Discontinuing NSAIDs in Veterans With Knee Osteoarthritis
Discontinuing NSAIDs in Veterans With Knee Osteoarthritis
Knee osteoarthritis (OA) is now recognized as a major health problem. It is the number one
 cause of lower extremity disability and has significant deleterious effects on quality of
 life. While there are numerous therapies available for knee OA, most have limited efficacy.
 Of particular concern, is the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs)
 for this disorder. Veterans, as a group, are at high risk for both gastrointestinal and
 cardiovascular NSAID-induced complications. In this study the investigators propose to
 examine whether replacing NSAIDs with cognitive behavioral therapy delivered by telephone is
 an effective strategy for Veterans with knee OA. Telephone-administered therapy is
 particularly appealing since Veterans with knee OA are more likely to have limited mobility.
 If successful, this program may result in significant cost-savings for both Veterans
 (decreased co-pays and transportation costs) and the VA (decreased hospitalizations due to
 NSAID induced toxicity).
Knee osteoarthritis (OA) is a major cause of disability among Veterans and is the primary
 indication of knee replacement in the VA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are
 the most commonly prescribed medications for knee OA. Though short-term studies have
 demonstrated that NSAIDs are more effective than placebo and acetaminophen, there are no
 long-term data supporting their use. This is of concern, because long-term use of NSAIDs is
 associated with significant morbidity and mortality. Guidelines have been published to
 improve safe use of NSAIDs; however, adherence to these evidence-based recommendations is low
 in the VA. There is therefore an important need to determine if the long-term use of NSAIDs
 offers any incremental benefit over safer alternatives. This is especially true for Veterans,
 a population at high risk for NSAID-induced toxicity.

 Cognitive behavioral therapy (CBT) is an effective and safe treatment alternative for OA.
 This modality is becoming increasingly available in the VA for treatment of chronic pain as
 well as other chronic disorders such as depression, post-traumatic stress disorder and
 insomnia. CBT can be successfully administered over the telephone and thus stands to benefit
 Veterans living in more remote areas with limited access to hospital or community-based
 outpatient clinics.

 In this study, the investigators propose to conduct a 2-phase randomized withdrawal trial
 (RWT). The trial will focus on recruiting Veterans with knee OA who have been using NSAIDs
 for at least 3 months.

 In the first phase of the study, 544 Veterans with knee OA will be randomized to continue
 NSAIDs or to placebo for 4 weeks. This double-blind phase will enable us to infer whether
 placebo is non-inferior to continued NSAID use. In the second phase, subjects in the NSAIDs
 group will continue NSAIDs and those on placebo will stop taking the placebo and participate
 in a 10-week CBT program. The second, single-blind, phase will allow us to infer whether CBT
 is non-inferior to NSAIDs. All study data will be collected over the telephone thus enabling
 Veterans who have difficulty arranging transportation to the VA to participate.

 The investigators will test for between-group differences in knee pain measured using the
 well-validated Western Ontario and McMaster Universities Osteoarthritis Index (primary
 outcome) at 4 and 14 weeks. The investigators will also test for between group differences in
 lower extremity disability, subjects' global impression of change and use of co-therapies
 (secondary outcomes). As recommended for non-inferiority trials, the investigators will
 perform both an intent to treat and per protocol analysis. Lastly, the investigators will
 estimate the potential cost-effectiveness of the CBT protocol compared with continued NSAID
 use.

 Though it would be ideal for subjects randomized to the active study drug to continue their
 current NSAID, having the VA pharmacy formulate multiple different active drugs and
 maintaining the blind is not possible. Therefore, the investigators will include a 2-week
 run-in period where study subjects will replace their NSAID with meloxicam. Meloxicam was
 chosen as the study drug because it is the most commonly prescribed at the investigators'
 center and has a favorable safety profile compared to other NSAIDS.

 If successful, the trial will improve the quality of care delivered to Veterans with chronic
 knee pain due to OA. The proposed strategy is particularly appealing because it replaces the
 widespread use of NSAIDs with a safer alternative, enables delivery of care to Veterans with
 limited access, and is likely to be cost saving.
Inclusion Criteria:

 Subjects will include those for whom a discontinuation trial of NSAIDs is most appropriate:
 1) Veterans with knee pain despite NSAID use and/or 2) Veterans at relatively higher risk
 of NSAID toxicity 55-59 as ascertained by meeting 1 or more of the following 4 criteria:

 -  Answer affirmatively to the question: "Do you have some knee pain on most days over
 the past 3 months?"

 -  Have 1 or more risk factors for NSAID-induced nephrotoxicity (age greater than 60
 years, atherosclerotic cardiovascular disease, current diuretic use, chronic renal
 insufficiency, congestive heart failure (New York Heart Association class I-II. Note,
 Class III and IV are excluded).

 -  Have 1 or more risk factors for NSAID-induced gastrointestinal toxicity (history of
 peptic ulcer disease, age > 65 years, concurrent use of daily ASA or corticosteroids),
 and are currently on a gastro-protective agent.

 -  Have 1 or more risk factors for NSAID-induced cardiovascular toxicity (prevalent
 cardiovascular disease, hypertension, hypercholesterolemia, diabetes, smoking, family
 history of early heart disease or age greater than 55 years for women).

 In addition, subjects must:

 -  Be age 20 years or older. While the usual cut off for knee OA is approximately 40
 years, the investigators chose to lower the age cutoff as younger Veterans have a
 higher than expected risk of OA (see B.1).

 -  Have radiographic evidence of knee OA reported in the VistA electronic system.

 -  Be using an NSAID (other than daily ASA) for knee pain on most days of the month for
 at least the past 3 months.

 -  Be able to understand and speak English and have a telephone.

 -  Be willing to engage in a CBT program, to discontinue (or replace) their NSAID, and to
 restrict co-therapies to acetaminophen for 14 weeks.

 Exclusion Criteria:

 -  Subjects desiring escalation of analgesics for their current level of knee pain as
 determined by endorsement of the following statement: "Is your knee pain bad enough
 that you want to talk to your doctor about taking stronger pain medications?"

 -  Current use of opioids and/or Celebrex.

 -  Current use of an NSAID (not including ASA) for a painful condition in addition to
 knee OA.

 -  Contraindications to chronic NSAID use: current use of warfarin or antiplatelet agent
 other than ASA, allergy to any NSAID, active upper gastrointestinal ulceration in the
 previous 30 days, upper gastrointestinal bleeding in the past year, history of
 gastroduodenal perforation or obstruction, cardiovascular event within the past 6
 months (myocardial infarction, cerebrovascular event, coronary-artery bypass graft,
 invasive coronary revascularisation, or new-onset angina), severe congestive heart
 failure (New York Heart Association class III-IV), evidence of serious anemia,
 hepatic, renal (including nephrotic syndrome), or blood coagulation disorders, and
 pregnancy.

 ***Though the investigators are proposing a RWT - and thus will not be initiating NSAID
 therapy - it would not be appropriate to continue NSAIDs (even when prescribed) in
 high-risk patients. The investigators acknowledge that these exclusion criteria limit
 generalizability, but the investigators feel justified to ensure subjects' safety.***

 -  Previous hyaluronic acid knee injections (within 6 months) or corticosteroid knee
 injections (within 3 months).

 -  Scheduled knee hyaluronic acid or corticosteroid injections, arthroscopy, or knee
 surgery.

 -  Co-morbid conditions that include the following: known other causes of arthritis
 (infectious arthritis, rheumatoid arthritis, connective tissue disease, or psoriatic
 arthritis), gout or pseudogout attack within the last 12 months, peripheral neuropathy
 or cardiopulmonary disease that limits walking more than knee pain, bone metastases or
 Paget's disease involving the lower extremities, and history of drug or alcohol abuse
 within the past 2 years, bilateral knee replacements or knee pain in the replaced knee
 only.

 -  Current involvement in litigation or receiving workmen's compensation.

 -  Hearing, cognitive impairment or mental illness, as determined by chart review that
 would preclude participation in a CBT program.

 -  For Women of Childbearing Age: Must not currently be pregnant, agree to avoid getting
 pregnant during the course of the study and should inform the study team if pregnancy
 occurs at any time during study participation.

 -  Previous meloxicam use discontinued due to lack of effective symptom relief

 -  Contraindications to prolonged NSAID use, per PI discretion.