Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs

A. Maetzel, A. Wong, V. Strand1, P. Tugwell2, G. Wells and C. Bombardier3

University Health Network, Toronto, Ontario, Canada
1 Division of Immunology, Stanford University, Stanford CA, USA,
2 Department of Medicine and The Loeb Health Research Institute, Clinical Epidemiology Unit, University of Ottawa, Ontario,
3 Arthritis & Autoimmunity Research Centre, University Health Network, Toronto, Ontario and Clinical Epidemiology and Healthcare Research Program, University of Toronto, Ontario, Canada


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To summarize the evidence on treatment withdrawal rates reported in observational studies and randomized controlled trials (RCTs) of methotrexate (MTX), parenteral gold (GST), sulphasalazine (SSZ) and hydroxychloroquine (HCQ) among patients with rheumatoid arthritis (RA).

Methods. Two independent Medline searches were used to retrieve relevant studies published between 1966 and 1997. Those which disclosed information on the number of patients withdrawing from the drug were retained. Cumulative probabilities of survival on treatment were then computed using actuarial survival estimates, and differences were tested using log-rank, Wilcoxon and Cox proportional hazards tests.

Results. A total of 159 studies provided withdrawal information, and the numbers of patients who withdrew, in general or because of inefficacy or toxicity, could be abstracted from 110 studies contributing 142 treatment arms (MTX, 48; GST, 56; SSZ, 22; HCQ, 16). Data for HCQ were available only up to 24 months, but combined percentages of patients estimated to have continued MTX, GST or SSZ, respectively, for 60 months were 36, 23 and 22% when all failures were considered, 75, 73 and 53% when withdrawals due to lack of efficacy alone were considered, and 65, 36 and 48% when only withdrawals due to toxicity were taken into account. The Cox proportional hazards test performed on all withdrawals, after adjusting for year of publication and type of study, revealed that patients remained on MTX significantly longer than they did on the other three agents; however, the patients stayed significantly longer on GST than MTX when withdrawals for inefficacy were analysed separately. No significant differences in withdrawal rates were noted between observational studies and RCTs.

Conclusion. Patients with RA stay significantly longer on MTX than on other disease-modifying anti-rheumatic drugs. Higher withdrawal rates among those given GST are mainly due to high toxicity, whereas the majority of withdrawals from SSZ and HCQ result from lack of efficacy. Withdrawal rates in observational studies are similar to those reported in RCTs.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Given the chronic nature of rheumatoid arthritis (RA), it is important to obtain long-term evidence of the success of therapy with disease modifying anti-rheumatic drugs (DMARDs). This may be provided by the findings of observational studies or randomized controlled trials (RCTs).

Compared with observational studies, RCTs generate more detailed and standardized data concerning the therapeutic response [1], but are generally conducted over periods that rarely exceed 1 yr. The therapeutic potential of the study drugs must therefore often be extrapolated beyond the period of investigation. Furthermore, patient populations in RCTs are highly selected and monitoring is intense. Some investigators have argued that observational studies, which typically document treatment failure as the proportion of patients who withdraw from therapy due to lack of efficacy, treatment toxicity or reasons unrelated to therapy, provide more realistic estimates of how patients respond to therapy [27].

Observational studies of drug therapy often use survival analysis to assess treatment withdrawal rates. For outcomes such as time to treatment failure, the product limit method is a fundamental part of this approach, allowing the estimation of withdrawal rates even when patients enter a study at different times and are therefore observed for varying periods [8]. However, because estimates of survival become unstable at follow-up periods reached by only a few patients, such analyses are usually stopped when too few subjects remain on treatment for reasonable inferences to be drawn. It is therefore advantageous to combine data from several observational studies in order to increase sample size, particularly at the tail end of the survival curve.

A number of observational studies of DMARD therapy in RA have now been published, creating an important opportunity to summarize their findings in combination with those of RCTs. Agents considered in the present meta-analysis are parenteral gold (GST), hydroxychloroquine (HCQ), methotrexate (MTX) and sulphasalazine (SSZ). The primary objective was to determine overall treatment withdrawal rates and to look at how they break down according to lack of efficacy and toxicity. A secondary objective was to compare treatment withdrawal rates from observational studies with those from RCTs.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Selection of references
The Medline database from 1966 to August 1997 was searched by combining the keyword ‘rheumatoid arthritis’ with text words and keywords for GST, SSZ, MTX and HCQ, including common synonyms. Letters, editorials and comments were excluded, as were articles written in languages other than English, French, German and Spanish. The resulting references were reduced to a set of 1387 by excluding all those that did not address efficacy or toxicity. A further 1035 references derived from a broader search conducted by the RA subgroup of the Cochrane Musculoskeletal Review Group were added, to give a total of 2422. The Cochrane set of references was retrieved from the Excerpta Medica and Medline electronic databases, using key words and text words for (1) randomized clinical trial, (2) clinical trial, (3) comparative study, (4) evaluation study, (5) follow-up study, (6) prospective study, combined with all references indexed under (7) arthritis, rheumatoid.

Screening and assessment of references
Based on information in titles and abstracts, the 2422 references resulting from both searches were classified according to the four agents of interest and the design of the study. Eligible designs were RCTs, observational studies including case series, case–control studies and cohorts, and case reports. Paper copies were obtained of all clearly relevant papers, plus those with uninformative titles and/or abstracts. A total of 445 investigations were found that provided original information. These were then assessed by two authors according to the following criteria: (1) does the study document the experience of patients from the day therapy was initiated? (2) does the study provide data for one of the four therapies of interest? (3) does the study provide information on treatment withdrawal rates? (4) do all included patients have a documented diagnosis of RA? Investigations meeting all four criteria were retained as the set of studies providing withdrawal information. Of these, only studies disclosing the actual number of patients withdrawing from the study drug were used for the meta-analysis. Authors of four large excluded studies were approached with a request to provide additional information but were either unable to provide the data or declined to collaborate.

All observational studies were further appraised according to the following criteria: (1) was reporting of termination rates a primary or secondary objective? (2) was outcome ascertainment prospective or retrospective? (3) was the clinical response specifically defined? (4) with regard to follow-up, were (a) all patients followed over a fixed interval independent of treatment status (no censoring), or were (b) patients followed over intervals varying from a few months to several years depending on study entry and treatment termination (with censoring)? (5) were lifetable or Kaplan–Meier survival analysis techniques applied? (6) did the study provide information about the numbers of patients at risk, censored and terminating treatment at each interval?

Data extraction
Numbers of patients reported to have withdrawn from treatment with each DMARD were abstracted independently by two of the authors, whose findings were checked for agreement and corrected where necessary. The data set was then constructed. Take, for example, the treatment arm of a study of 6 months' duration in which five of 20 patients had withdrawn from treatment by 6 months. Those five patients were coded as one observation and classified as treatment failures at the midpoint of the interval (month 3), whereas the 15 patients who continued treatment were coded as a second observation and classified as censored at the end of the study (month 6). Each observation was weighted by the number of patients, such that the first counted as contributing five patients and the second as contributing 15. Observations from a few studies conducted over long periods without providing detailed interval information were modified by apportioning withdrawals to 6-month intervals assuming a constant failure rate.

Analysis
Survival analysis and statistical comparisons were then performed. Actuarial survival curves stratified by DMARD were plotted for all studies entered into the database using four definitions of failure: (1) withdrawal due to lack of efficacy, toxicity or other reason; (2) withdrawal due to lack of efficacy or toxicity; (3) withdrawal due to lack of efficacy; and (4) withdrawal due to toxicity. For the purposes of analyses 2, 3 and 4, withdrawals not defined as treatment failure were coded as treatment continuations up to the midpoint of the interval.

Statistical comparisons were undertaken in two steps: first, the cumulative survival probabilities for treatment with each of the four DMARDs were compared pairwise using log-rank and Wilcoxon statistics; secondly, withdrawal rates for each agent were compared using Cox's proportional hazards model (proc PHREG in SAS) with adjustment for study type and year of publication. As many treatment failures occurred at the same time-point, the exact algorithm for tied events was used. HCQ treatment was excluded from the comparisons because of the limited amount of data available and because it is generally prescribed in mild RA, although survival curves are presented. Three statistical comparisons were performed within each of the four groups: (1) MTX vs GST; (2) MTX vs SSZ; and (3) SSZ vs GST. Further subgroup analyses compared the effect of study type on treatment withdrawal rates for MTX, SSZ and GST separately. A time limit of 24 months was set and the same statistical approaches were used.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Of the initial 445 studies, 159 satisfied all four screening criteria (A list of all 159 references is available from the author upon request.); 71 were RCTs and 88 observational studies. Reasons for the 286 exclusions were as follows: 132 (46.2%) did not evaluate an inception cohort, 220 (76.9%) did not provide information on treatment withdrawal, 32 (11.2%) studied diagnoses other than RA, and 45 (15.7%) evaluated drugs other than MTX, GST, HCQ or SSZ (some studies were excluded for more than one reason). Among the 159 studies were 110 that provided withdrawal information detailed enough to be included in the present meta-analysis.

Further assessment of the observational studies for methodological characteristics showed that provision of information on treatment termination rates was a primary objective in 42 studies (48%) and outcome ascertainment was prospective in 62 (70%); treatment success or failure was defined by explicit criteria in 21 (24%). Follow-up over a fixed interval independent of treatment status was documented in 38 studies (43%), and of the remaining 50 observational studies that reported a variable follow-up, 26 presented the data using Kaplan–Meier survival analysis techniques. Raw numbers of patients at risk, censored, and terminating treatment at within-study intervals were reported in only 13, four and seven papers, respectively.

The 110 studies included in the meta-analysis contributed 142 arms, the majority of them reporting results with GST or MTX administration. Only three observational study arms provided withdrawal information for HCQ (Table 1Go). The maximum observation time on HCQ treatment was only 24 months, whereas data for GST, MTX and SSZ were reported for as long as 72 months.


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TABLE 1. Number of patients at risk and duration of treatment in study arms from observational studies and randomized clinical trials reported in the literature providing information on treatment withdrawals of patients

 
Survival on therapy curves including all types of withdrawals indicated that 36, 23 and 22% of the patients continued MTX, GST and SSZ, respectively, for 60 months (Fig. 1Go), with median survival times of 41, 24 and 18 months, respectively. The combined number of patients at risk at baseline for each of the three drugs was 2875 (MTX), 3155 (GST) and 1418 (SSZ). When considering only withdrawals for lack of efficacy or toxicity (excluding administrative reasons or relocation), the percentage of patients estimated to have continued MTX compared with GST or SSZ increased to 51%, indicating that a considerable proportion failed to continue MTX for reasons other than lack of efficacy or toxicity (data not shown as a figure).



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FIG. 1. Survival curves representing the percentage of patients withdrawing from each agent because of inefficacy, toxicity or other reasons. Six-month interval data were generated from studies providing withdrawal information for intervals larger than 12 months. The data are from observational studies and randomized controlled trials.

 
Data on withdrawals for lack of efficacy only (Fig. 2Go) indicated that 75, 73 and 53% of patients receiving MTX, GST and SSZ, respectively, continued therapy for 60 months. For this subgroup analysis, the combined number of patients at risk at baseline for each of the three drugs was 2013 (MTX), 2233 (GST) and 1392 (SSZ). Analysis of withdrawals due to toxicity (treating all other withdrawals as non-informative) revealed that 65, 36 and 48% of the patients continued MTX, GST and SSZ, respectively, for 60 months (Fig. 3Go).



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FIG. 2. Survival curves representing the percentage of patients withdrawing from each agent because of inefficacy. Six-month interval data were generated from studies providing withdrawal information for intervals longer than 12 months. The data are from observational studies and randomized controlled trials.

 


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FIG. 3. Survival curves representing the percentage of patients withdrawing from each agent because of toxicity. Six-month interval data were generated from studies providing withdrawal information for intervals longer than 12 months. The data are from observational studies and randomized controlled trials.

 
Combined data from all published studies indicated that, after adjusting for study type and year of publication, patients treated with SSZ were up to 1.9 times more likely to fail therapy than patients treated with MTX (Table 2Go). Patients treated with GST were up to 2.3 times more likely to fail therapy than patients treated with MTX. However, when looking at failures for lack of efficacy only, it turns out that patients treated with GST were significantly less likely to discontinue therapy than patients on MTX. This finding is significant only after adjusting for type of study and year of publication. Patients on SSZ were more likely than patients on GST to withdraw from therapy overall, and more than twice as likely as patients receiving GST to withdraw because of lack of efficacy. Patients on SSZ, however, were less likely than those taking GST to withdraw because of toxicity.


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TABLE 2. Statistical comparisons of treatment withdrawal rates between drugs by means of the log-rank, Wilcoxon and Cox proportional hazards regression tests

 
The comparison of withdrawal rates between observational studies and RCTs involving MTX, GST and SSZ revealed no statistically significant differences for up to 24 months (Fig. 4Go).



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FIG. 4. Percentage of patients withdrawing due to inefficacy, toxicity or other reasons in observational studies and randomized controlled trials. The comparison was limited to 24 months’ duration and showed no statistically significant difference in withdrawal rates between observational studies and randomized controlled trials for all three agents.

 


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The present study summarizes rates of treatment withdrawal in published observational studies and RCTs of MTX, GST, SSZ and HCQ. Analysis of the combined data shows that patients stayed longest on single DMARD therapy with MTX. However, nearly two-thirds of all subjects started another therapy within 5 yr because of lack of efficacy, treatment-associated adverse events or other factors. When withdrawals due to lack of efficacy alone were considered, there were more patients withdrawing from MTX than GST, and it was noted that a large proportion of patients who withdrew from MTX did so for reasons other than inefficacy or toxicity.

This is not the first investigation to make a formal attempt to review withdrawals from treatment with selected DMARDs [2, 9, 10], but it is the first to combine data from observational studies and RCTs, and to specifically compare rates of withdrawal due to lack of efficacy, toxicity and other reasons. Wolfe [11] noted in a review that estimates of 5-yr treatment withdrawal vary considerably, those for MTX ranging from 30 to 75%. Wolfe combined the 5-yr estimates of MTX therapy, weighting them according to the sample size of patients at risk at baseline; however, this may not be appropriate as the precision of the survival estimates is determined by the number of patients at risk not only at baseline but throughout the study period. Felson et al. [10] compared withdrawal rates between DMARDs but restricted their review to RCTs. Furthermore, they compared overall withdrawal rates and withdrawals due to toxicity, but did not calculate combined survival curves.

Some investigations that were not included in the present meta-analysis—because they did not disclose the actual number of patients withdrawing—documented higher rates of MTX maintenance at the 5-yr interval. For example, Wolfe et al. [12] estimated that ~45% of subjects remained on MTX at 5 years, and Pincus et al. [13] put the figure at ~65% beyond 5 yr. Inclusion of these data would have slightly increased the combined percentage of patients continuing MTX for up to 5 yr. In fact, the year of publication independently contributed to survival differences for MTX and SSZ. Withdrawal rates on MTX and SSZ have therefore declined in recent years. Year of publication was insignificant for HCQ and GST, documenting no change in survival on therapy for these drugs over the years. This is confirmed by the similarity of the present 5-yr treatment survival estimate of 23% to those by Wolfe et al. [12] and Pincus et al. [13], who noted, respectively, that 20 and 28% of patients continued GST therapy for up to 5 yr.

Even though the combined rates of survival on therapy presented here were obtained from several studies, only two treatment arms each for GST [14, 15] and SSZ [15, 16], and three for MTX [1719], contributed information for up to 60 months. However, survival on therapy curves for the combined studies reveal a consistent pattern within the first 2 yr and most are parallel, suggesting that additional studies of the same agents would be unlikely to make a considerable difference. More detailed information concerning the disease status and demographic characteristics of patient populations would probably facilitate analysis of subgroups exhibiting different rates of survival on therapy, but that level of detail could not, unfortunately, be achieved. Thus, this meta-analysis can offer only a rough guide to physicians who want to know how long a particular patient is likely to continue treatment with an individual DMARD.

A further limitation of the present study is the lack of adjustment for meaningful covariables in the statistical comparisons. Although information was sought on common variables such as joint count, rheumatoid factor status, disease duration and the number of prior DMARDs, it had too seldom been collected by investigators to allow more detailed analysis. Earlier studies might have included patients with more severe disease, leading to lower treatment survival rates, particular with GST.

Examination of the underlying reasons for treatment withdrawal in the present meta-analysis indicated that, after adjustment for year of publication, patients on GST were significantly less likely to withdraw from therapy because of lack of efficacy than MTX patients. These data do not reveal how many patients achieved remission or significant clinical improvement during treatment with these two agents, but they do encourage us to take a closer look. GST is one of the least favoured DMARDs [20], despite efficacy comparable to MTX having been demonstrated by RCTs [21, 22], on large databases [23, 24] and in the meta-analysis by Felson et al. [10]. The present results suggest that toxicity is the main reason for GST being out of favour. It is likely that most of the problems relate to the cutaneous rash that, it has been speculated, occurs more often in patients more likely to get into remission [9]. However, GST-associated adverse events can be managed in such a way as to avoid discontinuation of therapy [25] or promote initiation of a second course [2527]. Furthermore, withdrawal rates reported in the literature may obscure the true efficacy of GST, as it has been observed that patients who withdraw from GST are more likely to experience a sustained improvement than patients withdrawing from MTX [28]. This finding may be a direct consequence of using implicit judgement to classify patients as toxicity or inefficacy withdrawals. In this meta-analysis we had to rely on the original author's classification of withdrawals, which was often performed without clear guidance by specific criteria, which in turn leaves the possibility for classification biases that may artificially favour one drug over others.

It is encouraging that, contrary to current opinion, there was no apparent difference in withdrawal rates between observational studies and RCTs. Theoretically, withdrawal rates in RCTs could be either higher (because of protocol-mandated withdrawals or patients fearing that they are taking placebo) or lower (because subjects participating in RCTs receive more care and attention than is usual in the real world). However, although the present results show that equal trust can be placed in reported withdrawal rates, whether they originate from RCTs or observational studies, the relevant comparison was possible for only up to 24 months of follow-up.

The product limit calculation of treatment survival probabilities is a routine method employed in the reporting of treatment success of various DMARDs. However, it is possible that the method is often applied to data which violate some basic assumptions for its use [29]. For example, survival estimates in many older studies may be biased downwards, as these patients generally received their first DMARD late in the disease course, but also because survival on a specific treatment may improve as rheumatologists gain experience with it [29]. This better survival for patients will not be given its due respect when all patients are grouped together for the purpose of the survival analysis. The results presented here will only repeat the same potential biases that may afflict the underlying studies, unless these biases cancel each other out.

The decision to withdraw therapy is often made implicitly in observational studies. Those that adopt explicit definitions of clinical response and follow common methodological reporting standards will enhance the short-term results provided by RCTs and supply valuable information on the long-term performance of antirheumatic therapies to physicians, patients and researchers.


    Acknowledgments
 
The authors wish to acknowledge the assistance of Dr Maria Suarez-Almazor and the RA Subgroup of the Cochrane Musculoskeletal Review Group in providing a second set of references to be assessed as part of this review, and the assistance of William Francis in editing the manuscript.

Disclosure

This study was supported by an unrestricted grant to the Arthritis and Autoimmunity Research Centre from Aventis Canada Inc. The terms of the contract stipulated that the authors should retain the right to absolute control of the methods, conclusions and means of publication of the study. Drs Bombardier, Tugwell, Strand and Wells are consultants to Aventis. Dr A Maetzel is supported by a Ph.D. fellowship (health research) from the Medical Research Council of Canada.


    Notes
 
Correspondence to: A. Maetzel, University Health Network, 610 University Avenue, Room 16-741, Toronto, Ontario M5G 2M9, Canada. Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 22 October 1999; revised version accepted 24 February 2000.