Major Finding: Among older patients treated topically for knee osteoarthritis for 12 weeks, adverse events occurred in 56% of those using diclofenac sodium 1% gel and in 44% of those using placebo, with one serious adverse event possibly related to treatment.

Data Source: A post hoc analysis of data on 538 patients aged 65 years or older from three double-blind, randomized, controlled trials.

Disclosures: Dr. Barthel conducted the study under a research contract for Novartis, which makes the gel. His associates in the study were employees of Novartis or of Endo Pharmaceuticals, which markets the gel.

LONG BEACH, CALIF. — A higher rate of adverse events in older patients with knee osteoarthritis treated topically for 12 weeks with a nonsteroidal anti-inflammatory drug, compared with placebo, was caused mainly by application-site reactions but included one serious cardiovascular event that might have been related to the drug treatment, a post hoc analysis of data on 538 patients found.

The investigators analyzed data on people aged 65 years and older with symptomatic knee osteoarthritis (433 of them with comorbid hypertension, diabetes, or cardiovascular disease). Their source was three larger randomized, double-blind trials—two of them unpublished—that had looked at broader populations. Patients applied 4 g/day of either diclofenac sodium 1% gel (Voltaren) or the drug's vehicle to one painful knee.

One 80-year-old woman with hypertension and diabetes, among 274 patients on diclofenac sodium 1% gel, developed deep vein thrombosis and pulmonary embolism that possibly was related to treatment, Dr. H. Richard Barthel and associates reported in a poster presentation at the annual meeting of the American Medical Directors Association.

Overall, 56% of patients on diclofenac gel developed adverse events, compared with 44% of 264 patients treated with placebo, added Dr. Barthel, a rheumatologist in Santa Barbara, Calif., who conducts research under contract for Voltaren maker, Novartis.

The study was not powered to assess statistical significance. Voltaren is approved to treat osteoarthritis pain in joints amenable to topical treatment, such as knees and hands.

NSAIDs are known to increase risk for cardiovascular or renal problems in a dose-related fashion, especially in older patients and people with hypertension, diabetes, or cardiovascular disease. Topical formulations may reduce this risk by reducing systemic exposure to NSAIDs compared with oral formulations. The ad hoc analysis compared the gel only to placebo, not to oral therapy, and found higher rates of adverse events for the drug vs. placebo.

Application-site reactions occurred in 8.8% on diclofenac gel and 1.1% on placebo. Serious adverse events occurred in 2.6% on diclofenac and 1.1% on placebo. Adverse cardiovascular events were seen in 2.6% on diclofenac and 1.1% on placebo. Adverse renal events were seen in 1.1% on diclofenac and 0.4% on placebo.

Among more common adverse events, 11% of subjects on diclofenac and 10% on placebo reported headache, 8% on diclofenac and 7% on placebo reported arthralgia, and 8% on diclofenac and 6% on placebo reported back pain.

The analysis included 307 patients with hypertension, 84 with diabetes, and 42 with cardiovascular disease. The investigators looked at rates of adverse events in patients with one of these comorbidities, compared with events in patients without the comorbidity. For example, in the hypertension subgroup, adverse events were seen in 54% of 159 people randomized to diclofenac gel, compared with 45% of 148 people using placebo. In patients without hypertension, adverse events occurred in 58% of 115 on diclofenac gel and 42% of 116 on placebo.

In the diabetes subgroup, adverse events occurred in 19 (51%) of 37 patients treated with diclofenac and in 21 (48%) of 47 treated with placebo. In patients without diabetes, adverse events occurred in 56% of 237 on diclofenac and in 44% of 217 on placebo.

In the subgroup with cardiovascular disease, adverse events occurred in 15 (56%) of 27 people on diclofenac and in 2 (13%) of 15 on placebo, although none developed an adverse cardiovascular event.

My Take

Topical Diclofenac Can Fill a Tx Gap

The therapy of osteoarthritis remains insufficient in many patients. It is particularly problematic in the elderly who often have concomitant diseases that limit our options for several of the oral medications, particularly NSAIDs and potent analgesics. The recent Food and Drug Administration approval of diclofenac has changed the therapeutic paradigm. Diclofenac gel 1% has been approved for osteoarthritis of the knee, hand, and other superficial joints, and Pennsaid has been approved for osteoarthritis of the knee.

In this post hoc pooled analysis of 538 patients, we see an increase in irritation at the site of application, but a minimal increase in adverse events involving blood pressure, renal function, hepatic dysfunction, and gastrointestinal ulcer disease. Pharmacokinetic studies have demonstrated that systemic absorption of the topical diclofenac is 40 times less than oral diclofenac. This improved safety allows us to provide therapy to patients otherwise unable to receive anti-inflammatory drugs. It will be no surprise if the guidelines for therapy of osteoarthritis from the United States will soon approximate those from Europe, where topical NSAIDs are part of the therapeutic algorithm for osteoarthritis. Are they completely safe? No. Is there no long-term cardiovascular risk? It has not been studied. Hence, the “black box” warning is applied to these agents that primarily list topical changes under adverse events.

ROY D. ALTMAN, M.D., is professor of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He has been a consultant to Novartis, Eli Lilly, Ferring Pharmaceuticals, and Rottapharm/Madaus.

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