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Cardiovascular Thrombotic Events and COX-2 Inhibitors: Results in Patients with Osteoarthritis Receiving Rofecoxib

To the Editor:

Recent reports have dealt with the issue of whether selective cyclooxygenase-2 (COX-2) inhibitors, including rofecoxib, are associated with an increased risk of thrombotic events^1-3. We would like to contribute to this topical question by reporting the rate of cardiovascular thrombotic events recorded in a large 24 week open label randomized clinical trial conducted in community derived patients with osteoarthritis (OA) of the knee or hip and aimed at evaluating nonpharmacological treatments⁴.

All participating patients were given rofecoxib at a starting dose of 12.5 mg/day for the first month, with the option of increasing to 25 mg/day thereafter if needed for efficacy. As the patients might have been assigned to perform an exercise program, those with a recent history of myocardial infarction (MI) were excluded, as were patients with serious comorbidities and/or a contraindication to rofecoxib use (known hypersensitivity to the drug, active gastrointestinal disease, severe renal or hepatic disorder). The protocol included 4 study visits for all patients. In addition to the screening visit, patients were seen at Weeks 4, 12, and 24. Thrombotic events were recorded as part of ongoing adverse event surveillance. We recorded all untoward events that occurred throughout the study, but considered only events occurring during treatment and within 14 days after discontinuation of rofecoxib.

In all, 2896 patients (2035 women, 861 men) were involved in the safety analysis. Their mean (SD) age was 66.8 (9.9) years and 631 (21.8%) were 75 years or older. There were 913 patients (31.5%) with hypertension and 151 (5.2%) with diabetes. Further, 78 patients (2.7%) had a history of angina and/or MI. Ongoing use of low dose aspirin was recorded in 26 patients (0.9%). The mean (SD) duration of rofecoxib treatment was 139 (62) days. The dosage of rofecoxib was increased to 25 mg/day in 773 patients after the 4th week, and in 1035 after the 12th week of the study.

A total of 6 cardiovascular thrombotic events was recorded. One patient with a history of MI, coronary angioplasty, diabetes, and hypertension experienced a fatal MI while taking rofecoxib. Further, nonfatal strokes occurred in 5 patients during the period of treatment. Accordingly, the annualized incidence rates of MI and stroke were 0.09 (95% CI 0-0.50) and 0.45 (95% CI 0.16-1.05), respectively. Of note, 2 further thrombotic events (one MI and one stroke) were observed after the 14 day window; they occurred at Day 31 and Day 60, respectively, after discontinuation of rofecoxib.

Although comparison of raw event rates across mutiple studies is hazardous, the annualized thrombotic cardiovascular event rate observed in our study is comparable with that found in controls (weighted mean 0.92%/year, range 0.67% to 1.71%/year) who participated in 4 randomized controlled trials of aspirin for primary prevention⁵. It is also in agreement with the incidences of the Anti-Platelet Trialists' Collaboration (APTC) combined endpoints that were observed in the rofecoxib OA development program⁶. The incidence of APTC endpoints [(1) cardiovascular, hemorrhagic, and unknown death; (2) MI; and (3) cerebrovascular accident] was similar between the rofecoxib (0.96/100 patient-yrs) and nonselective NSAID (1.42/100 patient-yrs) treatment groups on the one hand, compared to the rofecoxib (1.36/100 patient-yrs) and placebo (1.93/100 patient-yrs) groups⁶. In spite of its limitations, including the absence of a control group, ignorance of possible silent MI, and duration of treatment limited to 24 weeks, our study provides further indirect evidence for a lack of excess of cardiovascular thrombotic events in OA patients receiving rofecoxib 12.5-25 mg/day. This should be confirmed by large controlled clinical trials with a longer followup period.

BERNARD BANNWARTH, MD, Service de Rhumatologie, Groupe Hospitalier Pellegrin, 33076 Bordeaux Cedex, and Division of Therapeutics, University Victor Segalen, Bordeaux; PHILIPPE RAVAUD, MD, PhD, Department of Epidemiology and Biostatistics, Hôpital Bichat, Paris; MAXIME DOUGADOS, MD, Department of Rheumatology, Hôpital Cochin, Paris, France. E-mail: bernard.bannwarth@u-bordeaux2.fr

Supported by Laboratoires MSD-Chibret, France. Dr. Bannwarth, Dr. Ravaud, and Dr. Dougados have received research support, grants, honoraria and/or consultancy fees from Laboratoires MSD-Chibret France.

REFERENCES

1. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-9.

2. Cleland LG, James MJ, Stamp LK, Penglis PS. COX-2 inhibition and thrombotic tendency: a need for surveillance. Med J Aust 2001;175:214-7.

3. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-42.

4. Ravaud P, Giraudeau B, Logeart I, et al. Management of osteoarthritis with patient-administered assessment tools and/or unsupervised home-based exercises program. A 2 x 2 factorial design cluster randomized controlled trial [abstract]. Arthritis Rheum 2001;44 Suppl:S355.

5. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart 2001;85:265-71.

6. Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). Am J Cardiol 2002;89:204-9.

Diabetes Mellitus Type 1 and Stiff Hips

To the Editor:

We describe a patient who has diabetes mellitus type 1, DISH (diffuse idiopathic skeletal hyperostosis), Dupuytren's contractures, and elements of the syndrome of limited joint mobility or diabetic cheiroarthropathy, who has developed a restricted range of motion of both hips.

A 47-year-old man with diabetes mellitus type 1 diagnosed at the age of 21 and DISH diagnosed at age 44 presented with increasing difficulty with walking secondary to hip and back pain and generalized stiffness. He had bilateral Dupuytren's contractures. A previous surgery for the left hand had failed, as the contracture returned after surgery. He also described a year-long history of progressively worsening stiffness of both hips. The stiffness, constant throughout the day, was accompanied by pain and was severe enough that he was spending most of his time in bed. He denied any history of trauma and had not had any episodes of reflex sympathetic dystrophy. He also denied a history of depression, anxiety, or other psychiatric problems. Over the previous 5 months, the pain in his hips had become increasingly severe, especially with movement.

Examination revealed obvious palmar contractures involving the 4th digits of both hands as well as contractures of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the same digits. He had a prominent prayer sign and decreased extension of the wrists, with no evidence of diabetic sclerodactyly. He had only 85° to 90° of extension and abduction in both shoulders. His hips were in 15° of flexion even while he attempted to lie supine, and he was unable to fully extend his hips so that even when he stood, he was flexed 15° at the hips with lumbar hyperextension. Left hip examination revealed 15° of internal rotation, 30° external rotation, 20° abduction, and 10° adduction. The right hip had 15° internal rotation, 20° external rotation, 10° abduction, and 10° adduction. Attempts at passive range of motion produced pain, particularly at the extremes of his limited range of motion. Active motion appeared to be less painful but more restrictive. Low back examination revealed slight point tenderness along the spine without paraspinal tenderness. There was only 5° of spine extension, and spine flexion was markedly limited as well; attempts at both flexion and extension were painful.

Thoracic and lumbar spinal radiographs revealed flowing anterior osteophytes typical of DISH. There was relative preservation of intervertebral disc spaces of the involved regions, and there was no evidence of apophyseal joint ankylosis, sacroiliac joint erosions, sclerosis, or intraarticular bony ankylosis. Bilateral hip radiographs revealed only minimal narrowing of the joint spaces. Magnetic resonance image (MRI) of hip joints with gadolinium was unremarkable. A computerized tomographic (CT) arthrogram showed a normal joint capsule. Blood tests revealed an elevated Westergren erythrocyte sedimentation rate of 43 mm/h (normal 0-15), elevated IgA of 514 mg/dl (normal 70-400), and negative HLA-B27. He had reasonable control of his diabetes, with the highest hemoglobin A1C over the past year of 7.8%. He had preserved renal function (blood urea nitrogen 19, creatinine 0.8) and annual ophthalmologic examinations reportedly revealed no evidence of proliferative retinal microvascular disease.

The syndrome of limited joint mobility (SLJM), also known as diabetic cheiroarthropathy, diabetic hand syndrome, or stiff hand syndrome, is characterized by joint contractures. The flexion contractures of SLJM occur predominantly in the PIP and MCP joints, although eventually there may be decreased range of motion in larger peripheral joints as well as the axial skeleton¹. The pathogenesis of this disorder is not entirely understood; however, it has been postulated to involve contractile myofibroblasts producing increased amounts of collagen in response to microvascular ischemia²; this theory is supported by the correlation between SLJM and the presence of microvascular disease^1,2.

DISH is a diagnosis that relies principally on the radiographic appearance of the thoracic spine³. However, it is a systemic disease, and in peripheral joints a stiffening arthropathy can also be seen⁴. Among other features, a painless reduction of internal rotation of the hips has been described, but there are no adequate controlled studies on the clinical features of extraspinal DISH⁴. There is an association between hyperinsulinemia and DISH^4,5, and it appears that insulin acts as a growth factor leading to connective tissue proliferation and eventual deposition of new bone⁴. DISH has been associated with diabetes mellitus type 2, impaired glucose tolerance, and obesity⁶; however, cases have also been described in association with type 1 diabetes mellitus⁶.

Adhesive capsulitis is another rheumatologic disorder that has been associated with diabetes mellitus². This disorder has usually been described as occuring primarily in the shoulder joint, although adhesive capsulitis of the hip and ankle have also been described⁷. At first we felt our patient had an adhesive capsulitis of bilateral hips, but the finding of a normal joint capsule on CT arthrogram excluded this diagnosis.

This patient exhibits some rheumatologic disorders common to people with diabetes mellitus, namely DISH, SLJM, and Dupuytren's contractures. In general, he has a tendency toward joint stiffening without actual pathology in the joints, as evidenced by his persistent Dupuytren's contractures, even after surgery. He had markedly reduced range of motion with stiffening and pain in bilateral hip joints; however, the radiographs and MRI do not reveal enough pathology to account for this stiffening. This may indeed be a large-joint manifestation of SLJM. It may also be a peripheral joint manifestation of DISH. In either case, this decreased range of motion appears to be related to stiffening of the soft tissues surrounding the hips.

Our patient failed to improve after an intensive inpatient physical therapy program in a rehabilitation hospital. Multiple sessions of passive stretching in a Hubbard tank did not increase his hip range of motion. Therefore, the emphasis in rehabilitation became fall prevention and joint protection. He received isometric muscle strengthening of the hip girdle and back muscles and instructions on floor-to-stand transfers should a fall occur. He was able to walk 300 feet with the assistance of bilateral Lofstrand crutches. The occupational therapy department reviewed his dressing program and other activities of daily living and dispensed the appropriate assistance devices such as a dressing stick and reachers. He was able to achieve a reasonable level of comfort with only a modest reduction in his expectations of total function.

ANDREW M. ROPP, MD, Resident in Family Practice, St. Clare's Hospital, Schenectady, New York; JAMES M. STROSBERG, MD, Attending Rheumatologist, Sunnyview Hospital and Rehabilitation Center, Schenectady, New York, Associate Professor of Clinical Medicine, Albany Medical College, Albany, New York, USA.

REFERENCES

1. Kapoor A, Sibbitt WL Jr. Contractures in diabetes mellitus: the syndrome of limited joint mobility. Semin Arthritis Rheum 1989;18:168-80.

2. Sergent JS. Arthritis accompanying endocrine and metabolic disorders. In: Ruddy S, Harris ED, Sledge CB, et al., editors. Kelley's textbook of rheumatology. 6th ed. Philadelphia: W.B. Saunders Co.; 2001:1581-2.

3. Weissman BN, Resnick D, Kaushik S, et al. Imaging. In: Ruddy S, Harris ED, Sledge CB, et al., editors. Kelley's textbook of rheumatology. 6th ed. Philadelphia: W.B. Saunders Co.; 2001: 674-6.

4. Smythe H, Littlejohn GO. Diffuse idiopathic skeletal hyperostosis. In: Klippel JH, Dieppe PA, editors. Rheumatology, 2nd ed. Philadelphia: Mosby; 1998:8.10.1-6.

5. Littlejohn GO. Insulin and new bone formation in diffuse idiopathic skeletal hyperostosis. Clin Rheumatol 1985;4:294-300.

6. Coaccioli S, Fatati G, Di Cato L, et al. Diffuse idiopathic skeletal hyperostosis in diabetes mellitus, impaired glucose tolerance and obesity. Panminerva Med 2000;42:247-51.

7. Dihlmann W, Hopker WW. Adhesive (retractile) capsulitis of the hip joint in diabetes mellitus. Fortschr Geb Rontgenstr 1992;157:235-8.