Beta-blockers in CV risk reduction across continuum(6) copy.pptx

Beta-blockers in CV risk reduction

1. Beta-blockers in CV risk reduction across continuum -A Note on Metoprolol

2. Global Cardiovascular disease Burden Percentage change in CVD death rate from 2010 - 2019 CVDs no.1 cause of death globally. CVD cases nearly doubled from 257 to 285 million in 1990 to 523 million in 2019 No. of cv Deaths WHO estimates by 2030, CVD as main cause of death throughout India, i.e. >35% of all deaths Rothetal , 2020global burden of cardiovascular diseases, JACC VOL.76(25),:2020:2982–3021. World Economic Forum, The Global Economic Burden of Non-communicable Diseases, Harvard School of Public Health, 2011

3. What is CV Continuum? Dyslipidemia Hypertension Diabetes Obesity Smoking Atherosclerosis LVH Coronary Artery Disease Myocardial Ischemia (angina) Coronary Thrombosis Myocardial Infarction Arrhythmias Remodeling Ventricular Dilation Chronic Heart Failure End-Stage Heart Disease, Death Dzau v, resolved and unresolved issues in prevention of CAD, Am journal 1991,121: 1244-1263 Heart failure is considered as end-point of CV continuum Initial risk factors are hypertension, diabetes etc Hypertension to heart failure is a journey

4. Beta-blockers can intervene at many points in the cardiovascular continuum SO Dyslipidemia Hypertension Diabetes Obesity Smoking Atherosclerosis LVH Coronary Artery Disease Myocardial Ischemia (angina) Coronary Thrombosis Myocardial Infarction Arrhythmias Remodeling Ventricular Dilation Chronic Heart Failure End-Stage Heart Disease, Death European Heart Journal Supplements (2009) 11 (Supplement A), A1–A2 BETA BLOCKERS LVH: left ventricular hypertrophy SO: Sympathetic Overactivity

5. Beta-blockers in Hypertension

6. Hypertension in India among young & middle age population 20–44 years 22.4% Indian young hypertensive patients vs 10% US hypertensive patients. Sympathetic overdrive: leading cause of hypertension amongst young India patients due to stressed lifestyle. Sivasubramanian Ramakrishnan , Prevalence of hypertension among Indian adults: Results from the great India blood pressure survey , IHJ, Vol 71, sissue 9, 2019, p-309-313 T.N.C. Padmanabhan , IHJ (65)2014. P686-690

7. Heart rate as an independent risk factor of CVD across cv continuum The incidence of mortality shows a upward trend from various causes with increasing HR over a mean period of 11.8 years of follow-up in the Göteborg Primary Prevention Trial B.N. Singh, Increased heart rate as a risk factor for cardiovascular disease, European Heart Journal Supplements (2003) 5 (Supplement G), G3—G9

8. >62% Indian hypertensives have sympathetic Overactivity Indian heart J. 2014 Nov-Dec; 66(6): 626 -690. Int J Psychophysiol . 2013; 88(2): 124-35. J Am ColCardiol 1983; 1: 421-26 Prevalence of sympathetic overactivity in Indian hypertensives Sympathetic overactivity is further elevated in patients with Diabetes Smoking Obesity Stress

9. Metoprolol REDUCES sympathetic overactivity Indian Heart J. 2014 Nov-Dec; 66(6): 686–690. Eur J Clin Pharmacol (1988) 33 (suppl): 53-57 Average reduction in heart rate 14.53 bpm Uniqueness of metoprolol Metoprolol is rapidly and completely absorbed throughout the GI-tract, including the distal regions. Half life 3-4 hours Excretion through Hepatic Route No accumulation of drug in late-stage CKD patients No active metabolites

10. Elevated HR Significantly Increased the Risk of Mortality in Patients with Coronary Heart Disease Diaz A, et al. Eur Heart J. 2005; 26(10): 967-74 Patients with stable coronary heart disease had significantly increased risk for cardiovascular death and total mortality with elevation of HR The study assessed the relationship between resting heart rate at baseline and cardiovascular mortality/morbidity, while adjusting for risk factors. A total of 24,913 patients with suspected or proven CHD from the CASS registry were studied for a median follo -up of 14.7 years. The purpose was to investigate the effects of HR on prognosis in patients with stable coronary heart disease

11. Metoprolol reduces the risk of All cause death and sudden cardiac death in patients with HTN and sympathetic overactivity Wkstrand J et al JAMA 1988 All Cause Death Sudden Cardiac Death

12. Beta-blockers in IHD

13. Beta-blockers in Ischemic Heart Disease ( IHD) Beta-blockers in IHD with proven mortality benefit: During AMI (intravenous administration) In chronic administration after AMI In patients with coronary disease without previous AMI.

14. Metoprolol Significantly reduced the HR by 24% in patients with acute inferior wall MI Priti K, et al. Cardiovasc Ther . 2017; 35(4): e12266. 24%

15. Reduction in AMI size and subsequent increase in LVEF Reduction in Reinfarction and VF 29% Reduction in mortality Main trials of Beta-blockers(Metoprolol) in ACS Juan Martı´nez -Milla, Role of Beta-blockers in Cardiovascular Disease in 2019; Rev Esp Cardiol . 2019;72(10):844–852 MIAMI STUDY (1985) METOCARD-CNIC (2013) COMMIT STUDY (2005)

16. Early Metoprolol on infarct size in STEMI patients undergoing PCI P=0.012 P=0.0024 Borja Ibanez, Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial, Circulation 2013; 128:1495-503 In patients with anterior Killip class II or less STEMI undergoing primary PCI , early I.V. metoprolol before reperfusion R educed infarct size I ncreased LVEF

17. % Reduction Am J Cardiol 1994; 74: 1095-1098 -31% -27% - 54% -51% -70 -60 -50 -40 -30 -20 -10 Total no. of Ischemic Episodes/24 h Total duration of Ischemic Episodes/24 h Diltiazem 60 mg qid Metoprolol extended-release 200 mg N=32; crossover; 3 wks each Amb ECG on last 3 days Metoprolol Extended-release reduces the number and duration of ischemic episodes v/s Diltiazem

18. BCAPS: RESULTS Hedbald B et al. Circulation 2001; 103: 1721-6 P<0.001 P<0.018

19. Egstrup K, et al. The antianginal efficacy and tolerability of controlled-release metoprolol once daily: a comparison with conventional metoprolol tablets twice daily. Eur J Clin Pharmacol . 1988;33 Suppl:S45-9. 115 patients with stable effort angina pectoris treated with c ontrolled -release (CR) preparation of metoprolol, given once daily or conventional metoprolol tablets, given twice daily 1 Metoprolol Extended-release improves exercise capacity

20. Metoprolol, a β -1 selective blocker, can be used safely at the maximum dose in CAD patients with COPD. Objective: To evaluate the safety of -1 selective blocker agents in CAD patients with COPD. Heart Vessels (2003) 18:188–192. Metoprolol, a -1 selective blocker, can be used safely in coronary artery disease patients with chronic obstructive pulmonary disease Basal 1 st visit 2 nd visit 3 rd visit DBP 87.4 ± 10 77 ± 8.8 76 ± 9.4 73 ± 9 SBP 136.4 ± 15.7 122.4 ± 12.5 119.4 ± 11.7 119 ± 11 FEV 1 (%) Metoprolol 49.6 ± 14.5 51.3 ± 13.8 53 ± 14 53.2 ± 12.8 Metoprolol CR 54.5 ± 13.4 55.2 ± 12.6 55.3 ± 13 54.3 ± 13 Pulse Rate 71 ± 6 66.6 ± 4.5 64.5 ± 4.2 62.5 ± 4 Systolic and diastolic blood pressures (SBP and DBP), FEV1, and pulse rates Basal and the last mean FEV1 measurements were 54.5% 13.4% and 54.3% 13%, respectively, in the metoprolol CR group, and 49.6% 14.5% and 53.2% 12.8%, respectively, in the conventional metoprolol group. According to those results, both formulations had neither a positive nor a negative effect on FEV1.

21. Beta-blockers in post-MI

22. GMT: Gotenborg Metoprolol Trial-Metoprolol consistently reduces mortality in post MI patients at 2 years Follow-up 120 100 80 60 40 20 20 3 12 24 C u m u l a t i v e n u m b e r o f d e a t h s Time (months) metoprolol placebo AJC 1984; 53:9D-14D N = 1395 MI patients Metoprolol IV followed by conventional dose of 100 mg twice daily vs placebo p = 0.017 p = 0.043 p = 0.024 Greater reduction in overall mortality at 3 months and 2 years of follow-up 36% 31% 23% Total mortality reduction 36% in first 3 months(p<0.03) Infarct size was significantly reduced in patients treated within 12 hrs (p<0.01)

23. Goteborg Metoprolol trial A Hjalmarson , The Göteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction ;Circulation 1983. 67;126-32 Greater reduction in ST-elevation observed with metoprolol

24. Long-term Treatment with Metoprolol Controls the HR of Patients After Mi Early-stage studies suggested that 1 long –term mortality reduction in patients after MI with Beta-blockers treatment was associated with decreased HR (r=0.06, p<0.05) Kjekshus JK. AM J Cardiol . 1986; 57(12): 43F-49F Metoprolol

25. MERIT-HF post-MI subgroup analysis J aonsi.et.al Metoprolol CR/XL in post myocardial infarction patients with chronic heart failure: Experiences from MERIT-HF Am Heart J 2003;146:721–8

26. Beta-blockers in Cardiac Arrhythmias

27. Beta-blockers in Cardiac Arrhythmias Eleonora GrandiCrystal M. Ripplinger , Antiarrhythmic mechanisms of beta blocker therapy; Pharmacol Res. 2019 August ; 146: 104274. doi:10.1016/j.phrs.2019.104274. F irst-line treatment in arrhythmias I ncluding atrial fibrillation and ventricular tachycardia.

28. Beta-blockers And Cardiac Arrhythmias β 1-receptors constitute 80% of the adrenergic receptors in the heart. By blocking these receptors, BBs counteract the proarrhythmic effect of sympathetic activity on the myocardium. The antiarrhythmic effect of BBs is the result of: Juan Martı´nez -Milla, Role of Beta-blockers in Cardiovascular Disease in 2019; Rev Esp Cardiol . 2019;72(10):844–852 Direct cardiac electrophysiological action- By reducing heart rate, Decreasing the spontaneous activation of ectopic pacemakers Slowing down the conduction of electrical impulses, Increasing the refractory period of the atrioventricular node. Other mechanisms- Inhibition of sympathetic activity, Reduction of myocardial ischemia, Effect on baroreflex function, and Decreased mechanical stress. BBs have limited proarrhythmic effects and thus have an excellent efficacy and safety profile

29. Beta-blockers for Ventricular Arrhythmias Clinical situations with proven benefits of beta-blockers for the prevention of sudden death due to ventricular arrhythmias. Juan Martı´nez -Milla, Role of Beta-blockers in Cardiovascular Disease in 2019; Rev Esp Cardiol . 2019;72(10):844–852

30. 5 Pooled PMI Trials: Reduction in mortality and arrhythmias at 3 years follow-up Olsson G, et al. Eur Heart J 1992; 13:28-32 42% 45% 34% Marked reduction in sudden deaths Reduction in ventricular reinfarction Reduction in Mortality

31. The group of patients receiving metoprolol had significantly fewer arrhythmias (11%) than the control group(24%) Eraldo de Azevedo Lúcio , Effectiveness of metoprolol in preventing atrial fibrillation and flutter in the postoperative period of coronary artery bypass graft surgery , Arq. Bras. Cardiol. vol.82 no.1 São Paulo Jan. 2004 Effectiveness of Metoprolol in Atrial Fibrillation in post-OP CABG Variable Control N=100 Metoprolol N=100 p RR/95% CI NNT AFF (all) 24% 11% 0.02 0.46/ (0.24-0.88) 8 AFF (>70 y) 10/19 (53%) 2/19 (11%) 0.01* 0.20/ (0.05 – 0.79) 2 Incidence of atrial fibrillation and flutter (AFF)

32. Beta-blockers in heart failure

33. Benefits of beta-blockers in heart failure & reduced LVEF Juan Martı´nez -Milla, Role of Beta-blockers in Cardiovascular Disease in 2019; Rev Esp Cardiol . 2019;72(10):844–852 BB’s show significant reduction in: All-cause mortality Sudden death CVD Hospitalizations for HF Beta-blockers in heart failure

34. Total mortality in major heart failure trials evaluating β-blockers. BBs are associated with reduced disease progression, as shown by the lower rates of directly related death (sudden and HF) and HF hospitalizations in the various trials Juan Martı´nez -Milla, Role of Beta-blockers in Cardiovascular Disease in 2019; Rev Esp Cardiol . 2019;72(10):844–852 Beta-blockers In Heart Failure: major Trials

35. The four Pivotal Beta-blocker Trials in Heart Failure (HF) The efficacy and tolerability of bisoprolol, carvedilol and metoprolol CR/XL are similar in patients with systolic HF, irrespective of NYHA class or ejection fraction Wikstrand J, Wedel H, Castagno D, J.J.V. 2013. The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: results from CIBIC-II, COPERNICUS and MERIT-HF

36. Beta-Blockers for Treating Heart Failure: Strong Evidence for Metoprolol

37. Primary objectives Objective: To determine whether metoprolol XL reduces: Total mortality The combined end point of all-cause mortality and all-cause hospitalization in patients with HF (NYHA Class II–IV) MERIT-HF Study Group. Lancet 1999; 353: 2001-7.7 Copyright by The Lancet Ltd 2000

38. MERIT-HF Study Group. Lancet 1999; 353: 2001-7.7 Copyright by The Lancet Ltd 2000 Total mortality Sudden death Cardiovascular Mortality Death from HF MERIT-HF STUDY RESULTS 34% 41% 49% 38%

39. Beta-blockers in hf with comorbidities (Elderly, Diabetes & Renal impairment)

40. Prakash.c.Dedwania.et.al eurheartj /article/25/15/1300/510027 ALL CAUSE MORTALITY SUDDEN DEATH DEATH FROM WORSENING HF MERIT-HF subgroup analysis Elderly patients

41. Prakash.c.Dedwania.et.al American Heart Journal Jan2005 D iabetes is associated with increased risk (MERIT-HF Placebo arm)

42. MERIT-HF subgroup analysis diabetes patients Risk of Hospitalizations for HF in diabetics by 37% & 35% in Non Diabetics. Severe Heart failure by 53% in diabetics & 44% in Non Diabetics. Prakash.c.Dedwania.et.al American Heart Journal Jan2005

43. Jalal.K.Ghali.et.al Journal of Cardiac Failure Vol. 15 No. 4 2009 Metoprolol CR/XL was effective in reducing death and hospitalizations for worsening HF in patients with eGFR <45 as in those with eGFR >60. MERIT-HF subgroup analysis in impaired renal function patients

44. Metoprolol reduces mortality related to heart rate (MERIT-HF, Goteborg trial) Mortality related to baseline heart rate among placebo and metoprolol CR/XL subjects in the MERIT-HF trial Mortality related to heart rate at baseline (below or above median) in patients with suspected acute myocardial infarction on arrival in the emergency room and in the placebo and metoprolol groups of the Göteborg Metoprolol Trial.

45. Metoprolol vs. Newer beta blockers

46. Metoprolol vs. Newer beta blockers Metoprolol Bisoprolol Nebivolol FDA approved indication Across CV Continuum: HTN, CAD, ANGINA, MI, ARRHYTHMIAS & HF HTN & CAD (HF IN EU ONLY) HTN ONLY Trials on SCD Reduction Across CV Continuum: MAPHY (HT), SMT (MI), & MERIT HF (HF) Only in HF patients (CIBIS) None Long term trials for mortality reduction Across CV Continuum: MAPHY (HT), SMT (MI), GMT (MI) & MERIT HF (HF) Only in HF patients (CIBIS) None Reduction in atherosclerosis Yes (BCAPS/ELVA) NO NO Prevention of stroke & coronary events Yes NO* NO

47. Metoprolol vs. Newer beta blockers Metoprolol Bisoprolol Nebivolol PK dependent on acetylator status NO NO YES Oral Bioavailability Consistent Consistent Highly variable from 12-96% Elimination t1/2 Consistent Consistent Highly variable from 10-50 hrs Dosage strengths 25, 50 & 100 mg 5 & 10 mg 2.5 & 5 mg Parenteral dosage formulations Yes ( i.v. ) NO NO Dose modification in severe renal failure NOT required Required Required

48. Guidelines for using Beta-blockers

49. Guidelines recommendations for Beta Blockers Canadian Journal of Cardiology Volume 37 2021. CCS 2021 GUIDELINES AHA 2021 GUIDELINES Thomas M. Maddox et al. J Am Coll Cardiol 2021; 77:772-810.

50. European Heart Journal (2021) 42, 12891367 ESC 2021 GUIDELINES Guidelines recommendations for Beta Blockers

51. ESC 2019 GUIDELINES FOR SINUS TACHYCARDIA ESC 2019 GUIDELINES FOR SINUS FLUTTER Guidelines recommendations for Beta Blockers

52. 2020 ESC/ESH Guidelines for the management of arterial hypertension. European Heart Journal 2020, vol 38, issue 6, pg 982-1004 ISH 2020 GUIDELINES FOR UNCOMPLICATED HYPERTENSION Guidelines recommendations for Beta Blockers

53. Guidelines recommendations for Beta Blockers At Risk for HF (Stage A) Primary Prevention Pre-HF (Stage B) Preventing the Syndrome Patients with hypertension Optimal control of BP (1) Patients with Type 2 diabetes and CVD or high risk for CVD SGLT2i (1) Patients with CVD Optimal management of CVD (1) Patients with exposure to cardiotoxic agents Multidisciplinary evaluation and management (1) First-degree relatives of patients with genetic or inherited cardiomyopathies Genetic screening and counselling (1) Patients at risk for HF Natriuretic peptide screening (2a) Patients at risk for HF Validated multivariable risk score (2a) Patients with LVEF ≤ 40% ACEi (1) Patient with recent MI and LVEF ≤ 40 % ARB if ACEi intolerant (1) Patients with LVEF ≤ 40% Beta blocker (1) Patient with LVEF ≤ 30 %; >1 y survival; >40 d post MI ICD (1) Patients with nonischemic cardiomyopathy Genetic counselling and testing (2a) Continue Lifestyle modification and management strategies implemented in Stage A, through Stage B Abbreviations: ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CVD, cardiovascular disease; HF, heart failure; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MI, myocardial infarction; and SGLT2i, sodium glucose cotransporter 2 inhibitor. Recommendations for Patients at Risk of HF & Pre-HF Heidenreich P.A. et al. 2022. AHA/ACC/HFSA Guidelines for Heart Failure. Circulation 2022. AHA/ACC/HFSA Guidelines for HF

54. Guidelines recommendations for Beta Blockers NOTE: *Participation in investigational studies is appropriate for stage C, NYHA class II and III HF. Abbreviations: ACEi indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi , angiotensin receptor- neprilysin inhibitor; CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical therapy; HF, heart failure; HFrEF , heart failure with reduced ejection fraction; hydral -nitrates, hydralazine and isosorbide dinitrate; ICD, implantable cardioverter-defibrillator; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; MRA, mineralocorticoid receptor antagonist; NSR, normal sinus rhythm; NYHA, New York Heart Association; SCD, sudden cardiac death; and SGLT2i, sodium-glucose cotransporter 2 inhibitor. STEP 1 Established diagnosis of HFrEF Address congestion Initiate GDMT STEP 2 Titrate to Target dosing as tolerated, labs, health status, and LVEF STEP 3 Consider these patient scenarios STEP 4 Implement additional GDMT and device therapy, as indicated STEP 5 Reassess symptoms, labs, health status, and LVEF STEP 6 Referral for HF specialty care for additional therapy Continue GDMT with serial reassessment and optimize dosing, adherence and patient education, address goals of care HFrEF LVEF ≤40% (Stage C) ARNI in NYHA II-III; ACEi or ARB in NYHA II-IV (1) Beta blocker (1 ) MRA (1) SGLT2i (1) Diuretics as needed (1) LVEF ≤40% Persistent HFrEF (Stage C) LVEF >40% HFImpEF (Stage C) NYHA I-III; ambulatory IV; LVEF ≤35%; NSR and QRS ≥150 ms with LBBB NYHA I-III; LVEF ≤35%; >1 y survival NYHA III-IV, in African American patients Consider additional therapies CRT-D (1) ICD (1) Hydral -nitrates (1) Symptoms improved Refractory HF (Stage D) Investigational studies* Palliative care (1) (Can be initiated before Stage D) Cardiac transplant (1) In Selected patients, durable MCS (1) Heidenreich P.A. et al. 2022. AHA/ACC/HFSA Guidelines for Heart Failure. Circulation Treatment of HFrEF Stages C and D 2022. AHA/ACC/HFSA Guidelines for HF

55. Guidelines recommendations for Beta Blockers Heidenreich P.A. et al. 2022. AHA/ACC/HFSA Guidelines for Heart Failure. Circulation Take Home Point: A n important aspect of HF care, Class 1 recommended medical therapies for HFrEF have very high value (low cost). In patients: With previous or current symptoms of chronic HFrEF , in whom ARNi is not feasible, tx with ACEi or ARB provides high economic value. Value Statement: High Value (A) With chronic symptomatic HFrEF , tx with an ARNi instead of an ACEi provides high economic value. Value Statement: High Value (A) With HFrEF and NYHA class II to IV symptoms , MRA therapy provides high economic value. Value Statement: High Value (A) With HFrEF , with current or previous symptoms , beta-blocker therapy provides high economic value. Value Statement: High Value (A) With symptomatic chronic HFrEF , SGLT2i therapy provides intermediate economic value. Value Statement: Intermediate Value (A) Self-identified as African American with NYHA class III to IV HFrEF who are receiving optimal medical therapy with ACEi or ARB, beta blockers, and MRA, the combination of hydralazine and isosorbide dinitrate provides high economic value. Value Statement: High Value (B-NR) Value Statements for GDMT for HFrEF 2022. AHA/ACC/HFSA Guidelines for HF

56. Guidelines recommendations for Beta Blockers

57. Summary The global burden of cardiovascular disease is increasing, CVD remains the main cause of mortality in INDIA Beta blockers play a central role in the management of CV Continuum Metoprolol is FDA approved significantly effective beta blocker effective in all stages of the CV continuum The latest AHA/ACC/HFSA 2022 HF guidelines state , beta-blocker therapy provides high economic value.

58. THANK YOU C laude Monet