fixed-dose combinations allow administration of two agents within a single tablet, thus optimizing compliance Fixed-dose combinations reduce the number of tablets to be taken, and this has some advantages on compliance Whenever possible, use of single-tablet combinations should be preferred, because simplification of treatment causes advantages for compliance to treatment The 2013 ESH/ESC guidelines favor the use of combinations of two antihypertensive drugs at fixed doses in a single tablet, because reducing the number of pills to be taken daily improves adherence and increases the rate of BP control

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