Article Text

Patient preferences for treatment of rheumatoid arthritis
1. L Fraenkel1,2,
2. S T Bogardus2,
3. J Concato1,2,
4. D T Felson3,
5. D R Wittink4
1. 1VA Connecticut Healthcare System, West Haven, CT 06516, USA
2. 2Department of Medicine, Yale University, New Haven, CT 06520, USA
3. 3Department of Medicine, Boston University, Boston, MA 02118, USA
4. 4School of Management, Yale University, New Haven, CT 06520, USA
1. Correspondence to:
Dr L Fraenkel
Yale University, Department of Internal Medicine, Section of Rheumatology, PO Box 208031, 333 Cedar Street, New Haven, CT 06520-8031, USA; liana.fraenkelyale.edu

## Abstract

Objective: To elicit treatment preferences of patients with rheumatoid arthritis (RA) for disease modifying antirheumatic drugs (DMARDs) with varying risk profiles.

Methods: Patient values for 16 DMARD characteristics were ascertained using published data about side effects, effectiveness, and cost. Patient preferences were determined by Adaptive Conjoint Analysis, an interactive computer program that predicts preferences by asking patients to make trade-offs between specific treatment characteristics. Simulations were run to derive preferences for four drugs: methotrexate, gold, leflunomide, and etanercept, under different risk-benefit scenarios. Infliximab was not included because it is given with methotrexate, and we did not include preferences for combination therapy. Based on each patient’s expressed preferences, and the characteristics of the treatments available at the time of the study, the option that best fitted each patient’s perspective was identified.

### Patient utilities

Table 1 presents the patient values (utilities) for each characteristic. The large standard deviations reflect substantial interpatient variability in the values that respondents placed on particular characteristics. Pertinent information is found in the relative differences between utilities. For example, patients felt that decreasing the risk of nausea from 10% to 0 (value = 49 additional utility units) was of similar importance as changing the route of administration from twice weekly subcutaneous injections to a daily oral drug (value = 46 additional utility units). Patients valued eliminating the risk of hepatotoxicity (value = 82 additional utility units) about 2.5 times more than improving the chance of benefit by 25% (value = 32 additional utility units).

Figure 1 demonstrates how much patients valued the maximal improvement in each benefit (that is, the difference between the best and worst levels) and elimination of the risk of each adverse effect studied. In general, patients valued the elimination of risk of both common reversible, as well as rare but more serious, adverse effects more than the maximum improvement of specific benefits. For example, patients felt that that improving the chance of benefit by 30% (value = 54 additional utility units) was less important than eliminating the risk of troublesome adverse effects, such as diarrhoea (value = 89 additional utility units) or nausea (value = 82 additional utility units) as well as rare but potentially more serious adverse effects, such as hepatotoxicity (value = 82 additional utility units), pneumonitis (value = 91 additional utility units), or a theoretical risk of cancer (value = 79 additional utility units). We found no association between the patient values displayed in fig 1 and age or health status.

Figure 1

y axis: change in utility reflects how much patients valued elimination of the risk of specific adverse effects or maximal gains in improvement. x axis: range of benefits and risk of adverse effects associated with the DMARDs studied. Yellow: drug characteristics describing benefits; blue: drug characteristics describing common reversible adverse effects; red: drug characteristics describing less common, but potentially more serious, adverse effects.

### Simulations

#### Base case

Drug characteristics for the base case scenario are listed in Appendix 2, and table 2 reports the results of the simulations. For the base case scenario, which predicted preferences for the maximum benefits reported in the literature, a low probability of adverse effects, and low equal monthly co-pays, 95% of the respondents preferred an option akin to etanercept over the other treatment options.

Table 2

Predicted treatment preferences

#### Sensitivity analyses

When all four options were described as being equally effective (equivalent chance of benefit and ability to prevent bone erosions), the vast majority continued to prefer etanercept. Increasing etanercept’s co-pay to $30.00 (the maximum co-pay for covered drugs in our state), while keeping the other options at$5.00, decreased the percentage of patients preferring this option to 80%.

In sensitivity analyses describing the “best case” scenario for methotrexate (as effective as etanercept and risk of pneumonitis lowered to 0.1%), 10% of patients preferred methotrexate over the other options. Describing etanercept as being associated with a rare (0.1%) but serious risk of infection decreased the number of patients choosing TNF inhibitors from 95% to 79%.

## DISCUSSION

We found that most of the patients with RA surveyed in this study preferred etanercept over the other options studied. Note that patients did not evaluate treatment alternatives directly. Rather, ACA calculates utilities based on respondent’s answers to specific trade-off questions. These utilities are then used to predict which option most closely suits each patient’s individual priorities.

Patients’ values for the drug characteristics studied help explain the treatment preferences found in this study. Firstly, our results indicate that older patients place an almost equal value on the risk of common adverse events as they do on much rarer, but potentially more serious, reactions. These results are in keeping with other studies demonstrating that arthritic patients, especially older patients, are reluctant to accept the risk of common, albeit reversible, adverse effects.20–22 It follows, therefore, that patients would prefer drugs with few short term risks and an uncertain long term safety profile rather than those with a greater number of established risks. This may explain why so many patients preferred etanercept even when it was not described as being more effective than the other options.

Secondly, “amount of physician experience” was viewed as one of the lesser important drug characteristics by patients. For physicians, “amount of experience” may be a proxy for rare, but serious, unknown long term side effects. In the case of TNF inhibitors, these risks are primarily related to infection and malignancy. Inclusion of both these risks, however, was not enough to overcome patients’ aversion to the risk of more common side effects associated with methotrexate, gold, and leflunomide.

Our results must be interpreted in view of the limitations of the study. The majority of patients recruited were older, white, female, and well educated, thereby limiting the generalisability of the results. In addition, we surveyed patients in their homes, and not at the time of actual decision making.

Like Ho et al22 and Pullar et al,23 we did not find any relationship between arthritis related health status and willingness to accept toxicity. Willingness to accept risk may be more closely associated with the acuteness or recency of perceived health loss. The lack of association between health status and willingness to accept risk in this study may be due to the fact that most patients surveyed had longstanding disease and may have adapted to their current health state.24

We did not examine preferences for patients without prescription drug plans, because the more expensive drugs would not be reasonable options for most patients if they had to pay the total cost. Given the modest decrease in the percentage of patients preferring etanercept when its co-pay was increased relative to the other options, we would expect that drug plans which ask patients to pay a percentage of total drug costs (as opposed to a fixed co-pay) would significantly diminish preferences for TNF inhibitors.

Cost is often cited as one of the compelling reasons underlying physicians’ preference for methotrexate as the initial preferred DMARD for most patients with RA. Physicians’ concerns about cost are based on the dramatic difference between the annual cost of methotrexate ($265.36) and TNF inhibitors (more than$12 000). Whether significantly more expensive drugs, with fewer adverse effects or modest incremental benefits, should be covered by third party payers or prescribed by physicians is a continuing debate likely to intensify as an increasing number of costly drugs for varied diseases are developed.

We did not include risk of extremely rare but serious adverse events (such as gold associated enterocolitis, drug induced lymphoma, or TNF associated demyelinating diseases) because all four options have been associated with extremely rare, but very serious, reactions, thereby effectively cancelling each other out.

ACA assumes that utilities for individual treatment characteristics are additive and does not permit exploration of interaction effects. In addition, as with all questionnaires, the description of the attributes may influence respondents’ judgment. However, ACA also has several properties which may help overcome the known difficulties in communicating complex risk information.

Previous research has demonstrated that respondents tend to employ simplifying tactics to compensate for information overload when presented with as few as four attributes.25,26 One of the main advantages of ACA is that it is interactive. This feature allows the investigator to evaluate a large number of attributes without information overload or respondent fatigue. This is an extremely important advantage because most complex medical decisions involve multiple trade-offs.

In addition, ACA constructs utilities based on trade-offs between specific drug characteristics. This method has three important advantages. Firstly, it minimises the biases associated with the context in which choices are presented. Secondly, because ACA can be programmed to present treatment characteristics in random order, it eliminates ordering effects.6 Thirdly, by asking respondents to consider specific treatment advantages and disadvantages, it makes trade-offs between competing options explicit. Careful consideration of the trade-offs involved in complex decisions has been shown to improve the quality of decision making.7

In summary, we found that many older patients with RA prefer a DMARD with fewer established adverse effects and an unknown long term safety profile over better established drugs with a greater number of common, albeit reversible, adverse effects, and well known long term risk profiles. The results of this study are not meant to be prescriptive, but do highlight the importance of eliciting and incorporating patient values into treatment decisions involving the initiation of one or more DMARDs.

## APPENDIX 1: CHARACTERISTIC EXPLANATIONS PROVIDED TO THE RESPONDENTS

• One pill taken once a day in the morning

• Subcutaneous injection: An injection given right under the skin, like an insulin injection. You can give it yourself or have someone else do it. It can be given at home or in a clinic.

• Intramuscular injection: An injection given into the muscle (usually your upper arm or buttock), like the flu vaccine. It is given by a nurse in a clinic.

Experience: This refers to the amount of experience doctors have with the drug.

Time for the drug to start working: You can use other drugs like anti-inflammatory drugs (celebrex, naprosyn, ibuprofen) or prednisone until the new drug starts working.

Benefit of the drug:

• Better means that you feel much more energetic and less achy since taking the drug.

• Some of your joints still bother you, but you are in much less pain then you were before starting the drug.

• You are able to perform all your daily activities like shopping and housework on most days with little if any difficulty.

• You are able to engage in leisure activities with your friends on most days with little if any difficulty.

Bone damage: This refers to the number of people who develop new or more bone damage as shown by x ray examination after 1 year. The bone damage can be seen by x ray examination only.

Injection site reaction: This refers to a red itchy localised rash at the site of the injection. These usually stop happening after a few weeks.

Itchy rash: The rash can be treated with drugs and creams to stop the itch. The rash goes away in a few weeks after the dose of the drug is lowered or, if necessary, when the drug is stopped.

Mouth sores: The arthritis drug can cause painful mouth sores. The sores feel like canker sores. The sores can be treated with a gel or a mouth rinse. The sores go away when the dose of the drug is lowered or, if necessary, when the drug is stopped.

Hair thinning: The drug can cause some hair thinning. Your hair will grow back after the dose of the drug is lowered or, if necessary, when the drug is stopped.

Nausea/vomiting: The arthritis drug can cause mild or moderate nausea and vomiting (you sometimes feel a little queasy and vomit about once a day). The nausea and vomiting go away after the dose of the drug is lowered or, if necessary, when the drug is stopped.

Diarrhoea: The arthritis drug can cause moderate diarrhoea (you have occasional stomach cramps and have watery bowel movements about two to three times a day). The diarrhoea goes away after the dose of the drug is lowered or, if necessary, when the drug is stopped.

Cancer: Theoretical risk of cancer means that because the drug affects the immune system it has the potential to increase cancer risk with long term use. An increased risk has not been shown in studies of this drug, but the studies have followed up patients for <5 years. If the drug does turn out to increase the risk of cancer after long term use, the risk might be 1/1000.

Kidney damage: The drug can cause reversible damage to the kidneys. This type of kidney damage doesn’t usually cause any symptoms, but some patients can develop swelling in their legs. The kidneys recover once the drug is stopped.

Liver damage: The arthritis drug can cause liver damage. People with liver damage may become tired, weak, and lose their appetite. Many patients do not get other symptoms, but in some, the liver damage gets worse, and can cause yellow skin, intense itching, and bloating of the stomach.

Lung damage: The arthritis drug can cause lung problems, leading to a dry cough, shortness of breath, and fever. Patients with this side effect need to be admitted to the hospital for treatment with oxygen and intravenous drugs (steroids by vein). Treatment takes an average of 2 weeks.

Costs: Cost refers to your co-pay (that is your out of pocket costs) per month.

## APPENDIX 2: BASE CASE SCENARIO

Table 3 shows the base case scenario.

Table 3

Base case scenario

## Acknowledgments

We thank Drs RT Schoen, J Kenney, C DiSabatino, A Liebling, J Evans, D Trock, and JA Magaldi for their help in recruiting patients, and Dr T Fried for reviewing the manuscript. Most importantly, we thank all the patients who participated in this study for their time and effort.

This work was supported by VA Advanced Career Development Awards (Drs Fraenkel and Concato), and an Arthritis Investigator Award (Dr Fraenkel). This study was not supported by pharmaceutical industry funds.

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