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The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses.

Felson DT, Anderson JJ, Meenan RF.

Boston University Arthritis Center, Massachusetts.

We performed 2 metaanalyses of placebo-controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX), injectable gold, D-penicillamine (DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs, the second-line drugs most commonly used to treat rheumatoid arthritis (RA).
 
For the efficacy study, we applied a set of inclusion criteria and focused on trials which provided information on tender joint count, erythrocyte sedimentation rate, or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest, and for each drug, we combined the treatment groups. For each outcome, results showed that AUR tended to be weaker than other second-line drugs.
 
The results of the 3 outcome measures were synthesized into a composite measure of outcomes, and AUR was significantly weaker than MTX (P = 0.006), injectable gold (P less than 0.0001), DP (P less than 0.0001), and SSZ (P = 0.009) and was slightly, but not significantly, weaker than antimalarial agents (P = 0.11).
 
We also found heterogeneity among antimalarial agents, in that patients treated with chloroquine did better than those treated with hydroxychloroquine.
 
We found little difference in efficacy between MTX, injectable gold, DP, and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g., AUR) second-line drugs. None of the reported interdrug comparative trials we reviewed were this large.
 
For the toxicity study, our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug.
 
Overall, 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P less than 0.05) and higher total dropout rates (P less than 0.01) than any other drug; 30% of gold-treated patients dropped out because of side effects versus 15% of all trial patients.
 
 Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus, of the commonly used second-line drugs, AUR is the weakest, and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication Types:
  • Clinical Trial
  • Meta-Analysis

PMID: 1977391 [PubMed - indexed for MEDLINE
 
Health Canada is advising Canadians of new safety information related to the selective COX-2 inhibitor CELEBREX® (celecoxib), a nonsteroidal anti-inflammatory drug (NSAID). CELEBREX® is a prescription drug approved for use in Canada for the acute and chronic treatment of osteoarthritis and rheumatoid arthritis in adults.

This advisory is in addition to a letter issued by the manufacturer of CELEBREX®, following discussions with Health Canada, to health professionals reminding them of the following safety information.

In a large clinical trial, "Celecoxib Long-term Arthritis Safety Study (CLASS)", the gastrointestinal safety of CELEBREX® (400 mg twice daily) and two other NSAIDs, diclofenac (75 mg twice daily) and ibuprofen (800 mg three times daily), was compared in arthritis patients.

No differences were shown in the risk of ulcer complications (gastrointestinal bleeding, perforation and obstruction) alone among the three treatment groups.

The risk of ulcer complications and symptomatic ulcers (ulcers with abdominal pain, dyspepsia, nausea, diarrhea or vomiting) was shown to be lower for CELEBREX® than for ibuprofen, but not different from diclofenac.

Results also showed the risk of ulcer complications in patients taking CELEBREX® and low dose ASA (Aspirin® or other ASA brands) was 4 times that of patients taking CELEBREX® alone.

As with all other NSAIDs, patients who experience gastrointestinal symptoms such as abdominal pain and blood in stools while taking CELEBREX® (with or without ASA) should inform their physician immediately.

All NSAIDs, including CELEBREX®, should not be used in patients with a history of:

  • Active peptic ulcer, active gastric bleeding, active inflammatory disease of the bowel;
  • Active liver diseases;
  • Severe kidney problems.

As with all other NSAIDs, fluid retention (swelling of the legs) has been observed in some patients taking CELEBREX® (celecoxib). Patients with a medical history of hypertension (high blood pressure), fluid retention or heart failure are advised to discuss their medical condition with their treating physician before taking CELEBREX®. Patients who develop fluid retention or swelling, shortness of breath, weakness, fatigue, excessive weight gain or chest pain while on CELEBREX® therapy should inform their physician immediately.

Patients taking other NSAIDs, including other selective COX-2 inhibitors, are also advised to inform their physician if they experience any of the above symptoms.

These drugs do not affect the kidneys or blood pressure adversely in those who have no problems with their kidneys or blood pressure. In those that do have such problems, all NSAID's including the coxibs are hazardous. They can worsen the blood pressure, fluid retention (edema and heart failure) and kidney function. Celebrex appears to be no different than ibuprofen and diclofenac in these matters but Vioxx seems to be worse for heart failure and high blood pressure.
 
In summary: If you have no risk factors for peptic ulcers, heart attacks or strokes, high blood pressure, fluid retention or kidney disease, then you can use NSAID's or coxibs. If you only have risk factors for peptic ulcers, then use coxibs. If you only have risk factors for heart attacks or strokes, then take NSAID's (naproxen may be one of the best) and probably Celebrex but not Vioxx. If you have high blood pressure, fluid retention or kidney disease or use diuretics, then all NSAID's and coxibs could make these problems worse but Vioxx is probably more of a problem than the others.Try some other treatment if possible. If you have problems in more than one of these groups, then try some other treatment if possible. If not possible, choose the NSAID or coxib of least risk for the the greatest problem that you have.

he August 22/29, 2001 issue of the Journal of the American Medical Association features a meta-analysis entitled "Risk of cardiovascular events associated with selective COX-2 inhibitors" which has stirred considerable and immediate media attention and raises concerns about possible thromboembolic risks facing patients taking COX-2 inhibitors and physicians who prescribed them.

This meta-analysis studied two large randomized post-marketing trials of rofecoxib and celecoxib (VIGOR, CLASS respectively), as well as other published and unpublished data submitted to the relevant FDA committees. The VIGOR study with 8076 patients was designed to evaluate gastrointestinal toxicity of rofecoxib vs. naproxen in a large rheumatoid arthritis cohort2. Low dose aspirin use was not permitted. There were 46 cases of serious thrombotic cardiovascular events (e.g., MI, TIA and stroke) in the rofecoxib group, and 20 events in the naproxen group (RR 2.38; p <0.001). The CLASS study with 8059 patients evaluated GI toxicity of celecoxib vs. ibuprofen vs. diclofenac3. Aspirin use was permitted. There were no significant differences in cardiovascular events between groups in the CLASS study. The cardiovascular risk seen in the rofecoxib and celecoxib studies was then compared to a meta-analysis of two previous unrelated studies using aspirin vs. placebo for prevention of cardiovascular events (the US Physicians Health Study and the UK Doctors Study). This analysis suggested that the annualized MI rate for the placebo group from the US/UK studies was 0.52%, statistically significantly lower that for both rofecoxib (0.74%; p=0.04) and celecoxib (0.80%; p = 0.02).

The meta-analysis of Mukherjee et al has important limitations. It is well appreciated that selective COX-2 inhibitors do not significantly inhibit platelet aggregation, one of several factors influencing thrombotic cardiovascular disease. Conventional NSAIDs inhibit both thromboxane and PGI2. It has been suggested that by decreasing antithrombotic PGI2 production and not affecting thromboxane production, selective COX-2 inhibitors could cause an increase in thrombotic cardiovascular events. This hypothesis was not directly studied by Mukherjee et al. At the same time, all NSAIDs, including selective COX-2 inhibitors, may have important effects in reducing the inflammatory component of atherogenesis and actually reduce cardiovascular risk. Patients in the COX-2 trials were heterogeneous; the CLASS study included patients with both OA and RA; patients with RA have a higher risk for MI, a fact that likely had important, but unknown meaning for the study conclusions. Finally, none of the studies examined in the meta-analysis was actually designed to evaluate differences in the rates of cardiovascular events.

Current evidence indicates that available selective COX -2 inhibitors are associated with a significant reduction in major NSAID related GI toxicity, especially in high-risk patients. These GI toxicities have been and continue to be a major source of morbidity and mortality in patients with arthritis. The decision to use selective COX-2 inhibitors is multidimensional, and must balance possible risks for major cardiovascular events against the benefits of these agents. For the individual patient, it is important to consider factors that affect the risk/benefit ratio of the therapeutic choice and the patient's willingness to accept therapy recommendations. These factors include risks for major GI toxicity, cardiovascular events, renal failure, cost and others. These are balanced against measures that can ameliorate these risks, including where appropriate, concomitant low dose aspirin, gastric mucosal protection, and use of effective analgesics and antiinflammatories with minimal GI toxicities. A well-designed study focusing on cardiovascular risk and benefit of selective COX-2 inhibitors will be needed to properly examine this issue.


 

DMARDs:

It is not known which is the best initial DMARD for patients with RA. Because of safety, convenience, and cost, HCQ or SSZ is often the initial selection for patients with milder disease. Generally well tolerated, HCQ requires no laboratory monitoring, although patients need periodic ophthalmologic examinations for early detection of reversible retinal toxicity (i.e., maculopathy manifested by decreased night vision or loss of peripheral vision) . SSZ requires monitoring (i.e., periodic CBC) for rare hematologic complications. Within 1-6 months, the response to these agents should be apparent and the need for a change in therapy may be determined.

Many rheumatologists select MTX as the initial DMARD, especially for patients with severe disease as evidenced by the presence of RF positivity, erosions, or extraarticular manifestations. MTX is the DMARD with the most predictable benefit. More than 50% of patients taking MTX continue the drug beyond 3 years, longer than any other DMARD . Disadvantages of MTX include its expense and the need for laboratory monitoring. Stomatitis, nausea, diarrhea, and perhaps alopecia from MTX use may decrease with concomitant folic acid or folinic acid  treatment, without loss of efficacy. Liver disease, renal impairment, significant lung disease, or alcohol abuse are relative contraindications for MTX therapy. The risk of liver toxicity is small, but liver function must be monitored . The ACR guidelines for monitoring liver toxicity in patients receiving MTX state that liver biopsy should be performed in patients who develop liver function blood test abnormalities that persist during treatment with, or after discontinuation of, the drug . Rare but potentially serious and even life-threatening pulmonary toxicity may occur any time with MTX at any dosage. Rarely, lymphoproliferative disorders may occur in patients taking MTX , but the relationship to the medication is unclear. This relationship is addressed in more detail in the guidelines for monitoring drug treatment in RA .

Intramuscular gold treatment is effective , but weekly intramuscular injections are required for 22 weeks before less frequent maintenance dosing is initiated. Monitoring for proteinuria, thrombocytopenia, and neutropenia should be performed prior to each weekly injection. In patients receiving long-term gold therapy (>6 months), toxicity monitoring may be performed with every other injection. Although oral gold is more convenient than injectable gold, there is a long delay (up to 6 months) before benefit is evident, and it is less efficacious .

DP is effective , but its use is limited by an inconvenient dosing schedule (i.e., slow increases in dosage) and infrequent but potentially serious complications of autoimmune diseases such as Goodpasture's syndrome or myasthenia gravis. AZA, a purine analog myelosuppressant, has demonstrated benefit for controlling RA . Low-dose cyclophosphamide is effective, but carcinogenic. Although studies have documented the efficacy of cyclosporin A in the treatment of RA, it has not yet received Food and Drug Administration (FDA) approval for use in RA , and its use is limited by cost and potential renal toxicity.

For women of childbearing age, effective contraception is required when most DMARDs are prescribed . The drug regimen will need modification if the patient is or wishes to become pregnant, or if breastfeeding is contemplated.

Whether DMARDs should be given in a sequential or additive manner for patients with persistently active disease remains controversial . Rheumatology referral is strongly recommended for patients with refractory disease in whom combination DMARDs are considered. Some rheumatologists initiate treatment with a combination of several DMARDs and gradually withdraw the drugs as disease control is achieved . Most rheumatologists use combinations of DMARDs to treat patients who have had a partial response to a DMARD or whose disease has been refractory to different individual DMARDs. The most commonly used combinations are MTX/ HCQ, MTX/SSZ, and gold/HCQ . Studies are needed to determine the most effective combination of DMARDs for use in RA.

The majority of patients with active RA receive an NSAID and at least 1 DMARD, with or without low-dose oral glucocorticoids. If disease remission is observed, regular NSAID or systemic glucocorticoid treatment may no longer be needed. DMARDs control RA but usually do not cure the disease. For that reason, if remission or optimal control of RA is achieved with a DMARD, it should be continued at a maintenance dosage. Discontinuing a DMARD may reactivate disease or cause a ``rebound flare,'' with no assurance that disease control will be reestablished upon resumption of the medication. -------ACR Management of Rheumatoid Arthritis