Combination therapy Giuseppe M.C. Rosano, MD, PhD, MSc, FESC, FHFA St George s Hospitals NHS Trust University of London

Combination therapy Giuseppe M.C. Rosano, MD, PhD, MSc, FESC, FHFA St George s Hospitals NHS Trust University of London KCS Congress: Impact through collaboration CONTACT: Tel. +254 735 833 803 Email: kcardiacs@gmail.com Web: www.kenyacardiacs.org

Disclosures I have no conflicts of interest for this talk Travel and accommodation provided by Les Laboratories Servier

Global Variations in Mortality among Patients with Heart Failure The INTER-CHF Study Clinical Variables Overall N=5823 Africa N=1294 India N=858 SE Asia N=811 M. East N=1000 China N=991 S Amer. N=869 Age (years, SD) 59 (15) 53 (14) 56 (15) 57 (14) 56 (16) 66 (16) 67 (15) Male Sex (%) 61 52 62 59 72 57 61 Reduced LVEF + (<40%) (%) 50 54 53 39 73 27 53 Valve disease + (%) 46 57 42 40 50 41 48 NYHA class III/IV (%) 40 56 50 16 37 56 32 HF cause: Ischemic heart disease (%) 39 20 46 56 50 45 25 Hypertensive heart disease (%) 17 35 14 15 10 14 21 Dilated cardiomyopathy (%) 12 14 11 3 18 15 15 Valvular heart disease (%) 11 11 12 12 8 11 13 INTER-CHF Investigators, HFA Congress 2017

Unadjusted mortality rates within one year, by region and cause Death rate at 1 year (%) 35 30 25 Cardiac death Non-Cardiac Death Unknown Cause of Death 20 15 10 5 0 Region INTER-CHF Investigators, HFA Congress 2017

Lowering systolic blood pressure reduces mortality SPRINT study (2015) 1 Targeting systolic BP <120 mm Hg vs <140 mm Hg in older patients further improves CV outcomes 1. SPRINT Research Group. N Engl J Med. 2015;373:2103-2116. 5

NICE guidelines recommendations for the management of arterial hypertension A: Renin Angiotensin System Antagonist, C: Calcium Channel Blocker; D: Diuretic 1. NICE guidelines. Hypertension: Clinical management of primary hypertension in adults [CG127]. Published August 2011. http://www.nice.org.uk/guidance/cg127/chapter/1-recommendations. Accessed September 28, 2015. 6

Indapamide is more potent than HCTZ at reducing systolic blood pressure Roush meta-analysis (2015) 1 Indapamide is significantly more potent than HCTZ at reducing systolic blood pressure, which is not the case with chlorthalidone Systematic review and metaanalysis; head-to-head RCTs comparing HCTZ vs indapamide (10 RCTS, n=813) and HCTZ vs chlorthalidone (3 RCTS, n=70). 1. Roush et al. Hypertension. 2015;65:1041-1046. 7

Unlike all other diuretics, Indapamide is metabolically neutral Indapamide SR preserves lipid and glucose metabolism in the short and long term 1 1. Ambrosioni E et al. J Hypertens. 1998;16:1677-1684. 8

Indapamide reduces left ventricular hypertrophy Indapamide SR significantly reduces left ventricular hypertrophy LIVE study (2000) 1 1. Gosse P et al. J Hypertens. 2000;18:1465-1475. 9

Thiazide-like diuretics are better than thiazide-type diuretics in reducing stroke Chen meta-analysis (2007) 1 Stroke reduction with thiazide diuretics is mainly driven by thiazide-like diuretics and not thiazidetype diuretics 1. Chen P et al. Am J Hypertension. 2015;28:1453-1463. 10

Thiazide-like diuretics have strong evidence of cardiac protection Olde Engberink meta-analysis (2015) 1 1. Olde Engberink RH et al. Hypertension. 2015;65:1033-1040. 11

Indapamide provides effective protection on mortality, stroke and heart failure Protection against stroke with indapamide Indapamide reduces the risk of heart failure Indapamide based treatment reduces the risk of death from cardiovascular causes HYVET study (2008) 1 1. Beckett N et al. N Engl J Med. 2008;358:1887-1898. 12

NICE guidelines recommendations for the management of arterial hypertension A: Renin Angiotensin System Antagonist, C: Calcium Channel Blocker; D: Diuretic 1. NICE guidelines. Hypertension: Clinical management of primary hypertension in adults [CG127]. Published August 2011. http://www.nice.org.uk/guidance/cg127/chapter/1-recommendations. Accessed September 28, 2015. 13

CCBs are still one of the best classes for reducing strokes Mukete meta-analysis (2015) 1 Risk ratios for stroke comparing treatment with calcium channel blockers versus other antihypertensive agents(ace) inhibitors 1. Mukete B et al. Am J Cardiovasc Drugs. 2015;15:243-257. 14

Amlodipine provides effective protection against stroke Wang meta-analysis (2007) 1 Protection against stroke with amlodipine vs placebo, angiotensin receptor blockers (ARBs), or angiotensin- converting enzyme (ACE) inhibitors Effects of antihypertensive treatment on stroke in trials comparing amlodipine with placebo or other classes of antihypertensive drugs, including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors. 1. Wang et al. Hypertension. 2007;50:181-188. 15

Amlodipine effectively reduces myocardial infarction Wang study (2007) 1 Effects of antihypertensive treatment on myocardial infarction in trials comparing amlodipine with placebo or other classes of antihypertensive drugs, including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors 1. Wang JG et al. Hypertension. 2007;50:181-188. 16

Amlodipine reduces mortality Kaplan-Meier curves for time to first primary composite end point in ACCOMPLISH ACCOMPLISH study (2008) 1 1. Jamerson K et al. N Engl J Med. 2008;359:2417-2428. 17

CCB/thiazide-like diuretic combinations are more effective at reducing stroke than other combinations Rimoldi meta-analysis (2015) 1 Risk ratios for stroke comparing treatment with combination CCB/thiazide-like diuretic vs other combinations CCB, calcium channel blocker; CI, confidence interval, Diu, diuretic; RR, risk ratio. 1. Rimoldi SF et al. J Clin Hypertens (Greenwich). 2015;17:193-199.

JNC8 guidelines for the treatment of arterial hypertension JNC8 guidelines recommend a CCB or a diuretic, alone or in combination for patients over 60 1 1. James PA et al. JAMA. 2014;311(5):507-520. 19

South African hypertension practice guideline 2014 In black hypertensive patients a diuretic and/or a CCB is recommended. [ ] Compared to whites, blacks respond poorly to ACEI and β-blockers as monotherapy 20

Two complementary modes of action Two complementary effects: renal and vascular 1-4 1. Waeber B et al. Expert Opin Pharmacother. 2012;13:1515-1526. 2. Leenen FH et al. Curr Med Res Opin. 1983;8 (suppl 3):47-52. 3. Hamet P et al. J Hypertens.32(e-suppl 1):e269-e270. 4. Cappuccio FP et al. J Hum Hypertens. 1991;5:115-119. 21

Two of the most effective drugs at lowering systolic blood pressure Indapamide SR and amlodipine effectively reduce systolic BP. Baguet meta-analysis (2007) 1 1. Baguet et al. Clin Drug Invest. 2007;27:735-753. 22

Two drugs providing full 24-hour BP control and reduce BP variability Trough-to-peak ratio for different antihypertensive drugs. 1-7 Comparisons of 24-hour systolic blood pressure variability 1. Lacourciere Y et al. Am J Hypertens. 1995;8:1154-1159. 2. Oparil MD et al. Clin Ther. 2010;32:1252-1269. 3. Staessen JA et et al. Hypertension. 1995;26:942-949. 4. Yusoff K et al. Int J Clin Pract. 1999;53:277-280. 5. Zannad F et al. J Hypertens. 1999;17:137-146. 6. Hermida RC et al. Hypertension. 2003;42:283-290. 7. Mallion JM et al. Arch Mal Coeur. 1996;89;27-38. 23

Amlodipine/Indapamide (Natrixam) further reduces Systolic blood pressure versus placebo EFFICIENT study (2014) 1 Efficient and rapid blood pressure (BP) decrease (global population). Blood pressure (BP) lowering efficacy of Natrixam in grade 3 hypertensive patients. BP, blood pressure. 1. Jadhav U et al. PLoS One. 2014;9:e92955. 24

Amlodipine/indapamide (Natrixam) further reduces systolic blood pressure versus ARB/CCB combination 006 study (2016) 1 Reduction in office SBP at week 12 in 216 patients with sustained hypertension (baseline ambulatory blood pressure monitoring >130/80 mm Hg 1. Dominiczak A, Asmar R et al. Abstract ESH 2016. 25

Amlodipine/Indapamide (Natrixam) further reduces systolic blood pressure versus ACEI/CCB combination Long-term efficacy of indapamide SR + amlodipine 10 mg vs enalapril + amlodipine 10 mg >130/80 mm Hg NESTOR CCB sub-study (2015) 1 BP, blood pressure. 1. Hanon O et al. Am J Hypertens. 2015;28:1064-1071. 26

Safety profile of Amlodipine/Indapamide (Natrixam) NESTOR CCB over 65 years old substudy (2016) 1 Superiority of indapamide + amlodipine over enalapril + amlodipine in reducing edema 1. Hanon O et al. Am J Hypertens. 2015;28:1064-1071. 27

Compensatory mechanisms of action of CCBs, diuretics and RAAS-blockers on vascular and renal function, sympathetic and Renin-Angiotensin-Aldosterone activity Natriuresis Vasodilation CCB Diuretic RAAS-blocker RAAS SNS RAAS SNS Adapted from Sever P S et al. European Heart Journal 2011

The PIANIST Study: antihypertensive effect of the triple combination Perindopril/Indapamide/Amlodipine Tòth K, on behalf of PIANIST Investigators. Am J Cardiovasc Drugs. 2014

The PIANIST Study: antihypertensive effect of the triple combination Perindopril/Indapamide/Amlodipine ABPM Tòth K, on behalf of PIANIST Investigators. Am J Cardiovasc Drugs. 2014

PIANIST Study: side effects Ankle edema 0.2% Hypotension 0.1% Cough 0.08% Dizziness 0.08% Tòth K, on behalf of PIANIST Investigators. Am J Cardiovasc Drugs. 2014

Conclusion Arterial hypertension is one of the major noncommunicable causes of mortality and morbidity in sub-saharian Africa The therapeutic approach of arterial hypertension in patients of sub-saharian origin should include a diuretic and a calcium-channel blocker either alone or in association Amlodipine/indapamide (Natrixam) is effective and safe in all hypertensive patients and should represent the treatment of choice for sub-saharian patients with arterial hypertension 32

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Systolic blood pressure is the best predictor of stroke risk in hypertensive patients Stroke mortality rate in each decade of age vs. usual systolic blood pressure at the start of the decade. 1 1. Rahimi K et al. Circ Res. 2015;116:925-936. 34

Systolic blood pressure is the most difficult BP parameter to control Mean BP results for 158 876 treated patients 1 Clinic blood pressure levels in hypertensive patients included in observational studies or clinical surveys on hypertension between 2005 and 2011 in Italy. Histograms represent average systolic BP and diastolic BP levels in each study included in the analysis. Data are expressed as mean standard deviation. 1. Tocci G et al. J Hypertens. 2012;30:1065-1074. 35

Indapamide is metabolically neutral Frequency of hypokalemia with indapamide SR in the 6th week of treatment 1 1. Ambrosioni E et al. J Hypertens. 1998;16:1677-1684. 36

Indapamide provides effective renal protection Madkour study (1996) 1 Effects of long-term therapy with indapamide SR or hydrochlorothiazide on creatinine clearance in patients with impaired renal function and hypertension 1. Madkour et al. Am J Cardiol. 1996;77:23B-25B. 39

Amlodipine effectively reduces myocardial infarction End points (first occurrence in each category). VALUE trial (2004) 1 1. Julius S et al. Lancet. 2004;363:2022-2031. 40

Two drugs providing full 24-hour blood pressure control Trough-to-peak ratio: high for both indapamide SR and amlodipine 43

Natrixam further reduces systolic blood pressure in older patients NESTOR CCB over 65 years old substudy (2016) 1 Reduction in systolic blood pressure from baseline to 52 weeks in patients aged 65 years 1. Hanon O. NESTOR CCB over 65. Accepted Abstract. 26e Journées Européenes de la Société Française de Cardiologie (JESFC) 2016. 46

Natrixam is recommended for older hypertensive patients ESH/ESC guidelines suggest a CCB or a diuretic may be particularly useful for elderly patients 1 1. Mancia G et al. Eur Heart J. 2013;34:2159-2219. 47

Hypertension is the biggest contributor to the global burden of disease and mortality Deaths attributable to individual risk factors 1 1. Ezzati M, Riboli E. N Engl J Med. 2013;369:954-964. 48

Amlodipine effectively reduces myocardial infarction Wang study (2007) 1 Protection against myocardial infarction with amlodipine vs placebo, angiotensin receptor blockers (ARBs), or angiotensinconverting enzyme (ACE) inhibitors 1. Wang JG et al. Hypertension. 2007;50:181-188. 49

Amlodipine effectively reduces myocardial infarction VALUE trial (2004) 1 Reduction in myocardial infarction with an amlodipine-based regimen vs a valsartan-based regimen CI, confidence interval, HR, hazard ratio. 1. Julius S et al. Lancet. 2004;363:2022-2031. 50

Natrixam further reduces systolic blood pressure versus placebo Systolic blood pressure (BP) decrease for 10 mm Hg decrease of diastolic BP 1 BP, blood pressure. 1. Jadhav U et al. PLoS One. 2014;9:e92955.