COX-2 Inhibitors and Other NSAIDs Increase Mortality in Acute MI Patients

From Medscape Medical News

by Martha Kerr

Nov. 15, 2005 (Dallas) — An analysis of data from a nationwide registry shows that the use of selective cyclooxygenase-2 (COX-2) inhibitors is contraindicated in acute myocardial infarction (MI) patients. The data also show that only low doses of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) should be used in this population, because the drugs work through both the COX-1 and COX-2 pathways.Data on 58,432 patients in the Danish National Patients' Registry discharged from hospitals between 1995 and 2002 after a first MI were presented here by Gunnar H. Gislason, MD, from Bispebjerg University in Copenhagen, Denmark, at the American Heart Association 2005 Scientific Sessions. Patients in the analysis had taken NSAIDs, including COX-2 inhibitors, at least once. Of these, 5.2% had taken rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% had taken other NSAIDs. "The treatment time [with NSAIDs] on average was about one month, corresponding to the expectation that these drugs were being used for various sources of pain," Dr. Gislason told Medscape. He and his colleagues reported that all NSAIDs were associated with an increased risk of all-cause mortality, which increased further when higher doses were used. However, NSAIDs, including selective COX-2 inhibitors, did not increase the risk of recurrent MI. "Differences in risk within NSAIDs were as great as between selective COX-2 inhibitors and other NSAIDs," the researchers noted in their study abstract. "There was a trend for slightly elevated risk of recurrent MI associated with the COX-2 inhibitors [hazard ratio, 1.5], but this was not statistically significant," Dr. Gislason announced. "One possible explanation was that the increased mortality was due to the higher occurrence of fatal MIs, which caused patients to die before they reached hospital. We are currently looking at death certificates to explore if there is some specific cause of death more common than another."Hazard ratios for all-cause mortality according to specific NSAIDs included celecoxib at more than 200 mg/day, 4.24; rofecoxib at more than 25 mg/day, 5.03; diclofenac at more than 100 mg/day, 3.76; ibuprofen at more than 1,200 mg/day, 1.96; unspecified NSAIDs, 1.22 (P < .001 for all comparisons)."Since all patients had suffered a previous MI, the majority were taking prophylactic aspirin. Aspirin could therefore play a key role in preventing thrombosis in patients taking NSAIDs or COX-2 inhibitors, but there were other harmful mechanisms of [NSAIDs and COX-2 inhibitors] that increased mortality," Dr. Gislason said.Robert O. Bonow, MD, chief of the division of cardiology at Northwestern Feinberg School of Medicine in Chicago, Illinois, and past president of the American Heart Association, told Medscape that the proven benefits of aspirin after MI may have diluted the adverse effects seen with NSAIDs. "This is a major limitation of the study," he pointed out.Dr. Gislason said that "patients who suffer from MI are in an age class where rheumatic problems are common and an indication for an NSAID [or a COX-2 inhibitor] is often present. With the results of the current study, the advice to post-MI patients should be to not use COX-2 inhibitors and use NSAIDs only at low doses.""Physicians should discuss the risks involved with these drugs with their patients," Dr. Bonow advised. "You need to evaluate the risks of NSAIDs for high-risk heart patients against their benefits. For instance, being active is good for the heart, and NSAIDs may facilitate exercise."AHA 2005 Scientific Sessions: Abstract 1838. Presented Nov. 13, 2005.

FDA Safety Labeling Changes: Celebrex

News Author: Yael Waknine
From Medscape Medical News

Nov. 9, 2005 — The U.S. Food and Drug Administration (FDA) has approved safety labeling revisions to advise that celecoxib therapy is linked to risks for cardiovascular, gastrointestinal, renal, and dermatologic adverse events.

Celecoxib (Celebrex) Linked to Multiple Adverse Events
On July 29, the FDA approved safety labeling revisions for the nonsteroidal anti-inflammatory (NSAID) drug celecoxib (Celebrex capsules, made by Pfizer Global Pharmaceuticals) to warn of contraindications and warnings associated with this class of drugs and to emphasize the need to minimize its use to the lowest effective dose for the shortest possible duration.

Use of a NSAID similar to celecoxib for pain management during the first 10 to 14 days after coronary artery bypass graft (CABG) surgery has been linked to an increased risk for myocardial infarction (MI) and stroke; use of celecoxib in this setting is therefore contraindicated.

The FDA also warned that chronic use of celecoxib may be linked to an increased risk for serious and potentially fatal cardiovascular thrombotic events, MI, and stroke. As with other NSAIDs, these risks may increase in the presence of existing cardiovascular disease and/or related risk factors.

The warning was based on results of the Prevention of Sporadic Colorectal Adenomas with Celecoxib trial in 1,356 patients, showing that use of 400 mg of celecoxib twice daily was linked to a 3.4-fold increase in the composite risk of cardiovascular death, MI, or stroke, relative to placebo (95% confidence interval [CI], 1.4 - 8.5). In patients receiving 200 mg of celecoxib twice daily, the relative risk was 2.4 (95% CI, 1.0 - 6.4).

The FDA notes that there is no consistent evidence that concurrent use of low-dose aspirin mitigates the increased risk for serious cardiovascular thrombotic events associated with celecoxib use.

Also, data from the Celecoxib Long-Term Arthritis Safety Study (CLASS) of 8,000 patients have linked concomitant use of low-dose aspirin and 400 mg of celecoxib twice daily to an increased risk for serious gastrointestinal adverse events compared with celecoxib alone (2.19% vs 0.78%). This risk was further increased in the elderly (3.06% vs 1.40%).

A 400-mg dose of celecoxib twice daily is twofold and fourfold the recommended dose for osteoarthritis and rheumatoid arthritis, respectively, and the approved dose for familial adenomatous polyposis.

As with all NSAIDs, use of celecoxib can lead to the onset of new hypertension or worsening of preexisting disease, either of which may lead to an increased incidence of cardiovascular events.

Fluid retention and edema have also been observed in patients receiving NSAIDs, such as celecoxib. In the CLASS study, the Kaplan-Meier cumulative rates of peripheral edema at nine months in patients receiving 400 mg of celecoxib twice daily, 800 mg of ibuprofen three times daily, and 75 mg of diclofenac twice daily were 4.5%, 6.9%, and 4.7%, respectively.

The FDA advises that celecoxib be prescribed with caution in patients with fluid retention or heart failure. Because concurrent use of NSAIDs may impair response to treatment with thiazides or loop diuretics, close monitoring of blood pressure is recommended.

In the CLASS study, hypertension was observed in 2.4%, 4.2%, and 2.5%, respectively, in patients receiving celecoxib, ibuprofen, and diclofenac.

Celecoxib and other NSAIDs are also associated with an increased risk for serious and potentially fatal gastrointestinal adverse events, particularly in the elderly. Bleeding, ulceration, and perforation of the stomach or intestines may occur at any time during therapy and without warning symptoms; only one in five patients who develop a serious upper gastrointestinal tract adverse event while receiving NSAID therapy is symptomatic.

The FDA notes that the risk of developing a gastrointestinal bleed is 10-fold greater in patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding, and NSAIDs should therefore be prescribed with extreme caution in this population.

Other factors that increase the risk of bleeding include concomitant use of oral corticosteroids, anticoagulants, longer duration of therapy, smoking, alcohol consumption, advanced age, and poor general health status. Because most spontaneous reports of fatal gastrointestinal events are in elderly or debilitated patients, special care should be taken in treating this population.

Papillary necrosis and other renal injuries have been observed with long-term administration of celecoxib and other NSAIDs. In patients for whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion, NSAIDs may cause a dose-dependent reduction in prostaglandin formation that may precipitate overt renal decompensation.

Patients with impaired renal function, heart failure, liver dysfunction, the elderly, and those taking diuretics and angiotensin-converting enzyme inhibitors are at greatest risk for this reaction. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

The FDA notes that no controlled clinical trials of celecoxib in patients with advanced renal disease have been performed; its use is therefore not recommended in this population. If celecoxib therapy must be initiated, close monitoring of renal function is advised.

As a sulfonamide, celecoxib can cause serious and potentially fatal dermatologic adverse events, such as exfoliative dermatitis, Steven Johnson syndrome, and toxic epidermal necrolysis. These can occur without warning and in patients with no history of sulfa allergy. The FDA advises discontinuation of celecoxib therapy at the first appearance of skin rash or any other sign of hypersensitivity.

Celecoxib capsules are indicated for the relief of signs and symptoms associated with rheumatoid arthritis in adults, osteoarthritis, and ankylosing spondylitis; treatment of acute pain in adults; treatment of primary dysmenorrhea; and for use as an adjunct to usual care to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis.

Folic Acid Reduces Methotrexate Efficacy

By Anne Harding

NEW YORK (Reuters Health) Nov 08 - A new study provides additional evidence that folic acid can reduce the efficacy of methotrexate.
Methotrexate inhibits dihydrate folate reductase and thus reduces levels of folate in the body, Dr. Dinesh Khanna of the University of Cincinnati in Ohio noted in an interview with Reuters Health. This can lead to mouth sores and other side effects.
While nearly all US patients on methotrexate receive folic acid to prevent side effects, Dr. Khanna said, European physicians tend only to prescribe folic acid when such side effects actually occur.
"There has been a debate for a while in the medical field on whether folic acid can affect efficacy," he added.
To investigate, Dr. Khanna and his team pooled data from a US and a European study of rheumatoid arthritis patients receiving methotrexate as a comparator in randomized controlled trials of leflunomide. They analyzed primary outcome data at 52 weeks for a total of 668 patients, 225 of whom were taking folic acid and 443 of whom were not.
The researchers used a statistical technique called propensity scoring to adjust for the substantial baseline differences between the patients who were taking folic acid and those who were not.
Seventeen percent more patients in the group that did not receive folic acid met American College of Rheumatology (ACR) improvement criteria by week 52 of the study, while ACR 50% responses were 14% higher in the non-folic acid group and ACR 70% responses were 12% higher.
Twenty nine-percent of patients in the US study, most of whom were on folic acid, had elevated liver transaminase levels, compared with 62% of patients in the European study, most of whom were not taking folic acid.
The current findings are based on post-hoc analysis, and should be considered "hypothesis generating," the researchers write in the October issue of Arthritis & Rheumatism.
However, Dr. Khanna added, physicians should be aware that when their rheumatoid arthritis patients taking methotrexate are started on folic acid, they may have a flare-up of the disease. "This is something to keep in mind," he said. "These patients may require a higher dose of methotrexate."

Arthritis Rheum 2005;52:3030-3038.

New guidelines for steroid-induced osteoporosis

Rheumawire news (from Jointandbone.org)

November 7, 2005 Janis Kelly

Brussels, Belgium - Dr Jean-Pierre Devogelaer and colleagues in the Belgian Bone Club report a set of evidence-based guidelines for the prevention and treatment of glucocorticoid (GC)-induced osteoporosis in Osteoporosis International [1]. The guidelines largely validate what has been standard practice for many clinicians but carry a heightened warning about the risk of osteoporosis associated with even low doses of glucocorticoids.

"There is no safe GC dose. Bone-mineral density [BMD] should be checked soon after start of GC therapy. Effective preventive therapy for osteoporosis exists!" Devogelaer tells rheumawire.

Treatment, BMD monitoring recommended with GC use
The guidelines recommend that physicians treating patients on GCs:

Give all patients taking GCs supplemental calcium and vitamin D.
Urge them to exercise regularly and to avoid tobacco and alcohol.
Consider hormone-replacement therapy in young postmenopausal females as well as in postmenopausal women and in men with low androgen levels.
Add calcitonin or bisphosphonates in cases of long-term GC use.
"These recommendations are not frankly different from the former ones, but they are necessary because preventive therapy is still too infrequently prescribed in prevention of GC osteoporosis," Devogelaer says. He notes that all patients on GCs are threatened with osteoporosis and that prevention and/or therapy should be considered for osteopenic premenopausal females and for males on a daily dose equivalent to 7.5 mg/day or more of prednisolone, as well as for postmenopausal women.

The authors write, "Supplemental calcium and vitamin D should be considered as the first-line therapy because of the decrease in intestinal calcium absorption provoked by GCs. They also could be considered either as isolated therapy in patients taking less than 7.5 mg prednisolone daily and/or for a predicted period shorter than three months or as adjuvant therapy to other more potent drugs."

The guidelines recommend maintaining therapy as long as the patient is taking GCs but note that it might be stopped after weaning from GCs because there is evidence that BMD recovers when GCs are stopped.

The analysis did not demonstrate any benefit from combining two antiresorptive agents or one antiresorptive agent plus an anabolic agent.

Several questions remain about the optimal agents and schedule for preventing GC-related bone loss. Devogelaer pointed to the need for prospective studies to determine the appropriate duration of bisphosphonate therapy.

Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists.

From Biocritique.com

The goal of this study was to determine the cancer pattern of patients with rheumatoid arthritis (RA) from both prevalent and incident RA cohorts and understand the risk of solid cancer after treatment with tumor necrosis factor (TNF) inhibitors. The investigators took a population based study of 3 RA cohorts (1 prevalent), admitted to the hospital 1990 – 2003 (N=53,060), 1 incident, diagnosed 1995 – 2003 (N=3,703), and one treated with TNF antagonists from 1999 – 2003 (N=4,116), which were linked to a Swedish nationwide cancer registry and followed up for cancer occurrence through 2003. The main conclusions from this study were that the cancer pattern in patients treated with TNF antagonists is very similar to those of other contemporary as well as historic RA cohorts. The consistent increase in smoking-associated cancers in patients with RA emphasizes the potential for smoking cessation as a cancer preventative measure in RA. In essence, the author’s report that these cohorts, 3,339 cancers observed in the prevalent RA cohort was at largely increased overall risk of solid cancer with 20% - 50% increase risk for smoke-related cancer and a 70% increase risk for non-melanoma skin cancer. However, there was a decreased risk for breast and colorectal cancer of 20% and 25%, respectively. This report from Sweden is timely in that it helps us address one of our unanswered questions regarding the long-term risk of malignancy in patients treated with TNF antagonists. It provides data that there is no increased risk of malignancy due to TNF antagonists. Of note, these data demonstrate a significant decreased risk for breast and colorectal cancer in RA patients. These data provide provocative hypothesis as to the potential reasons for the decrease in colorectal cancer might be attributable to non-steroidal anti-inflammatory drugs, as these are used as one of the mainstay therapies for RA. This type of registry and detailed information from large cohorts of patients will be critical to evaluate the increased risk, if any, of perhaps uncommon but yet clinically significant adverse risks involved in other new therapies over the next several years. This data is reassuring that to date there has been no confirmatory data to suggest any serious problem with long-term risk of increased malignancies in patients who have been treated with anti-TNF therapies. --Larry Moreland, MD

Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists.
J Askling, CM Fored, L Brandt, E Baecklund, L Bertilsson, N Feltelius, L Cöster, P Geborek, LT Jacobsson, S Lindblad, J Lysholm, S Rantapää-Dahlqvist, T Saxne, L Klareskog
Ann Rheum Dis 2005 10;64(10):1421-6

Exercise May Improve Knee Cartilage in Patients at Risk for [Osteoarthritis]

Author: Laurie Barclay, MD.

From: Medscape

Oct. 28, 2005 — Exercise improves the glycosaminoglycan (GAG) content of the knee in patients at risk for osteoarthritis (OA), according to the results of a randomized trial reported in the November issue of Arthritis & Rheumatism.
"The effects of exercise on human cartilage are largely unknown because, until recently, investigators have been unable to examine the biochemical properties of cartilage tissue in vivo," write Ewa M. Roos, MD, and Leif Dahlberg, MD, from the Lund University and Malmo University Hospital in Sweden. "Delayed gadolinium-enhanced MRI [magnetic resonance imaging] of cartilage (dGEMRIC) estimates cartilage quality by measuring the fixed-charge density of tissue, comprising GAGs. GAGs are building blocks of proteoglycans and are crucial for the important viscoelastic properties of cartilage.
In this study, 45 subjects who underwent partial medial meniscus resection three to five years previously were randomized to supervised exercise three times weekly for four months or to a nonintervention control group. There were 16 women and 29 men; mean age was 46 years, and mean body mass index was 26.6 kg per m2. Cartilage GAG content was estimated using dGEMRIC, with results expressed as the change in T1(Gd) relaxation time.
Of the 45 subjects, 30 had dGEMRIC both at baseline and follow-up. Compared with the control group (n = 14), the exercise group (n = 16) had an improvement in the T1(Gd) (15 vs -15 millisecond; P = .036). To determine the dose response, the investigators examined the correlation between change in the T1(Gd) and self-reported change in physical activity level. There was a strong correlation in the exercise group (n = 16; rS = 0.70; 95% confidence interval [CI], 0.31 - 0.89) and in the pooled group of all subjects (n = 30; rS = 0.74; 95% CI, 0.52 - 0.87).
"This in vivo cartilage monitoring study in patients at risk of knee OA who begin exercising indicates that adult human articular cartilage has a potential to adapt to loading change," the authors write. "Moderate exercise may be a good treatment not only to improve joint symptoms and function, but also to improve the knee cartilage GAG content in patients at high risk of developing OA."
Study limitations include limited applicability to other groups at risk for OA, loss to follow-up, methodologic issues related to dGEMRIC, clinical significance of the results, and short follow-up time.
"Moderate, supervised exercise improves knee-cartilage GAG content in patients at risk of OA," the authors conclude. "Exercise may have important implications for disease prevention in patients at risk of developing knee OA."
The Swedish Research Council, the Swedish National Centre for Research in Sports, the Knut and Alice Wallenberg Foundation, the Zoega Medical Foundation, the Swedish Rheumatism Association, Lund Medical Faculty, and Malmö University Hospital have disclosed that they supported this study.

Arthritis Rheum. 2005;52:3507-3514