Gastrointestinal Review Highlights of the VIGOR Trial Lawrence Goldkind M.D.

Slides:



Advertisements
Similar presentations
Overview of Aspirin and NSAID’s Label Warnings William E. Gilbertson, PharmD. Division OTC Drug Products 1.
Advertisements

NSAIDs and GI and Renal Complications Lessons from Tennessee Medicaid population studies (and selected others)
Pablo M. Bedano M.D. Community Regional Cancer Care.
Update on Anti-platelets Gabriel A. Vidal, MD Vascular Neurology Ochsner Medical Center October 14 th, 2009.
Basic Design Consideration. Previous Lecture Definition of a clinical trial The drug development process How different aspects of the effects of a drug.
VTE in abdominal-pelvic surgery patients
CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study Purpose To determine whether the ACE inhibitor enalapril reduces mortality in patients.
CAPRIE: Clopidogrel versus Aspirin in Patients at risk of Ischemic Events Purpose To assess the relative efficacy of the antiplatelet drugs clopidogrel.
Study by: Granger et al. NEJM, September 2011,Vol No. 11 Presented by: Amelia Crawford PA-S2 Apixaban versus Warfarin in Patients with Atrial Fibrillation.
1 Bayer Corporation Consumer Care Division September 20, 2002 Allen H. Heller, MD Vice President, Global Research & Development Consumer Care NDAC Hearing.
Clinical Trial Efficacy Senior Biostatistician Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut James Street, PhD.
Core Topic UCI Internal Medicine Residency Learning Objectives Review the major causes of upper GI bleeding and important elements of the history.
1 The Chemoprevention of Sporadic Colorectal Cancer Issues Surrounding a Benefit/Risk Analysis in Clinical Trials Mark Avigan MD CM Medical Officer Division.
An Update on NSAID Labeling and Data Review DSaRM Advisory Committee February 10, 2006 Sharon Hertz, M.D. Deputy Director Division of Anesthesia, Analgesia,
Copyright © 2008 Lippincott Williams & Wilkins. Introductory Clinical Pharmacology Chapter 18 Nonopioid Analgesics: Nonsteroidal Anti-Inflammatory Drugs.
Hormone Refractory Prostate Cancer A Regulatory Perspective of End Points to Measure Safety and Efficacy of Drugs Hormone Refractory Prostate Cancer Bhupinder.
The Role of Thromboprophylaxis in Elective Spinal Surgery The Role of Thromboprophylaxis in Elective Spinal Surgery VA Elwell, N Koo Ng, D Horner & D Peterson.
Coordinator: Dr. Anca Negovan Author: Andreea Bianca Stoica Co-authors: Drd. Monica Pantea Adrian Stoica Roxana Spac Gavriela Radoiu.
1 Ethical issues in clinical trials Bernard Lo, M.D. February 10, 2010.
An epidemiologic perspective on etoricoxib David J. Graham, MD, MPH Office of Surveillance and Epidemiology April 12, 2007.
Laura Mucci, Pharm.D. Candidate Mercer University 2012 Preceptor: Dr. Rahimi February 2012.
A New Oral Direct Thrombin Inhibitor, Dabigatran Etexilate, Compared With Enoxaparin for Prevention of Thromboembolic Events Following Total Hip or Knee.
1 ENTEREG ® (Alvimopan) Special Safety Section Marjorie Dannis, M.D. Division of Gastroenterology Products Office of Drug Evaluation III CDER, FDA The.
Interventional angiography Initial success rates for patients with acute peptic ulcer bleeding are between %, with recurrent bleeding rates of 10.
Update of TARGET ( T reatment a nd R elief of G astroint e s t inal disorder) DR NORITA YASMIN MORNING READ 19/9/13 1.
AIRE: Acute Infarction Ramipril Efficacy study Purpose To determine whether the ACE inhibitor ramipril reduces mortality in patients with evidence of heart.
1 Lotronex Postmarketing Experience Ann Corken Mackey, R.Ph., M.P.H. Allen Brinker, M.D., M.S. Zili Li, M.D., M.P.H., formerly of ODS Office of Drug Safety.
VIOXX ™ Gastrointestinal Outcome Research (VIGOR) Arthritis Advisory Committee Meeting February 8, 2001 Lourdes Villalba, M.D. DAAODP, CDER, FDA.
Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting November 29, 2006 Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia,
Safety of Cyclooxygenase-2 (COX-2) inhibitors, Valdecoxib and Parecoxib, versus Placebo for Post CABG Pain Management Presented at American College of.
NSAID Gastropathy Group B Lim, Imee – Lim, Mary. NSAIDS Weak organic acids that inhibit biosynthesis of prostaglandins Anti-inflammatory, analgesic, antipyretic,
Cardiovascular Risk and NSAIDs Arthritis Advisory Committee Meeting April 12, 2007 Sharon Hertz, M.D. Deputy Director Division of Analgesia, Anesthesia,
B-1 Pravastatin-Aspirin Combination René Belder, M.D. Executive Director Clinical Design and Evaluation, Metabolics Pharmaceutical Research Institute Bristol-Myers.
Advisory Committee Presentation on Vioxx (Rofecoxib) Discussion on the meta analyses for cardiovascular risk assessment Qian Li, Sc. D.
Summary Pattern of Specific COX II Inhibitors Use Physician prescribed appropriate COX II use in high risk was 40.08% and inappropriate COX II use in low.
NDAs /772 Etoricoxib Robert B. Shibuya, M.D. Medical Officer Division of Anesthesia, Analgesia, and Rheumatology Products.
C-1 Efficacy of the Combination: Meta-Analyses Donald A. Berry, Ph.D. Frank T. McGraw Memorial Chair of Cancer Research University of Texas M.D. Anderson.
STUDY 303 A Phase III, Randomized, Multi-Center, Open-Label, 12 to 14 Month Extension Study to Evaluate the Safety and Tolerability of Mesalamine Given.
A Phase 3 Prospective, Randomized, International Study (MMY-3021) Comparing Subcutaneous and Intravenous Administration of Bortezomib in Patients with.
BGD 1 Group A: Discuss Upper GI Bleeding due to PUD Gatchalian, Gaw, Geraldoy, Geronimo, Geronimo, Geronimo, Go, Go, Go, Go, Go, Go, Go, Go, Go January.
What about VIOXX?. Adenomatous Polyp Prevention on Vioxx (APPROVe) Vioxx (rofecoxib) versus Placebo Basic Clinical Trial Objective: Assess whether Vioxx.
Small Bowel Toxicity of Nonselective NSAIDs Revealed by Capsule Endoscopy: Results From a Pivotal Clinical Trial Glenn M. Eisen, M.D., M.P.H. Associate.
Hot Topic Presentation Lars Halford, GP ST3 March 2010
Drug Regulation in Controversy: Vioxx November 10, 2004 Sandra L. Kweder, M.D. Deputy Director, Office of New Drugs Center for Drug Evaluation and Research.
Carla Chieffo, David Cook, Qinfang Xiang, and Lawrence A. Frohman Efficacy and Safety of an Octreotide Implant in the Treatment of Patients With Acromegaly.
Journal Club Leona Isabella von Köckritz.
Peptic Ulcer Bleeding Risk. The Role of Helicobacter Pylori Infection in NSAID/Low-Dose Aspirin Users C. Sostres, MD, P. Carrera-Lasfuentes, PhD, R. Benito,
Famotidine Is Inferior to Pantoprazole in Preventing Recurrence of Aspirin-Related Peptic Ulcers or Erosions FOOK–HONG NG, SIU–YIN WONG, KWOK–FAI LAM,
Joseph J.Y. Sung, MD et al. Am J Gastroenterol 2010;105. R3 김민경.
Omeprazole before Endoscopy in Patients with Gastrointestinal Bleeding James Y. Lau, M.D., Wai K. Leung, M.D., Justin C.Y. Wu, M.D., Francis K.L. Chan,
Ryonho Koh, MD,1 Kingo Hirasawa, MD,1 Sei Yahara, MD,1 Hiroyuki Oka, MD,1 Kazuya Sugimori, MD,1 Manabu Morimoto, MD,1 Kazushi Numata, MD,1 Atsushi Kokawa,
Am J Gastroenterol 2012; 107:405–410 Fellow : Kim Jung Wook.
Clinical Knowledge Summaries CKS Analgesia – mild to moderate pain Prescribing analgesics for mild to moderate pain in adults and children. Educational.
Review on NOACs Studies DR. KOUROSH SADEGHI TEHRAN UNIVERSITY OF MEDICAL SCIENCES.
GI For Rehabilitation.
Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis.
Non-Variceal Upper GI Bleeding in Patients Already Hospitalized for Another Condition Tanja Muller, MD, Alan N. Barkun, MD, CM, MSc, Myriam Martel , BSc.
Reporter : R1 林柏任.
GASTROENTEROLOGY 2009;137:892–901 R2. 정 회 훈.
Selection of NSAIDs for Osteoarthritis
Bleeding and cancer risk in patients with vascular disease COMPASS Steering Committee and Investigators.
Volume 120, Issue 3, Pages (February 2001)
Vascular Overviews Group
Krop I et al. SABCS 2009;Abstract 5090.
PRECISION Trial design: Patients with arthritis and increased cardiovascular risk were randomized to celecoxib 100 mg twice daily (n = 8,072) vs. ibuprofen.
Nonsteroidal anti-inflammatory drug gastropathy
Care of Patients with Stomach Disorders
Gastrointestinal Effects of NSAIDs and Coxibs
ASPIRE CLASS 6: Interpreting Results and Writing an Abstract
LRC-CPPT and MRFIT Content Points:
Presentation transcript:

Gastrointestinal Review Highlights of the VIGOR Trial Lawrence Goldkind M.D.

Outline of Presentation Study hypothesis and definitions of endpoints Review of results High risk populations Review of meta-analysis of phase IIb and III studies presented by the sponsor Conclusions

VIGOR Study Design Organ-specific endpoints – PUB’s (Perforation, Symptomatic Ulcers, Bleeding) – Complicated PUB’s (excludes only symptomatic ulcers) Statistical plan : All patients will be followed until: Minimum 120 confirmed PUBs or 40 confirmed complicated PUBs and 6 months after last patient randomized 95% power (  = 0.05 two-tailed) to detect a reduction in risk of at least 50% for the the primary GI hypothesis. –

Primary study hypotheses “The risk of confirmed PUBs during the treatment period will be reduced in the group of patients with rheumatoid arthritis taking 50 mg Vioxx daily, compared to the group of patients with rheumatoid arthritis taking naproxen 1000 mg daily. Vioxx administered at a dose of 50 mg daily will be safe and well tolerated.”

Endpoint definitions PUB (perforation, symptomatic ulcer, bleed) Complicated PUB

Confirmed Event PUB Any one of the following four clinical presentations 1. Ulcer: radiographic, endoscopic, surgical (identified based on clinical presentation including pain as the sole symptom/sign) 2. Perforation: radiographic, endoscopic, surgical, autopsy 3. Obstruction: postprandial nausea and vomiting and evidence of narrowing of the gastric outlet

Confirmed Event PUB (continued) 4. Upper GI hemorrhage: Health care provider witnessed: a. frank hematemesis b. coffee ground emesis c. NG aspiration of blood or coffee ground appearing gastric contents d. melena (distinguished from other causes of dark stool) e. Active UGI bleeding at endoscopy, surgery or angiography

Confirmed Event PUB (continued) OR Heme-positive stool/ patient reported melena or hematemesis associated with a documented UGI lesion judged by a healthcare provider to be the source of bleeding and associated with significant bleeding* or stigmata of recent bleeding at endoscopy *decrease of > 2 g/dl Hgb, orthostasis, hypotension, transfusion

Confirmed Complicated Event PUB Perforation Obstruction GU or DU associated with significant bleeding* *decrease of > 2 g/dl Hgb, orthostasis, hypotension, transfusion

Results

Confirmed PUB’s in VIGOR N n rate 1 rate 2 Rofecoxib (4047) % Naproxen (4027) % Relative Risk: 0.46 p<0.001* * cox proportional hazard model 1 Per 100 PYR. 2 cumulative rate

Confirmed Complicated PUBs N n rate 1 rate 2 Rofecoxib (4047) % Naproxen (4027) % Relative Risk: 0.43 p=0.005* * cox proportional hazard model 1 Per 100 PYR. 2 cumulative rate

Types of Confirmed PUBs

Subanalysis by Risk factor Prior history of PUB

Subanalysis by Risk factor Age

High risk populations If age and history of PUB are independent risk factors for ulcer disease...Findings of high risk in association with a therapy may represent intrinsic risk rather than drug effect (no causality) ? OR Interaction between underlying and drug related risk may produce an exaggerated/ higher risk attributable to therapy (causality) ?

High risk populations Outstanding question Should high risk patients be treated with “lower relative GI risk” NSAIDs……. or does overall residual GI risk continue to represent a relative contraindication for these patients? Usage implications

GI Risk in special populations Other questions GI Risk of co-administration of aspirin and Vioxx: data needed GI Risk of co-administration of aspirin and Vioxx in the elderly: data needed GI risk in elderly with a history of PUB ?

Generalizability of GI Safety Relative Risk: Vioxx < naproxen Degree of Absolute risk : data needed Relative Risk compared to other NSAIDs: data needed

Data from phase IIb and III studies Meta-analysis of PUBs “Vioxx vs NSAIDs” Three doses of Vioxx: 12.5 mg, 25 mg, 50 mg Two comparators: ibuprofen, diclofenac Duration: weeks

Data from phase IIb and III studies Meta-analysis of PUBs “Vioxx vs NSAIDs” N Duration* (weeks) Vioxx 12.5 mg: Vioxx 25 mg: Vioxx 50 mg: Ibuprofen: Diclofenac: * at least 200 subjects present at the end of the interval

Meta-analysis of cumulative PUB IIb and III Studies

Conclusion of meta-analysis of phase IIb and III studies Vioxx dose and duration of exposure affect associated rates Ibuprofen and diclofenac did not perform similarly NSAID as a composite comparator may not be appropriate Meta-analyses combining heterogeneous groups may be problematic

Overall Conclusions Vioxx 50 mg associated with a lower rate of symptomatic and complicated ulcers compared to Naproxen 1000 mg in patients with RA not requiring low dose aspirin use ( relative risks 0.46, 0.43) Risk reduction extends across high risk groups

Overall Conclusions High risk groups: elderly and those with history of prior PUB continue to have a significant absolute risk of PUBs Generalizability of GI risk reduction to patients requiring low dose aspirin ? Generalizability to other/all traditional NSAIDs ?