Cilacar TC CME Deck.pptx

Hypertension

1. TRIPLE COMBINATION IN HYPERTENSION MANAGEMENT TODAY : WHEN AND HOW?

2. The concept of initial combination therapy is not new because one of the first large clinical trials published in the late 1960s, the Veteran Affairs Cooperative Study, showed reduced morbidity with improved BP control using triple therapy combinations .

3. HISTORY OF COMBINATION THERAPY The use of combination therapies started in the 1950s, when pills containing reserpine were introduced. Several other formulations in the 1960s and 1970s that contained thiazide diuretics, including the triple combination pill of hydralazine and hydrochlorothiazide and reserpine, as well as in combination with potassium- sparing diuretics, beta-blockers, and clonidine. In the 1980s, thiazides were combined with angiotensin-converting enzyme (ACE) inhibitors In 1990s, a combination of an ACE inhibitor and calcium channel blocker (CCB) was approved Hala Yamout and George L. Bakris. Use of Combination Therapies. HYPERTENSION A Companion to Braunwald’s Heart Disease. Third Edition . 2018

4. RATIONALE FOR INITIAL COMBINATION THERAPY : GUIDELINE INERTIA Although combination BP lowering therapy was available and proven to reduce BP and mortality in clinical trials, the control of BP with stepwise management was advocated by early guidelines The first report favoring combination therapy as an initial approach was seen in 1997 by the JNC VI panel. Since this report, it is clear that initial use of single pill combination therapy is superior to a stepwise approach in controlling hypertension, with 12% more patients at their target BP.

5. RATIONALE FOR INITIAL COMBINATION THERAPY : MULTIFACTORIAL CAUSES OF BP Multiple systems that regulate BP ; sympathetic nervous system (SNS), renin-angiotensin system (RAS), and volume modulators from the kidney and heart like natriuretic peptides. It is difficult to determine with certainty which system is dominant in a particular patient Use of different classes of medications will increase the chance of controlling BP faster and more effectively . An increase dose of a single agent is less likely to achieve BP control than adding lower doses of a second agent.

6. RATIONALE FOR INITIAL COMBINATION THERAPY : EFFECTIVE BP CONTROL Addition of an antihypertensive agent from a different class is five times more effective in improving BP control than doubling the dose of a single drug. Improvement in BP control occurs when even half the dose of the individual drugs are used in a combination pill compared with full doses of each as monotherapy Comparison of observed versus expected effects of a single pill combination versus doubling the dose of an antihypertensive medication. Hala Yamout and George L. Bakris. Use of Combination Therapies. HYPERTENSION A Companion to Braunwald’s Heart Disease. Third Edition . 2018

7. RATIONALE FOR INITIAL COMBINATION THERAPY : COUNTER REGULATORY MECHANISM Diuretics used alone can result in relative volume depletion and activate the RAS and to a lesser extent the SNS. The use of agents that block these systems, such as ACE inhibitors or beta-blockers, counteract the body’s response to diuretics and are complementary to diuretic action to low BP . To offset the body’s counter- regulatory mechanisms to a particular agent Hala Yamout and George L. Bakris. Use of Combination Therapies. HYPERTENSION A Companion to Braunwald’s Heart Disease. Third Edition . 2018

8. CV RISK REDUCTION Every 20 mmHg increase in systolic blood pressure, there is an approximate doubling of cardiovascular (CV) risk , by use of combination therapy there is better achievement of target BP goals thereby reduction in CV risk. Monotherapy especially with beta blockers results in variability in visit to visit BP recordings which is a strong predictor of both stroke and myocardial infarction this effect is reduced with combination drug therapy AU Mahajan, Zohaib Shaikh. Combination Drug Therapy in Hypertension . Medicine update . 2017

9. Illustration of various drug class combinations to lower blood pressure and CV event Hala Yamout and George L. Bakris. Use of Combination Therapies. HYPERTENSION A Companion to Braunwald’s Heart Disease. Third Edition . 2018 Solid black lines demonstrate additive effects on blood pressure (BP) lowering; Orange lines demonstrate outcome based reduction in either cardiovascular events or kidney disease progression

10. IMPROVE PATIENT ADHERENCE Even when the same two drugs are given as individual pills, adherence rates with combination therapy are significantly higher and can reduce nonadherence by up to 24% Hala Yamout and George L. Bakris. Use of Combination Therapies. HYPERTENSION A Companion to Braunwald’s Heart Disease. Third Edition . 2018 Adherence with single pill combinations compared with free- drug combinations

11. Forest plot for medication persistence. Meta- analysis confirmed that FDC therapy, compared with free- equivalent combinations, was associated with better medication adherence or persistence for patients with hypertension. It can be reasonable for physicians, to facilitate the use of FDCs for patients who need to take two or more antihypertensive drugs

12. COMPARISON BETWEEN DIFFERENT HYPERTENSION MANAGEMENT STRATEGIES

13. AMERICAN SOCIETY OF HYPERTENSION EVIDENCED- BASED FIXED- DOSE ANTIHYPERTENSIVE COMBINATIONS Hala Yamout and George L. Bakris. Use of Combination Therapies. HYPERTENSION A Companion to Braunwald’s Heart Disease. Third Edition . 2018

14. Hypertension drug treatment strategies Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press Increasing dose of initial monotherapy (side effects/ineffective) Substitution with another monotherapy ( time consuming/low adherence/ineffective) Stepped- case approach,i.e.monotherapy with sequential addition of other drugs (therapeutic inertia)

15. Rationale for triple - drug combination therapy in most patients Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press Greater BP reduction vs monotherapy Reduced heterogeneity of the BP response No /Small increase in hypotensive episodes More frequent BP control after 1 year Better adherence to treatment Reduced therapeutic inertia Reduced CV events

16. Faster reduction of BP Greater possibility of achieving target BP Neutralization of the counterregulatory pathway activated by monotherapies Improved tolerability Decreased side effects than up- titrating single agents Cardiac Failure Review 2017;3(1):40–5 Single Pill Combinations

17. Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press The recommended treatment strategy (evidence- based) to improve BP control Initial combination treatment, especially useful in the context of lower BP targets Single-pill- based combination therapy, to improve adherence to treatment To be used in most patients Initial monotherapy reserved to BP in the high- normal range/very old patients/ frail older patients)

18. J Clin Pharmacol. 1998;38(6):477–491. J Clin Pharmacol. 1995;35(11):1060–1066. Am J Cardiol. 1995;76(8):595–597.

19. ESC/ ESH HYPERTENSION GUIDELINE RECOMMENDS DUAL COMBINATION THERAPY AS A INITIAL THERAPY First look at the new 2018 European Guidelines for the treatment ofhigh blood pressure. 2018 ESC and ESH joint guidelines for themanagement of arterial hypertension. Available from URL:ht tp:/ /www.eshonline.org/esh-annual-meeting/

20. TRIPLE DRUG COMBINATION About 24% to 32% of patients with HTN will require more than two drugs to achieve their BP target. A rational combination in this setting would be an RAAS inhibitor, a CCB, and a diuretic.

21. Single- pill triple combinations of different classes of drugs with complementary mechanisms of action help to treat patients to goal with improved efficacy and better adherence to treatment Journal of Human Hypertension (2017) 31, 501–510; Triple drug fixed dose combination of Telmisartan, Amlodipine and hydrochlorothiazide was found to be effective and safe option for the optimal management of hypertension .

22. TRIPLE DRUG COMBINATION Curr Vasc Pharmacol. 2017;16(1): 61- 65. Triple fixed- dose drug combinations should be reserved only for patients with uncontrolled BP with 2 agents, poor adherence in complex therapeutic regimens or on inappropriate free- drug combinations. Triple therapy may help overcome clinical inertia by prescribing more potent antihypertensive formulations in one pill. Beyond the choice between different triple fixed- dose combinations it is important to evaluate at shortterm whether BP is controlled within target and whether the administered fixed- dose treatment is associated with good compliance

23. Curr Vasc Pharmacol. 2017;16(1):61- 65.

24. How to build up appropriate triple drug combinations. Curr Vasc Pharmacol. 2017;16(1):61- 65.

25. ESC/ ESH HYPERTENSION GUIDELINE RECOMMENDS TRIPLE COMBINATION THERAPY IF BP NOT CONTROLLED BY DUAL THERAPY First look at the new 2018 European Guidelines for the treatment ofhigh blood pressure. 2018 ESC and ESH joint guidelines for themanagement of arterial hypertension. Available from URL:ht tp:/ /www.eshonline.org/esh-annual-meeting/

26. CHANGING TRENDS IN PHARMACOTHERAPY FOR HYPERTENSION IN INDIA 47 53 10 20 30 40 50 60 70 Mono Combo Malhotra et al. Eur J Clin Pharm. 2001;57:535 49 51 10 20 30 40 50 60 70 Mono Combo Sreedharan et al. Int J Clin Pharm Ther. 2011;49:277 27 73 10 20 30 40 50 60 70 Mono Combo Gupta R, et al. 2018. Unpublished.