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Evaluation of an immunosuppressant side effect instrument

Progress in Transplantation September 1, 2004 | Winsett, Rebecca P; Arheart, Kris; Stratta, Robert J; Alloway, Rita; Et al Background-Clinicians continue to be compelled to evaluate the impact of immunosuppressive medication side effects on the quality of life of transplant recipients. We were asked to develop an instrument to measure side effects in immunosuppressed transplant recipients.

Objective-To construct an instrument that measures the impact and severity of side effects of immunosuppressive medications used in transplantation and to assess the reliability and validity of the newly developed instrument called the Memphis Survey.

Design-The instrument was constructed by a panel of physicians, nurses, and pharmacists with experience in treating transplant recipients. A small group of kidney transplant recipients (n= 13) provided pilot data for refining and testing the instrument. A national sample of kidney, liver, and heart transplant recipients (n = 505) provided data that were used to further develop the instrument.

Analysis-Factor analysis was used to determine the psychological dimensions underlying the instrument and to guide the construction of scales from the survey items. The instrument scales were then computed from the dataset of 505 transplant recipients to quantify the impact of immunosuppressant side effects on the quality of life of transplant recipients.

Results and Conclusion-Analyses showed the final instrument scales to be valid and reliable. Exploratory analysis suggests the need for further testing of the instrument to determine gender differences. (Progress in Transplantation. 2004;14:210-216,240) The current paradigm shift from short-to long-term outcomes after transplantation emphasizes the excellent survival rates and improved quality of life (QOL) achieved for most solid-organ recipients. With the improvement in survival rates, transplant clinicians can now focus on promoting long-term health and QOL. Transplant clinicians are particularly concerned about the long-term effects of immunosuppwssive agents. A review of the literature indicates that 2 psychometrically sound instruments have been developed specifically for heart and lung transplant recipients.1,2 At the time we undertook the development of the instrument presented in this article, psychometric properties for the 2 known instruments had not been published. A third instrument to evaluate symptom distress has not been published nor psychometric properties examined,1 We chose to develop and test an instrument specific to immunosuppresslve medications that may cross organ lransplanl types, thus providing an additional transplant-specific instrument. This article outlines the steps undertaken to develop and evaluate such an instrument.

Problem To maintain graft function, transplant recipients must take immunosuppressive medications to protect the transplanted organ from rejection. Yet these medications are not without adverse side effects, and these side effects are believed to be associated with medication nonadherence. Nonadherenee to medications has been identified as the third leading cause of graft failure after acute rejection and infection.4 Furthermore, healthcare providers perceive disturbing side effects to be an influential factor in nonadherence.5 Therefore, clinicians continue to question the effect of the immunosuppressive medications on short- and longterm outcomes. The framework for the development of this instrument is based on the clinicians’ perception that side effects of medications, particularly immunosuppressive medications, influence long-term health and QOL outcomes. It is because of the strength of that belief that we agreed to undertake the enormous task of developing a transplant-specific side effect instrument. This does not discount the conceptualization of patient symptom distress of which the literature supports.6-11 The combined effort of seeking clinician input in patient side effects coupled with recipients’ perceptions of side effect severity would provide empirical data for us to examine the effects of immunosuppressive drugs on QOL in the future.

Using a psychometrically sound instrument to measure the impact of side effects may assist clinicians in identifying patients at risk of medication nonadherence and may facilitate the use of tailored medication maintenance protocols to balance optimal immune suppression while minimizing drug-related side effects. Currently, only 1 instrument has been developed to assess the effect of immunosuppressive drugs on QOL.12 This instrument measured frequency and distress in the precyclosporine era. Because this instrument was developed in the early cyclosporine era, it has recently been revised to include side effects associated with new immunosuppressive drugs used in transplantation.11 Symptom distress has also been addressed in another instrument3,7,13,14; however, the psychometric properties of the instrument have not been published.

Purpose of Study The purpose of this study was to construct and to assess the psychometric properties of a newly developed instrument to measure the impact of immunosuppressive treatment. The institutional review board at the University of Tennessee Health Science Center in Memphis, Tenn, approved the study protocol with regard to the protection of human subjects.

Design and Methods An expert panel was used for the initial survey development including the evaluation of content and face validity. The pilot instrument was administered to a small group of transplant recipients to further refine the instrument. A nationwide sample of transplant recipients completed the survey to provide data for scale construction, which was accomplished using factor analysis. Cronbach ? procedure was used to check internal reliability.

Survey Construction An expert panel met to discuss the most common side effects of the current immunosuppressive therapy used in transplantation. The panel consisted of 2 transplant surgeons, 1 transplant nephrologist, 1 doctor of pharmacy, 2 nurse practitioners, and 3 clinical nurse researchers. Each member of the panel had more than 5 years of experience with transplantation, with an overall average of 10 years (range 5-21).

The panel focused on the side effects of prednisone, azathioprine, cyclosporine, tacrolimus, and mycophenolate mofetil. It was important to link each side effect with a possible drug effect rather than to underlying disease or other comorbidity. After an additional review of the drug package insert panels by the research team, a list of the most common side effects known and seen clinically was compiled. The panel was reconvened to examine the list for content and face validity. After some revision of the list, the panel reached a consensus list of 100 side effects with content and face validity.

In order to link the patients’ perceived experience of a side effect with the impact on QOL, it was necessary to obtain not only the presence of the side effect, but also the perceived impact of the side effect on patients’ daily activities. Therefore, the questionnaire had 2 questions per item: (1) “Do you have this (side effect or symptom)?” and (2) “How troubling is it (the side effect)?” Each question was rated on a 5-point Likert-type scale, with anchors 0 (not at all) to 4 (all the time or extremely).

The survey was printed in large font with easy-toread instructions. A separate demographic cover sheet was constructed to obtain age, time since transplantation, gender, ethnicity, and education level. A medication sheet listing the brand and generic names of immunosuppressant medications was included to collect data on the drug regimen of each patient. The panel was concerned that the side effects of drugs used to treat comorbid conditions might influence the patients’ perceptions of side effects linked to immunosuppressant therapy. Therefore, the researchers added a section to the instrument to obtain medications used to treat hypertension, bone disease, cardiovascular disease, diabetes, and hormonal abnormalities. In this way, the influence of a number of other medications on the presence or severity of side effects could be evaluated in the future.

Survey Pilot Test Once the survey was developed, a group of 13 (7 men and 6 women; 11 whites) kidney transplant recipients was asked to complete the survey. The pilot group was asked to critique the survey with regard to the completeness of the list of side effects, the accuracy of the side effect descriptions, and the reading level. This group was also asked whether they thought the survey accurately characterized the impact of their immunosuppressive therapy side effects on their daily lives.

The 13 patients provided evidence that the survey had content and face validity as well as construct validity. They made suggestions to clarify some of the more difficult medical terminology (ie, osteoporosis changed to hip and joint pain), and recommended including 7 additional items.

National Survey The revised 107-item version of the survey was sent to a national sample of 1136 transplant recipients recruited from 11 transplant centers across the United States and from members of the Transplant Recipient International Organization. Of the surveys mailed, 528 (46%) were returned with 505 suitable for analysis. The respondents included 102 heart (20%), 226 kidney (44.5%), 32 pancreas (6.4%), and 148 liver (29.1%) recipients. The gender distribution was nearly equal with 258 men (52.1%) and 237 women (47.8%); racial distribution was 79 (15%) African Americans, 398 (77%) whites, and 42 (8%) were members of other ethnic groups. These data are similar to the distribution by organ type reported by the United Network for Organ Sharing that tracks all organ recipients across the United States.15 Time since transplantation was 5.5 ?±3.3 years (mean?±SD) and ranged from 1 to 21 years. Age ranged from 18 to 79 years (50.6?± 12.6). The mean education level of this sample was 14.3?± 3.0 years. The medication profiles depicted in Table 1 indicate that most patients received their transplant during the cyclosporine era and remained on prednisone. Patients were instructed to complete the questionnaire on the basis of the perception of the side effects they were currently experiencing. this web site nexium side effects

Factor Analysis An exploratory factor analysis was performed on the data from the national survey to reduce the information contained in the 107 items to a few interpretable dimensions while retaining as much of the information as possible.16,17 These dimensions guide the formation of the raw data into scales that represent the dimension. By examining the scree plot of a principal factor analysis it was determined that 22 factors were possible. A factor loading ?0.30 was chosen as the criterion for choosing items that belonged to a factor. A varimax rotation of the 22 factors showed that many scales would have only 4 to 5 items, with factor loadings of 0.30 or greater and that many of the factors would not be interpretable. To obtain a more usable set of factors that one would interpret as subscales of the final instrument, factor analyses with 10 or fewer factors were explored. After multiple examinations of the data, the instrument consisted of 4 factors.

Internal Consistency and Conceptualization of the Instrument Once the 4 factors were identified, internal consistency was measured using Cronbach ? reliability17,18 to determine scale reliability. The researchers met after each run of the internal consistency analyses to discuss the outcome and to make decisions on whether an item reflected the concept underlying a specific side effect better than another item. It was important to have both clinical and analytical input during this stage. As the factors emerged, several side effect items appeared to have the same level of correlation to the factor. At this point, it was determined that one side effect captured the concept better than another. For example, having trouble with slow recovery from infections and restless legs correlated with the factor that was later named mobility. Because these 2 items could represent a problem in mobility but did not present as a “side effect” they were withdrawn from the analysis. The analysis was repeated with and without the symptoms to assess whether one item would change the conceptual underpinning of the factor. Each time, reliability was assessed using the Cronbach ? reliability coefficient. If there were no changes, the item that best represented a side effect as seen in clinical practice was used. Table 2 depicts the multiple runs to establish the mobility subscale. These steps were repeated until the factors had a clear conceptual framework and the instrument was stable. Using both a clinical and research-based construction model, a questionnaire was developed that would be clinically useful, conceptually sound, and be able to identify the side effects pertinent to a transplant population.

The initial instrument consisted of 4 factors (subscales), which were labeled emotional burden (EB) with 11 items, life and role involvement (LR) with 11 items, gastrointestinal distress (GI) with 6 items, and mobility (MO) with 7 items. An additional subscale (miscellaneous [MISC]) was added after discovering that items reported to be most troubling to more recent recipients and of concern to transplant clinicians had not factored out in the initial analyses. These items did not initially emerge as significant factors in the original analysis, perhaps because of the influence of time on the symptom experience. Consequently, the survey data from patients 1 to 2 years after transplantation were reanalyzed by factor analysis using the same procedure noted above. (The inclusion criterium for the study was >1 year after transplantation.) Twenty-seven new items appeared in the factors that did not previously meet the criteria for inclusion; therefore, the transplant clinicians were asked to identify 10 items that were clinically important for inclusion in a fifth subscale. The end result of the factor analyses was a 45-item survey with 5 subscales (EB, LR, GI, MO, MISC). Items are included in Table 3.

Instrument Scoring The subscales scores were tabulated by multiplying the frequency item score by the impact item score, summing these, and dividing by the number of items in each respective subscale. To standardize the score, the weighted (frequency ?— impact) subscale was multiplied by 10. Subscale scores ranged from O to 160 with lower scores representing less impact of the side effect. The median score of 80 would therefore indicate the side effects of that particular item were perceived to be at a moderately high level most of the time. Individual frequency scores (Do you have this?) and impact scores (How troubling is it?) can also be calculated. A total scale score was calculated by adding each weighted item score (frequency ?— impact), dividing by the total number of items (45) and multiplying by 10. The total scale score ranges from O to 160.

Findings After the construction and testing of the survey was completed, the data of the final 45-item survey were analyzed to determine if immunosuppressive side effects differed among organ transplant types. Results are reported as means + standard errors unless otherwise noted. Differences between groups were identified by appropriate descriptive statistics with an a priori significance level set at = 0.05. There were no differences found in the subscale scores by recipient transplant type for side effects related to EB, LR, or MO (Figure 1). Data from the MISC subscale, which covers side effects seen most often early after transplantation, also showed no significant differences by recipient transplant type. The greatest variability in side effects was noted in the GI distress subscale with liver recipients reporting more GI distress than heart recipients (19.2+ 1.73 vs13.8 + 2.09; P? .05); however, for both groups, the scores were moderately low, indicating little frequency or impact from these side effects. Kidney-pancreas recipients reported the poorest GI scores, though not significantly different from other groups. The total score for all subjects regardless of organ received (25.4 ?±19.9) were moderately low, suggesting that in general, immunosuppressant side effects, while present, were not troublesome for most study participants.

To determine the influence of ethnicity or gender, an exploratory analysis for differences among these groups was undertaken. No differences were found in the 5 subscale scores (EB, LR, MO, GI, MISC) on the basis of race, and except for the MISC subscale, no differences were found on the basis of gender (data not shown). Women reported significantly more side effects in the MISC subscale (36.9 ?±1.48 vs 32.4 ?± 1.42, P< .05). To investigate this further, the dataset underwent factor analysis by gender to determine if the conceptual constructs differed between men and women. The results did suggest women and men conceptually view side effects differently; however, the number of subjects in the analysis was considered too low to generalize the findings.

A second exploratory analysis was undertaken to determine the influence of time since transplantation on side effects. Study patients were categorized into 4 eras. The eras chosen represented periods in posttransplant care that are clinically relevant. Time 1 represented fewer than 2 years after transplantation, a time frame in which immunosuppression is the greatest and maintenance schedules are being achieved. Time 2 represented more than 2 and fewer than 5 years, a period of stability. Time 3 represented more than 5 and fewer than 10 years after transplantation, considered as long-term, but with the potential for chronic allograft dysfunction to emerge. Time 4 represented the ultimate in graft survival, the achievement of more than 10 years graft survival. The scores calculated by time eras were fairly low, suggesting that side effects did not impact greatly or that perhaps the large range of time from the transplantation may have attenuated the data. When time since transplantation was taken into account, EB side effects appeared to diminish significantly between times 2 and 3 (25.6 vs 20.3; P? .05), with the EB scores diminishing between time eras. GI distress tended to decrease with time and significantly between times 2 and 4 (19.0 vs 11.9; P? .05). Although no statistical significance was observed for the MlSC subscale between time eras, the scores were higher for this subscale than for all other subscales. Mobility subscale scores increased between time eras for the entire study sample and although not statistically different between time eras, this may represent a symptom area that is clinically troublesome for transplant recipients. Because a cross-sectional approach was used in this study, it is unclear whether the mobility symptoms change because of recipient age, length of immunosuppressive therapy, associated bone morbidity or some other comorbidity. go to website nexium side effects

Because clinicians perceive immunosuppression as a factor in long-term QOL outcomes, we subjected the data to an exploratory preliminary analysis on the basis of maintenance drug therapy. When differences were evaluated for the entire sample on the basis of cyclosporine- (n = 344) versus tacrolimus-based (n = 111 ) therapy, there were no significant differences in the EB, LR, MO, and MISC subscales (Figure 2). However, recipients using cyclosporine had significantly fewer GI side effects than those who used tacrolimus (15.8 vs 21.2; P? .05), which is congruent with clinical observations. Liver transplant recipients reported worse scores for GI distress on cyclosporine-based therapy compared with other organ types (data not shown). Data were insufficient to compare differences between drug therapy and time eras.

Discussion Side effects were present in moderately low levels in participating transplant recipients irrespective of the type of organ transplanted, and in 4 of the 5 subscales, symptoms diminished, except for MO, between time eras. Perhaps one explanation for moderately low levels of perceived impact of side effects in this study could be explained by the fact that only recipients more than 1 year from transplantation were included in the sample. Patients may have adjusted to their medications during this initial year to the point that the side effects were considered “normal” and a desirable trade-off with regard to their pretransplant health status. In addition, a recipient of a successful transplant would be expected to have accommodated to the mediation regimen and perhaps have tolerable immunosuppressive side effects. This survey detected the presence of very low levels of side effects; side effects that were present at some level on a daily basis, but that individuals found a way to tolerate.

The MO and MISC subscale scores were generally higher than other subscales, suggesting that the items included in these subscales had a greater impact on the lives of study participants. The MO subscale included items about muscle strength, problems with climbing stairs, walking, stiff joints, and joint pain. The mean age of respondents was 50 years, so it is difficult to determine whether these side effects reflect long-term immunosuppressive therapy versus normal age-associated mobility discomfort. The MISC subscale included items clinicians considered important and included side effects such as high blood pressure, easy bruising, sexual performance, sleep disturbances, weight gain, hair growth, and difficulty with infections. The conceptual tie linking these unrelated items is the clinicians’ perceptions of frequency of symptoms found in day-to-day practice settings. In the initial factor analysis, these side effects did not cluster, and did not meet the criteria for inclusion within the survey; however, when extracted by further analysis, the data revealed, independent of type of organ transplanted, that these symptoms were experienced in moderate levels suggesting that these side effects have impact on the lives of transplant recipients. A MISC subscale item analysis by drug therapy is the next step to be performed to determine specific side effects that appear to impact QOL and perhaps identify a specific immunosuppressive regimen responsible for a greater proportion of the distressing symptoms. A separate item analysis of drug therapy over time would also help determine the pattern of side effects. As stated previously, this study was cross-sectional and conclusions regarding associations of side effects over time cannot be drawn. Longitudinal studies using the survey are underway to help determine associations in the future.

The influence of gender on medication symptom perception has been reported in oncology patients,19 transplant QOL research,20 as well as the symptom distress work in Europe.21 To evaluate the impact of gender on self-report of side effects, the immunosuppressive survey data underwent a separate factor analyses to compare side effect profiles by gender. This analysis revealed differences between men and women (unpublished data), although the sample size was considered inadequate to generalize the findings. For power to detect differences, a 1:10 ratio subject to item would need to be obtained.18 Therefore, the researchers plan to continue to explore gender differences in future projects.

Transplant clinicians often discuss GI distress as an important concern observed in patients receiving immunosuppressive medications and have associated these symptoms with patient compliance; however, the scores for GI distress were low, including recipients of kidney-pancreas transplants. GI distress is an expected complaint in kidney-pancreas recipients because of the autonomie dysfunction associated with long-term diabetes, and as such, the relatively low level of side effects reported in the kidney-pancreas subgroup was surprising. No particular explanation accounts for this finding except perhaps the long-term successful kidney-pancreas recipient has improved GI function and the moderately low scores reflect the success of the pancreas transplant itself. Overall, patients on tacrolimus-based therapy reported more GI distress than those on cyclosporine-based therapy, which is congruent with clinical observation.

A full range of scores was reported although the mean scores were generally low. Longitudinal sampling design is needed to determine if attenuation of the side effects occurs because of time since the transplantation. Construct reliability has been established and further studies are underway to evaluate longitudinal impact of immunosuppressive side effects. Criterionrelated validity will need to be established with comparison to a psychometrically sound measurement of general QOL.

It is presumptuous at this point to say that moderately low self-report of side effects is linked with good QOL. We know that QOL studies have shown improvement, both with and without correlation to medication side effects. This also appears to be true in studies that have explored adherence to the immunosuppressive medication regimen indicating adherence is not related to side effects,7,14,22,23 as well as studies that have found positive correlations.5,11,21,24 Nonadherence to medications will most likely continue to be problematic in transplant recipients, and imbedded in the reasons for this nonadherence are side effects of immunosuppressive medications. This instrument was developed and evaluated for use in the patient who must take a lifelong immunosuppressive regimen to sustain good health and found to have construct validity, internal consistency reliability, as well as usefulness in identifying immunosuppressive-related side effects of transplant recipients 1 to 21 years after transplantation.

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[Author Affiliation] Rebecca P. Winsett, PhD, Kris Arheart, Robert J. Stratta, MD, Rita Alloway, PharmD, Mona N. Wicks, PhD, A. Osama Gaber, MD, Donna K. Hathaway, PhD University of Tennessee Health Science Center, Memphis, Tenn (RPW, rwinsett@utmem.edu), University of Miami, Miami, Fla (KA), Wake Forest University Baptist Medical Center, Winston-Salem, NC (RJS), University of Cincinnati, Cincinnati, Ohio (RA), University of Tennessee Health Science Center, Memphis, Tenn (MNW, AOG, DKH) To purchase reprints, contact:

The InnoVision Group 101 Columbia, Aliso Viejo, CA 92656 Phone (800) 809-2273 (ext 532) or (949) 448-7370 (ext 532) Fax (949) 362-2049 Winsett, Rebecca P; Arheart, Kris; Stratta, Robert J; Alloway, Rita; Et al