ACTUALIZACION EN BETABLOQUEADORES Dr. Fèlix Nunura A. Dpto.de Medicina UNMSM/UNFV Servicio de Cardiologìa HCFAP.

Presentación del tema: "ACTUALIZACION EN BETABLOQUEADORES Dr. Fèlix Nunura A. Dpto.de Medicina UNMSM/UNFV Servicio de Cardiologìa HCFAP."— Transcripción de la presentación:

1 ACTUALIZACION EN BETABLOQUEADORES Dr. Fèlix Nunura A. Dpto.de Medicina UNMSM/UNFV Servicio de Cardiologìa HCFAP

2  -Blockade: La panacea Universal ? Hipertensiòn Angina Infarto de Miocardio Insuficiencia Cardiàca Arritmias cardiàcas Prolapso Valv. Mitral MCHipertròfica Migraña Glaucoma Temblor Tirotoxicosis Feochromocitoma Aneurisma disecante Ao Sindrome de Marfan Hipertensiòn Portal Sir James Black Inventor of propranolol 1964 Nobel Laureate for Medicine 1988 Control Perioperatorio de la FC y la PA Reducciòn del Riesgo Cardiàco Perioperatorio Ansiedad y Pànico Muerte sùbita Ateroesclerosis

3 Mecanismos hemodinàmicos de los betabloqueadores 1. Disminuciòn del gasto cardiàco 2. Inhibiciòn del sistema renina- angiotensina 3. Disminuciòn del eflujo simpàtico central 4. Readaptaciòn de los baroreceptores 5. Otros

4 BETABLOQUEADORES: Antagonistas ß adrenérgicos Sin actividad ß - agonista Propranolol Nadolol Timolol Labetalol Atenolol Metoprolol Esmolol Bisoprolol Con actividad ß - agonista Penbutolol Pindolol Acebutolol No selectivos ß1 selectivos

5 Beta bloqueadores Los Beta bloqueadores disminuyen consumo de oxígeno miocárdico –Frecuencia cardíaca –Contractililidad –Tensión sistólica Los Beta bloqueadores mejoran perfusion del subendocardio por aumentar el tiempo de perfusión diastólica

6 Frecuencia Cardiàca : un factor independiente de riesgo en enfermedad cardiovascular Åke Hjalmarson The Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden Large epidemiological studies have demonstrated that elevated heart rate is an independent risk factor for mortality and morbidity in healthy individuals with and without hypertension and in patients with coronary artery disease (CAD), myocardial infarction, and congestive heart failure. Elevated heart rate has been found to be a more powerful predictor of later death than depressed left ventricular function. This means that heart rate in patients with congestive heart failure is not only reflecting depressed cardiac function. Heart rate should be viewed in the same light as other risk factors, such as elevated blood pressure or cholesterol, smoking, cardiac dysfunction, or diabetes. It is well documented that interventions against these risk factors improve prognosis, in terms of both primary and secondary prevention. Several large placebo-controlled trials of patients with acute myocardial infarction or congestive heart failure have demonstrated that beta-blocking agents reduce mortality and morbidity. In fact, the effects seem to be more marked in patients with higher pre-treatment heart rates, and these patients also demonstrate a more marked reduction in heart rate. It seems reasonable to believe that heart rate reduction per se is of major importance for the effects of beta-blockers. Beneficial effects on the prognosis after myocardial infarction have also been shown for some calcium antagonists, which also reduce heart rate. Heart rate should be considered as an important risk factor in patients at risk of CAD or with established CAD. Treatment should be started to reduce heart rate to a normal level, similar to the aim in the treatment of patients with hypertension. 2008 European Society of Cardiology Oxford Journals Oxford University Press

7  Promotes endothelial injury  Promotes release of growth factors  Increases vessel wall permeability  Negatively affects metabolic control  Increased risk for CV events stress BP HR Flow disturbances Endothelial injury Platelet activation (PDGF) Lipid transport Proliferation of SMC and fibrous tissue Cholesterol accumulation Foam cell formation Atheroma progression EFECTO DELETEREO DE LA ACTIVACION SIMPATICA

8 MUERTE SUBITA The most common death in patients with  hypertension  post-myocardial infarction  heart failure Wikstrand J et al, Eur Heart J 1992;13 Suppl D:111-20

9 Sudden death - Risk reduction with metoprolol Primary prevention Years of follow-up 510 (p=0.017, n=3234) The MAPHY study Risk reduction 30% 50 Cumulative no Secondary prevention (p=0.002, n=5474) Years of follow-up 123 Months of follow-up Five pooled studies Risk reduction 42% Heart failure Metoprolol CR/XL 61218 (p=0.0002, n=3991) The MERIT-HF study Risk reduction 41% 12 Cumulative no 120 Olsson G et al, Am J Hypertens 1991;4:151-8 Olsson G et al, Eur Heart J 1992;13:28-32 MERIT-HF Study Group, Lancet 1999;353:2001-7 Cumulative % Metoprolol Diuretics Placebo

10 Östlund-Lindqvist A-M et al, Arterioscler 1988;8:40-5 10 20 30 40 50 60 % ArcusThoracicAbdom- inal Atherosclerosis, aorta Control Metoprolol p<0.015 Experimental atherosclerosis (rabbits) ControlMetoprolol-treated

11 To test the hypothesis that metoprolol CR/XL, when given to patients with hypercholesterolaemia on concomitant lipid- lowering therapy, provides an additional antiatherosclerotic effect to that provided by the statins, measured as carotid intima-media thickness (IMT) Wiklund O et al, Stroke 2002;33:572-7 ELVA - Aim

12 Randomised, double-blind, placebo- controlled, single-centre, 3-year study 92 men and women with severe hyper- cholesterolaemia and signs of early athero- sclerosis in the right carotid artery Metoprolol CR/XL 100 mg once daily vs matching placebo Progression of carotid IMT (ultrasound) ELVA - Study design Wiklund O et al, Stroke 2002;33:572-7

13 Total cholesterol >6.5 mmol/l, LDL cholesterol >5.0 mmol/l and serum triglycerides <4.5 mmol/l Signs of early atherosclerosis in the carotid artery (CCA IMT max >1.0 mm or plaque) ELVA - Inclusion criteria Wiklund O et al, Stroke 2002;33:572-7

14 Women (%) Age (years) ELVA - Baseline characteristics Heart rate (bpm) SBP (mm Hg) DBP (mm Hg) 48 60 70 138 81 50 60 71 138 80 Wiklund O et al, Stroke 2002;33:572-7 PlaceboMetoprolol CR/XL n=52n=40

15 HDL cholesterol (mmol/l) LDL cholesterol (mmol/l) 2.09 1.27 6.70 8.62 1.87 1.38 7.32 9.38 Total cholesterol (mmol/l) ELVA - Baseline lipid levels Wiklund O et al, Stroke 2002;33:572-7 Serum triglycerides (mmol/l) PlaceboMetoprolol CR/XL n=52n=40

16 Plaque occurrence (%) Lumen diameter (mm) Carotid bulb IMT (mm) 79 6.33 1.26 0.90 80 6.29 1.40 0.89Common carotid IMT (mm) ELVA - Baseline ultrasound characteristics Wiklund O et al, Stroke 2002;33:572-7 PlaceboMetoprolol CR/XL n=52n=40

17 0 2 4 6 8 10 012301230123 Years of follow-up Total cholesterol LDL cholesterol HDL cholesterol mmol/l ELVA - Serum cholesterol Wiklund O et al, Stroke 2002;33:572-7 Placebo Metoprolol CR/XL

18 ELVA - Change in heart rate and blood pressure after 3 years HR decreased by 5.1 bpm SBP no significant change DBP no significant change

19 -0.20 -0.15 -0.10 -0.05 0 0.05 0.10 1-yearfollow-upp=0.0043-yearfollow-upp=0.011 ELVA - Change in composite IMT variable Wiklund O et al, Stroke 2002;33:572-7 Placebo Metoprolol CR/XL  IMT composite (CCA+bulb):2 (mm)

20 ELVA - Summary The first clinical data to show an anti- atherosclerotic effect of beta-blockade as additional therapy to statins The data indicate that statin treatment and treatment with a beta-blocker affect different mechanisms in the atherosclerotic process and have additive beneficial effects Wiklund O et al, Stroke 2002;33:572-7

21 BCAPS and ELVA - Summary Studies with beta-blockers have shown  antiatherosclerotic effect in numerous animal experiments  antiatherosclerotic effect in two ultrasound studies in man Hedblad B et al, Circulation 2001;103:1721-6 Wiklund O et al, Stroke 2002;33:572-7

22 TREATMENT:Metoprolol 15 mg iv over 15 mins, then 200 mg oral daily vs matching placebo INCLUSION:Suspected acute MI (ST change or LBBB) within 24 h of symptom onset EXCLUSION:Shock, systolic BP <100 mmHg, heart rate <50/min or II/III AV block 1  OUTCOMES:Death & death, re-MI or VF/arrest up to 4 weeks in hospital (or prior discharge) Mean treatment and follow-up: 16 days COMMIT: Study design

23 Characteristic Metoprolol Placebo (n=22,928) (n=22,923) Aged 70+ 26.1%26.0% Time delay <6 h 34.0%33.5% SBP <120 mmHg33.7%33.5% Anterior infarct49.8%49.6% Killip class II20.0%19.8% III 4.1%4.2% Fibrinolytic given 49.8%49.7% COMMIT: Baseline characteristics

24 COMMIT: Effects of METOPROLOL on Reinfarction MetoprololPlaceboOdds ratio & 95% CI Metop. betterPlacebo better Outcome after Re-MI (22,927)(22,922) Died206226(0.9%)(1.0%) Survived261342(1.1%)(1.5%) ALL COMBINED467568(2.0%)(2.5%) 18% SE 6 (2P = 0.002) 0.40.71.01.31.61.9

25 ß-blockerControlOdds ratio & 95% CI ß-blocker betterControl better Trial (33,841) (33,813) MIAMI85111(3.0%)(3.8%) ISIS-1148161(1.8%)(2.0%) COMMIT467568(2.0%)(2.5%) OVERALL700840(2.1%)(2.5%) 17% SE 5 (2P = 0.0003) 0.40.60.81.01.21.41.6 Effects of iv then oral  -blocker on reinfarction in 3 major trials of acute MI

26 COMMIT: Effects of METOPROLOL on Cardiac Arrest MetoprololPlaceboOdds ratio & 95% CI Metop. betterPlacebo better Events (22,927)(22,922) VF582699(2.5%)(3.0%) 17% SE 5 Other arrest882899(3.8%)(3.9%) 2% SE 5 ANY OF ABOVE12671332(5.5%)(5.8%) 5% SE 4 (2P > 0.1; NS) 0.40.71.01.31.61.9

27 COMMIT: Effects of METOPROLOL on Death in hospital Days since randomisation % dead Metoprolol: 1776 deaths (7.7%) Placebo: 1798 deaths (7.8%) 1% (SE 3) relative risk reduction (2P=0.7)

28 COMMIT: Effects of METOPROLOL on Death by attributed cause(s) MetoprololPlaceboOdds ratio & 95% CI Metop. betterPlacebo better Cause(s) (22,927)(22,922) Arrhythmia388498(1.7%)(2.2%) 22% SE 6 Shock496384(2.2%)(1.7%) -29% SE 8 Other causes892916(3.9%)(4.0%) 3% SE 5 ANY DEATH17761798(7.7%)(7.8%) 1% SE 3 (2P > 0.1; NS) 0.40.71.01.31.61.9

29 COMMIT: Effects of METOPROLOL on Death, Re-MI or Arrest by prognosis & fibrinolytic MetoprololPlaceboOdds ratio & 95% CI Metop. betterPlacebo better Baseline features (22,927) (22,922) Prognostic index Good248284(3.3%)(3.7%) Average575642(7.5%)(8.4%) Poor13501338(17.6%)(17.5%) Lytic given Yes10311137(9.0%)(10.0%) No11421127(9.9%)(9.8%) ALL21732264(9.5%)(9.9%) 4% SE 3 (2P > 0.1; NS) 0.40.60.81.01.21.41.6

30 COMMIT: Conclusions  Metoprolol (15 mg iv, then 200 mg oral daily) in acute MI did not significantly reduce mortality in hospital  It reduced the absolute risks of reinfarction by 5 per 1000 (P=0.001) and of VF by 5 per 1000 (P<0.001)  But, overall, it increased the risk of cardiogenic shock by 11 per 1000 (P<0.00001), chiefly on days 0-1  In acute MI, it may be better to start beta- blocker when the patient is stable (and then continue long-term) Slides available on: www.commit- ccs2.org

31 La Hipertension is un factor de riesgo significativo para : –Enfermedad cerebrovascular –Enfermedad arterial coronaria –Insuficiencia Cardiàca –Insuficiencia renal –Enfermedad vascular perifèrica –Demencia –Fibrilaciòn Auricular Hipertensiòn como Factor de Riesgo

32 BETABLOQUEADORES EN HIPERTENSION ARTERIAL

33 JAMA 2003;289 (19):2560-2572

34

35 Intention-to-treat LIFE Study : Stroke Fatal y no Fatal Losartan Atenolol Adjusted risk reduction 24·9%, P=0·001 Unadjusted risk reduction 25·8%, P=0·0006 Study Month Proportion of patients with first event (%) 1 2 3 4 5 6 7 8 06121824364248546066 30 Dahlof B, et al. Lancet. 2002;359:995-1003.

36 B. Dahlof (Co-chair), P. Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen E. O’Brien, J. Östergren, on behalf of the ASCOT Investigators Lancet 2003;361:1149-1158 A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design

37 Study design atenolol ± bendroflumethiazide amlodipine ± perindopril 19,257 hypertensive patients PROBE design ASCOT-BPLA Investigator-led, multinational randomised controlled trial placebo atorvastatin 10 mg Double-blind ASCOT-LLA 10,305 patients TC ≤ 6.5 mmol/L (250 mg/dL)

38 ASCOT: BPLA and LLA combined: Insight into optimal CV prevention (2) Endpoint Amlodipine  perindopril + atorvastatin Atenolol  thiazide + placebo Relative risk reduction Non-fatal MI and fatal CHD 4.89.2 48% Fatal and non-fatal stroke4.68.2 44% Rates / 1000 patient years

39 Circulation, 2006

40 CAFÉ:Menor PA aòrtica central con el regimen antihipertensivo amlodipino-IECA vs Atenolol-Tiazida a pesar de similar PA braquial.

41 BHS Guidelines for the management of hypertension BHS IV, 2004 and Update of the NICE Hypertension Guideline, 2006 Guidelines for management of hypertension: report of the fourth Working Party of the British Hypertension Society, 2004 BHS IV B Williams et al: J Hum Hyp (2004); 18: 139-185.

42

43 Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lindholm LHLindholm LH, Carlberg B, Samuelsson O.Carlberg BSamuelsson O Department of Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden. Beta blockers have been used widely in the treatment of hypertension and are recommended as first- line drugs in hypertension guidelines. However, a preliminary analysis has shown that atenolol is not very effective in hypertension. We aim to substantially enlarge the data on atenolol and analyse the effect of different beta blockers. METHODS: The Cochrane Library and PubMed were searched for beta blocker treatment in patients with primary hypertension. 13 randomised controlled trials (n=105 951) were included in a meta-analysis comparing treatment with beta blockers with other antihypertensive drugs. Seven studies (n=27 433) were included in a comparison of beta blockers and placebo or no treatment. FINDINGS : The relative risk of stroke was 16% higher for beta blockers (95% CI 4-30%) than for other drugs. There was no difference for myocardial infarction. When the effect of beta blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta blockers (7-29%), about half that expected from previous hypertension trials. There was no difference for myocardial infarction or mortality. NTERPRETATION: In comparison with other antihypertensive drugs, the effect of beta blockers is less than optimum, with a raised risk of stroke. Hence, we believe that beta blockers should not remain first choice in the treatment of primary hypertension and should not be used as reference drugs in future randomised controlled trials of hypertension. Lancet. 2005 Oct 29-Nov 4;366(9496):1545-53

44 Guias 2007 ESH-ESC- para el manejo de la Hipertensiòn Arterial Mancia G et al. J Hypertens September 2007; 25 (9) :1105-1187.

45 Mancia G et al. J Hypertens 2007; 25:1105-1187. Tratamiento Antihipertensivo: Drogas preferidas Evento ClinicoTratamiento ACV PrevioCualquier antihipertensivo IMA PrevioBetabloquer, IECA, Bloqueador receptor de angiotensina Angina pectorisBetabloquer, calcioantagonista ICC Beta blocker, Diurètico, IECA, BRA, agentes antialdosterona

46 Mancia G et al. J Hypertens 2007; 25:1105-1187. Tratamiento antihipertensivo: Drogas preferidas Evento ClinicoTratamiento Fibrilaciòn Auricular RecurrenteBRA ò IECA PermanentBetabloquer, Calcioantagonista No dihidropiridìnico EREF ProteinuriaIECA, Bloqueador receptor de angiotensina, diurètico de asa Arteriopat ì a Calcioantagonistas

47 Mancia G et al. J Hypertens 2007; 25:1105-1187. Tratamiento antihipertensivo : Drogas preferidas Condiciòn Tratamiento HSA (anciano)Diureticos, calcioantagonista Sindrome Metabòlico IECA, BRA II, calcioantagonistas Diabetes mellitusIECA, BRA II EmbarazoBetabloquer, Calcioantagonista, metildopa Raza negraDiureticos, calcioantagonista

48 Evidencia en el beneficio del tratamiento antihipertensivo subrayan el rol crucial de la reducciòn de la PA.Los estudios que comparan diferentes drogas no han sido capaces de demostrar conclusivamente que para la misma reducciòn en la PA, diferentes drogas (ò combinaciones) reducen en diferentes grados los eventos CV (ACV,IAM,ICC) y subrayan el rol crucial de la reducciòn de la PA. 2007 Guidelines for the management of Arterial Hypertension J Hypertens 2007;25:1105-87.

49 BETABLOQUEADORES INSUFICIENCIA CARDIACA

50 Pathophysiology of Heart Failure and Left Ventricular Dysfunction Myocardial injury Fall in LV performance Activation of RAAS, SNS, ET, and others Myocardial toxicity Peripheral vasoconstriction Hemodynamic alterations Remodeling and Progressive Worsening of LV Function Heart failure symptoms Morbidity and mortality ANP BNP RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; ET, endothelin; ANP, atrial natriuretic peptide; BNP, brain natriuetic peptide. Shah M et al. Rev Cardiovasc Med. 2001;2:S2–S6.

51 Effects of Sympathetic Activation in Heart Failure  1 - receptors  Cardiac sympathetic activity  Sympathetic activity to kidneys + blood vessels  2 - receptors  1 - receptors Activation of RAS Vasoconstriction Sodium retention Myocyte death Increased arrhythmias Disease progression 1-1- 1-1-  CNS sympathetic outflow

52 Selectivity of  -Blocking Agents Sympathetic Activation  1 receptors  2 receptors  1 receptors Cardiotoxicity  1 -selective blockade  -nonselective blockade  1,  2,  1 blockade MI, HTN, DM, Insulin Resistance MI, myocardial infarction; HTN, hypertension; DM, diabetes mellitus.

53 Heart disease No symptoms HF Risk Factors No Heart disease No symptoms Asymptomatic LV dysfunction Refractory HF symptoms Prior or current HF Symptoms Stages in the evolution of Heart Failure A B C D AHA / ACC HF guidelines 2001

54 Heart disease (any) Hypertension Diabetes, Hyperchol. Family Hx Cardiotoxins Asymptomatic LV dysfunction Systolic / Diastolic Marked symptoms at rest despite max. therapy Dyspnea, Fatigue Reduced exercise tolerance Stages in the Evolution of Heart Failure Clinical Characteristics A B C D AHA / ACC HF guidelines 2001

55 ACE-i  blockers Treat risk factors Avoid toxics ACE-i in selected p. In selected patients Palliative therapy Mech. Assist device Heart Transplant ACE-i  blockers Diuretics / Digitalis Stages in the Evolution of Heart Failure Treatment A B C D AHA / ACC HF guidelines 2001

56 8070605040302054-60 >60 50 40 30 20 10 0 Post MI n=196 <30 31-35 36-45 46-53 Cardiac Mortality % LVEF Brodie B. et al Am J Cardiol 1992;69:1113 Prognosis

57 Treatment Objectives Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms

58 ß-Adrenergic Blockers Clinical Effects ß-Adrenergic Blockers Clinical Effects Improve symptoms (only long term) Reduce remodelling / progression Reduce hospitalization Reduce sudden death Improve survival Improve symptoms (only long term) Reduce remodelling / progression Reduce hospitalization Reduce sudden death Improve survival

59 US Carvedilol HF NEJM 1996; 334: 1349-55 Carvedilol(n=696) Placebo(n=398) Risk reduction = 65% p<0.001 050100150200250300350400 1.0 0.9 0.8 0.7 0.6 ß-Adrenergic Blockers 0.7 0.8 0.9 1.0 Survival% Days I-II HF

60 P< 0.00005 Annual Mortality: bisoprolol=8.2%; placebo=12% Mean Follow-up 1.4 years Days Bisoprolol11.8% Placebo17.3% 1 0.9 0.8 0.7 0.6 0.5 Survival ICCC NYHA III-IV n=2647 0 800 400 600 200 CIBIS-II Lancet 1999;353:9 ß-Adrenergic Blockers

61 15 10 5 MERIT-HF Lancet 1999; 353: 2001 Months Mortality% 036912151821 0 Placebo Metoprolol p=0.0062 Risk Reduction 34% ß-Adrenergic Blockers NYHA II-IV N=3991

62 MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure - RESULTS continued - MERIT-HF Study Group.Lancet 1999;353:2001–7. No patients lost to follow up MERIT-HF trial profile 3991 patients randomized 2001 patients placebo 217 patient deaths 1784 patients alive 1539 patients on treatment 145 patient deaths 1990 patients metoprolol CR/XL 1845 patients alive 1614 patients on treatment

63 MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure Metoprololol CR/XL once daily in addition to optimum standard therapy: Was well tolerated and did not increase risk in any of subgroups analyzed Improved survival in clinically stable patients, equating to prevention of 1 death per 27 patients treated per year

64 100 90 80 60 70 50 2402016128428 Placebo Carvedilol Months N = 2289 III-IV NYHA COPERNICUS NEJM 2001;344:1651 Survival% ß-Adrenergic Blockers p=0.00014 35% RR

65 Symptomatic heart failure Asymptomatic ventricular dysfunction - LVEF < 35 - 40 % After AMI Symptomatic heart failure Asymptomatic ventricular dysfunction - LVEF < 35 - 40 % After AMI AHA / ACC HF guidelines 2001 ESC HF guidelines 2001 ß-Adrenergic Blockers Indications

66 InitialTarget Bisoprolol 1.25 / 24h 10 / 24h Carvedilol 3.125 / 12h25 / 12h Metoprolol tartrate6.25 / 12h 75 / 12h Metoprolol succinnate 12,5-25 / 24h200 / 24h Start Low, Increase Slowly Start Low, Increase Slowly Increase the dose every 2 - 4 weeks Increase the dose every 2 - 4 weeks ß-Adrenergic Blockers Dose (mg)

67 ß-Adrenergic Blockers Contraindications Asthma (reactive airway disease) Asthma (reactive airway disease) AV block (unless pacemaker) AV block (unless pacemaker) Symptomatic hypotension / Bradycardia Symptomatic hypotension / Bradycardia Diabetes is NOT a contraindication Diabetes is NOT a contraindication

68 Incontrovertible Evidence for Benefits of  -Blockade in Heart Failure 34%  Cumulative Mortality (%) Days 20 15 5 0 10 P=.0062 (adjusted) Metoprolol CR/XL (n=1990) Placebo (n=2001) US Carvedilol Trials 1 Probability of Event-free Survival  Carvedilol (n=696) Placebo (n=398) Days P<.001 0.0 0100200300400 65%  1.0 0.8 0.7 0.9 MERIT-HF 2 Survival (% of Patients) 100 90 80 60 70 0 6000400300200100 Days Carvedilol (n=1156) Placebo (n=1133) 500 6000400300200100500 35%  P=.00013 COPERNICUS 4 Days 0.0 200400800 1.0 0.8 0.6 P<.0001 34%  Bisoprolol (n=1327) Placebo (n=1320) CIBIS-II 3 0600 Survival 1. Packer M et al. N Engl J Med. 1996;334:1349–1355. 2. MERIT-HF Study Group. Lancet. 1999;253:2001–2007. 3. CIBIS-II Investigators. Lancet. 1999;353:9–13. 4. Packer M et al. N Engl J Med. 2001;344:1651–1658.

69 Are There Clinically Relevant Differences Between  -Blockers?

70 Bucindilol in Chronic Heart Failure (BEST) 03691215182124 Follow-up (months) 0 20 40 60 80 100 Survival Proportion Bucindolol Placebo RR 0.90 P=.105 n=1352 n=1354 2708 patients with CHF Class III–IV, average age 60 and LVEF 0.23 randomized to Bucindolol (3 mg titrated to 50 mg PO bid). BEST Investigators. N Engl J Med. 2001;344:1659–1667.

71 COMET Carvedilol or Metoprolol European Trial  Designed to compare the effects of treatment with metoprolol tartrate, a  1-selective  -blocker, to carvedilol, a nonselective  -blocker with  1-blocking, antioxidant, antiapoptotic, and anti- ischemic properties  A randomized “head-to-head” comparison in 3000 patients with stable heart failure receiving standard therapy, including ACEIs  The study was designed to continue until 1020 deaths occurred

72 Number at risk Carvedilol 15111367 125911551002383 Metoprolol 15181359 1234 1105 933352 Time (years) Mortality (%) 0 10 20 30 40 012345 Hazard ratio 0.83, 95% CI 0.74-0.93, P=.0017 Metoprolol Carvedilol Primary Endpoint of Mortality

73 Primary results Endpoint Carvedilol (n=1511) (%) Metoprolol (n=1518) (%)p All-cause mortality 33.9%39.5%0.0017 All-cause mortality or all-cause hospitalization 73.9%76.4%0.1222 Poole-Wilson PA et al. Lancet 2003;362:7-13

74 COMET trial review Dr Eric Topol “I don’t think it measures up to the optimal clinical trial.” –Advances the field with some confusing results

75 ¿ Perioperative Beta-Blockade to prevent cardiac morbidity and mortality ?

76 Pathophysiology TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting InflammationHypercoagulabilityStress stateHypoxic state Plaque fissuring Plaque fissuring Coronary thrombosis  O 2 demand  O 2 delivery Myocardial ischaemia PMI

77 NEJM 1999:341:1789-94

78 PJ Devereaux, H Yang, S Yusuf, G Guyatt, K Leslie, JC Villar, D Xavier, S Chrolavicius, L Greenspan, J Pogue, P Pais, L Lisheng, SC Xu, G Malaga, A Avezum, M Chan, V Montori, M Jacka, P Choi, on behalf of the POISE Investigators Presented at the AHA meeting in Orlando, Florida on November 7 th 2007

79 Conclusions The POISE Study –Largest perioperative trial ever conducted –Major cardiovascular events are common –METOPROLOL prevents perioperative MIs –Huge impact on burden of cardiac disease –Significant risk with perioperative use Clinicians and their patients will have to weigh the potential risks and benefits of perioperative beta- blocker treatment An improved model of postoperative care is required