BETABLOQUEADORES ACTUALIZACION

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ACTUALIZACION EN BETABLOQUEADORES : 

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

b-Blockade: La panacea Universal ? : 

b-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

Mecanismos hemodinàmicos de los betabloqueadores : 

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

BETABLOQUEADORES: Antagonistas ß adrenérgicos : 

BETABLOQUEADORES: Antagonistas ß adrenérgicos No selectivos ß1 selectivos

Beta bloqueadores : 

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

Slide 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

EFECTO DELETEREO DE LA ACTIVACION SIMPATICA : 

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

MUERTE SUBITA : 

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

Sudden death - Risk reduction with metoprolol : 

Sudden death - Risk reduction with metoprolol Primary prevention Years of follow-up 5 10 (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 1 2 3 Months of follow-up Five pooled studies Risk reduction 42% Heart failure Metoprolol CR/XL 6 12 18 (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 Metoprolol Diuretics Placebo Placebo

Slide 10: 

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

ELVA - Aim : 

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

ELVA - Study design : 

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

ELVA - Inclusion criteria : 

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

ELVA - Baseline characteristics : 

Women (%) Age (years) ELVA - Baseline characteristics Heart rate (bpm) SBP (mm Hg) DBP (mm Hg) Wiklund O et al, Stroke 2002;33:572-7 Placebo Metoprolol CR/XL n=52 n=40

ELVA - Baseline lipid levels : 

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) Placebo Metoprolol CR/XL n=52 n=40

ELVA - Baseline ultrasound characteristics : 

Plaque occurrence (%) Lumen diameter (mm) Carotid bulb IMT (mm) Common carotid IMT (mm) ELVA - Baseline ultrasound characteristics Wiklund O et al, Stroke 2002;33:572-7 Placebo Metoprolol CR/XL n=52 n=40

ELVA - Serum cholesterol : 

0 2 4 6 8 10 0 1 2 3 0 1 2 3 0 1 2 3 Years of follow-up Total cholesterol LDL cholesterol HDL cholesterol mmol/l ELVA - Serum cholesterol Wiklund O et al, Stroke 2002;33:572-7

ELVA - Change in heart rateand blood pressure after 3 years : 

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

ELVA - Change in composite IMT variable : 

-0.20 -0.15 -0.10 -0.05 0 0.05 0.10 1-year follow-up p=0.004 3-year follow-up p=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)

ELVA - Summary : 

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

BCAPS and ELVA - Summary : 

BCAPS and ELVA - Summary Studies with beta-blockers have shown antiatherosclerotic effect in numerousanimal 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

Slide 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

Slide 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 mmHg 33.7% 33.5% Anterior infarct 49.8% 49.6% Killip class II 20.0% 19.8% III 4.1% 4.2% Fibrinolytic given 49.8% 49.7% COMMIT: Baseline characteristics

Slide 24: 

COMMIT: Effects of METOPROLOL on Reinfarction Metoprolol Placebo Odds ratio & 95% CI Metop. better Placebo better Outcome after Re-MI (22,927) (22,922) Died 206 226 (0.9%) (1.0%) Survived 261 342 (1.1%) (1.5%) ALL COMBINED 467 568 (2.0%) (2.5%) 18% SE 6 (2P = 0.002) 0.4 0.7 1.0 1.3 1.6 1.9

Slide 25: 

ß-blocker Control Odds ratio & 95% CI ß-blocker better Control better Trial (33,841) (33,813) MIAMI 85 111 (3.0%) (3.8%) ISIS-1 148 161 (1.8%) (2.0%) COMMIT 467 568 (2.0%) (2.5%) OVERALL 700 840 (2.1%) (2.5%) 17% SE 5 (2P = 0.0003) 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Effects of iv then oral -blocker on reinfarction in 3 major trials of acute MI

Slide 26: 

COMMIT: Effects of METOPROLOL on Cardiac Arrest Metoprolol Placebo Odds ratio & 95% CI Metop. better Placebo better Events (22,927) (22,922) VF 582 699 (2.5%) (3.0%) 17% SE 5 Other arrest 882 899 (3.8%) (3.9%) 2% SE 5 ANY OF ABOVE 1267 1332 (5.5%) (5.8%) 5% SE 4 (2P > 0.1; NS) 0.4 0.7 1.0 1.3 1.6 1.9

COMMIT: Effects of METOPROLOL on Death in hospital : 

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)

Slide 28: 

COMMIT: Effects of METOPROLOL on Death by attributed cause(s) Metoprolol Placebo Odds ratio & 95% CI Metop. better Placebo better Cause(s) (22,927) (22,922) Arrhythmia 388 498 (1.7%) (2.2%) 22% SE 6 Shock 496 384 (2.2%) (1.7%) -29% SE 8 Other causes 892 916 (3.9%) (4.0%) 3% SE 5 ANY DEATH 1776 1798 (7.7%) (7.8%) 1% SE 3 (2P > 0.1; NS) 0.4 0.7 1.0 1.3 1.6 1.9

Slide 29: 

COMMIT: Effects of METOPROLOL on Death, Re-MI or Arrest by prognosis & fibrinolytic Metoprolol Placebo Odds ratio & 95% CI Metop. better Placebo better Baseline features (22,927) (22,922) Prognostic index Good 248 284 (3.3%) (3.7%) Average 575 642 (7.5%) (8.4%) Poor 1350 1338 (17.6%) (17.5%) Lytic given Yes 1031 1137 (9.0%) (10.0%) No 1142 1127 (9.9%) (9.8%) ALL 2173 2264 (9.5%) (9.9%) 4% SE 3 (2P > 0.1; NS) 0.4 0.6 0.8 1.0 1.2 1.4 1.6

COMMIT: Conclusions : 

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

Hipertensiòn como Factor de Riesgo : 

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

BETABLOQUEADORES EN HIPERTENSION ARTERIAL : 

BETABLOQUEADORES EN HIPERTENSION ARTERIAL

JAMA 2003;289 (19):2560-2572 : 

JAMA 2003;289 (19):2560-2572

JAMA 2003;289 (19):2560-2572 : 

JAMA 2003;289 (19):2560-2572

LIFE Study : Stroke Fatal y no Fatal : 

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 0 6 12 18 24 36 42 48 54 60 66 30 Dahlof B, et al. Lancet. 2002;359:995-1003.

Slide 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

Study design : 

Study design atenolol ± bendroflumethiazide amlodipine ± perindopril 19,257 hypertensive patients PROBE design ASCOT-BPLA

ASCOT: BPLA and LLA combined: Insight into optimal CV prevention (2) : 

ASCOT: BPLA and LLA combined: Insight into optimal CV prevention (2) Rates / 1000 patient years

Slide 39: 

Circulation, 2006

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

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

BHS Guidelines for the management of hypertension : 

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.

Slide 43: 

Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lindholm LH, Carlberg B, Samuelsson 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

Guias 2007 ESH-ESC-para el manejo de la Hipertensiòn Arterial : 

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

Tratamiento Antihipertensivo: Drogas preferidas : 

Mancia G et al. J Hypertens 2007; 25:1105-1187. Tratamiento Antihipertensivo: Drogas preferidas

Tratamiento antihipertensivo:Drogas preferidas : 

Mancia G et al. J Hypertens 2007; 25:1105-1187. Tratamiento antihipertensivo:Drogas preferidas

Tratamiento antihipertensivo : Drogas preferidas : 

Mancia G et al. J Hypertens 2007; 25:1105-1187. Tratamiento antihipertensivo : Drogas preferidas

Evidencia en el beneficio del tratamiento antihipertensivo : 

Evidencia en el beneficio del tratamiento antihipertensivo 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.

BETABLOQUEADORES : 

BETABLOQUEADORES INSUFICIENCIA CARDIACA

Pathophysiology of Heart Failureand Left Ventricular Dysfunction : 

Pathophysiology of Heart Failureand 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.

Effects of SympatheticActivation in Heart Failure : 

Effects of SympatheticActivation in Heart Failure b1- receptors  Cardiac sympathetic activity  Sympathetic activity to kidneys + blood vessels b2- receptors a1- receptors Activation of RAS Vasoconstriction Sodium retention Myocyte death Increased arrhythmias Disease progression a1- b1-  CNS sympathetic outflow

Selectivity of -Blocking Agents : 

Selectivity of -Blocking Agents MI, myocardial infarction; HTN, hypertension; DM, diabetes mellitus.

Slide 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

Slide 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

Slide 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

Slide 56: 

54-60 >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

Slide 57: 

Treatment Objectives

Slide 58: 

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

Slide 59: 

US Carvedilol HF NEJM 1996; 334: 1349-55 Carvedilol (n=696) Placebo (n=398) Risk reduction = 65% p<0.001 0 50 100 150 200 250 300 350 400 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

Slide 60: 

P< 0.00005 Annual Mortality: bisoprolol=8.2%; placebo=12% Mean Follow-up 1.4 years Days Bisoprolol 11.8% Placebo 17.3% 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

Slide 61: 

15 10 5 MERIT-HF Lancet 1999; 353: 2001 Months Mortality % 0 3 6 9 12 15 18 21 0 Placebo Metoprolol p=0.0062 Risk Reduction 34% ß-Adrenergic Blockers NYHA II-IV N=3991

MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure- RESULTS continued - : 

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

MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure : 

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

Slide 64: 

100 90 80 60 70 50 24 0 20 16 12 8 4 28 Placebo Carvedilol Months N = 2289 III-IV NYHA COPERNICUS NEJM 2001;344:1651 Survival % ß-Adrenergic Blockers p=0.00014 35% RR

Slide 65: 

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

Slide 66: 

Initial Target Bisoprolol 1.25 / 24h 10 / 24h Carvedilol 3.125 / 12h 25 / 12h Metoprolol tartrate 6.25 / 12h 75 / 12h Metoprolol succinnate 12,5-25 / 24h 200 / 24h Start Low, Increase Slowly Increase the dose every 2 - 4 weeks ß-Adrenergic Blockers Dose (mg)

Slide 67: 

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

Incontrovertible Evidence forBenefits of -Blockade in Heart Failure : 

Incontrovertible Evidence forBenefits 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 Trials1 Probability ofEvent-free Survival Carvedilol (n=696) Placebo (n=398) Days P<.001 0.0 0 100 200 300 400 65%  1.0 0.8 0.7 0.9 MERIT-HF2 Survival (% of Patients) 100 90 80 60 70 0 600 0 400 300 200 100 Days Carvedilol (n=1156) Placebo (n=1133) 500 600 0 400 300 200 100 500 35%  P=.00013 COPERNICUS4 Days 0.0 200 400 800 1.0 0.8 0.6 P<.0001 34%  Bisoprolol (n=1327) Placebo (n=1320) CIBIS-II3 0 600 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.

Are There Clinically Relevant Differences Between b-Blockers? : 

Are There Clinically Relevant Differences Between b-Blockers?

Bucindilol in Chronic Heart Failure (BEST) : 

Bucindilol in Chronic Heart Failure (BEST) 0 3 6 9 12 15 18 21 24 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.

COMETCarvedilol or Metoprolol European Trial : 

COMETCarvedilol or Metoprolol European Trial Designed to compare the effects of treatment with metoprolol tartrate, a b1-selective b-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

Primary Endpoint of Mortality : 

Number at risk Carvedilol 1511 1367 1259 1155 1002 383 Metoprolol 1518 1359 1234 1105 933 352 Time (years) Mortality (%) 0 10 20 30 40 0 1 2 3 4 5 Hazard ratio 0.83, 95% CI 0.74-0.93, P=.0017 Metoprolol Carvedilol Primary Endpoint of Mortality

Primary results : 

Primary results Poole-Wilson PA et al. Lancet 2003;362:7-13

COMET trial review : 

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

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

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

Pathophysiology : 

Pathophysiology TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Inflammation Hypercoagulability Stress state Hypoxic state Plaque fissuring Plaque fissuring Coronary thrombosis O2 demand O2 delivery Myocardial ischaemia PMI

Slide 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 7th 2007

Conclusions : 

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

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