| Safety Scrutiny for New Class of Musculoskeletal Pain Drugs |
by David W. Sharp |
|
WHAT'S HOT IN MEDICINE
|
| Rank |
Paper |
Citations
This
Period
Jul-
Aug 01 |
Rank
Last
Period
May-
Jun 01 |
| 1 |
S. Yusuf, et al., “Effects of angiotensin-converting enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients,” New Eng. J. Med.,
342(3):145-53, 20 January 2000. [Hamilton Gen. Hosp., Ont., Canada] *275ZT |
33 |
6 |
| 2 |
C. Bombardier, et al.,
“Comparison of upper
gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid
arthritis,” New Engl. J. Med., New Engl. J. Med., 343(21):1520-8, 23
November 2000. [14 institutions
worldwide] *375PR |
33 |
† |
| 3 |
P.M. Ridker, et al.,
“C-reactive protein and other
markers of inflammation in the prediction of cardiovascular disease in women,” New
Engl. J. Med., 342(12):836-43, 23 March 2000. [Brigham & Women's Hosp.,
Boston, MA; Harvard U. Sch. Med., Boston; Children's Hosp., Boston] *296FU |
31 |
10 |
| 4 |
A. Kugler, et al., “Regression of human metastatic renal cell carcinoma after vaccination
with tumor cell-dendritic cell hybrids,”
Nature Medicine, 6(3):332-6,
March 2000. [U. Gottingen, Germany; U. Tubingen, Germany; Humboldt U., Berlin,
Germany] *288TL |
31 |
5 |
| 5 |
F.E.
Silverstein, et al., “Gastrointestinal toxicity with celecoxib
vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid
arthritis. The CLASS study: a randomized controlled trial,” JAMA-J.
Amer. Med. Assn., 284(10):1247-55, 13 September 2000. [12 U.S. institutions] *350WL |
30 |
† |
| 6 |
A.M.J. Shapiro,
et al., “Islet transplantation in seven patients with type 1 diabetes mellitus
using a glucocorticoid-free immunosuppressive regimen,” New
Engl. J. Med., 343(4):230-8, 27 July 2000. [U. Alberta, Edmonton, Canada]
337Q |
28 |
7 |
| 7 |
T.C. Quinn, et al., “Viral load and heterosexual transmission
of human immunodeficiency virus type 1,”
New Engl. J. Med.,
342(13):921-9, 30 March 2000. [Johns Hopkins U., Baltimore, MD; NIAID,
Bethesda, MD; Columbia U., New York, NY; Makerere U., Uganda] *299DC |
23 |
† |
| 8 |
G.R. Bernard, et al.,
“Efficacy and safety of recombinant
human activated protein C for severe sepsis,” New Engl. J. Med.,
344(10):699-709, 8 March 2001. [9
institutions worldwide] *408AX |
22 |
† |
| 9 |
S. Singhal, et al., “Antitumor activity of thalidomide in
refractory multiple myeloma,” New Engl. J. Med., 341(21):1565-71, 18 November 1999. [U. Arkansas Med. Sch., Little Rock; U. South Carolina, Columbia;
Rockefeller U., New York, NY] *256GF |
21 |
3 |
| 10 |
D.J. Slamon, et al.,
“Use of chemotherapy plus a monoclonal
antibody against HER2 for metastatic breast cancer that overexpresses HER2,” New
Engl. J. Med., 344(11):783-92, 15 March 2001. [9 institutions
worldwide] *410LA |
21 |
† |
SOURCE:
ISI’s Hot
Papers Database. 
the Legend. |
|
 ast
summer the media on both sides of the Atlantic drew attention to the safety of
a new group of drugs called selective cyclooxygenase type 2 (COX-2) inhibitors
or “coxibs.” This is also the subject of three papers in
the latest Science Watch listings:
#2 on rofecoxib, #5 on celecoxib, and #13, which is an overview of eight
trials of rofecoxib by M.J. Langman and coleagues in JAMA (282(20):1929-33, November 24, 1999; 18
citations this period). The development of COX-2 inhibitors stemmed from
research into the mechanism of action of nonsteroidal antiinflammatory drugs,
or NSAIDs. Or perhaps we should say mechanisms of action, because NSAIDs
inhibit the synthesis of two sorts of prostaglandin, one involved in pain and
the other involved in protecting the gastrointestinal tract. For alleviation of
pain in the musculoskeletal system there was a price to be paid elsewhere, in
the gut. Selective COX-2 inhibitors leave COX-1 and the protective role alone.
Enzyme studies of the COX-2 inhibitors
celecoxib and rofecoxib were encouraging, as were gastroscopic findings in
people taking these drugs. Papers #2, #5 and #13 are more directly related to
everyday clinical practice and point to a reduction, by roughly 50%, of
gastrointestinal risks in comparison with well-established, non-selective
NSAIDs, with no loss of efficacy. However, both JAMA papers (#5 and #13) were
accompanied by cautious editorials along the linesof “better but less than perfect” and “firmer cost-benefit evidence required” (the quotes are mine but
this is the gist). Caution is understandable; for one thing U.S. prescriptions
for NSAIDs amounted to almost $2 billion, on one 1999 estimate.
In August, 2001, JAMA published a paper
from Dr. Eric J. Topol and colleagues at the Cleveland Clinic in Ohio (see D.
Mukherjee, S.E. Nissen, E.J. Topol, 286[8]:954-9, 2001). This raised a "cautionary flag" concerning the risk of cardiovascular events with COX-2 inhibitors.
Most of the data used in this analysis came from the VIGOR trial (the Vioxx
Gastrointestinal Outcomes Research Study—Vioxx being the trade name of
rofecoxib), where the incidence of myocardial infarction was significantly
higher with rofecoxib than in the control (naproxen) group, and from the CLASS
trial (Celecoxib Longterm Arthritis Safety Study), published as #2 and #5, respectively.
The waving of this flag from Cleveland
attracted a lot of attention, and as 2001 came to a close its meaning was still
being fiercely debated—for example, in opinion pieces in the journal Clinical
and Experimental Rheumatology (19[6 Suppl. 25]:S31-6, 2001).
Two-edged swords are often encountered in
clinical pharmacology, and with the cyclooxygenases the further complication,
in cardiovascular terms, is that COX-2 inhibitors interfere with prostacyclin
production in vessel walls, providing a possible explanation for any increase
in cardiovascular risk with such drugs, were that to be confirmed. The other
explanation offered for the VIGOR data is that naproxen (the control drug) was
cardioprotective but a recent retrospective study of non-aspirin NSAIDs,
including naproxen (see W.A. Ray, et al., Lancet, 359[9301]:118-23, 12 January
2002), casts some doubt on this .
Mr. David W. Sharp, M.A. (Cambridge), was deputy editor of
The Lancet, London, U.K., from 1976 to May, 2001; he is currently a contributing editor to that journal.
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