UPDATE IN INTERNAL MEDICINE

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Published on June 22, 2008

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UPDATE IN INTERNAL MEDICINE : UPDATE IN INTERNAL MEDICINE 2006-2007 Part 1 OBJECTIVE : OBJECTIVE Upon completion of this activity, we should be able to: 1. Understand new therapeutic advances in Internal Medicine 2. Understand scientific evidence in support of accepted medical practices 3. Gain insight into the difference between statistical and clinical significance Catheter related infections : Catheter related infections Slide 4: Wenzel R and Edmond M. N Engl J Med 2006;355:2781-2783 Annual Patient Stays in the 6000 Acute Care Hospitals and Associated ICUs in the United States Central venous line surveillance : Central venous line surveillance 1/35 x 1000 = 28.57 per 1000 catheter days Catheter related infections : Catheter related infections Historically it has been acceptable for a hospital's rate of catheter-related blood stream infections (CR-BSIs) to be at or below the Centers for Disease Control's (CDC's) rate of 5.7 per 1,000 catheter days. Today the goal is zero. Slide 7: Katneni R and Hedayati SS (2007) Central venous catheter-related bacteremia in chronic hemodialysis patients: epidemiology and evidence-based management Nat Clin Pract Nephrol 3: 256–266 doi:10.1038/ncpneph0447 Figure 1 Relationships between factors associated with hemodialysis central venous catheter-related blood stream infections Slide 8: An Intervention to Decrease Catheter-Related Bloodstream Infections in the ICU Peter Pronovost, M.D., Ph.D., Dale Needham, M.D., Ph.D., Sean Berenholtz, M.D., David Sinopoli, M.P.H., M.B.A., Haitao Chu, M.D., Ph.D., Sara Cosgrove, M.D., Bryan Sexton, Ph.D., Robert Hyzy, M.D., Robert Welsh, M.D., Gary Roth, M.D., Joseph Bander, M.D., John Kepros, M.D., and Christine Goeschel, R.N., M.P.A. N Engl J Med Volume 355(26):2725-2732 December 28, 2006 Study Overview : Study Overview Catheter-related bloodstream infections are associated with significant morbidity In Michigan, a statewide initiative to reduce catheter-related bloodstream infections in intensive care units (ICUs) was implemented This simple intervention included (1)washing hands, (2)using full-barrier precautions with central-line placement, (3)cleaning the skin with chlorhexidine, (4)avoiding the femoral site if possible, and(5) removing unnecessary catheters The median rate of infection per 1000 catheter-days decreased from 2.7 at baseline to 0 throughout all periods after implementation of the study intervention Slide 10: Catheter-Related Bloodstream Infections in Adults, as Defined by the National Nosocomial Infections Surveillance System Pronovost P et al. N Engl J Med 2006;355:2725-2732 Slide 11: Characteristics of 103 Participating ICUs, According to the Period of Implementation of the Intervention to Reduce the Rate of Catheter-Related Bloodstream Infections Pronovost P et al. N Engl J Med 2006;355:2725-2732 Slide 12: Baseline Data Pronovost P et al. N Engl J Med 2006;355:2725-2732 Slide 13: Rates of Catheter-Related Bloodstream Infection from Baseline (before Implementation of the Study Intervention) to 18 Months of Follow-up Pronovost P et al. N Engl J Med 2006;355:2725-2732 Slide 14: Incidence-Rate Ratios for Catheter-Related Bloodstream Infections Pronovost P et al. N Engl J Med 2006;355:2725-2732 Catheter Associated Infections... : Catheter Associated Infections... Study conclude that many of the 80,000 infections and 28,000 deaths can be prevented Savings up to 2.3 billion dollars What it takes: Funding Incentives Reinforcement Why cant we do it here? Slide 16: Figure 2 Management of central venous hemodialysis catheter-related bacteremia Slide 18: Colonoscopic Withdrawal Times and Adenoma Detection during Screening Colonoscopy Robert L. Barclay, M.D., Joseph J. Vicari, M.D., Andrea S. Doughty, Ph.D., John F. Johanson, M.D., and Roger L. Greenlaw, M.D. N Engl J Med Volume 355(24):2533-2541 December 14, 2006 Study Overview : Study Overview In this study of 12 experienced gastroenterologists who performed colonoscopic screening, the duration of withdrawal of the colonoscope varied widely among physicians Rates of detection of polyps were higher among endoscopists who took more time These findings suggest that the effectiveness of colonoscopy in preventing colon cancer may be influenced by procedure times Slide 20: Enrolment of Subjects Barclay RL et al. N Engl J Med 2006;355:2533-2541 Slide 21: Baseline Characteristics of the Physicians and Subjects Barclay RL et al. N Engl J Med 2006;355:2533-2541 Slide 22: Withdrawal Times and Rates of Detection of Lesions for Individual Physicians Barclay RL et al. N Engl J Med 2006;355:2533-2541 Slide 23: Rates of Detection of Lesions According to Mean Withdrawal Time for Procedures in Which No Polyps Were Removed Barclay RL et al. N Engl J Med 2006;355:2533-2541 Slide 24: Mean Rates of Detection of Adenomas According to Mean Colonoscopic Withdrawal Times for 12 Endoscopists Barclay RL et al. N Engl J Med 2006;355:2533-2541 Conclusion : Conclusion In this large community-based gastroenterology practice, we observed greater rates of detection of adenomas among endoscopists who had longer mean times for withdrawal of the colonoscope The effect of variation in withdrawal times on lesion detection and the prevention of colorectal cancer in the context of widespread colonoscopic screening is not known Ours was a preliminary study, so implications for clinical practice need to be determined by future studies Measuring the Quality of Colonoscopy : Measuring the Quality of Colonoscopy Even in the best of hands, invasive cancer may develop within three years of colonoscopy and polyp removal (NEJM 355(24), 2006) Accompanying editorial notes that procedure is performed too frequently and not in compliance with guidelines for optimal withdrawal times Frequency and Brevity? Slide 27: Success is not final, failure is not fatal: it is the courage to continue that counts. Winston Churchill Slide 29: Original Article Coronary Intervention for Persistent Occlusion after Myocardial Infarction Judith S. Hochman, M.D., Gervasio A. Lamas, M.D., Christopher E. Buller, M.D., Vladimir Dzavik, M.D., Harmony R. Reynolds, M.D., Staci J. Abramsky, M.P.H., Sandra Forman, M.A., Witold Ruzyllo, M.D., Aldo P. Maggioni, M.D., Harvey White, M.D., Zygmunt Sadowski, M.D., Antonio C. Carvalho, M.D., Jamie M. Rankin, M.D., Jean P. Renkin, M.D., P. Gabriel Steg, M.D., Alice M. Mascette, M.D., George Sopko, M.D., Matthias E. Pfisterer, M.D., Jonathan Leor, M.D., Viliam Fridrich, M.D., Daniel B. Mark, M.D., M.P.H., Genell L. Knatterud, Ph.D., for the Occluded Artery Trial Investigators N Engl J Med Volume 355(23):2395-2407 December 7, 2006 Study Overview : Study Overview In the Occluded Artery Trial (OAT), 2166 patients who had myocardial infarction with ST-segment elevation 3 to 28 days before enrolment and an occluded infarct-related coronary artery were randomly assigned to percutaneous coronary intervention (PCI) or medical therapy At 4 years, the estimated rate of death, reinfarction, or class IV heart failure was 17.2% with PCI and 15.6% with medical therapy These findings suggest that PCI should not be performed to open an occluded infarct-related artery after the currently accepted period for myocardial salvage has passed Slide 31: Medication Use on Discharge Hochman JS et al. N Engl J Med 2006;355:2395-2407 Slide 32: Medication Use on Discharge Hochman JS et al. N Engl J Med 2006;355:2395-2407 Slide 33: Kaplan-Meier Curves for the Primary End Point, According to the Intention-to-Treat Analysis Hochman JS et al. N Engl J Med 2006;355:2395-2407 Slide 34: Kaplan-Meier Curves for the Secondary End Points, According to the Intention-to-Treat Analysis Hochman JS et al. N Engl J Med 2006;355:2395-2407 Slide 35: Subgroup Analysis Hochman JS et al. N Engl J Med 2006;355:2395-2407 Conclusion : Conclusion PCI did not reduce the occurrence of death, reinfarction, or heart failure, and there was a trend toward excess reinfarction during 4 years of follow-up in stable patients with occlusion of the infarct-related artery 3 to 28 days after myocardial infarction Open a closed vessel… : Open a closed vessel… Like HRT , it seem to make intuitive sense that a vessel is better open than closed Yet this study and others found no such benefit Where are the incentives aligned: to treat conservatively or aggressively; What about patient expectations? Slide 38: Clinical Therapeutics Primary PCI for Myocardial Infarction with ST-Segment Elevation Ellen C. Keeley, M.D., and L. David Hillis, M.D. N Engl J Med Volume 356(1):47-54 January 4, 2007 Case Vignette : Case Vignette A 58-year-old man has chest pain at 9:30 a.m.; 3 hours later, he calls for an ambulance. Paramedics arrive, provide standard treatment, and transport him to the nearest emergency department. On his arrival at a small hospital at 1 p.m., the findings are diagnostic of a myocardial infarction with ST-segment elevation. The emergency department physician recommends immediate transfer to a hospital 1 hour away for primary percutaneous coronary intervention (PCI). Slide 40: Keeley E and Hillis L. N Engl J Med 2007;356:47-54 Myocardial Infarction with ST-Segment Elevation before, during, and after PCI Recommendations : Recommendations The patient in the vignette has an anterior myocardial infarction with ST-segment elevation. He was initially taken to a small community hospital that lacked interventional capabilities. Since he has no contraindication to fibrinolytic therapy, he could receive this therapy there or, alternatively, he could be transferred urgently for primary PCI. Recommendations : Recommendations Because his symptoms have been present for more than 3 hours and he has high-risk features (i.e., tachycardia, rales, and anterior location of the infarction), we recommend his transfer for PCI, provided that the procedure can be performed in a timely fashion by an experienced operator in a high-volume catheterization laboratory. On the basis of the data available on facilitated PCI, we do not recommend administration of a fibrinolytic agent or glycoprotein IIb/IIIa inhibitor before the transfer. WHAT ABOUT FACILITATED PCI? : WHAT ABOUT FACILITATED PCI? The Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction (ASSENT-4 PCI) Trial : The Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction (ASSENT-4 PCI) Trial ASSENT- 4 PCI Trial Presented at The European Society of Cardiology Hot Line Session 2005 Presented by Dr. Frans Van de Werf Slide 45: Full-dose TNK + Primary PCI 60 IU/kg, maximum 4000 IU n=829 GP IIb/IIIa inhibitors allowed only for bail out use 1667 patients age > 18 years with ST elevation myocardial infarction (summed ST deviation > 6 mm); time from symptom onset within 6 hrs; intent to perform primary PCI Randomized Mean follow-up: 6 mos (30 days reported to date) 63% of patients received clopidogrel/ticlopidine during PCI Additional UFH was given to 67.4% in the TNK + PCI group and 70.1% in the PCI alone group Presented at ESC 2005 Primary PCI 70 IU/kg, no maximum dose n=838 GP IIb/IIIa inhibitors allowed at physician discretion Primary Endpoint: Composite of death, shock, or congestive heart failure at 90 days. Secondary Endpoint: Composite of death, shock, or congestive heart failure at 30 days; shock or CHF at 90 days; single components of the composite endpoint. Slide 46: ASSENT- 4 PCI Trial: PCI Patients undergoing PCI among two treatment groups (%) p=0.01 Patients undergoing PCI with stent (%) Presented at ESC 2005 p=0.02 p=0.97 PCI was performed at a median of 104 minutes following TNK bolus administration Median time from symptom onset to randomization was 140 minutes in the combined therapy group and 135 minutes in the PCI alone group 19% of patients were randomized in the ambulance Slide 47: Presented at ESC 2005 ASSENT- 4 PCI Trial: TIMI Flow Grade TIMI grade 3 flow prior to PCI and TIMI grade 2/3 flow post-PCI (%) p<0.001 TIMI grade 3 flow prior to PCI was present more frequently in the TNK + PCI arm (43.6% vs 15.0%) TIMI grade 2/3 post-PCI was slightly higher in the PCI alone group (95.3% vs 97.6%) p=0.03 Slide 48: Presented at ESC 2005 ASSENT- 4 PCI Trial: Abrupt Closure, Re- infarction, and Repeat TVR Analysis of in-hospital abrupt closure, re-infarction, and repeat TVR (%) p<0.001 In-hospital abrupt closure occurred more often in the TNK + PCI treatment group (1.9% vs 0.1%) Re-infarction occurred more often in the TNK + PCI treatment group (4.1% vs 1.9%) Repeat TVR occurred more often in the TNK + PCR treatment group (4.4% vs 1.0%) p<0.001 p=0.01 ASSENT- 4 PCI Trial: Mortality at 30 days : ASSENT- 4 PCI Trial: Mortality at 30 days The primary endpoint of mortality was higher in the TNK + PCI treatment group compared with the PCI alone group (6.0% vs 3.8%, p=0.04) at 30 days Analysis of mortality at 30 days (%) p = 0.04 Presented at ESC 2005 n=50 n=32 ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview : ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview Outcomes in the TNK + PCI treatment group were significantly higher compared with the primary-PCI overview Outcomes in the PCI alone treatment group did not differ from the primary-PCI overview Analysis of ICH among ASSENT-4 and those in the primary-PCI overview (%) Presented at ESC 2005 ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview : ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview Outcomes in the TNK + PCI treatment group were higher compared with the primary-PCI overview Outcomes in the PCI alone treatment group were significantly lower compared with the primary-PCI overview Analysis of total stroke among ASSENT-4 and those in the primary-PCI overview (%) Presented at ESC 2005 ASSENT- 4 PCI Trial: Summary : ASSENT- 4 PCI Trial: Summary Presented at ESC 2005 What about Rescue PCI? : What about Rescue PCI? Facilitated PCI increased mortality! Slide 54: Rescue Angioplasty after Failed Thrombolytic Therapy for Acute Myocardial Infarction Anthony H. Gershlick, M.B., B.S., Amanda Stephens-Lloyd, R.N., M.Sc., Sarah Hughes, R.N., B.A., Keith R. Abrams, Ph.D., Suzanne E. Stevens, M.Sc., Neal G. Uren, M.D., Adam de Belder, M.D., John Davis, M.B., B.S., Michael Pitt, M.B., B.S., Adrian Banning, M.D., Andreas Baumbach, M.D., Man Fai Shiu, M.D., Peter Schofield, M.D., Keith D. Dawkins, M.D., Robert A. Henderson, M.D., Keith G. Oldroyd, M.D. and Robert Wilcox, M.D. N Engl J Med Volume 353;26:2758-2768 December 29, 2005 Study Overview : Study Overview In this multicenter trial, patients in whom thrombolytic therapy for acute myocardial infarction failed were randomly assigned to repeated thrombolysis, conservative therapy, or emergency percutaneous coronary intervention (rescue PCI) Event-free survival was better among patients assigned to rescue PCI Slide 56: Criteria for Inclusion and Exclusion and Definitions of Trial End Points Gershlick, A. et al. N Engl J Med 2005;353:2758-2768 Slide 57: End-Point Events Occurring within Six Months of Treatment Gershlick, A. et al. N Engl J Med 2005;353:2758-2768 Slide 58: Kaplan-Meier Estimates of the Cumulative Rate of the Composite Primary End Point (Death, Recurrent Myocardial Infarction, Severe Heart Failure, or Cerebrovascular Event) within Six Months Gershlick, A. et al. N Engl J Med 2005;353:2758-2768 Slide 59: Adjusted Hazard Ratios for the Occurrence of the Composite Primary End Point (Death, Recurrent Myocardial Infarction, Severe Heart Failure, or Cerebrovascular Accident) among the Trial Groups Gershlick, A. et al. N Engl J Med 2005;353:2758-2768 Conclusion : Conclusion Event-free survival after failed thrombolytic therapy was significantly higher with rescue PCI than with repeated thrombolysis or conservative treatment Rescue PCI should be considered for patients in whom reperfusion fails to occur after thrombolytic therapy A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: the WEST (Which Early ST-elevation myocardial infarction Therapy) study : A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: the WEST (Which Early ST-elevation myocardial infarction Therapy) study Paul W. Armstrong European Heart Journal2006 27(13):1530-1538; Study design: : Study design: They enrolled 100 patients in each of the three treatment arms in this feasibility study. All patients received aspirin (160–325 mg) and subcutaneous enoxaparin (1 mg/kg) at randomization with subsequent use recommended every 12 h for a minimum of 72 h; additional intravenous enoxaparin (0.3–0.5 mg/kg) was permitted during PCI in Group C and its use post-PCI was discretionary. Patients were randomized in open label fashion to one of three treatment groups. Study design, treatment : Study design, treatment Endpoints: : Endpoints: The primary efficacy endpoint of this study was a 30-day composite of death, re-infarction, refractory ischaemia, congestive heart failure, cardiogenic shock and major ventricular arrhythmia. Slide 65: Armstrong, P. W. et al. Eur Heart J 2006 27:1530-1538; doi:10.1093/eurheartj/ehl088 Kaplan-Meier curves of the primary efficacy endpoint according to study treatment groups Slide 66: Armstrong, P. W. et al. Eur Heart J 2006 27:1530-1538; doi:10.1093/eurheartj/ehl088 Relative difference in the primary efficacy endpoint between Groups A and B combined and Group C with 90% confidence limits and pre-specified 15% rMID boundary Slide 67: Armstrong, P. W. et al. Eur Heart J 2006 27:1530-1538; doi:10.1093/eurheartj/ehl088 Kaplan-Meier curves of 30-day death/re-MI according to study treatment groups PCI or RESCUE PCI : PCI or RESCUE PCI Selecting a Reperfusion Therapy The relevant question for clinicians is: Presentation delay Is there cardiogenic shock? Any contraindications to thrombolysis? PCI related delay? ( less than 60 minutes) FUTURE ISSUES…… : FUTURE ISSUES…… Slide 70: Piek J. N Engl J Med 2007;356:1880-1882 Sequence of Distal Embolization during PCI and Stent Placement Slide 71: Original Article Survival of Patients with Stage I Lung Cancer Detected on CT Screening The International Early Lung Cancer Action Program Investigators N Engl J Med Volume 355(17):1763-1771 October 26, 2006 Study Overview : Study Overview Slide 73: Diagnoses of Lung Cancer Resulting from Baseline Screening and Annual Screening with CT The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771 Slide 74: I-ELCAP Participants, According to the Smoking Status, Exposure to Secondhand Smoke, and Occupational Exposures The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771 Slide 75: Frequency Distribution of Lung-Cancer Diagnoses on Baseline and Annual CT Screening, According to Age and Median Pack-Years of Cigarette Smoking The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771 Slide 76: Kaplan-Meier Survival Curves for 484 Participants with Lung Cancer and 302 Participants with Clinical Stage I Cancer Resected within 1 Month after Diagnosis The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771 Slide 77: Extent of Spread of Cancer in 375 Participants Who Underwent Resection of Clinical Stage I Lung Cancer According to Whether Cancer was Detected on Baseline or Annual CT Screening The International Early Lung Cancer Action Program Investigators. N Engl J Med 2006;355:1763-1771 Conclusion : Conclusion Annual spiral CT screening can detect lung cancer that is curable Slide 79: Original Article Randomized Comparison of Strategies for Reducing Treatment in Mild Persistent Asthma The American Lung Association Asthma Clinical Research Centers N Engl J Med Volume 356(20):2027-2039 May 17, 2007 STUDY OVERVIEW : STUDY OVERVIEW Slide 81: Study Design Slide 82: Kaplan-Meier Estimates of Cumulative Percentages of Patients with Treatment Failure The merican Lung Association Asthma Clinical Research Centers. N Engl J Med 2007;356:2027-2039 Conclusion : Conclusion Patients with asthma that is well controlled with the use of twice-daily inhaled fluticasone can be switched to once-daily fluticasone plus salmeterol without increased rates of treatment failure A switch to montelukast results in an increased rate of treatment failure and decreased asthma control; however, patients taking montelukast remained free of symptoms on 78.7% of treatment days Slide 84: Original Article Rescue Use of Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma Alberto Papi, M.D., Giorgio W. Canonica, M.D., Piero Maestrelli, M.D., Pierluigi Paggiaro, M.D., Dario Olivieri, M.D., Ernesto Pozzi, M.D., Nunzio Crimi, M.D., Antonio M. Vignola, M.D., Paolo Morelli, Ph.D., Gabriele Nicolini, Pharm.D., Leonardo M. Fabbri, M.D., for the BEST Study Group N Engl J Med Volume 356(20):2040-2052 May 17, 2007 Study Overview : Study Overview Patients with mild persistent asthma are often advised to use inhaled corticosteroids on a regular schedule In this trial, such patients treated themselves with inhaled beclomethasone (250 mg per puff) and albuterol (100 mg per puff) only when they had symptoms of asthma The mean morning peak expiratory flow rate in this group was similar to that in the group receiving inhaled corticosteroids regularly Controller treatments may not be needed on a regular basis in patients with asthma Slide 86: Study Design Papi A et al. N Engl J Med 2007;356:2040-2052 Slide 87: Screening, Randomization, and Study Completion Papi A et al. N Engl J Med 2007;356:2040-2052 Slide 88: Mean (±SE) Morning Peak Expiratory Flow (PEF) Rates in the Modified Intention-to-Treat Population Papi A et al. N Engl J Med 2007;356:2040-2052 Slide 89: Kaplan-Meier Estimates of the Time to First Asthma Exacerbation in the Modified Intention-to-Treat Population Papi A et al. N Engl J Med 2007;356:2040-2052 Conclusion : Conclusion In patients with mild asthma, the symptom-driven use of inhaled beclomethasone (250 mg) and albuterol (100 mg) in a single inhaler is as effective as regular use of inhaled beclomethasone (250 mg twice daily) and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid HRT AND YOUNG AT HEART : HRT AND YOUNG AT HEART MEDICAL OPINION : MEDICAL OPINION Opinion is like a pendulum and obeys the same law. If it goes past the centre of gravity on one side, it must go a like distance on the other; and it is only after a certain time that it finds the true point at which it can remain at rest." Slide 93: Original Article Estrogen Therapy and Coronary-Artery Calcification JoAnn E. Manson, M.D., Dr.P.H., Matthew A. Allison, M.D., M.P.H., Jacques E. Rossouw, M.D., J. Jeffrey Carr, M.D., Robert D. Langer, M.D., M.P.H., Judith Hsia, M.D., Lewis H. Kuller, M.D., Dr.P.H., Barbara B. Cochrane, Ph.D., Julie R. Hunt, Ph.D., Shari E. Ludlam, M.P.H., Mary B. Pettinger, M.S., Margery Gass, M.D., Karen L. Margolis, M.D., M.P.H., Lauren Nathan, M.D., Judith K. Ockene, Ph.D., Ross L. Prentice, Ph.D., John Robbins, M.D., Marcia L. Stefanick, Ph.D., for the WHI and WHI-CACS Investigators N Engl J Med Volume 356(25):2591-2602 June 21, 2007 Study Overview : Study Overview In the previously published Women's Health Initiative comparing conjugated equine estrogens with placebo in women who had undergone hysterectomy, there was a substantially lower rate of events related to coronary heart disease among the women receiving estrogen The current substudy showed that coronary-artery calcium scores were lower in women receiving estrogen than in those receiving placebo Since estrogen has complex effects, the new findings should not be construed as being clinically directive Slide 95: Distribution of Coronary-Artery Calcium Scores after Trial Completion, According to Randomized-Group Assignment Manson JE et al. N Engl J Med 2007;356:2591-2602 Conclusion : Conclusion Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways Slide 97: Original Article Eltrombopag for the Treatment of Chronic Idiopathic Thrombocytopenic Purpura James B. Bussel, M.D., Gregory Cheng, M.D., Mansoor N. Saleh, M.D., Bethan Psaila, M.D., Lidia Kovaleva, M.D., Balkis Meddeb, M.D., Janusz Kloczko, M.D., Habib Hassani, Ph.D., Bhabita Mayer, M.Sc., Nicole L. Stone, Ph.D., Michael Arning, M.D., Drew Provan, M.D., and Julian M. Jenkins, M.Sc. N Engl J Med Volume 357(22):2237-2247 November 29, 2007 Slide 98: Eltrombopag is a novel dipeptide linked to the Fc fragment of IgG It is structurally unrelated to thrombopoietin but can stimulate the thrombopoietin receptor Slide 99: Structure of Eltrombopag Bussel JB et al. N Engl J Med 2006;355:1672-1681 Study Overview : Study Overview This trial tested the efficacy of eltrombopag, a small nonpeptide agonist of the thrombopoietin receptor, in patients with immune thrombocytopenia who had not had a response to at least one previous treatment for the disorder At a dose of 50 or 75 mg, the agonist, which had been shown to increase platelet production in normal volunteers, increased platelet counts to a clinically safe level (≥50,000 per cubic millimeter) in most patients Slide 101: Enrollment, Group Assignments, and Outcome Bussel JB et al. N Engl J Med 2007;357:2237-2247 Slide 102: Analyses of Platelet Counts and Responses Bussel JB et al. N Engl J Med 2007;357:2237-2247 Slide 103: Incidence of Bleeding Symptoms during and after Treatment According to Treatment Group Bussel JB et al. N Engl J Med 2007;357:2237-2247 Conclusion : Conclusion Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP Impact of Platelet Reactivity on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease : Impact of Platelet Reactivity on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease Dominick J. Angiolillo, MD, PhD; Esther Bernardo, BSc; Manel Sabaté, MD, PhD; Pilar Jimenez-Quevedo, MD; Marco A. Costa, MD, PhD; Jorge Palazuelos, MD, PhD; Rosana Hernández-Antolin, MD, PhD; Raul Moreno, MD; Javier Escaned, MD, PhD; Fernando Alfonso, MD, PhD; Camino Bañuelos, MD; Luis A. Guzman, MD; Theodore A. Bass, MD; Carlos Macaya, MD, PhD; Antonio Fernandez-Ortiz, MD, PhD Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Platelet Function and T2DM: Background : Platelet Function and T2DM: Background High platelet reactivity (HPR) has been associated with short- to mid-term atherothrombotic complications despite the use of aspirin and clopidogrel therapy. Most studies associating HPR with clinical outcomes were based on functional assessments performed in the early phases of clopidogrel treatment and in the context of patients undergoing percutaneous coronary intervention (PCI). HPR is more common in patients with type 2 diabetes mellitus (T2DM) than in nondiabetic patients, even when treated with dual antiplatelet therapy. Whether HPR is associated with long-term atherothrombotic complications in T2DM patients remains to be investigated. Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Objective and Study Hypothesis : Objective and Study Hypothesis The aims of this study were to assess platelet function profiles selectively in T2DM patients while in their chronic steady-state phase of dual antiplatelet therapy and to evaluate the long-term clinical implications of HPR. The study hypothesis was that HPR is associated with worse long-term clinical outcomes in T2DM patients than in those without HPR. Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Patient Population : Patient Population At study entry, platelet function assessment was performed and patients were divided into 4 groups based on quartile distribution of maximal 20 mmol/L adenosine diphosphate (ADP)–induced aggregation (Aggmax). Patients were followed up for 2 y post blood sampling. Treatment with clopidogrel had been prescribed for 12 mo. Aspirin was used indefinitely. Major adverse cardiovascular events (MACE) were defined according to ACC definitions and included cardiovascular death, ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation acute coronary syndrome (non-STEMI [NSTEMI] and unstable angina [UA]), and stroke. 1st 2nd 3rd 4th Platelet function analysis Quartile distribution of platelet reactivity 3–6 mo-post–platelet function analysis Clopidogrel withdrawal 24-mo post–platelet function analysis End of clinical follow-up Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Methods : Methods Platelet aggregation was assessed using light transmittance aggregometry according to standard protocols following 20 mmol/L ADP stimuli. Aggregation was measured at peak (Aggmax) and at 5 min (Agglate). In addition to stimuli with ADP, other agonists nonspecific to the purinergic receptors were used to define platelet function profiles. These included collagen (6 g/mL), epinephrine (20 mmol/L), and thrombin receptor agonist peptide, or TRAP (25 mmol/L). Platelet activation was determined by assessing platelet surface expression of activated glycoprotein (GP) IIb/IIIa and P-selectin according to standard protocols. GP IIb/IIIa activation was assessed using a PAC-1 antibody and a polyclonal fluorescein isothiocyanate (FITC)–conjugated rabbit anti-human fibrinogen antibody. P-selectin expression was assessed using a phycoerithrin (PE)–conjugated anti-CD62P. Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Results: Baseline Platelet Function : Results: Baseline Platelet Function A total of 173 consecutive patients met the study inclusion criteria and were enrolled from January 2003 to February 2005. Overall, Aggmax following ADP stimuli was 52.0±13.7%, which was highly variable and followed a normal bell-shaped distribution. Platelet reactivity quartile cutpoints for the 25th, 50th, and 75th percentiles of the study population were 44.0%, 52.0%, and 62.0%. Aggmax was 34.2±8.4%, 47.6±2.7%, 56.8±2.8%, and 68.6±6.5%, from the lowest to highest quartile, respectively (P<0.0001). Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Results: Clinical Outcome : Results: Clinical Outcome A total of 41 MACE occurred in 34 patients (19.6%) during the 2-year study follow-up period. MACE occurred in 15.2%, 12.2%, 12.2%, and 37.7% of patients from the lowest to highest quartile, respectively (P=0.005). MACE rates were driven by UA/NSTEMI, which occurred in 9.8%, 10.9%, 12.2%, and 33.3% of patients from the lowest to highest quartile, respectively (P=0.007). There were no differences in the rates of the other individual cardiovascular events. Patients with MACE had higher Aggmax (56.8±13.8% vs 50.9±13.6%; P=0.03) than those with uneventful follow-up. Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Cumulative Event-Free Survival From Cardiovascular Events According to Quartile (Q) Distribution of Maximal ADP (20mmol/L)-Induced Platelet Aggregation : Cumulative Event-Free Survival From Cardiovascular Events According to Quartile (Q) Distribution of Maximal ADP (20mmol/L)-Induced Platelet Aggregation Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Cumulative Event-Free Survival From Cardiovascular Events According to the Optimal ROC-Defined Cutoff Value of 62% ADP-Induced Platelet Aggregation : Cumulative Event-Free Survival From Cardiovascular Events According to the Optimal ROC-Defined Cutoff Value of 62% ADP-Induced Platelet Aggregation Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Conclusions : Conclusions High platelet reactivity determined in T2DM patients with CAD while on chronic dual antiplatelet therapy is associated with a higher risk of long-term adverse cardiovascular events, suggesting the need for tailored antithrombotic drug regimens in these high-risk patients. Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-1547. Slide 115: Original Article Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes Rury R. Holman, M.B., Ch.B., F.R.C.P., Kerensa I. Thorne, M.Sc., Andrew J. Farmer, D.M., F.R.C.G.P., Melanie J. Davies, M.D., F.R.C.P., Joanne F. Keenan, B.A., Sanjoy Paul, Ph.D., Jonathan C. Levy, M.D., F.R.C.P., for the 4-T Study Group N Engl J Med Volume 357(17):1716-1730 October 25, 2007 Study Overview : Study Overview In an open-label trial, patients with type 2 diabetes with a suboptimal glycated hemoglobin level while receiving a maximally tolerated dose of metformin and sulfonylurea were randomly assigned to receive biphasic, prandial, or basal insulin The addition of a single analogue-insulin formulation resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. Regimens of biphasic or prandial insulin had greater efficacy than did the basal regimen but were associated with greater risks of hypoglycemia and weight gain Slide 117: Enrollment and Outcomes Holman RR et al. N Engl J Med 2007;357:1716-1730 Slide 118: Primary and Secondary Outcomes at 1 Year Holman RR et al. N Engl J Med 2007;357:1716-1730 Slide 119: Mean (±SE) Percentage Change from Baseline to 1 Year in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, and Body Weight (Panel A) and Mean (+SD) Hypoglycemic-Event Rate (Panel B) Holman RR et al. N Engl J Med 2007;357:1716-1730 Conclusion : Conclusion A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain Slide 121: Original Article Effects of Torcetrapib in Patients at High Risk for Coronary Events Philip J. Barter, M.D., Ph.D., Mark Caulfield, M.D., M.B., B.S., Mats Eriksson, M.D., Ph.D., Scott M. Grundy, M.D., Ph.D., John J.P. Kastelein, M.D., Ph.D., Michel Komajda, M.D., Jose Lopez-Sendon, M.D., Ph.D., Lori Mosca, M.D., M.P.H., Ph.D., Jean-Claude Tardif, M.D., David D. Waters, M.D., Charles L. Shear, Dr.P.H., James H. Revkin, M.D., Kevin A. Buhr, Ph.D., Marian R. Fisher, Ph.D., Alan R. Tall, M.B., B.S., Bryan Brewer, M.D., Ph.D., for the ILLUMINATE Investigators N Engl J Med Volume 357(21):2109-2122 November 22, 2007 Study Overview : Study Overview Torcetrapib, a cholesteryl ester transfer protein inhibitor, markedly raises levels of high-density lipoprotein cholesterol Unexpectedly, in the ILLUMINATE trial, torcetrapib therapy in combination with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes The drug also raised blood pressure HDL Metabolism in CETP Deficiency : HDL Metabolism in CETP Deficiency CE FC FC LCAT ABCA1 Macrophage A-I CE FC CETG CETP B VLDL/LDL Delayedcatabolism X Slide 124: Enrollment and Outcomes Barter PJ et al. N Engl J Med 2007;357:2109-2122 Slide 125: Kaplan-Meier Curves for Death from Any Cause and for the Primary Composite Outcome Barter PJ et al. N Engl J Med 2007;357:2109-2122 Conclusion : Conclusion Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition Slide 127: Copyright ©2007 American Heart Association Tall, A. R. et al. Arterioscler Thromb Vasc Biol 2007;27:257-260 The adverse outcome of the ILLUMINATE study in patients receiving Torcetrapib indicates that potential adverse effects outweighed beneficial effects The Failure of Torcetrapib : Success is not final, failure is not fatal: it is the courage to continue that counts. Winston Churchill The Failure of Torcetrapib Molecule or the Mechanism? So is this the awakening from a dream of a highly effective way to raise HDL, or is it simply a nightmare created by unintended pharmacological effects of this particular CETP inhibitor? Slide 129: Success is not final, failure is not fatal: it is the courage to continue that counts. Winston Churchill Slide 130: Original Article Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia Tilman B. Drüeke, M.D., Francesco Locatelli, M.D., Naomi Clyne, M.D., Kai-Uwe Eckardt, M.D., Iain C. Macdougall, M.D., Dimitrios Tsakiris, M.D., Hans-Ulrich Burger, Ph.D., Armin Scherhag, M.D., for the CREATE Investigators N Engl J Med Volume 355(20):2071-2084 November 16, 2006 Study Overview : Study Overview Slide 132: Enrollment and Outcomes Singh AK et al. N Engl J Med 2006;355:2085-2098 Slide 133: Mean Monthly Hemoglobin Levels (Panel A) and Mean Weekly Doses of Epoetin Alfa (Panel B) Singh AK et al. N Engl J Med 2006;355:2085-2098 Slide 134: Kaplan-Meier Estimates of the Probability of the Primary Composite End Point and Secondary End Points of Individual Components - Hospitalization for Congestive Heart Failure (CHF) without Renal Replacement Therapy (RRT), Myocardial Infarction, Stroke, and Death Singh AK et al. N Engl J Med 2006;355:2085-2098 Slide 135: Secondary End Points Singh AK et al. N Engl J Med 2006;355:2085-2098 Conclusion : Conclusion The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life Slide 137: Success is not final, failure is not fatal: it is the courage to continue that counts. Winston Churchill Comments… more is harmful!! : Comments… more is harmful!! As these studies demonstrate, higher doses of EPO and higher HB concentrations are just as likely ( or more so) to produce harm than benefit. Slide 139: Study Design Papi A et al. N Engl J Med 2007;356:2040-2052

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