8 INITIAL MANAGEMENT OF HYPERTENSION COMBINATION THERAPY IS POTENTIALLY BENEFICIAL.pptx

8 INITIAL MANAGEMENT OF HYPERTENSION COMBINATION THERAPY IS POTENTIALLY BENEFICIAL

1. COMBINATION THERAPY IS POTENTIALLY BENEFICIAL INITIAL MANAGEMENT OF HYPERTENSION Dr. Kamal Kishore Consultant Physician Geetanjali Hospital, Hisar

2. Learning Objectives At the end of this presentation, participants will be able to: Elucidate the importance of appropriate and timely intervention in hypertension Achieve blood pressure (BP) target reduction to reduce the risk factors Understand the need and practical necessity of a combination therapy over monotherapy Integrate recent guideline recommendations for hypertension management including Use of fixed-dose combination or single-pill combination (SPC) Use of β -blocker, diuretic and/or calcium channel blocker (CCB) as fixed dose combination (FDC) or SPC Benefits of complementary action of β -blocker and CCB Additive effects of β -blocker and diuretic FDC INITIAL MANAGEMENT OF HYPERTENSION

3. Hypertension – ‘The Silent Killer’ Globally, hypertension is a common health problem. It is important to regularly monitor BP as it does not have any signs or symptoms. 1 More than 1 in every 8 d eath is due to h ypertension. 2 4 th Hypertension contributes to premature death 3 In developed countries 7 th In developing countries Role of hypertension in global mortality 2 INITIAL MANAGEMENT OF HYPERTENSION

4. Nearly 1 billion adults (> quarter of the world’s population) had hypertension in 2000, and this is predicted to increase to 1.56 billion by 2025. 2 23.10%* 22.60%* *over 25 years old # May 2012 26% of the adult population is hypertensive. 1 According to WHO statistics # in India Globally 1 Hypertensive INITIAL MANAGEMENT OF HYPERTENSION Burden of Hypertension Highly Prevalent Condition

5. Hypertension A Major Preventable Risk Factor of CVDs Uncontrolled hypertension increases the risk of CV events and death. 1 CVDs- cardiovascular diseases INITIAL MANAGEMENT OF HYPERTENSION Coronary events Stroke Heart failure Peripheral vascular disease P rogression to kidney disease Hypertension if not treated appropriately and timely 2 LEADS TO:

6. Rationale for the Treatment Globally , uncontrolled BP is the primary cause of death in hypertensive patients. 2 + R ecent advances Increased physician and patients awareness Insignificant or suboptimal BP control 1 INITIAL MANAGEMENT OF HYPERTENSION Despite

7. Reduction in BP, Reduces the Risk Most patients with hypertension requires pharmacotherapy to achieve target BP reduction and reduce the associated risks that affect quality of life. 2,3 Reduction in BP offers: 1 Risk of stroke 30 to 40 % About 20 % SBP- systolic blood pressure, DBP- diastolic blood pressure, CAD- coronary artery disease. or = Risk of fatal coronary events 1 DBP 10 mmHg SBP 20 mmHg Risk of CAD* INITIAL MANAGEMENT OF HYPERTENSION

8. Concept of Monotherapy Up-titration Concept of monotherapy up-titration to achieve target BP has been repetitively challenged. Several studies have demonstrated that monotherapy up-titration is unlikely to achieve the same BP-lowering effect in comparison with combination therapy. 1 40 % Patients respond to monotherapy 30 % Patients reach BP control vs. Whereas 75 % -80 % Patients do respond to combination therapy Need for combination therapy 2 INITIAL MANAGEMENT OF HYPERTENSION

9. Monotherapy vs. Combination Treatment The combination therapy in comparison to increasing the dose of monotherapy provides greater protection to target organ . 1 INITIAL MANAGEMENT OF HYPERTENSION Criteria Monotherapy Combination Mechanism Acts on one or at best two of the hypertensive mechanisms Acts on several different hypertensive mechanisms Efficacy Antihypertensive effect is possibly nominal 2-5 times greater antihypertensive effect Reduction in the risk Increasing dose reduces coronary events by 29% and cerebrovascular events by 40% Reduces coronary events by 40% and cerebrovascular events by 54%

10. Combination Therapy – A Practical Necessity More efficacious vs. monotherapy 3 Better efficacy and tolerability 1 Better compliance and simplicity 2 Significantly improves compliance and persistence Improves overall efficacy with better BP control Lowers BP to a greater degree compared with monotherapy Neutralizes the dose-dependent side-effects Acts against several mechanisms and provides greater antihypertensive power Provides greater protection to target organs and reduces potential side-effects due to high-dose of monotherapy INITIAL MANAGEMENT OF HYPERTENSION

11. Guideline Recommendations for Combination Therapy Several international guidelines endorse combination therapy as the preferred strategy to treat hypertension. 1-3 European Society of Hypertension (ESH) 1 European Society of Cardiology (ESC) 1 American Society of Hypertension (ASH) 1 British Hypertension Society Guidelines (BHS) 2 Eight Joint National Committee (JNC 8) 3 INITIAL MANAGEMENT OF HYPERTENSION

12. 2018 ESC/ESH Guidelines Recommendation Combination treatment is recommended for most hypertensive patients as initial therapy. 1 It is also recommended that beta-blockers may be combined with any of the other major drug classes in specific clinical situations*. 1 *Angina , post-myocardial infarction, heart failure, or heart rate control. 2013 ESC/ESH vs. 2018 ESC/ESH Guidelines - What is new and what has changed. 1 2013 ESC/ESH 2018 ESC/ESH Antihypertensive therapy should be initiated with a two-drug combination in patients with markedly high baseline BP or at high CV risk. Recommended to initiate an antihypertensive treatment with a two-drug combination, preferably in a single-pill combination ( SPC). The exceptions being frail older patients and those at low risk and with Grade 1 hypertension (particularly if SBP is <150 mmHg). Grade IIb Grade I INITIAL MANAGEMENT OF HYPERTENSION

13. 2017 ACC/AHA Guidelines Recommendation Class of Recommendation Level of Evidence 2017 ACC/AHA Class 1 C-EO Recommendation Is recommended Is indicated/useful/ effective/beneficial Should be administered Consensus of expert opinion based on clinical experience Initiate antihypertensive therapy with 2 first-line drugs of different classes, either as separate agents or in a fixed-dose combination is recommended in adults*. *With stage 2 hypertension and an average BP more than 20/10 mmHg above their BP target. Evidences favoring the recommendation is elucidated mainly from FDC studies proving greater BP reduction as well as better adherence against monotherapy. 1 INITIAL MANAGEMENT OF HYPERTENSION

14. 2017 ACC/AHA Guidelines Recommend β-blocker + CCB / Diuretic Class of Recommendation Level of evidence 2017 ACC/AHA Class 1 SBP: B-R DBP: C-EO Recommendation Is recommended Is i ndicated/useful/ effective/beneficial Should be administered B-R: Moderate-quality evidence from 1 or more RCTs and/or meta-analyses. C-EO: Consensus of expert opinion based on clinical experience. Adults with SIHD and hypertension (BP ≥130/80 mmHg) should be treated with medications ( β -blockers, ACE inhibitors, or ARBs) for compelling indications (e.g., previous MI, stable angina) as first-line therapy, with the addition of other drugs (e.g., dihydropyridine CCBs, thiazide diuretics, and/or mineralocorticoid receptor antagonists) as needed to further control hypertension. SIHD- Stable Ischemic Heart Disease, β -blockers- Beta blockers, ACE- Angiotensin converting enzyme, ARBs- Angiotensin receptor blockers, MI- Myocardial infarction, CCBs- Calcium channel blockers. INITIAL MANAGEMENT OF HYPERTENSION

15. SPC vs. Free Combination Which is Better? Single Pill Combination (SPC) offers improved adherence, simplified therapy, better efficacy and tolerability. 1 Table 1: Comparison between different HTN management strategies. Single-pill combination therapy is noted to be advantageous that includes all the mentioned criteria such as efficacy, time to reach BP target, flexibility, compliance and tolerability. 1 INITIAL MANAGEMENT OF HYPERTENSION Low-dose monotherapy High-dose monotherapy Free combination therapy Single-pill combination therapy Efficacy - + ++ ++ Time to reach BP target - + ++ ++ BP variability - - + + Simplicity + + - + Flexibility + + + + Compliance + + - + Tolerability + - + ++

16. Ideal Requirements for Combination Therapy Multiple factors regulate BP Antihypertensive drug classes include: Diuretics, β-blockers, CCBs, ACEIs, ARBs, DRIs, α-blockers, and centrally acting agents. 1 For combination therapy, antihypertensive drugs should be based on better: 1 Synergistic efficacy Compliance Tolerability Outcomes Intravascular volume, cardiac output, and systemic vascular resistance . Physiological mechanisms Above factors are fine-tuned by RAAS and sympathetic nervous system RAAS- renin angiotensin aldosterone system INITIAL MANAGEMENT OF HYPERTENSION

17. Classification of Combinations International guidelines classify various combination therapy in hypertension as preferred, acceptable, or not acceptable depending on large, outcome-driven clinical trials on safety and efficacy (Table 1). 1 Table 1: Combination therapy in patients with hypertension according to international guidelines. Abbreviations: HTN, hypertension; ACEI, angiotensin-converting enzyme inhibitor; ARB , angiotensin receptor blocker; DHP, dihydropyridine; CCB, calcium channel blocker ; RAAS, Renin angiotensin aldosterone system; DRI, direct renin inhibitor. INITIAL MANAGEMENT OF HYPERTENSION Preferred Acceptable Not acceptable ACEI or ARB/ DHP CCB ACEI or ARB/diuretic Beta-blocker/diuretic DHP CCB/diuretic DHP CCN/beta-blocker Thiazide diuretic/ potassium sparing diuretic DHP CCB/non-DHP CCB DRI/DHP CCB DRI/diuretic RAAS inhibitor/non-DHP CCB Dual RAAS inhibition RAAS inhibitor/ beta-blocker Non-DHP CCB/ beta-blocker Centrally acting agent/ Beta-blocker

18. Combination of β- blocker/CCB C ombination of beta-blocker ( β -blocker) and CCB results in a additive BP-lowering effect. The combination provides: 1 Long-term BP control Long-term compliance Reduced overall side-effects compared to high-dose monotherapy INITIAL MANAGEMENT OF HYPERTENSION

19. β- blocker/CCB Combination Complementary Action β-blocker controls acute reflux increase caused by CCB in sympathetic activity and in turn CCB compensates the peripheral vasospasm and decrease in cardiac output that occurs due to β-blocker. 1 β-blocker CCB Side-effect Peripheral vasospasm Decreased cardiac output + Complementary Action Side-effect Controls Compensates Acute reflux INITIAL MANAGEMENT OF HYPERTENSION

20. FDC of Metoprolol + Amlodipine Complementary Action in Hypertension Significantly reduce systolic BP and diastolic BP ( p<0.001 ) Modes of action are different yet their action on BP is complementary Normalize overall BP Table 1: Difference in systolic and diastolic BP with treatment A statistically significant reduction was observed in systolic BP and diastolic BP at week 4 and 8, respectively (p<0.001). INITIAL MANAGEMENT OF HYPERTENSION Visit comparison N Difference between means Simultaneous 95% confidence interval Significance Systolic BP Week 4-baseline 99 -18.86 -21.38 -16.35 *** Week 8-baseline 99 -22.78 -24.83 -20.73 *** Week 8- Week 4 99 -3.91 -5.78 -2.05 *** Diastolic BP Week 4-baseline 99 -10.98 -12.85 -9.12 *** Week 8-baseline 99 -13.98 -15.78 -12.19 *** Week 8- Week 4 99 -3.00 -4.35 -1.64 *** BP: Blood pressure; ***Statistically significant

21. Metoprolol + Amlodipine Effective and Safe in Mild-Moderate Hypertension Metoprolol in combination with amlodipine offers: 1 Greater reduction or superior control in BP Superior efficacy against monotherapy No serious adverse event Figure 1. Mean sitting systolic blood pressure (A ) and mean diastolic blood pressure (B) by treatment and visit INITIAL MANAGEMENT OF HYPERTENSION

22. FDC of Metoprolol + Amlodipine Effective, Safe, and Well-tolerated as Losartan + Amlodipine Metoprolol XL in combination with amlodipine offers: 1 Similar efficacy and safety in comparison to losartan plus amlodipine Low-dose combination achieves the same effect as high-dose monotherapy M etoprolol extended release 50 mg/ amlodipine 5 mg ( M +A) or losartan 50 mg plus amlodipine 5 mg (L+A), DBP= diastolic blood pressure, SBP= systolic blood pressure. Figure 1. Changes in mean SBP and DBP through out the study At 12 weeks both therapies were comparable with respect to mean decrease in SBP (p=0.484 ), DBP ( p=0.650 ) and response rate ( p=0.134 ). INITIAL MANAGEMENT OF HYPERTENSION

23. SPC of Metoprolol + Amlodipine More Effective vs. Double D ose of Single-drug Superior to monotherapy in reducing BP Greatest reduction in both systolic BP and diastolic BP No serious adverse effects SPC of metoprolol + amlodipine is effective in achieving BP goals more frequently, improving patient adherence, and has reduced adverse effects. Figure 1 (A). Mean DBP changes with treatment Figure 1 (B). Mean SBP changes with treatment *Indicated more reduction in SBP compared to other group. *Indicated more reduction in DBP compared to other group. INITIAL MANAGEMENT OF HYPERTENSION

24. β- blocker/Diuretic Combination Additive Effect Combination of beta-blocker ( β -blocker) and diuretic is well-established in the management of hypertension as it results in an additive BP-reduction effect. 1 Normalizes blood pressure 2 Improves patient compliance 2 No metabolic adverse effects 3 INITIAL MANAGEMENT OF HYPERTENSION

25. Metoprolol + Diuretic Effective in the Treatment of Hypertension Low-dose combination achieves the same effect as a high dose regimen Translate into additive BP reduction Fixed combination is bioequivalent to the concomitant use of individual agents The figure shows changes from baseline to week 8/LOCF in trough sitting diastolic blood pressure (intent-to-treat population; ATTACH Trial ). ATTACH: Assessment of Toprol-XL Taken in Combination with Hydrochlorothiazide; HCTZ ¼ hydrochlorothiazide; LOCF: last observation carried forward; SBP: systolic blood pressure. The ATTACH study conclusion: Combination therapy is more effective than monotherapy in patients with severe hypertension. The combination therapy reflects the additive contribution of its components. Figure 1. Dose-response surface from polynomial regression. INITIAL MANAGEMENT OF HYPERTENSION

26. Metoprolol + Chlorthalidone Effective, Safe, & Well-tolerated in Treatment of Hypertension Provides long-term effective BP control lasting at least 24 hours after administration Better patient compliance, well-tolerated, and safe in patients with hypertension C hlorthalidone plus metoprolol proved to be twice as effective as chlorthalidone monotherapy in patients with a high initial DBP (79.6 % vs. 28.2%, respectively). Figure 1(A) and 1(B): Supine blood pressure and heart rate values (mean±S.E.-**p<0·01) Both blood pressure and heart rate, in supine and upright position , revealed a consistent reduction (p<0·01 ) as compared with baseline levels. INITIAL MANAGEMENT OF HYPERTENSION

27. Metoprolol + Chlorthalidone Effective in Long-term Treatment of Arterial Hypertension Significantly reduces the plasma potassium levels Normalize BP values (Diastolic BP less than 95 mmHg ) Minimal adverse effects Figure 1. P atients (%) responding to chlorthalidone plus metoprolol vs. chlorthalidone monotherapy after 8 weeks of treatment against baseline. C hlorthalidone plus metoprolol proved to be twice as effective as chlorthalidone monotherapy in patients with a high initial DBP (79.6 % vs. 28.2%, respectively). INITIAL MANAGEMENT OF HYPERTENSION

28. Metoprolol + Chlorthalidone Effective and Well-tolerated as Metoprolol/HCTZ Significantly more patients responded to study drug than metoprolol XL/HCTZ Significant mean reduction was observed in both SBP and DBP Graph 1. Mean BP for responders at the end of 4 weeks of therapy on metoprolol XL 25 mg + chlorthalidone 6.25 mg and metoprolol XL 25 mg + HCTZ 12.5 mg. C: Chlorthalidone, H: Hydrochlorothiazide, M: Metoprolol XL, BP: blood pressure, SBP: systolic BP, DBP: diastolic BP. * The upper end of the bar indicates the value of SBP and lower end of the bar indicates the value of DBP. Significantly increased number of patients responded to therapy with chlorthalidone 12.5 mg/metoprolol XL 50 mg group as compared to HCTZ 12.5 mg/metoprolol XL 50 mg group ( p=0.045). INITIAL MANAGEMENT OF HYPERTENSION

29. Summary Globally, hypertension is a common health problem. 1 More than 1 in every 8 death is due to h ypertension. 2 Several international guidelines endorse combination therapy as the preferred strategy to treat hypertension. 3 Single Pill Combination (SPC) offers improved adherence, simplified therapy, better efficacy, and better tolerability. 3 β-blocker and CCB therapy offers complementary action by reducing side-effects of individual drug, long-term BP control, and compliance. 4 β-blocker/diuretic combination offers additive effect as it normalizes BP and improves the patient compliance. 4,5 FDC of Metoprolol/Amlodipine and Metoprolol/Chlorthalidone is effective, safe, and w ell-tolerated in treatment of hypertension. 6,7 INITIAL MANAGEMENT OF HYPERTENSION

30. CLINICAL SCENARIO

31. Age: 48 Sex: Male Occupation: School teacher Height: 5.9” Weight: 78 kg BP at check-up: 168/105 mmHg Medical History: Stage 1 hypertension Physical activity: Walks 30 mins, 4─5 times/week Previous dietary intake: 4 g Na diet Pharmacologic agent: Hydrochlorothiazide 25 mg Chief complaint: D ifficult to adhere salt reduction in the diet. Also, food tastes bland and tasteless. Recurrent headache with lot of sweating during transits. CLINICAL SCENARIOS What's Next? Biochemical factors Patient Readings Doctors References Total cholesterol 298 mg/dL 140─199 LDL cholesterol 135 mg/dL <130 HDL cholesterol 35 mg/dL >40 Triglycerides 250 mg/dL <160 Case 1

32. Case 2 Age: 55 Sex: Male Occupation: Marketing Executive Height: 5.6” Weight: 69 kg BP at check-up: 155/95 mmHg Medical history: Long history of HTN (>10 years) Physical activity: Nil (More travel in work) Previous dietary intake: 4 g Na diet Pharmacologic agent: 2 drugs – Enalapril, Hydrochlorothiazide Chief complaint: Recurrent headache Giddiness Biochemical factors Patient Readings Doctors References Total cholesterol 285 mg/dL 140-199 LDL cholesterol 160 mg/dL <130 HDL cholesterol 30 mg/dL >40 Triglycerides 230 mg/dL <160 What's Next? Chest pain radiating to left shoulder Fatigue and shortness of breath CLINICAL SCENARIOS