Impact of a pharmaceutical care programme on health-related quality of life among women with epilepsy: a randomised controlled trial (IPHIWWE study)

Epilepsy is a complex neurological disorder that has deep physical, social, emotional and economic repercussions for patients and their environment. According to the World Health Organization, more than 20 million women worldwide suffer from epilepsy and 85% of them live in developing countries.

For the treatment of epilepsy, the gender of the patient should be considered because there are conditions, including hormonal (menstrual cycle, contraception and menopause), reproductive (fertility, pregnancy and lactation) and role (childcare) conditions, that can affect and be affected by anticonvulsant therapy and that change during the different stages of life of women. In women with epilepsy (WWE), major adverse reactions such as reproductive endocrine disorders, hirsutism, polycystic ovarian syndrome, obesity and sexual dysfunction have been reported, making the treatment of women more complex [1]-[3].

Several studies have shown that people with epilepsy have lower health-related quality of life (HRQOL), especially women [4]-[6], and have associated it with depression, adverse effects, a greater number of anticonvulsants and a higher frequency of seizures [7]-[10].

Anticonvulsants are considered the cornerstone of the treatment of epilepsy and are characterised by a narrow therapeutic index, high inter- and intraindividual variability, a large number of interactions and side effects and some of them have zero order kinetics.

It has been established that WWE require support and specific information in order to achieve adequate control of their condition. The European Declaration on Epilepsy recommends interdisciplinary action to help people with epilepsy understand their condition and make the search for a proper treatment possible in order to improve their quality of life [11],[12].

Pharmaceutical care (PC) is the practice that optimises pharmaceutical treatments contributing to an improvement in HRQOL (humanistic outcome of therapeutic relevance) which can be reported directly by the patient as a patient-reported outcome (PRO) without requiring an interpretation of the response by others [13]-[16].

The pharmacist, as a professional healthcare expert on drugs, can contribute to the optimisation of treatment using medication review follow-up (MRF), education in pathology and lifestyle in the management of epilepsy, therapeutic drug monitoring (TDM) and information on interactions, adverse effects and the appropriate use of medications [17],[18].

This clinical trial was designed with the aim of establishing the impact of the application of a pharmaceutical care programme on HRQOL in WWE.

The study was conducted in the Fundación Liga Central Contra la Epilepsia, sede Bogotá (LICCE), a non-profit organisation specialising in the treatment of outpatients with epilepsy and a referral centre for the management of this disorder in Colombia. Annually about 1000 patients consult for epilepsy, either referred by their health service or independently. An MRF service was implemented in the institution and a guide to medication review follow-up for patients with epilepsy was elaborated and used as the basis for the study intervention.

The study's protocol was approved by the Ethics Committee of the LICCE on August 11, 2009 (ref: IEC-A1 Act 18 of 2009). All patients signed to give their informed consent before entering the study. The patients were invited to participate by posting notices at the institution and via phone calls to the WWE who met the inclusion criteria according to the review of the medical records of patients who were attending the LICCE. Patient recruitment began on June 16, 2010 and was completed on March 10, 2012. The latest follow-up interview took place on September 27, 2012.

We invited 506 patients to participate, of whom 182 entered the study and 144 (79.1%) completed it, 70 in IG and 74 in CG. The Reasons for withdrawal were job, economic and family-related and in no case related to the outcome (Figure 1).

The most widely used anticonvulsant was valproic acid in 85 patients (46.7%), while carbamazepine was used in 42 (23%), levetiracetam in 22 (12.1%) and lamotrigine in 20 (11%). Most patients (116) were on monotherapy (63.7%), which is highly recommended for the management of this condition, and only four (2.7%) received three anticonvulsants.

The average value of the QOLIE-31 for the initial group of 182 patients was 54.56, and confidence interval (CI 95%) 53.79; 55,33. The two-sample Kolmogorov-Smirnov test between scores of the initial groups showed a p-value =0.1686. The homogeneity variances test of the initial scores of the groups resulted in F =1.02 and a p-value of 0.94. The t-test results relating to the difference of the initial mean scores between groups were t = 0.8499, and CI 95%: −2.56; 6.44, p-value: 0.397.

The t-test of the final mean scores of the QOLIE-31 between groups was t = −2.166, CI 95%: −10.125; −0.4625, p-value =0.0319.

The mean of the change (Δ) (after-before) in the QOLIE-31 scores in the final group of 144 patients was 12.45 points in the IG and 2.61 points for the CG. In the paired t-tests comparing initial and final scores, the following results were obtained: for the IG t =8.1878 (CI: 9.41; 15.48, p-value <0.001) and for the CG t = 1.8259 (CI: −0.24; 5.45, p-value =0.072).

An analysis was performed for each component of the QOLIE-31 to establish the effect of the PC programme. The changes (Δ) (after-before) indicated by the scores for each of the seven components of the QOLIE-31 are presented in Figure 2. Categorisation of the QOLIE-31 scores before and after application of the PC programme was performed according to quality of life (see Figure 3) [36].

The mean of the change (Δ) in the QOLIE-31 scores for IG patients who attended at least three MRF interviews (61/70) during the application of the PC programme (analysis per protocol) was 14.41 (CI: 11.37; 17.45).

The contingency table was made with an increase of 10.7 points in the QOLIE-31 score taken as the minimally important change [34]. Epidemiological parameters were calculated finding a RR of 2.17 (CI: 1.37; 3.43) and a NNT of 3.5. The RR was 3.22 for the best-case scenario and 1.06 for the worst-case scenario.

Attendance at health education conferences fluctuated between 28% and 3%. The seizure journal was returned six months after, at the end of the study, by 54 (37.5%) of the 144 patients.

The results of the Liverpool AEP, CES-D, Haynes- Sackett and Moriski– Green tests will be published in subsequent papers.

To our knowledge this is the first RCT investigating the impact of a programme of PC on HRQOL among patients with epilepsy.

The number of patients lost to follow-up was similar in both groups. Table 1 reveals that the characteristics of the groups, after losses, do not differ from those of the entire group of patients who entered the study. The initial QOLIE-31's mean scores, of the patients who remained in the study, did not present statistically significant differences between groups (Table 2).

The t-test for the final scores of the QOLIE-31 established a statistically significant difference (p-value =0.0319) with an increase in the HRQOL after the application of the PC programme in the IG. The paired t-tests to compare the initial and final scores showed that there is a statistically significant difference in the change of the scores of the QOLIE-31 in the IG (p-value <0,001), but not in the CG (p-value =0,072) confirming that the intervention does serve to improve HRQOL in WWE.

The increase of 12.45 points in the QOLIE-31 scores of the IG is considered clinically significant according to the study by Borghs et al. and Cramer et al. of the Epilepsy Impact Project Group, where they established the minimally important change of 10.7 points for the QOLIE-31 in patients passing to monotherapy, who are the most similar to the patients in this study [34],[35].

The individual analyses of the seven components of the QOLIE-31 allowed us to establish that the changes (Δ) were positive in all cases and they were always higher for the IG (Figure 2). Seizure worry, social and cognitive functioning presented significant differences. It is possible that the improvements in social and cognitive functions are due to the clarifications made in the MRF interviews, to the WWE and his family, about the use of medications, diseases, lifestyle habits (allowed to have up to 2 beers/celebration, attend evening meetings, adjusting sleeping schedules to 7 h uninterrupted, the importance of hobbies and activities for stress management, etc.). Learning this information from a pharmacist and resolving their doubts could have led to a reduction in their fear of social activities and the self-stress of living with this disease. The increase in HRQOL in the drug component was small, possibly due to the fact that the follow-up period of six months is too short for evaluating the benefits of optimized drug therapy. Additionally, the QOLIE-31 includes only three questions to evaluate the effect of drugs and gives them the lowest weight (0.03) throughout the questionnaire, while a total of eleven questions are devoted to either social or cognitive function and they are given the greatest weight in the questionnaire (0.21 and 0.27 respectively) [23].

Most patients had bad HRQOL at baseline (Figure 3), which remained in the CG at the end of the study (p-value =0.1994), but decreased almost to half in the IG, presenting a statistically significant difference (p-value <0.001) which makes the positive effect of the PC programme on HRQOL among WWE evident [37].

Helde et al. conducted a RCT to evaluate the change in HRQOL with a two-year application of a structured nurse-led programme among patients with epilepsy [38]. They used the QOLIE-89, which is similar to the QOLIE-31, and found an initial value of 52.5 ± 1.3 (standardised error margin) and two years later a change (Δ) of 2.3 ± 7.0 in the IG and 1.5 ± 7.2 for the CG, which is not clinically significant, according to Wiebe et al., who established an MIC of 10.1 points for the QOLIE-89 [39].

In the per protocol analysis, an even greater increase in quality of life for IG patients who attended at least three interviews of the PC programme during the six months (Δ) was observed: 14.41 points (CI: 11.37; 17.45). This result highlights the importance of the continuity of the process.

The average value of the QOLIE-31 for the initial group of 182 patients was 54.56 ± 15.36 (SD), similar to the one found by Almeida Souza Tedrus et al. with a value of 58.37 ± 17.31 (SD) for WWE in Brazil [4], where the gap between women and men was statistically significant at 7.57 points (p-value: 0.012). It was also similar to the value of 53.4 ± 14.7 (SD) reported by Alanis-Guevara et al. for WWE in Mexico [5]. In both cases HRQOL was lower in women [6].

In a prospective study performed by Kanjanasilp et al., PC was provided for six months among patients with epilepsy treated with phenytoin; they measured HRQOL before and after the intervention with the QOLIE-31 and found that it increased from 61.15 ± 13.67 to 63.47 ± 16.11, showing a statistically significant increase of 2.32 points [40].

The increase in the QOLIE-31 scores in our CG in the second application could be due to the fact that during the first interview, according to Dáder's method, patients expressed their doubts regarding treatment and pathologies, and the pharmacist, for ethical reasons, had to answer the concerns and correct the patients when errors were found in the administration of medications, although this could lead to the contamination of the group. In a before-after study conducted in adults with epilepsy by Fogg et al. [41], the effect of a single 30-minute consultation with a pharmacist was evaluated using the QOLIE-10, and they found that HRQOL increased by 4.2 points (CI 95%: 0.4; 8.0). Although this is a different questionnaire, an increase in HRQOL due to a single consultation with a pharmacist was observed, just as it was in our CG.

The clinical significance of the implementation of the PC programme was evaluated (see Table 3), finding that the possibility of obtaining an MIC in the IG is 2.17 times the CG's one, even though that PC was presented to the CG during the first interview. The result could have been higher if this confounding bias had not been introduced.

By performing the sensitivity analysis, we found that for both the best- and the worst-case scenario the value of RR is higher than 1, confirming that the intervention does serve to improve HRQOL and that the result is due to the implementation of the PC programme. Sensitivity analysis also allows us to assess the impact of loss of follow-up. We found the values were not very different from each other (RR for the worst scenario: 1.06 and for the best scenario: 3.22). We deduce from this that the losses did not affect the validity of the study. Additionally, we believe that the results were not biased because the losses were not related to HRQOL. The effect of the intervention is notable because, despite the losses, which led to a significant reduction in sample size (and in the power of the study), clinically and statistically significant differences were found in both the ITT analysis and in the PP analysis.

The NNT found allows us to recommend the implementation of the PC programme for the additional benefit that would be obtained in patients' HRQOL.

Unfortunately, conference attendance was very low despite being scheduled six months in advance, with the most common reason for the absence being lack of time.

The seizure journal was delivered by only 54 (37.5%) of the 144 patients, possibly because they had never used it and therefore did not realise its importance, despite the explanation and recommendation about filling it out. This result could also be due to the fact that it was given at the end of the first interview, after about an hour of consultation with the application of five questionnaires, and patients were tired and may not have understood the purpose of completing this seizure journal.

We believe that the study by a single researcher, qualified and experienced in the management of patients with epilepsy and in the implementation of pharmaceutical care, allowed an homogeneous intervention. The bias of the researcher was minimised by measuring the outcomes with a patient-reported outcome questionnaire that does not require interpretation.

Initially, an inclusion criterion of having had at least one crisis in the last year (85.2% met this condition) was established, focussing on patients with greater difficulty controlling the disease, but given the slow rate of recruitment, the decision was made to extend this criterion to at least one seizure in the last three years.

The study allowed us to demonstrate that the application of a pharmaceutical care programme significantly improves HRQOL in WWE. The NNT we found allows the recommendation to implement the PC programme for the additional benefit that would be obtained in patients' HRQOL.

L-CM had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: L-CM. Acquisition of data: L-CM. Analysis and interpretation of data: L-CM. Drafting of the manuscript: L-CM. Critical revision of the manuscript for important intellectual content: G-PMF, G-DP, M-MF. Acquisition of funding: L-CM. Administrative, technical or material support: L-CM, G-DP, M-MF. Study supervision: G-PMF. All authors read and approved the final manuscript.

L-CM is a pharmacist with an MSc in Pharmacology, a Pharmacy Professor at the Universidad Nacional de Colombia (since 1999) and a PhD candidate in Farmacia Asistencial at the University of Granada, Spain, for which she conducted this RCT as her Doctoral Thesis.

G-PMF is a phisycian, with a PhD in Pharmacy. Professor at the Universidad Nacional de Colombia (since 1996). Head of Research Group FARMOL.

G-DP is a pharmacist with a PhD in Pharmacy, University expert in epidemiology and clinical research. Member of Research Group CTS-131 Pharmaceutical Care. Member of the scientific committee of the journal "Pharmacy Practice". Member of the scientific committee of the journal "Farmacéuticos Comunitarios".

M-MF is a pharmacist with a PhD in Pharmacy. Associate Professor (since 1984). Head of Research Group CTS-131 Pharmaceutical Care (since 1993). Director of Sandoz-Chair of Granada University Research and Teaching in Pharmaceutical Care (since 2003).