NSAID Hysteria -- Chicken Little Revisited

[Guest guest]

This is an excellent commentary on Bextra and other -2's, written by

2 rheumatologists.

NSAID Hysteria -- Chicken Little Revisited

Posted 4/13/2005

A. Goldman, MD, FACP, FACR, FASLMS, CCD; Sanford S. Hartman, MD,

MBA

Chicken Little felt a drop of rain and thought that the sky was

falling![1]

As practicing rheumatologists with over 65 (35 + 30) years in

rheumatology, we are disturbed by the data " sensationalizing " the

adverse gastrointestinal, renal, and cardiovascular outcomes associated

with nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase

(COX)-2 NSAIDs (COX-1 sparing).[2-12] This is not completely new

information (ie, some data are newer than others), and if one reviews

all of these drugs, many other adverse outcomes can be readily

noted.[2,3, 8-11] There are no side-effect-free medications, and the

physician tries the best that he or she can to minimize the

risk-benefit ratio of any therapeutic regimen. There are far more

dangerous drugs with potentially worse outcomes, and we use them all of

the time. (Would someone like to profile the potential toxicities of

corticosteroids, preparations that seem to be used far more glibly than

the COX-2 inhibitors?) If aspirin were first coming on the market now

as a medication for pain, arthritis therapy, headache therapy, and

fever control, would anyone feel any safer taking a medication with

life-threatening side effects, such as gastrointestinal bleeding and

other types of hemorrhage, potentially fatal allergic-like reactions

(including anaphylaxis), or less risky side effects (such as skin

purpura)? If accepted now, it would be required to have a " black box "

warning.

So, Chicken Little told Henny Penny . . .

We support all of these medications being available. Many of our

previous rofecoxib ( Vioxx ) patients are now without a suitable

alternative (translation -- miserable). They have tried other

anti-inflammatory agents without success or with side effects and/or

risks worse than the presumed risks of the COX-2s.[4-12] The COX-2s

have multiple benefits, including reduced adverse gastrointestinal

outcomes; a lack of antiplatelet activity; decreased rectal polyp

proliferation; preoperative pain relief with less need for narcotics

and less risk of bleeding; no interference with aspirin

cardioprophylaxis; control of pain; migraine therapy (available as a

liquid for children); and improvement in fever, headaches, arthritis,

and inflammation. We use them in different patients for different

reasons.

Then, Chicken Little and Henny Penny told Ducky Lucky . . .

Patients make choices all of the time. They are willing to take

medication risks when they believe that it is worth the possibilities

of escaping the misery of their diseases and leading more productive

and functional lives. We call this quality of life. Our patients have

many needs: work, child care, shopping, taking their children to the

circus, treating their migraines, cooking their food, and other

activities of daily living. As rheumatologists, like all physicians,

with patient guidance and consent, we have used medications with

varying levels of risk. Patients are much more aware of the risks of

medications than at any time in the past. They hear statements or

misstatements from a growing cadre of " experts " -- all the way from the

not-so-saintly press, to the opportunistic legal community, to the

bandwagon-jumping politicians. They also hear this information from

their local pharmacists (if they're allowed to have one in lieu of some

mail-off " bargain " ), their personal physicians (who one hopes are

properly informed), and the overzealous public media advertising that

is so near and dear to the hearts of the pharmaceutical industry. They

hear comments that they can use other NSAIDs because they are all the

same in studies. From criteria that are measured in studies, this may

appear to be so, but with individual patients these others may not

work. They are on rofecoxib after having tried all of the other " pain

relievers. " All this is confounded by the fact that the peer-reviewed

literature on the increased cardiovascular risk profiles of rofecoxib,

celecoxib ( Celebrex ), and valdecoxib ( Bextra )* have not been

completely published and are still under investigation. We are getting

" pundate data " from the press, and decisions are being made on a lack

of data. We, as physicians, have to treat patients with the " best data

we have available " (à la Rumsfeld), and we decry decreasing our

choices when we can risk-stratify and treat accordingly. In some, we

may have to add a baby aspirin a day even though we do not have

randomized, double-blind, controlled, 3-year studies to tell us that

this is the best choice to make. And there may be differences between

men and women.[13,14] In fact, we do not have randomized, controlled,

double-blind, 3-year cardiovascular studies on any of the other NSAIDs

or COX-2s beyond rofecoxib.[10] We suspect that we would see problems

with some or all of them, NSAIDs and COX-2s, in such a designed study.

The " best data we have available " are so far not good enough. We have

observational trial " signals, " which used to be called " trends " in our

literature.

Then, Chicken Little and Henny Penny and Ducky Lucky told Goosey Lucy .

.. .

The decision to remove rofecoxib from the market was a corporate

decision. Some agree with that decision, but we do not. We are from

Atlanta, Georgia, and remember another misguided corporate decision --

that of Coca Cola removing Classic Coke from the market for New Coke .

At least they were wise enough to eventually bring back Classic Coke .

We hope that Merck may see the wisdom of bringing rofecoxib back with

whatever warnings are necessary -- and maybe a little less (or

preferably no) TV, radio, and print media carrots of unreasonable

expectation. Instead of pharmaceutical companies " trash marketing "

their products to physicians and the public by denigrating the

competition, maybe a little honesty and full disclosure of " the good,

the bad, and the ugly " by the pharmaceutical industry will go a long

way. (Have we all sunk to the level of those running for office in this

country?) Good science would go a long way here. In one of our offices,

we have a sign on the drug closet -- the " Rheumatology No-Spin Zone. "

Then, Chicken Little and Henny Penny and Ducky Lucky and Goosey Lucy

all told Turkey Lurkey . . .

We have seen other public outcries over the years bring medical data to

the physician and public (daily aspirin, thalidomide, estrogens,

cholesterol, calcium, and L-tryptophan -- to name a few). In

rheumatology we are having a problem helping our patients with the

shortage or presumed shortage of injectable methotrexate. Other drugs

have recently been removed from the market, including cervastatin (

Bayco ), alosetron ( Lotronex ), cisaprid ( Prepulsid ), and

troglitazone ( Rezulin ). The controversy over hormone therapy after

the Woman's Health Initiative (WHI) and even now over whether children

or the elderly should get flu vaccines keeps this discussion timely.

Sometimes the fanfare outweighs the information; sometimes the

information is extremely helpful; and sometimes the conclusions of the

prematurely released information change when more information becomes

available. Interpretations and misinterpretations of data are rampant,

and, unfortunately, some of our own professional organizations are too

timid to enter the fray. Statistics -- even correct ones -- are open to

such disparate interpretations that Mark Twain probably stated it best

with his comment: " There are lies, damn lies and statistics.[15] "

Scientific data need rigorous evaluation and reevaluation. We encourage

adequately powered, controlled, head-to-head trials to ably tell the

differences between the products. These latter type of data should be

required by the US Food and Drug Administration (FDA) and by other

regulatory agencies in other countries. Now we have only placebo or

nonplacebo, controlled trials that may or may not compare " similar "

drugs.

Finally, Chicken Little, Henny Penny, Ducky Lucky, Goosey Lucy, and

Turkey Lurkey all looked up in the sky themselves . . .

We believe that the scientific community must take control. Allowing

the trial lawyers to run the show is akin to crying " fire " in a crowded

theater. ( " Have you been harmed by rofecoxib, celecoxib, or

valdecoxib? " " Or " ...over 100,000 people have died from

rofecoxib.... " ) Even worse, one critical pundant was on the board of a

hedge fund, Great Point Partners, whose investment successes are

potentially directly affected by his publicly expressing his " medical

opinion.[16] " Although he defended himself by saying that he never

discussed Merck and resigned as a $12,000/year advisor, this still

implies a serious conflict of interest.[17] Allow the scientific

community to see the data, and if that is really what it says, then let

the chips fall where they may. But let's get rid of the emotional and

outrageous attacks, and let's not allow our scientific peers to be

silent on a matter of such importance to our patients.

We had written this essay before the FDA hearings of February 16-18,

2005, and having only seen the press releases and reviews, we believe

that their critique is consistent with what we have written here.[18]

And, what did they find? It was only sprinkling.

*The removal of valdecoxib (Bextra) from the market on April 8, 2005

continues to confound this issue for our patients and confuses the

medical and patient community. As rheumatologists, we completely

disagree with this removal but would agree to " black box " warnings for

all of these medications. While patients in studies develop problems,

the quality-of-life issues for our patients are not completely covered

in studies, because studies are in groups and our patients are

individuals, whom we treat as individuals. Their specific problems

include their medical comorbidities, work status, family needs, and

psychological issues, which cannot be individualized in a study of

large populations. Every physician needs to approach a therapeutic

decision with all of this information. We need to access both the risks

and benefits with all medications, including these. See: FDA Public

Health Advisory. FDA announces important changes and additional

warnings for COX-2 selective and non-selective non-steroidal

anti-inflammatory drugs (NSAIDs). Available at:

http://www.fda.gov/cder/drug/advisory/COX2.htm. Accessed April 8, 2005.

References

1. The Story of Chicken Little (an English Fable, author unknown).

There are many versions with many items having fallen from the sky

(acorn, pebble, raindrop, etc) and with various outcomes (see Foxy

Loxy); all teach the same lesson.

2. Bombradier C, Laine L, Reicin A, et al; Vigor Study Group.

Comparison of upper gastrointestinal of rofecoxib and naproxen in

patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520-1528.

Abstract

3. Silverstein FE, Faich P, Goldstein JL, et al. Gastrointestinal

toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for

osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized

controlled trial. JAMA. 2000;284:1247-1255. Abstract

4. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M.

Risks of cardiovascular events and rofecoxib: cumulative meta-analysis.

Lancet. 2004;364:2021-2029. Abstract

5. Discontinuation of Vioxx correspondence. Lancet. 2005;365:23-28.

6. Kimmel SE, Berlin JA, Muredach R, et al. Patients exposed to

rofecoxib and celecoxib have different odds of nonfatal myocardial

infarction. Ann Intern Med. 2005;142:157-164. Abstract

7. Finckh A, Aronson MD. Cardiovascular risks of cyclooxygenase-2

inhibitors: where we stand now. Ann Intern Med. 2005;142:212-214.

Abstract

8. SD, McMurray JVJ, Pfeffer MA, et al; Adenoma Prevention

with Celecoxib (APC) Study Investigators. Cardiovascular Risk

Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma

Prevention. N Engl J Med. 2005;352:1071-1080. Available at:

http://content.nejm.org/cgi/content/short/352/11/1071 Accessed March 7,

2005.

9. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the

COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery. N Engl

J Med. 2005;352:1080-1091. Available at:

http://content.nejm.org/cgi/content/short/NEJMoa050330 Accessed March

7, 2005.

10. Bresalier RS, Sandler RS, Quan H, et al; Adenomatous Polyp

Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular

Events Associated with Rofecoxib in a Colorectal Adenoma

Chemoprevention Trial. N Engl J Med. 2005;352:1092-1102. Available at:

http://content.nejm.org/cgi/content/abstract/NEJMoa050493 Accessed

March 7, 2005.

11. Drazen JM. COX-2 inhibitors -- a lesson in unexpected problems. N

Engl J Med. 2005;352:1131-1132. Available at:

http://content.nejm.org/cgi/content/short/NEJMe058038 Accessed March 7,

2005.

12. Psaty BM, Furberg CD. COX-2 inhibitors -- lessons in drug safety.

Available at: http://content.nejm.org/cgi/content/short/NEJMe058042 N

Engl J Med. 2005;352:1133-1135. Accessed March 7, 2005.

13. Antithrombotic Trialists Collaboration. Collaborative

meta-analysis of randomised trails of antiplatelet therapy for

prevention of death, myocardial infarction, and stroke in high risk

patients. BMJ. 2002:324:71-86. [Erratum. BMJ. 2002;324:1421].

14. Ridker PM, Cook NR, Lee I-Min, et al. A randomized trial of

low-dose aspirin in the primary prevention of cardiovascular disease in

women. Available at:

http://content.nejm.org/cgi/content/abstract/NEJMoa050613 Accessed

March 7, 2005.

15. Columbia World of Quotation. 1996. Number: 16799. Available at:

http://www.bartleby.com/66/99/16799.html Accessed March 8, 2005.

16. McLean B. Ethics: a bitter pill for one Merck critic. Topol

sat on the medical advisory board of a hedge fund that was selling

Merck short. Fortune Magazine. Available at:

http://www.fortune.com/fortune/articles/0%2C15114%2C832265%2C00.html

Accessed March 8, 2005.

17. Herper M. Vioxx critic defends self. Forbes.com. December 1,

2004. Available at:

http://www.forbes.com/2004/12/01/cx_mh_1201topol_print.html Accessed

March 8, 2005.

18. The safety of COX-2 inhibitors: deliberations from the February

16-18, 2005 FDA Meeting. American College of Rheumatology " Hotline. "

Available at:

http://www.rheumatology.org/publications/hotline/0305NSAIDs.asp

Accessed March 7, 2005.

19. Okie S. Raising the safety bar -- the FDA's ib meeting. N Engl

J Med. 2005;352:1283-1285.

A. Goldman, MD, FACP, FACR, FASLMS, CCD , Clinical Professor of

Medicine, Rheumatology and Immunology, Department of Medicine, Division

of Rheumatology and Immunology, Emory University School of Medicine,

Atlanta, Georgia; Private Practice, Rheumatology, North Atlanta,

Georgia

Sanford S. Hartman, MD, MBA , Clinical Associate Professor of Medicine,

Rheumatology and Immunology, Department of Medicine, Division of

Rheumatology and Immunology, Emory University School of Medicine,

Atlanta, Georgia; Private Practice, Decatur, Georgia.

jointdoc@...

Disclosure: A. Goldman, MD, FACP, FACR, FASLMS, CCD, has disclosed

that he owns stock, stock options, or bonds in Amgen; that he has

received grants for clinical research from Amgen and Actelion; that he

has received grants for educational activities from Amgen, Merck,

Wyeth, Lilly, Procter & Gamble, Pfizer, and Abbott; and that he has

served as an advisor or consultant for Amgen. Dr. Goldman has also

disclosed that he was an investigator in the epidemiologic study called

" Uncover, " sponsored by Actelion; that he is a participant in and a

board member of RADIUS (Rheumatoid Arthritis DMARD Utilization Study);

and that he is chairman of the Third Party Payors Committee of the

Medical Association of Georgia.

Disclosure: Sanford S. Hartman, MD, MBA, has disclosed that he owns

stock, stock options, or bonds in Amgen; that he has served as an

advisor or consultant for Cypress Bioscience; and that he has been an

investigator for Amgen, Aventis, Immunex, MedImmune, Pfizer, and Roche.

Medscape General Medicine. 2005; 7 (2): ©2005 Medscape

http://www.medscape.com/viewarticle/501589