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Gastrointestinal Tolerability and Effectiveness of Rofecoxib versus Naproxen in the Treatment of Osteoarthritis: A Randomized, Controlled Trial

Jeffrey R. Lisse, MD; Monica Perlman, MD, MPH; Gunnar Johansson, MD; James R. Shoemaker, DO; Joy Schechtman, DO; Carol S. Skalky, BA; Mary E. Dixon, BS; Adam B. Polis, MA; Arthur J. Mollen, DO; Gregory P. Geba, MD, MPH, ADVANTAGE Study Group*
[+] Article, Author, and Disclosure Information

†For more data, see the following Letter to the Editor: Report of Specific Cardiovascular Outcomes of the ADVANTAGE Trial

From University of Arizona, Tuscon, Sun Valley Arthritis Center, Ltd., Glendale, and Southwest Health Institute, Phoenix, Arizona; Scripps Clinic, La Jolla, California; Uppsala University, Uppsala, Sweden; Ormond Medical Arts, Ormond Beach, Florida; and Merck & Co., Inc., West Point, Pennsylvania.

Acknowledgments: The authors thank Drs. John Yates, Thomas Dobbins, Desmond Thompson, Richard Petruschke, Douglas Watson, and Walter Straus for reviewing this manuscript and for providing helpful comments. They also thank Dr. Nicholas Bellamy for providing the AUSCAN Osteoarthritis Hand Index and Drs. Thomas Schnitzer, Marc Hochberg, Arthur Weaver, Walter Straus, and Glenn Gormley for their input into study design. In addition, they gratefully acknowledge the contribution of Kathy O'Brien for assistance with manuscript preparation and for comonitoring this trial and Dr. Martino Laurenzi for comonitoring sites outside the United States.

Grant Support: By Merck & Co., Inc.

Potential Financial Conflicts of Interest: Employment: C.S. Skalky (Merck and Co., Inc.), M.E. Dixon (Merck and Co., Inc.), A.B. Polis (Merck and Co., Inc.), G.P. Geba (Merck and Co., Inc.); Consultancies: J.R. Lisse (Merck and Co., Inc.); Honoraria: J.R. Lisse (Merck and Co., Inc.); Stock ownership (other than mutual funds): C.S. Skalky (Merck and Co., Inc.), M.E. Dixon (Merck and Co., Inc.), A.B. Polis (Merck and Co., Inc.), G.P. Geba (Merck and Co., Inc.).

Requests for Single Reprints: Gregory P. Geba, MD, MPH, Merck & Co., Inc., HM-202, PO Box 4, West Point, PA 19486-0004; e-mail, gregory_geba@merck.com.

Current Author Addresses: Dr. Lisse: Department of Rheumatology, University of Arizona, 1501 North Campbell, Tuscon, AZ 85724.

Dr. Perlman: Scripps Clinic and Research Foundation, 10666 North Torrey Pines, La Jolla, CA 92037.

Dr. Johansson: Uppsala University, Nyby vårdcentral, Topeliusgatan 18, 754 41 Uppsala, Sweden.

Dr. Shoemaker: Ormond Medical Arts, 77 West Granada Boulevard, Ormond Beach, FL 32174.

Dr. Schechtman: Sun Valley Arthritis Center, Ltd., 6525 West Sack Drive, Glendale, AZ 85308.

Ms. Dixon: Merck & Co., Inc., HM-220, PO Box 4, West Point, PA 19486-0004.

Mr. Polis: Merck & Co., Inc., HM-601, PO Box 4, West Point, PA 19486-0004.

Dr. Mollen: Southwest Health Institute, 4602 North 16th Street, Phoenix, AZ 85016.

Ms. Skalky and Dr. Geba: Merck & Co., Inc., HM-202, PO Box 4,West Point, PA 19486-0004.

Author Contributions: Conception and design: G. Johansson, M.E. Dixon, A.B. Polis, G.P. Geba.

Analysis and interpretation of the data: J.R. Lisse, G. Johansson, C.S. Skalky, A.B. Polis, G.P. Geba.

Drafting of the article: G. Johansson, J. Schechtman, C.S. Skalky, G.P. Geba.

Critical revision of the article for important intellectual content: J.R. Lisse, M. Perlman, G. Johansson, J.R. Shoemaker, J. Schechtman, A.B. Polis, A.J. Mollen, G.P. Geba.

Final approval of the article: J.R. Lisse, M. Perlman, G. Johansson, J.R. Shoemaker, J. Schechtman, A.B. Polis, A.J. Mollen, G.P. Geba.

Provision of study materials or patients: J.R. Lisse, M. Perlman, G. Johansson, J. Schechtman, C.S. Skalky, M.E. Dixon, A.J. Mollen.

Statistical expertise: A.B. Polis, G.P. Geba.

Obtaining of funding: M.E. Dixon.

Administrative, technical, or logistic support: C.S. Skalky, M.E. Dixon.

Collection and assembly of data: G. Johansson, J.R. Shoemaker, C.S. Skalky, M.E. Dixon, A.J. Mollen.

Ann Intern Med. 2003;139(7):539-546. doi:10.7326/0003-4819-139-7-200310070-00005
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Several previous clinical trials have shown that rofecoxib was as effective as high doses of NSAIDs for osteoarthritis treatment (1819). However, NSAIDs can lead to serious GI events, such as perforations, ulcers, and bleeding, as well as more common symptoms, such as dyspepsia and abdominal pain. These symptoms may lead patients to discontinue treatment or add gastroprotective medications to improve tolerability.

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Figure 2.
Cumulative incidence of discontinuation due to gastrointestinal adverse events.Top.Bottom.

The incidence among the overall study sample. The incidence among patients who used low-dose aspirin. For both parts, Kaplan-Meier curves display the time course of cumulative incidence of discontinuations due to gastrointestinal adverse events by treatment group.

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Submit a Comment/Letter
Missing Safety Data and Merck-y Ethics in the ADVANTAGE trial
Posted on August 3, 2005
David S Egilman
Brown University, BS
Conflict of Interest: None Declared

To the Editor,

In their recent letter to the editor, Braunstein and Polis address the omission of important cardiovascular safety results from an October 2003 article on the ADVANTAGE trial in the Annals of Internal Medicine (1,2). The 2003 article by Lisse and colleagues (including Polis) reported no statistically significant differences for any cardiovascular endpoints in comparisons of Vioxx (rofecoxib) and naproxen in ADVANTAGE, a 12-week clinical trial. In fact, almost three years earlier, Merck gave the FDA a data table showing a statistically significant relative risk of 7 for cardiac events amongst patients on Vioxx compared to naproxen in the ADVANTAGE trial. The Merck data table is included in a three-page January 19, 2001 letter responding to the FDA*s request for additional information on the ADVANTAGE trial; it shows 7 serious adverse cardiac events on Vioxx (6 events adjudicated as myocardial infarction and 1 event adjudicated as sudden/unknown death) and 1 cardiac event on naproxen (1 adjudicated MI) (3). Additionally, another event in the table "reported as hypertensive heart disease and death by Merck" was re-classified by the FDA in November 2001 as a sudden/unknown death, pushing the cardiac event relative risk for Vioxx to 8 (4).

Merck*s January 19, 2001 letter and the FDA*s re-classification are emphatic evidence of Merck*s knowledge that the ADVANTAGE trial showed that Vioxx use caused an important and statistically significant excess risk of cardiac events in patients on Vioxx, namely MI and sudden/unknown death. Merck*s omission of this important risk information from its 2003 article in the Annals presents a serious public health hazard because it misled the medical community. In their Annals letter, Braunstein and Polis say that Merck's pre-defined procedures kept the case of hypertensive heart disease and death from being externally adjudicated hence, its exclusion from the APTC "cardiac event" group. Since Merck defined an external adjudication events list that kept out relevant events such as hypertensive heart disease, it was fortunate that the FDA adjudicated the case. Merck still omitted this information when they published the trial.

Underlying this already egregious omission of safety data is more deeply disturbing evidence of medicine run amok. Internal Merck documents reveal that the ADVANTAGE trial did not have a medical purpose per se. Instead, it was a "seeding trial," meant to seed the medical community with Merck's new drug before it was approved for the market. Thus, the deaths of patients on Vioxx in the trial were deaths in an unnecessary trial. The real subjects of the trial were the physician "investigators" (non-participants served as controls) chosen to participate by Merck sales representatives (5). Merck intended to promote the drug to influential doctors and their patients and analyze the prescribing information of these physician-investigators for marketing purposes. A Merck public relations supervisor instructed employees to avoid revealing the true purpose of the trial, "I ELIMINATED THE REFERENCE TO SEEDING. IT MAY BE A SEEDING STUDY, BUT LET'S NOT CALL IT THAT IN OUR INTERNAL DOCUMENTS (6)." [emphasis in original]

Merck*s conduct in designing, conducting, analyzing, and publishing the ADVANTAGE trial is disturbing at best. The ethical ramifications of deaths-on-drug in a "seeding trial" deserve a more thorough examination than is possible here. The practice of selectively reporting drug safety data is evidence of the need for complete and public disclosure - perhaps on the internet - of clinical trial data for new drugs. If anything, ADVANTAGE teaches us we cannot rely on drug companies to honestly report all of the important data.

Some documents cited in this commentary were obtained in Vioxx litigation and were previously confidential but since have been entered as evidence at trial and have been unsealed.

David S. Egilman, M.D., M.P.H. Amos H. Presler, B.A. degilman@egilman.com Brown University

References (1)Braunstein N, Polis A, Report of Specific Cardiovascular Outcomes of the ADVANTAGE Trial. Ann Intern Med. 2005;143:158-159.

(2)Lisse et al., Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med. 2003;139:539-546

(3)Silverman RE, Merck Research Laboratories, Letter to FDA, CDER: NDA 21-042/S-007: VIOXX* (rofecoxib tablets) Response to FDA Request for Information, January 19, 2001. MRK-AAF0003308-MRK-AAF0003310.

(4)Medical Officer Review, NDA 21-042 and NDA 21-052 (Rofecoxib tablets and rofecoxib oral solution) Re: Complete response to Approvable letter for 21-042/S 007 and 21-052/S 004 Submission date (letter): July 12, 2001 End of Review date: November 28, 2001, at page 10 ,, Reviewer: Maria Lourdes Villalba, M.

(5)Smith B, to Webb J. Communication: Re: Vioxx Seeding Study Selection. MRK-AFB0001598

(6)Higbee, Rebecca email to: Lindemann, Kyra; Fanelle, Christine; Weiner, Jan D, Subject: ADVANTAGE ideas, Friday, March 19, 1999 MRK-ACX0002969- MRK-ACX0002974.

Conflict of Interest:

Dr. Egilman has served as an expert witness in Vioxx Litigation. Mr. Presler is employed by Dr. Egilman.

Posted on May 5, 2006
Harold C Sox
Annals of Internal Medicine
Conflict of Interest: None Declared

We recently published a letter by Egilman and Presler (1) that cited a letter from a Merck & Co. Inc. official to the US Food and Drug Administration (FDA) (reference 3 in the Egilman and Presler letter). The cited letter reported patients that Merck & Co. Inc. had adjudicated as having had a myocardial infarction (6 patients) and sudden death (one patient) while on Vioxx during the ADVANTAGE trial (2). Dr. Braunstein, another Merck & Co. Inc official, reviewed the cited letter at our request and wrote to say that it contained an error. The correct numbers of adjudicated events were 5 myocardial infarctions and 2 sudden deaths, as documented by materials submitted by Merck & Co. Inc. to the FDA along with the letter that contained the error. Table 2 of a Letter to the Editor from Dr. Braunstein also contains the correct number of events (3).

Harold C. Sox, M.D. Editor

Cynthia Mulrow, M.D., MSc Deputy Editor


1. Egilman and Presler letter

2. Lisse JR, Perlman M, Johansson G, Shoemaker JR, Schechtman J, Skalky CS, Dixon ME, Polis AB, Mollen AJ, Geba GP for the ADVANTAGE Study Group. Gastrointestinal Tolerability and Effectiveness of Rofecoxib versus Naproxen in the Treatment of Osteoarthritis: A Randomized, Controlled Trial. Ann Intern Med, Oct 2003; 139: 539 - 546.

3. Braunstein N, Polis A. Report of Specific Cardiovascular Outcomes of the ADVANTAGE Trial. Ann Intern Med, Jul 2005; 143: 158 - 159.

Conflict of Interest:

None declared

Submit a Comment/Letter

Summary for Patients

Gastrointestinal Side Effects of Rofecoxib and Naproxen

The summary below is from the full report titled “Gastrointestinal Tolerability and Effectiveness of Rofecoxib versus Naproxen in the Treatment of Osteoarthritis. A Randomized, Controlled Trial.” It is in the 7 October 2003 issue of Annals of Internal Medicine (volume 139, pages 539-546). The authors are J.R. Lisse, M. Perlman, G. Johansson, J.R. Shoemaker, J. Schechtman, C.S. Skalky, M.E. Dixon, A.B. Polis, A.J. Mollen, and G.P. Geba, for the ADVANTAGE Study Group.


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