ABSTRACT: Changes in recommendations for COX-2 inhibitors demand physicians carefully balance risks and benefits of pain medications for each patient.
CME OBJECTIVE: The reader will be aware of data behind the rapidly changing recommendation for nonsteroidal anti-inflammatory drugs and appropriate approaches to each patient's problems.
Kenneth G. Saag, MD, MSc, grants/research support & honoria Merck & Co., Inc., consultant Merck & Co., Inc. & Pfizer Inc.
The removal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market because of associated increases in cardiovascular events, along with stronger warning labels on nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), have limited pain relief options and generated concern about safety of both cyclooxygenase-2 (COX-2) selective inhibitors and traditional NSAIDs.
Since 1999, COX-2 inhibitors have been marketed to patients suffering from arthritis and other forms of chronic pain as a potentially safer alternative to nonselective NSAIDs. In vulnerable individuals and long-term users, traditional NSAIDs may increase risk of ulcer disease and potentially lethal gastrointestinal (GI) bleeding, UAB rheumatologist Kenneth G. Saag, MD, MSc, says.
"No study has shown COX-2 inhibitors relieve pain or inflammation more effectively than older medications, but certain COX-2s have an improved GI toxicity profile," he says. "All drugs have risks, and some arthritic patients respond better to certain medications, making a wide range of analgesic choices desirable. Studies of COX-2 inhibitors, each with different designs and patient populations, have yielded varying results, but it is clear that at higher doses some patients experienced cardiotoxic effects."
Cardiovascular Outcomes
• Rofecoxib
Rofecoxib's potential for adverse cardiovascular events was recognized during the 2000 Vioxx Gastrointestinal Outcomes Research (VIGOR) trial that compared the GI safety of Vioxx with naproxen. More than 8000 patients with rheumatoid arthritis were randomized to 50 mg of rofecoxib once a day or 500 mg of naproxen twice a day (N Engl J Med. 2000;343:1520-1528).
"Patients taking Vioxx had a higher risk of myocardial infarction (MI)," Saag says. "Subsequent studies were fairly consistent in showing an increase in cardiovascular events with Vioxx, with greatest risk associated with 50 mg doses."
The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, a study investigating rofecoxib's efficacy for prevention of colon polyps, was halted early when data confirmed the cardiovascular risks seen with VIGOR. APPROVe randomized participants to either placebo or rofecoxib (25 mg daily). After 3 years, cardiac and cerebrovascular event incidence was significantly higher with rofecoxib than with placebo (3.6% vs 2.0%). Increased risk of MI and stroke emerged after 18 months of treatment; during the first year and a half of APPROVe, event rates between the two groups were similar (N Engl J Med. 2005; 352:1092-1102).
• Valdecoxib
In April, concluding valdecoxib's risk versus benefit profile was unfavorable, the Food and Drug Administration (FDA) asked Pfizer Inc. to pull the drug off the market. Pfizer complied but disagreed with FDA's assessment.
FDA cited lack of adequate data on cardiovascular safety and long-term use, increased risk of adverse cardiovascular events in short-term coronary artery bypass (CABG) surgery trials, and reports of rare but unpredictable and potentially life-threatening Stevens Johnson syndrome in patients using valdecoxib. FDA also noted there is no evidence valdecoxib offers advantages, compared with other NSAIDs.
In a 10-day trial of pain relief after cardiac surgery, more than 1600 patients received either placebo, 40 mg of intravenous parecoxib (a prodrug of valdecoxib) for 3 days followed by 40 mg of valdecoxib for another 7 days, or intravenous placebo followed by oral valdecoxib. During 30 days of follow up, significantly more cardiovascular events occurred in the parecoxib/valdecoxib group than in the placebo group (N Engl J Med. 2005;352:1081-1089). Earlier short-term trials of valdecoxib and parecoxib for postsurgical pain relief did not show increased cardiovascular events, but patients in the treatment group had a higher rate of cerebrovascular complications and renal failure (J Thorac Cardiovasc Surg. 2003;125:1481-1492).
"FDA has come under fire for what some believe is inadequate postmarketing surveillance. By forcing Bextra's removal from the market, FDA has taken a conservative stance," Saag says. "Although this step was not inappropriate, it was motivated by both science and politics."
• Celecoxib
Data on celecoxib (Celebrex) and cardiovascular risk is mixed. "Most controlled trials of Celebrex do not show an increased risk of cardiovascular harm," Saag says. "However, one recent study — and some would argue it is the best study to date — did show increased risk of cardiovascular events when taking higher doses of Celebrex for longer periods."
The 3-year Adenoma Prevention with Celecoxib study compared safety and efficacy of two different doses of celecoxib — 200 mg or 400 mg twice a day — with placebo for prevention of colon and rectal polyps. Participants taking celecoxib had a dose-related increase in death from cardiovascular causes (N Engl J Med. 2005;352:1071-1080).
Celecoxib, the only COX-2 still on the market in the United States, now carries a "black box" warning — the FDA's strongest caveat — detailing risks of MI and stroke. "If Celebrex is prescribed, it should be used at the lowest effective dose for the shortest period of time possible," Saag says.
FDA has asked Pfizer to commit to long-term safety studies comparing celecoxib with naproxen and other drugs.
• Nonselective NSAIDs
Extensive labeling changes mandated by FDA include widely used prescription and nonprescription nonselective NSAIDs, such as diclofenac (Voltaren), meloxicam (Mobic), ibuprofen (Motrin), and naproxen (Aleve, Naprosyn).
Prescription NSAIDs now carry boxed warnings of potential adverse effects, including cardiovascular events and life-threatening GI complications, and notes the drugs are contraindicated for use in recent cardiac surgery patients.
Labels on over-the-counter NSAIDs warn dose and duration of treatment should be limited according to package instructions, have more specific information about possible risks, and advise patients to seek a physician's advice before use.
"Most over-the-counter drugs have not been rigorously investigated in terms of cardiovascular outcomes. The relative risk of cardiovascular events among COX-2s and nonselective NSAIDs cannot be adequately determined with available data, but all NSAIDs can lead to renal fluid retention and hypertension if taken at high doses for long periods," Saag says.
Safer Analgesic Use
"Before deciding on the most appropriate drug, physicians should evaluate patients — especially those needing long-term medication — for risk of side effects, particularly GI bleeding, fluid retention, and heart failure," he says.
To address issues of analgesic safety, Saag and colleagues developed a set of quality indicators (Arthritis and Rheumatism. 2004;51:337-349):
• IF patients are prescribed selective or nonselective NSAIDs, advise them of associated GI bleeding and renal risks and document GI risks.
• IF patients are prescribed low-dose aspirin <325 mg/day), advise them of associated GI bleeding risks.
• IF patients are treated with acetaminophen and have risk factors for liver disease or if patients are treated with high-dose acetaminophen (>4 mg/day), advise them of associated risk of liver toxicity.
• IF patients are treated with a nonselective NSAID and have risk factors for GI bleeding*, treat them concomitantly with either misoprostol or a proton pump inhibitor (PPI).
• IF patients are treated with a COX-2 inhibitor and take low-dose aspirin daily and have risk factors for GI bleeding*, treat them concomitantly with either misoprostol or a PPI.
• IF patients are treated with low-dose aspirin daily and have two or more risk factors for GI bleeding*, treat them concomitantly with either misoprostol or a PPI.
• IF patients are treated with daily selective or nonselective NSAIDs and have risk factors for GI bleeding†, order a complete blood count at baseline and during the first year after initiating therapy.
• IF patients are treated with daily NSAIDs and have risk factors for renal insufficiency‡, assess a serum creatine at baseline and at least once in the first year after initiating therapy.
* Aged >75 years, peptic ulcer disease, GI bleeding, or glucocorticoid use.
† Aged >75 years, peptic ulcer disease, GI bleeding, glucocorticoid or warfarin use.
‡ Aged >75 years, diabetes mellitus, hypertension, use of angiotensin-converting enzyme inhibitors, or diuretic use.
"Physicians must act cautiously when prescribing pain medications," Saag concludes. "There are serious concerns about the cardiovascular safety of COX-2 inhibitors, which perhaps have been prescribed too widely. Those risks must be weighed against potentially lethal GI bleeding — which may be lower with COX-2 inhibitors — as well as benefits of pain relief. We must balance all these benefits and risks, using the best available evidence to make the right decisions for each patient."
For more information
Dr. Kenneth Saag
1.800.UAB.MIST
mist@uabmc.edu
Published in UAB Insight, Summer 2005