Piotr Fatyga. Daniel Joshua Faulisi. Toni G Fayngersh. Gianna Rose Fazio. Robert Michael O Fea. Kevin Patrick Feeley. Ariel Alexander Feliz. Yongxin Feng. Thomas James Fenton. Matthew Ferentini. Emily K Ferguson. Hyun June H Ferrabolli. David Joseph Ferrara. Gabriella Anne Ferrara.

Our Fund Investment Focus: Our primary focus is on the development of novel therapeutics and platforms. In our investments we look for unmet need and clinical impact, novel proprietary science and understanding of mechanism, management and board experience and capital efficiency in the program. Invest Globally: We invest in,, and with approximately USD 800 million under management in committed capital and more than 40 portfolio companies.

We continue our strategy of making larger focused investments and anticipate total investments up to USD 30 million per company over its life. Invest Across Healthcare Sector: We make equity investments in life sciences companies across,. NVF is stage agnostic and engages in seed investments as well as later-stage investments. We typically lead or co-lead an investment and play an active role on company boards. Pipeline Overview of Biotechnology Portfolio The Novartis Venture Fund has investments across various therapeutic areas. We seek companies that are truly innovative, have the potential to offer significant patient benefit, have excellent management and are capital-efficient.

In total, our current portfolio companies have 21 clinical programs in Phase 1 or Phase 2. Autoimmune, Immunology, Transplantation 4 1 Cardiovascular, Metabolism 1 1 Dermatology 2 Hematology 1 2 Infectious Diseases 7 3 3 Nephrology 1 Neuroscience 4 1 2 Ophtalmology 3 1 1 Oncology 12 2 3 Respiratory 2 Woman's Health 1 Pre-Clinical Phase I Phase II Autoimmune, Immunology, Transplantation 4 1 Cardiovascular, Metabolism 1 1 Dermatology 2 Hematology 1 2 Infectious Diseases 7 3 3 Nephrology 1 Neuroscience 4 1 2 Ophtalmology 3 1 1 Oncology 12 2 3 Respiratory 2 Woman's Health 1 Pre-Clinical Phase I Phase II. Medical Devices and Diagnostics Seeking Healthcare Innovation Physicians use a combination of technologies to produce the best clinical outcome. The challenges and opportunities in healthcare are multi-factorial.

Our fund looks broadly to invest in all types of healthcare innovation that will to serve clinical need. The Novartis Venture Fund has invested in medical technologies and diagnostics since its inception in 1996.

Our device investments are led by Steven Weinstein in our Cambridge office. We currently have targeted 20% of our fund to medical device, diagnostics and other healthcare-related information technology opportunities. Our Focus Our definition of medical technologies is broad. The NVF seeks opportunities that can change the practice of medicine, produce meaningful patient benefit, or reduce costs of medical care. We look for underserved indications, or where a company’s technology enables a new treatment paradigm. In today’s more cost-conscious healthcare environment, we also look for companies whose technologies allow the healthcare system to reduce overall cost while maintaining or improving outcomes.

Our investment strategy is stage agnostic (seed to growth capital) and we are happy to lead an investment, and invest globally. Our Portfolio On-farm diagnostics platform to detect disease states and optimize overall health status of production animals.: Molecular diagnostic system for the ultra-rapid diagnosis of a broad range of infectious diseases. Implantable neurostimulation device for severe headaches such as cluster headaches and migraines. Genome mapping platform using nanochannel technology to visualize whole genomes of any organism, including humans. Computational solutions for drug discovery and systems biology research. Trans-apical and trans-femoral cardiac valve replacement. Bart Dzikowski is the Head of Legal for NVF in Basel, Switzerland.

During his time with Novartis, he has served as the Head of Corporate Legal M&A (a.i.) and as Senior Business Development & Licensing/M&A Counsel. Before joining Novartis in 2009, Bart was Vice President with the Investment Banking Division of Bank of America/Merrill Lynch in New York and, before that, he was an associate with the Corporate/M&A Group at the law firm of Allen & Overy LLP in New York. Bart holds degrees in common law (LL.B.) and civil law (B.C.L.) from McGill Law School in Canada and is a member of the New York State Bar. Giovanni Ferrara is a Venture Partner in Cambridge, MA, USA. Prior to joining NVF, he was a consultant to leading west coast venture capital firms and portfolio companies. Most recently, Giovanni was consulting Chief Business Officer to Sorbent Therapeutics. Previously, he was Managing Director and General Partner at Burrill & Company and began his venture capital career at GeneChem Management, where in addition to investing, he held operating positions in portfolio companies, including CEO of Targanta Therapeutics (then PhageTech, Inc.).

He began his career in healthcare as a pharmacist at a cancer treatment center researching experimental therapies. He received his MBA and MSc from McGill University. Giovanni serves on the board of Thesan Pharmaceuticals, E-scape and NeuroVia. Markus Goebel is a Managing Director in Cambridge, MA, USA. Prior to joining NVF, he worked as Head Novartis Pharmaceutical Corporate M&A and Head Nervous System Business Development & Licensing. A physician by training and certified, amongst others, in hematology/oncology, Markus worked for Farmitalia Germany and later held several positions in R&D, Marketing and Strategy at Roche headquarters before joining Novartis. Markus received an MD and a PhD from the Ludwig Maximilian’s University in Munich and an MBA from Henley.

Markus serves on the board of eFFECTOR and Macrolide. Campbell Murray is a Managing Director in Cambridge, MA, USA. Prior to joining NVF, he worked at the Novartis Institutes for BioMedical Research as the Director of Special Projects. Campbell is a New Zealand-trained physician and worked as a Medical House Officer at Auckland Hospital. He is a Kauffman Fellow and holds an MBA from Harvard Business School and an MPP (public policy) from the John F. Kennedy School of Government, where he was a Knox Fellow and Rotary Ambassadorial Scholar. Campbell serves on the boards of Annexon, Galera, and Lemonaid Health.

David Morris is a Venture Partner in San Francisco, CA, USA. Prior to joining NVF, he held multiple leadership roles in the Novartis Pharmaceuticals development organization including the Development Franchise Head of Respiratory, Development Franchise Head of Primary Care and, most recently, Global Head of Clinical Operations, Analytics and Regions where he was responsible for clinical trials operations and monitoring, statistics, data management, medical writing, submissions management and digital innovation.

Prior to joining Novartis in 2009, David worked in drug discovery and translational medicine at Roche in Palo Alto, California. Before joining industry, he was a faculty member at Yale University Medical School and, prior to that, the University of California, San Francisco (UCSF) Medical School. David received his Bachelors and Medical Degrees with distinction from the University of Rochester Medical School and trained in internal medicine at the Massachusetts General Hospital and in Pulmonary and Critical Care Medicine at UCSF.

He did his postdoctoral research training at the Lung Biology Center and Cardiovascular Research Institute at UCSF. Dave serves on the board of NeuroVia. Florian Muellershausen is a Principal in Basel, Switzerland.

Prior to joining Novartis Venture Fund, he worked as a Scientific Manager for the R&D Committee of the Novartis Board of Directors and, before that held various scientific and drug discovery roles at the Novartis Institute of Biomedical Research (NIBR) including as Laboratory Head in target discovery and in early clinical research as Translational Medicine Expert, Autoimmunity. Florian received his MSc degree in Biochemistry from Free University Berlin and his PhD degree with great distinction in Biochemistry from Ruhr University Bochum and completed his post-doctoral training at NIBR in Switzerland. Aaron Nelson is a Principal in Cambridge, MA, USA. Prior to joining NVF, he was an investor at dRx Capital, the joint investment company of Novartis and Qualcomm, focused on Digital Medicine.

DRx catalyzes the success of digital medicine products, services, and business models by investing in early-stage companies and leveraging networks in Pharma, Mobile/IT, and the investment community. Previously, Aaron worked on technology strategy across multiple Business Units within Novartis, including Strategic Project Leader for the Trials of The Future program and Group Head in the Investigative Toxicology organization.

Aaron studied medicine at Tufts University, cell and microbiology at the University of Pennsylvania and the Karolinska Institutet, and completed his undergraduate studies at Cornell University. Michal Silverberg is a Managing Director in Cambridge, MA, USA.

Prior to joining NVF, she was a Senior Director for External Innovation at Takeda Ventures and, before that, worked at Novo Nordisk in roles of increasing responsibility including as Senior Director Business Development and New Product Commercialization, serving as a member of the BioPharm leadership team. Since 1998, Michal has held positions in various sectors of the life science industry including in the Office of the Chief Scientist of Israel (The Incubator program), venture capital (Ofer Brothers Hi Tech) and global pharmaceutical and biotech companies, including various positions at MGVS, an Israeli biotech company and at OSI Pharmaceuticals in a business development role.

She received her B.A. In Economics and Business Management from Haifa University, her M.B.A from Tel-Aviv University in Israel and her Master’s degree in Biotechnology from Columbia University in New York. Michal serves on the board of Forma Therapeutics. Weinstein is a Managing Director in Cambridge, MA, USA. Steve focuses on both medical device and therapeutic investments for the fund. Steve has been investing in venture capital since 1999. Prior to joining NVF, he was a Principal at Prism Venture Partners where he focused on medical devices and served on the board of Sensitech (acquired by Carrier/UTX).

Prior to Prism, Steve was a Kauffman Fellow with Mid-Atlantic Venture Funds, where he focused on software startups. He started his career as a turnaround CEO, raising angel funds to buy a defunct distribution business out of bankruptcy and restart it. Steve holds an MBA with distinction from the University of Michigan Business School and a B.S. In mechanical engineering from Columbia University’s School of Engineering and Applied Science. He serves on the Innovation Advisory Board of Partners Healthcare, and is a member of the Virginia GAP BioLife Fund Investment Committee, the University of Michigan Wolverine Venture Fund Advisory Board. Steve serves on the boards of Autonomic Technologies, Cavion, Rox Medical and Viamet Pharmaceuticals. Harry Kirsch is the Chief Financial Officer of Novartis and a member of the Executive Committee of Novartis.

Prior to his current position, he served as CFO of the company’s Pharmaceuticals Division. Under his leadership, the division’s core operating income margin increased, in constant currencies, every quarter of 2011 and 2012 despite patent expirations. Harry joined Novartis in 2003 from Procter & Gamble in the United States, where he was a CFO of P&G’s global pharmaceutical business and held various finance positions at divisional, regional, country and manufacturing site level, as well as in P&G Global Business Services organization. Harry also represents Novartis on the board of the GSK Consumer Healthcare joint venture. Harry holds a degree in industrial engineering and economics from the University of Karlsruhe in Germany. Meier is the Chief Medical Officer at the University Hospital Basel and Professor at the Medical Faculty of the University of Geneva.

Prior to his current role, he was the Chief of the Department of Internal Medicine & Specialties and a member of the Board of Directors at Triemli Hospital in Zurich, Switzerland, as well as Chief of Endocrinology and Head of the Laboratory of Molecular Endocrinology at the University Hospital Geneva. Meier received his Medical Degree from the University of Basel in Switzerland and holds his Swiss Board Certification (FMH) in Internal Medicine and Endocrinology & Diabetology. Meier completed his medical residency at the University Hospital of Geneva and was a a Postdoctoral Fellow at the National Institutes of Health in the Molecular, Cellular Nutritional Endocrinology Branch in Bethesda, MD (USA). He was also a Howard Hughes Medical Institute Physician Fellow at the Division of Genetics, Brigham and Women's Hospital, as well as a Clinical Fellow in Endocrinology, Diabetes and Metabolism at the Massachusetts General Hospital, Harvard Medical School.

Raj Parekh is General Partner at Advent Life Sciences in London, UK. He joined Advent in 2005 bringing over 20 years of experience in biomedical research and as an entrepreneur and investor. After gaining an M.A. Degrees from Oxford University, Dr.

Parekh pursued a successful academic career in molecular medicine before co-founding Oxford GlycoSciences (IPO on LSE and NASDAQ). Following its sale to UCB-Celltech, he became Chairman of Galapagos and a founding Director of Celldex Therapeutics. He has been involved with portfolio companies primarily engaged in the discovery of new medicines, including Avila, EUSA and Thiakis. Parekh currently serves on the board of several portfolio companies including Arrakis, Aura Biosciences and Levicept. Beat Steffen is a Principal in Basel, Switzerland. Prior to joining Novartis Venture Fund, he worked at Novartis Pharmaceuticals in commercial roles in the US and in Switzerland launching several products mainly in the cardiovascular area.

Beat joined Novartis from Wellington Partners Venture Capital where he worked with biotech and medical device startup companies. Prior to that, he was at McKinsey & Company in Zurich working with clients in the pharmaceutical industry. Beat is a Swiss-trained physician having focused in cardiovascular surgery and intensive care.

He graduated from the University of Zurich Medical School and qualified as a Medical Doctor in Basel. Beat holds an MBA with distinction from INSEAD. Beat serves on the boards of Aelin Therapeutics and AlloCyte. Fiona Marshall is the Chief Scientific Officer and a founder of Heptares Therapeutics – a drug discovery and development biotechnology company. Sylenth1 Vtx Crack more.

She is also Executive VP and CSO of Sosei Group which acquired Heptares in 2015. Fiona has a BSc in biochemistry from Bath University and a PhD in neuroscience from Cambridge University. She has more than 25 years' experience in drug discovery including senior positions at GSK and Millennium. Fiona also has extensive experience working as an advisor to Venture Capital companies with an emphasis on start-up investments. Fiona is on the Board of Trustees of Alzheimer’s Research UK, the council of the Academy of Medical sciences and on advisory boards of the Crick Institute and the Wellcome Trust. She is chair of the MRC DPFS committee.

She won the 2012 WISE Women of Outstanding Achievement for Innovation and Entrepreneurship and the 2015 RSC Malcolm Campbell Award for chemistry. She was elected as a Fellow to the Academy of Medical Sciences in 2016. Reza Zadno is an Innovation Advisor to Novartis Venture Fund (NVF) located in San Francisco, CA, USA. Reza is a serial entrepreneur focused on sourcing new investments particularly in the area of medical devices.

Reza was the founder, President and CEO of Visiogen (a former NVF-portfolio company acquired by Abbott-Medical Optics) and co-founder of PercuSurge (acquired by Medtronic). Reza is also currently Executive in Residence at InterWest Partners. Prior to joining InterWest in 2012, Reza was a Venture Partner at New Leaf Venture Partners and, previously, an Entrepreneur in Residence at Three Arch Partners. Earlier in his career, he was with Cardiac Pathways (acquired by Boston Scientific) and with Raychem Corporation, now Tyco. Reza holds a Ph.D. From Ecole des Mines de Paris and has filed more than 100 U.S.

He serves on the boards of the following non-NVF companies, Carbylan, Gobiquity, Invuity, On Demand Therapeutics and Oraya Therapeutics. Advanced Animal Diagnostics is an animal health diagnostics company, developing highly accurate, rapid on-farm diagnostics.

The QScout® line of on-farm diagnostics will detect disease states at an early stage and optimize management of the reproductive, nutritional and overall health status of production animals, beginning with the dairy cow. The company’s platform diagnostic technology is designed to enhance the profitability of livestock production, improve animal welfare, and ensure a safe, abundant supply of animal protein. AMP was founded in 2009 as a spin-out from Prof. Ralf Hoffmann’s laboratory at the University of Leipzig. AMP is developing the next generation of broad-spectrum Gram-negative antibiotics for the treatment of drug-resistant infections. It has been estimated that approximately 30-40% of all hospital-acquired (nosocomial) infections worldwide are caused by Gram-negative bacteria.

Gram-negative pathogens are highly genetically flexible and thus develop resistance mechanisms that render most of the current therapies ineffective. BioNano has developed the Irys genome mapping platform using nanochannel technology to visualize whole genomes of any organism, including humans. By capturing extremely long DNA molecules at high resolution (hundreds of kilobases vs. Single nucleotides), Irys delivers genome maps that provide novel insight into structural variations, such as translocations, amplifications and deletions, that underlies phenotypic variation. The Irys platform can reveal relevant mutations in complex genomes filling the gap between the available cytogenetics and next-generation sequencing/microarray technologies to further advance genome research. Galera is a clinical stage drug development company with a portfolio of small molecule superoxide dismutase activators. Superoxide, a product of normal cellular oxygen metabolism and certain environmental stresses, is harmful to DNA, RNA, proteins and lipids.

This highly reactive molecule is managed by superoxide dismutases (SODs), but the SOD enzyme is deficient in certain disease states. Galera’s technology replaces this loss of function. The company is initially focusing on radiation-induced mucositis, cancer and pulmonary fibrosis. Merganser Biotech is developing new medicines that increase hepcidin activity for the treatment of rare hematological and iron overload diseases. Hepcidin is the master regulator of iron metabolism and controls iron absorption from the diet and iron transfer around the body. Hepcidin deficiency causes iron overload, leading to heart and liver damage and may contribute to the severity of ineffective erythropoiesis and anemia in beta thalassemia.

Merganser's hepcidin mimetic peptides prevent iron accumulation and reduce the severity of ineffective erythropoiesis in preclinical models of beta thalassemia. Altimmune is a clinical stage immunotherapeutic biotechnology company focused on the discovery and development of novel products that engage, stimulate and improve immune responses for the prevention and treatment of disease. By leveraging the complementary attributes of its two innovative vaccine delivery platforms, RespirVec™ and Densigen™, Altimmune is able to rationally design and rapidly develop immunotherapeutic products tailored to address the a wide range of disease indications including acute respiratory infections, chronic viral infections and cancer with fundamental advantages over competing products. Annexon is developing disease modifying therapeutics to protect neuronal connections (synapses) that are lost in nearly all forms of neurodegenerative disease. Annexon’s platform is focused on inhibiting C1q as the initiating molecule of the complement cascade responsible for aberrantly binding to functional synapses and triggering their elimination in neurodegenerative diseases. This pathway is also well known to contribute to pathology in a number of autoimmune diseases of the nervous system.

Annexon’s lead molecule, ANX005, effectively blocks this pathway and will have broad therapeutic application in both acute and chronic neurological diseases. Annexon’s initial focus will be in acute peripheral immune-mediated disorders. News Alios BioPharma acquired by Johnson & Johnson for ~$1.75 billion November 2014: Alios BioPharma, Inc. (Alios) was acquired by Johnson & Johnson (JNJ) for ~$1.75 billion in cash, strengthening JNJ’s existing pipeline in viral diseases. The acquisition included Alios’s portfolio of potential therapeutics for viral infections including compound AL-8176, an orally administered antiviral therapy currently in Phase 2 studies for the treatment of infants with respiratory syncytial virus (RSV). Alios developed a novel proprietary nucleoside/tide library to identify therapeutics for the treatment of several viral infections including HCV, RSV, rhinovirus, norovirus, influenza and other emerging viral diseases. Novartis Venture Fund was one of the original investors in Alios in 2009, participating in their Series A as well as successive financing rounds and was a member of the board of directors.

News Covagen AG acquired by Cilag GmbH International, an affiliate of the Janssen Pharmaceutical Companies of Johnson & Johnson August 2014: Covagen AG was acquired by Cilag GmbH International, an affiliate of the Janssen Pharmaceutical Companies of Johnson & Johnson, further strengthening Cilag’s immunology portfolio and capabilities. Covagen’s lead product, COVA 322, a bispecific anti-tumor necrosis factor (TNF)-alpha/anti-interleukin (IL)-17A FynomAb, is in Phase 1b study for psoriasis and holds potential as a treatment for a broad range of inflammatory diseases including rheumatoid arthritis. Covagen’s proprietary Fynomer platform creates fully human small binding proteins engineered to bind to target molecules with excellent affinity and specificity. Fynomers are fused to antibodies, creating FynomAbs, with tailored architecture and novel mode of action, these FynomAb therapeutics may offer enhanced efficacy in the treatment of a broad range of inflammatory diseases and other conditions.

Financial terms of the transaction have not been disclosed. Covagen was founded in 2009 with seed financing from Novartis Venture Fund and MP Healthcare Venture Management. Novartis Venture Fund continued to fund Covagen in the successive financing rounds and was a member of the board of directors. Contact Us Evaluation and Investment Process We are stage agnostic (seed to commercial companies) and invest in multiple therapeutic areas where there is clear unmet medical need. Our first step in the process is to review non-confidential information about the company, team, technology / data, financial and exit plan. The further evaluation of business proposals is then based on confidential presentations by the management team that starts the full due diligence process. Investments by the Novartis Venture Fund are made as equity participation typically as the lead or co-lead investor in a syndicate with a board seat.

Contact Us Please contact one of our offices closest to the company site for an initial review. We have offices in Basel, Switzerland and Cambridge, MA, USA and entrepreneurs should contact the office closest to their company. What is a cookie? Cookies are small text files that are sent to your computer when you visit a website.

Cookies on Novartis Group company (Novartis) web sites do lots of different jobs, like letting you navigate between pages efficiently, storing your preferences and generally improving your experience of a website. The EU Directive 2009/136/EC states that we can store cookies on your machine, if they are essential to the operation of this site, but that for all others we need your permission to do so. Novartis sites can use some non-essential cookies.

We do not do this to track individual users or to identify them, but to gain useful knowledge about how the sites are used so that we can keep improving them for our users. Without the knowledge we gain from the systems that use these cookies we would not be able to provide the service we do. The types of cookies we use If you decide to set the language, font-size or specific version of the site (e.g. High-contrast), we use “user interface customization cookies”. Once set, you do not need to specify your preferences again on another visit to the site. If you use parts of the site that require registration to access content, we will place an “authentication cookie” on your computer. This allows you to leave and return to these parts of the site without re-authenticating yourself.

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You can also delete cookies that have already been set. If you wish to restrict or block web browser cookies which are set on your device then you can do this through your browser settings; the Help function within your browser should tell you how. Alternatively, you may wish to visit, which contains comprehensive information on how to do this on a wide variety of desktop browsers. This Privacy Statement describes the ways in which we, Novartis AG, collect, hold and use information about individual persons who visit this website. BY USING THIS WEBSITE, YOU CONSENT TO THE COLLECTION AND USE OF INFORMATION AS SET FORTH IN THIS PRIVACY POLICY. YOU ALSO ACKNOWLEDGE THAT NOVARTIS AG MAY PERIODICALLY CHANGE, MODIFY, ADD OR REMOVE OR OTHERWISE UPDATE THIS PRIVACY POLICY AT ITS DISCRETION, WITHOUT PRIOR NOTIFICATION. However, we will always handle your Personal Information in accordance with the Privacy Policy that was in effect at the time of collection.

It is our intention to post changes to our privacy policy on this page so that you are fully informed concerning the types of information we are gathering, how we use it, and under what circumstances it may be disclosed. Our Privacy Policy is located on our homepage and is also available on any page where Personal Data are requested. At such data collection points, further explanation may be provided, where appropriate, as to the purposes for which the data will be used.

Pledge on Privacy The term 'Personal Data' as used in this Privacy Policy refers to information such as your name, birth date, e-mail address, mailing address, or telephone number that can be used to identify you. Generally, we will only process your Personal Data as described in this Privacy Policy. However, we reserve the right, to conduct additional processing to the extent permitted or required by law, or in support of any legal or criminal investigation. The next sections explain how and when we collect Personal Data from you. Intended Use of Personal Data Most of our services do not require any form of registration, allowing you to visit our site without telling us who you are. However, some services may require you to provide us with Personal Data.

In these situations, if you choose to withhold any Personal Data requested by us, it may not be possible for you to gain access to certain parts of the site and for us to respond to your query. We may collect and use Personal Data to provide you with products or services, to bill you for products and services you request, to market products and services which we think may be of interest to you, or to communicate with you for other purposes which are evident from the circumstances or about which we inform you when we collect Personal Data from you.

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However, Novartis has adopted Binding Corporate Rules, a system of principles, rules and tools, provided by European law, in an effort to ensure effective levels of data protection, in particular relating to transfers of personal information outside the EEA and Switzerland. Read more about your rights under the. 'Cookies' and Internet Tags We may collect and process information about your visit to this website, such as the pages you visit, the website you came from and some of the searches you perform. Such information is used by us to help improve the contents of the site and to compile aggregate statistics about individuals using our site for internal, market research purposes.

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If you would like more information about web tags and cookies associated with on-line advertising or to opt-out of third-party collection of this information, please visit the Network Advertising Initiative website. Google Analytics We use Google Analytics to rationalize our portfolio of websites by (i) optimizing traffic to and between corporate websites, and (ii) integrating and optimizing web pages where appropriate. “Google Analytics” is a service offered by Google Inc. “Google” that generates detailed statistics about a website's traffic and traffic sources and measures conversions and sales. Google Analytics uses “cookies” stored on your computer to help analyze how users use our website. The information generated by the cookies about your use of our website, including your IP address, will be transmitted to and stored by Google on servers in the United States. The IP address, however, will be shortened before being sent to Google and Google can then not use it any more to identify you or your computer.

Only in exceptional cases the full IP address will be transmitted to and shortened by Google in the US. On behalf of us, Google will use the information generated by the cookies for the purpose of evaluating the use of our website, compiling reports on website activity providing us with these reports for analytical purposes. Google may transfer this information to third parties in case of a statutory obligation or if a third party processes data on behalf of Google. Under no circumstances, Google will combine or associate your IP address with other data stored at Google. You may prevent or stop the installation and storage of cookies by your browser settings by downloading and installing the free Opt-out Browser Add-on available. We inform you that in such case you will not be able to wholly use all functions of our website. By using our website you consent to the processing of any personal data Google will collect on you in the way and for the purpose as described above.

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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis Claire Bombardier, M.D., Loren Laine, M.D., Alise Reicin, M.D., Deborah Shapiro, Dr.P.H., Ruben Burgos-Vargas, M.D., Barry Davis, M.D., Ph.D., Richard Day, M.D., Marcos Bosi Ferraz, M.D., Ph.D., Christopher J. Hawkey, M.D., Marc C. Hochberg, M.D., Tore K.

Kvien, M.D., and Thomas J. Schnitzer, M.D., Ph.D., for the VIGOR Study Group N Engl J Med 2000; 343:1520-1528 DOI: 10.1056/NEJM32103. Results Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P. Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly used medications in the world.

A major factor limiting their use is gastrointestinal toxicity. Although endoscopic studies reveal that gastric or duodenal ulcers develop in 15 to 30 percent of patients who regularly take NSAIDs, the chief concern is clinically important gastrointestinal problems, such as bleeding. It has been estimated that more than 100,000 patients are hospitalized and 16,500 die each year in the United States as a result of NSAID-associated gastrointestinal events. Most NSAIDs inhibit both cyclooxygenase-1 and cyclooxygenase-2, isoenzymes involved in the synthesis of prostaglandins. Cyclooxygenase-1 is constitutively expressed and generates prostanoids involved in the maintenance of the integrity of gastrointestinal mucosa and platelet aggregation, whereas at sites of inflammation, cyclooxygenase-2 is induced to generate prostaglandins that mediate inflammation and pain. The antiinflammatory effects of nonselective NSAIDs (those that inhibit both cyclooxygenase-1 and cyclooxygenase-2) therefore appear to be mediated through the inhibition of cyclooxygenase-2, whereas their harmful effects in the gastrointestinal tract as well as their antiplatelet effects are believed to occur primarily through the inhibition of cyclooxygenase-1. Agents that selectively inhibit cyclooxygenase-2 have antiinflammatory and analgesic effects that are similar to those of nonselective NSAIDs, but they induced significantly fewer ulcers in endoscopic trials.

Whether such a decrease in the number of ulcers translates into a similar decrease in the number of clinical gastrointestinal events is a matter of controversy. We performed a prospective, randomized, double-blind comparison of rofecoxib and naproxen in more than 8000 patients with rheumatoid arthritis. Study Population Patients with rheumatoid arthritis who were at least 50 years old (or at least 40 years old and receiving long-term glucocorticoid therapy) and who were expected to require NSAIDs for at least one year were eligible. Patients were excluded if they had a history of another type of inflammatory arthritis, upper gastrointestinal surgery, or inflammatory bowel disease; an estimated creatinine clearance of 30 ml or less per minute; a positive test for fecal occult blood (this test was performed at base line in all patients); an unstable medical condition; a history of cancer or alcohol or drug abuse in the five years before the study; a history of cerebrovascular events in the two years before the study; or a history of myocardial infarction or coronary bypass in the year before the study. Patients with morbid obesity and those who required or who had been receiving treatment with aspirin, ticlopidine, anticoagulants, cyclosporine, misoprostol, sucralfate, or proton-pump inhibitors or treatment with histamine H 2–receptor antagonists in prescription-strength doses were also excluded from the study. Patients enrolled in the study were not thought to require the use of these agents by their treating physicians.

Study Design The study was conducted at 301 centers in 22 countries. Three to 14 days after discontinuing NSAIDs, eligible patients were randomly assigned to receive either 50 mg of rofecoxib (Vioxx, Merck, Whitehouse Station, N.J.) once daily or 500 mg of naproxen (Novopharm Biotech, Toronto) twice daily. The groups were stratified according to the presence or absence of a history of gastroduodenal ulcer, upper gastrointestinal bleeding, and gastroduodenal perforation. Blinding was achieved through the use of a matching placebo for each study medication. Patients were permitted to take acetaminophen, non-NSAID analgesic medications, glucocorticoids, and disease-modifying drugs (e.g., methotrexate) to control their rheumatoid arthritis. Patients were also allowed to take antacids and H 2-receptor antagonists in the following maximal doses: ranitidine, 150 mg daily; famotidine, 20 mg daily; cimetidine, 400 mg daily; and nizatidine, 150 mg daily.

Nonstudy NSAIDs were not allowed. After randomization, the patients returned to the clinic at six weeks and at four months and every four months thereafter until the end of the study. Patients were contacted by telephone at week 10 and every four months thereafter. Compliance was assessed by pill counts at clinic visits and by questioning of patients during the scheduled telephone calls. Serum was obtained from all patients for Helicobacter pylori testing (HM-CAP, Enteric Products, Stonybrook, N.Y.). Investigators were not informed of the results of these tests during the study. The institutional review board or ethics review committee at each center approved the protocol, and all patients gave written informed consent.

A steering committee oversaw the study design, conduct of the trial, analyses of data, and drafting of this report. This committee was composed of 14 members, 2 of whom were employees of the sponsoring pharmaceutical company.

An independent data and safety monitoring board monitored the patients' safety. An independent, external (end-point) committee whose members were unaware of the patients' treatment assignments reviewed the data to determine which patients had reached the study end points. Because highly selective cyclooxygenase-2 inhibitors do not inhibit platelet aggregation, which is mediated by cyclooxygenase-1, there was a possibility that the incidence of thrombotic cardiovascular events would be lower among patients treated with nonselective cyclooxygenase inhibitors than among those treated with cyclooxygenase-2–selective inhibitors. Therefore, cardiovascular events were also assessed for a future meta-analysis by independent committees whose members were unaware of the patients' treatment assignments. A separate analysis of these events, however, was not specified in the study design.

Study End Points Patients who had potential clinical upper gastrointestinal events were evaluated and treated according to the standard practice of the physicians who were caring for them. Patients who stopped taking the study medication before the study ended were followed until the end of the study to determine whether an upper gastrointestinal event had occurred. Only events that were confirmed by the end-point committee according to prespecified criteria ( Table 1 Criteria for Gastrointestinal Events. ) and that occurred during treatment or within 14 days after the discontinuation of treatment were included in the primary analysis. In addition, the protocol called for the analysis of all episodes of gastrointestinal bleeding, including confirmed and unconfirmed episodes of upper gastrointestinal bleeding, and bleeding from a site beyond the duodenum that resulted in hospitalization, discontinuation of treatment, or a decrease in the hemoglobin level of at least 2 g per deciliter. Assessment of Efficacy For each patient both the investigator and the patient answered a Global Assessment of Disease Activity question at base line (after the discontinuation of prestudy NSAIDs), 6 weeks, 4 months, and 12 months and at the end of the study or when treatment was discontinued.

The score can range from 0 (“very well”) to 4 (“very poor”), and higher scores indicate more disease activity. The Modified Health Assessment questionnaire was administered only to patients enrolled at centers in the United States at base line, at six weeks, and at the end of the study or when treatment was discontinued. This questionnaire evaluates the extent of functional disability in eight types of tasks performed on a daily basis.

The level of effort required to perform each task is assessed on a 4-point scale on which a score of 0 indicates no difficulty in performing the task and a score of 3 indicates an inability to perform the task. Higher scores indicate more severe disability. Statistical Analysis The primary hypothesis was that the risk of confirmed upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers) would be lower among patients who were taking rofecoxib than among those who were taking naproxen. Secondary hypotheses were that the risk of confirmed complicated events (perforation, obstruction, and severe upper gastrointestinal bleeding) and the risk of both confirmed and unconfirmed upper gastrointestinal events would be lower among patients who were taking rofecoxib. Cox proportional-hazards analysis was used to compare the effect of treatment; the presence or absence of a history of gastrointestinal events was a stratification factor in the analysis. The scores for the Global Assessment of Disease Activity question and Modified Health Assessment questionnaire were analyzed in terms of the mean change from base line during the treatment period.

The primary population for analysis comprised all randomized patients. Subgroup analyses were conducted with use of Cox regression analysis. Interactions between treatments and subgroups were assessed to determine whether the effect of rofecoxib as compared with that of naproxen was consistent in the subgroups. We assessed data on general safety by evaluating 95 percent confidence intervals of the differences in the proportions of the treatment groups with each adverse event. All statistical tests were two-sided. Characteristics of the Patients Between January 1999 and July 1999, we screened 9539 patients and enrolled 8076; 4047 were randomly assigned to receive rofecoxib, and 4029 to receive naproxen.

The major reasons for exclusion were a contraindication to prolonged NSAID therapy (in the case of 246 patients), a positive test for fecal occult blood (203 patients), and a failure to meet inclusion criteria (355 patients). The median follow-up was 9.0 months in both treatment groups (range, 0.5 to 13). A total of 5742 patients (71.1 percent) continued to take their assigned medication until the end of the study. Rates of discontinuation were similar in the two groups: 29.3 percent in the rofecoxib group (16.4 percent because of adverse events, 6.3 percent because of a lack of efficacy, and 6.6 percent for other reasons) and 28.5 percent in the naproxen group (16.1 percent because of adverse events, 6.5 percent because of a lack of efficacy, and 5.9 percent for other reasons). Ninety-nine percent of the patients in both groups took their medication on at least 75 percent of the study days.

The base-line characteristics were similar in the two groups ( Table 2 Base-Line Characteristics of the Patients. Adverse Gastrointestinal Events Confirmed upper gastrointestinal events occurred in 177 patients. In 53 of these patients the event was complicated. An additional 13 patients had events that were reported by investigators but that were judged by the end-point committee to be unconfirmed.

The time to the development of a confirmed upper gastrointestinal event is shown in Figure 1 Cumulative Incidence of the Primary End Point of a Confirmed Upper Gastrointestinal Event among All Randomized Patients.. The rates per 100 patient-years and incidences of the prespecified clinical events are shown in Table 4 Incidence of Gastrointestinal Events in the Treatment Groups. And Table 5 Incidence of Confirmed Upper Gastrointestinal Events., respectively.

The relative risk of confirmed upper gastrointestinal events for patients in the rofecoxib group as compared with those in the naproxen group was 0.5 (95 percent confidence interval, 0.3 to 0.6; P. General Safety The safety of both rofecoxib and naproxen was similar to that reported in previous studies. The mortality rate was 0.5 percent in the rofecoxib group and 0.4 percent in the naproxen group. The rate of death from cardiovascular causes was 0. Construction Planning And Management By P S Gahlot Pdf Writer. 2 percent in both groups. Ischemic cerebrovascular events occurred in 0.2 percent of the patients in each group. Myocardial infarctions were less common in the naproxen group than in the rofecoxib group (0.1 percent vs.

0.4 percent; 95 percent confidence interval for the difference, 0.1 to 0.6 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7). Four percent of the study subjects met the criteria of the Food and Drug Administration (FDA) for the use of aspirin for secondary cardiovascular prophylaxis (presence of a history of myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, angioplasty, or coronary bypass) but were not taking low-dose aspirin therapy. These patients accounted for 38 percent of the patients in the study who had myocardial infarctions.

In the other patients the difference in the rate of myocardial infarction between groups was not significant (0.2 percent in the rofecoxib group and 0.1 percent in the naproxen group). When the data showing a reduction in the rate of myocardial infarction in the naproxen group became available after the completion of this trial, Merck, the manufacturer of rofecoxib, notified all investigators in ongoing studies of a change in the exclusion criteria to allow patients to use low-dose aspirin. There was no association between hypertension and myocardial infarction; only a single patient (in the rofecoxib group) had both hypertension and a myocardial infarction as adverse events.

The most common adverse events leading to discontinuation of treatment, excluding the gastrointestinal end points, were dyspepsia, abdominal pain, epigastric discomfort, nausea, and heartburn. In the rofecoxib group, significantly fewer patients discontinued treatment as a result of any one of these five upper gastrointestinal symptoms than in the naproxen group (3.5 percent vs. 4.9 percent). The rates of discontinuation for any gastrointestinal events, including gastrointestinal end points, were also significantly lower in the rofecoxib group than in the naproxen group (7.8 percent vs. 10.6 percent).

The incidence of adverse effects related to renal function was low and was similar in the two groups (1.2 percent in the rofecoxib group and 0.9 percent in the naproxen group); only 0.2 percent of patients in each group discontinued treatment because of these adverse effects. Discussion We found that, in patients with rheumatoid arthritis, treatment with rofecoxib at twice the maximal dose approved by the FDA for long-term use resulted in significantly lower rates of clinically important upper gastrointestinal events and complicated upper gastrointestinal events than did treatment with a standard dose (1000 mg per day) of naproxen. We also found that the incidence of complicated upper gastrointestinal bleeding and bleeding from beyond the duodenum was significantly lower among patients who received rofecoxib. Only 41 patients would need to be treated with rofecoxib rather than naproxen to avert one clinical upper gastrointestinal event in a one-year period.

Although the optimal dose of rofecoxib for the treatment of rheumatoid arthritis has yet to be determined, data from a prior study indicate that maximal efficacy is achieved at a daily dose of 25 mg. A prospective study that compared NSAIDs alone with NSAIDs plus misoprostol reported that 0.95 percent of patients with rheumatoid arthritis who were taking an NSAID alone had upper gastrointestinal complications over a period of six months, with a relative reduction in the risk of such complications with combination treatment of 40 percent during this period. These results are similar to our finding of a cumulative incidence of serious upper gastrointestinal events over a six-month period of 0.75 percent in the naproxen group and a relative reduction in risk of 67 percent in the rofecoxib group (data not shown). A 50 percent reduction in the incidence of clinically important upper gastrointestinal events with rofecoxib as compared with a nonselective NSAID was also found in a prespecified combined analysis of eight double-blind studies that included 4921 patients with osteoarthritis, none of whom received glucocorticoids.

Patients with rheumatoid arthritis have a higher risk of upper gastrointestinal events than do patients with osteoarthritis. Thus, the results of our study extend the results of the combined analysis to a group of patients at higher risk of bleeding. The results of a randomized, double-blind comparison of the cyclooxygenase-2–selective inhibitor celecoxib and the nonselective NSAIDs ibuprofen and diclofenac were recently published. In this trial of 7968 patients, 73 percent of whom had osteoarthritis and 27 percent of whom had rheumatoid arthritis, data were reported from the first 6 months of a study period that extended for up to 13 months. Treatment with celecoxib was associated with a nonsignificant (P=0.09) trend toward a decrease in the incidence of the primary end point (complicated ulcers and erosions) and a significant decrease (P=0.02) in the incidence of the secondary end point (complicated and symptomatic ulcers).

The incidence of clinically important gastrointestinal events was lower in the rofecoxib group than in the naproxen group in all subgroups we examined. Concomitant glucocorticoid and NSAID therapy has been reported to be associated with a higher risk of a clinical gastrointestinal event than is NSAID therapy alone. Therefore, a larger reduction in the incidence of events might have been expected in the subgroup that received both an NSAID and glucocorticoids. There was a greater reduction in the relative risk of events in the subgroup of patients who were taking glucocorticoids at base line than in the subgroup of patients who were not taking glucocorticoids at base line, but the difference between the groups was not significant. Whether ulcers identified by endoscopic examination are markers of a clinical gastrointestinal event has been a matter of controversy. The relative reduction in the risk of such ulcers in two identical studies that compared 50 mg of rofecoxib daily with 800 mg of ibuprofen three times a day was 71 percent at six months. Thus, our findings support the concept that the results of endoscopic studies of ulcers can be extrapolated to clinical gastrointestinal events.

In prior endoscopic studies, the frequency of ulcers was similar in patients taking rofecoxib and those taking placebo. We could not include a placebo group, and no studies have yet assessed whether a cyclooxygenase-2–selective inhibitor or the combination of nonselective NSAIDs plus gastroprotective drugs (such as misoprostol and proton-pump inhibitors) will achieve similar results. Gastrointestinal symptoms are extremely common with NSAID therapy, as demonstrated by the fact that, in our study, the five most common adverse events leading to the discontinuation of treatment were upper gastrointestinal symptoms. Although gastrointestinal symptoms are poorly correlated with endoscopic findings of ulcers or clinical gastrointestinal events, significantly fewer patients in the rofecoxib group than in the naproxen group discontinued treatment because of gastrointestinal symptoms. The overall mortality rate was similar in the two groups, as were the rates of death from gastrointestinal events and from cardiovascular causes. The rate of myocardial infarction was significantly lower in the naproxen group than in the rofecoxib group (0.1 percent vs.

0.4 percent). This difference was primarily accounted for by the high rate of myocardial infarction among the 4 percent of the study population with the highest risk of a myocardial infarction, for whom low-dose aspirin is indicated. The difference in the rates of myocardial infarction between the rofecoxib and naproxen groups was not significant among the patients without indications for aspirin therapy as secondary prophylaxis. Naproxen inhibits the production of thromboxane by 95 percent and inhibits platelet aggregation by 88 percent, and this effect is maintained throughout the dosing interval; therefore, the effects of regular use of naproxen may be similar to those of aspirin. Flurbiprofen, another NSAID that is a potent inhibitor of platelet-derived thromboxane, led to a 70 percent reduction in the rate of reinfarction as compared with placebo among patients in whom acute myocardial infarction was successfully treated with thrombolysis, angioplasty, or both.

Analyses of 7535 patients in double-blind trials comparing rofecoxib with placebo and other NSAIDs (diclofenac, ibuprofen, and nabumetone) that do not produce sustained, maximal inhibition of platelet aggregation revealed similar rates of myocardial infarction in all groups (and unpublished data). Thus, our results are consistent with the theory that naproxen has a coronary protective effect and highlight the fact that rofecoxib does not provide this type of protection owing to its selective inhibition of cyclooxygenase-2 at its therapeutic dose and at higher doses.

The finding that naproxen therapy was associated with a lower rate of myocardial infarction needs further confirmation in larger studies. In summary, the use of the cyclooxygenase-2–selective inhibitor rofecoxib resulted in significantly fewer clinically important upper gastrointestinal events than did treatment with naproxen, a nonselective NSAID. The two drugs had similar rates of clinical effectiveness.

Supported by a grant from Merck. Bombardier has received clinical research support from Aventis Pharma, Merck Research Laboratories, and Merck Frosst Canada.

She has served as a consultant to Knoll Pharmaceutical, Aventis Canada, Schering Canada, Merck Research Laboratories, and Wyeth–Ayerst. Laine has received clinical research support from Merck, Wyeth–Ayerst, and AstraZeneca. He has served as a consultant to Merck, Searle, Johnson & Johnson, AstraZeneca, Wyeth–Ayerst, and Tap Pharmaceuticals. Burgos-Vargas has received clinical research support from Merck Sharp & Dohme, Pfizer, and Boehringer Ingelheim.

He has served as a consultant to Merck and has been a member of a speakers' bureau sponsored by Merck Sharp & Dohme. Davis has served as a consultant to Mirvant, Merck Research Laboratories, Parke-Davis, and SmithKline Beecham. Day has received clinical research support from Merck, Searle, Pfizer, Roche, and Amgen. He has served as a consultant to Merck, Searle, and Pfizer. He has been a member of speakers' bureaus sponsored by Merck Sharp & Dohme, Searle, Pfizer, and SmithKline Beecham. Ferraz has received clinical research support from Bristol-Myers Squibb, Merck Sharp & Dohme, and Aventis Pharma.

He has served as a consultant to Aventis Pharma. Hawkey has received clinical research support from AstraZeneca, Asta Medica, Boehringer Ingelheim, Boots Healthcare International, Cell Tech, Eisai, Elan, Merck Research Laboratories, NicOx, and Novartis. He has served as a consultant to AstraZeneca, Abbott, Cell Tech, Eisai, Merck Research Laboratories, NicOx, Novartis, Parke-Davis, and Synthelabo Pharmacie. He has been a member of speakers' bureaus sponsored by AstraZeneca, Boehringer Ingelheim, Boots Healthcare International, Takeda, Wyeth Lederle, and Merck Research Laboratories. Hochberg has received clinical research support from Merck and Quintiles (Aventis Pharma). He has served as a consultant to Aventis Pharma, Biomatrix, Merck, Negma Laboratories, Procter & Gamble, Roche, and Wyeth–Ayerst. He owns stock in Johnson & Johnson, Eli Lilly, Merck, Procter & Gamble, and Schering-Plough.

Kvien has received clinical research support from Merck, Searle, Aventis Pharma, and Schering-Plough. He has served as a consultant to Merck, Searle, Aventis Pharma, and Schering-Plough. He has been a member of a speakers' bureau sponsored by Merck and Aventis Pharma. Schnitzer has received clinical research support from Abbott, Boehringer Ingelheim, Johnson & Johnson, McNeil Consumer Products, Merck, Novartis, Ortho-McNeil, Parke-Davis, Searle, and Wyeth–Ayerst. He has served as a consultant to Boehringer Ingelheim, Merck, Novartis, Ortho-McNeil, Searle, and SmithKline Beecham.

He has been a member of speakers' bureaus sponsored by Boehringer Ingelheim, Merck, Ortho-McNeil, Wyeth–Ayerst, and Searle. Weaver has received clinical research support from Merck, Searle, Immunex, Wyeth–Ayerst, Aventis Pharma, Pharmacia–Upjohn, Eli Lilly, Connetics, Parke-Davis, Procter & Gamble, Pfizer, Hoffmann–LaRoche, Centocor, Amgen, Cyprus Bioscience, Helsinn, Novartis, and Boehringer Ingelheim. He has served as a consultant to Merck, Searle, Immunex, Wyeth–Ayerst, Aventis Pharma, Pharmacia–Upjohn, Eli Lilly, Connetics, Parke-Davis, Procter & Gamble, Pfizer, Hoffmann–LaRoche, Centocor, Amgen, Cyprus Bioscience, Helsinn, Novartis, and Boehringer Ingelheim. He has been a member of speakers' bureaus sponsored by Merck, Searle, Immunex, Wyeth–Ayerst, Aventis Pharma, Pharmacia–Upjohn, Eli Lilly, Connetics, Parke-Davis, Procter & Gamble, Pfizer, Hoffmann–LaRoche, Centocor, Amgen, Cyprus Bioscience, Helsinn, Novartis, and Boehringer Ingelheim. He is on the board of directors of MGI Pharma. We are indebted to Christopher T.

Brett, Dayna Carroll, Russell Cender, Edward Chafart, Laurine Connors, Gary Gartenberg, Nicole Gillies, Richard Holmes, Paige Reagan, Douglas J. Watson, Debora P.L. Weiss, and Qinfen Yu for their substantial contributions.

Appendix The following persons participated in the study: International Steering Committee: C. Bombardier (chair), L. Laine (cochair), A. Burgos-Vargas, B.

Schnitzer, A. Weaver; Data Safety Board: M. Weinblatt (chair); D. Sturrock; End-Point Adjudication Committee: M.

Griffin (chair), D. Langman; Investigators: Argentina: E. DiGiorgio, H. Strusberg; Australia: J. Sharma; Brazil: R.

Bonfiglioli, C. Radominski, A. Souza; Canada: T. Anastassiades, M. Camerlain, J. Olszynski, P.

Pruzanski, K. Siminovitch, J.

Verdejo-Aguilar; Chile: L. Fuentealba, L.

Riedemann, L. Rossi; China (Hong Kong): C. Lau; Colombia: M. Molina; Costa Rica: R. Garcia-Sancho; Czech Republic: L.

Sealackova, J. Ahora; Ecuador: R. Villacis; Finland: M. Nissila; Germany: R. Gromnica-Ihle, H. Hantzschel, G.

Muller-Ladner, C. Schattenkirchner, M. Schneider, H. Waldorf-Bolten, H. Wassenberg; Guatemala: E. Palomo; Israel: D. Rosner; Malaysia: S.

Yeap; Mexico: R. Garcia de la Torre, F. Arozco Alcala; New Zealand: P. Rajapakse; Norway: H. Helgetveit, A. Johannessen, C.

Mikkelsen, B. Sidenwall; Peru: A. Calvo Quioz, M. Portocarrero, E.

Vera Bejar; Poland: J. Brzezicki, M. Fiedorowicz-Fabrycy, J.

Konieczna, S. Mackiewicz, J. Szczepanski, J. Szechinski; South Africa: I.

Jacovides, A. Tikly; United States: Alabama: G. Divititorio, S. Williams; Arizona: B. Maricic; California: E. Greenwald, D. Haselwood, M.

Higashida; Colorado: S. Van Kerchov; Connecticut: E. Feinglass, J. Schoen; Florida: M. Guttierrez, M. Lowenstein, A.

Offenberg, J. Torres; Georgia: J. Lieberman; Iowa: M. Brooks; Idaho: F. Wiesenhutter; Illinois: F. Liang; Indiana: C. Fife; Kansas: N.

Lies; Louisiana: W. Eversmeyer, P. Serebro; Maine: L.

Block; Maryland: R. Hochberg; Massachusetts: C.

Rapoport; Michigan: P. Roschmann, H. Taborn; Missouri: T. Weiss; Montana: S. English; Nebraska: W. Weaver; Nevada: S. Miller; New Hampshire: B.

Trice; New Jersey: S. Worth; New Mexico: K. Bordenave; New York: P. Ritchlin; North Carolina: G. Chmelewski, G.

Littlejohn, G. Schimizzi, R. Kashif; Ohio: T. Rothschild, D. Schumacher, R.

Rothenberg; Oklahoma: C. Jacobs; Pennsylvania: R.

Kimelheim, A. Makarowski, G.

McLaughlin, J. Weisberg; Rhode Island: J. Scott; South Carolina: C. Flint; Tennessee: C.

Tanner; Texas: A. Rutstein; Utah: J. Booth; Virginia: C. Goldstein; Washington: W. Ettlinger, R. Levy; Wisconsin: M. References • 1 Misoprostol for co-prescription with NSAIDs Drug Ther Bull 1990;28:25-26 • 2 Laine L.

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A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Arch Intern Med 2000;160:1781-1787 • 10 Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum 2000;43:978-987 • 11 Ehrich EW, Schnitzer TJ, McIlwain H, et al.

Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. J Rheumatol 19-2447 • 12 Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282:1921-1928 • 13 Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.

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