Liver transplantation (LTx) is the preferred treatment in patients with end-stage liver disease and hepatocellular carcinoma with 1-year patient survival exceeding 80%. However, survival rates gradually decline over time with 5-year and 10-year patient survival rates of respectively 71 and 61 % (European Liver and Intestine Transplant Association, 1985). Adherence to immunosuppressive medication and avoidance of contra-indicated drugs are two potential modifiable risk factors to improve long-term outcome (Neuberger et al., 2017). In addition, due to the development of comorbidities, LTx recipients will usually end up with multiple drugs over the years. Over 30 years of experience, we learned that medication errors contribute to a substantial amount of unplanned hospitalizations (Brennan et al., 1991; Beijer and de Blaey, 2002). In the Netherlands, the Hospital Admissions Related to Medication (HARM) study showed that 5.6% of all unplanned hospitalizations are drug related and that 46% of these were potentially preventable (Leendertse et al., 2008). Therefore, identification and management of medication-related problems (MRPs) opens opportunities to improve medication safety. Several studies have shown that a medication review might contribute to the detection, prevention and management of MRPs in all sorts of settings (Vink et al., 2011; Roane et al., 2014).

MRPs are defined as events or circumstances involving drug therapy that actually or potentially interferes with desired health outcomes (Pharmaceutical Care Network Europe (PCNE), 2019). Examples of MRPs are adverse drug reactions, drug interactions, nonadherence, unnecessary drug use and untreated indications.

In North-America clinical pharmacists (CP) have been involved in the direct patient care in transplantation since the early 1970s. (Sam et al., 2018). In the Netherlands, pharmacists working in the hospital as CPs are more recently starting to be involved in the direct care for hospitalized patients (Bosma et al., 2008). Only a few CPs are involved in the out-patient care as well. As far as we know, no CP has been structurally involved in the out-patient care of liver transplant recipients in the Netherlands.

Taber et al. showed that MRPs and adverse drug events commonly occur in kidney transplant recipients resulting in higher rates of acute rejection and lower graft survival rates (Taber et al., 2012). Despite the fact that LTx recipients take comparable drugs as kidney transplant recipients, so far no study describes the prevalence and types of MRPs in LTx recipients and the impact of interventions initiated by a CP in this population. By investigating MRPs in LTx recipients more information about MRPs in the transplantation population becomes available resulting in more awareness, possibly earlier detection of MRPs and better prevention strategies.

This study aimed to investigate the prevalence and types of MRPs in a cohort of liver transplant recipients in the outpatient setting in one of the three liver transplant centers of the Netherlands. The secondary objectives were to investigate the severity of the MRPs and the type and impact of interventions initiated by a CP to improve medication use.

The CP counseled 64 patients with a median age of 59.5°years (IQR: 47–66) and a median of seven medications (IQR: 5–8). The most prevalent indication for LTx was cirrhosis. Frequent comorbidities were chronic kidney disease (n = 26), cardiovascular disease (n = 26), and diabetes mellitus (n = 19); 11 patients had no comorbidities. Table 1 presents the clinical and demographical characteristics of the cohort.

In this cohort, LTx recipients experience a median of 2 MRPs with the majority of the errors causing potential harm to patients (68.3%). ADRs, nonadherence and the use of unnecessary drugs were the most frequently reported MRPs in this cohort. Interventions most frequently proposed by the CP were dosage optimization, individualized recommendation regarding drug compliance and drug discontinuation. The clinical relevance of this program by the CP is shown by a reduction in patients experiencing compliance issues and patients using drugs with indication issues.

Our results are in line with Taber et al., who evaluated MRPs in kidney transplant recipients (Taber et al., 2012). They showed that MRPs commonly occur in kidney transplant recipients with nonadherence and ADRs as most frequently reported MRPs in their cohort. Recently, another study by Hayward et al. found results comparable to ours with nonadherence and indication issues as most frequently reported MRPs in a cohort of ambulatory patients with cirrhosis (Hayward et al., 2019). Interestingly, they found more drug interactions, dose issues and monitoring issues in comparison with our study. An explanation for this difference is the fact that in the Netherlands a nationwide electronical medication monitoring system is implemented with clinical decision support and clinical rules (van der Sijs et al., 2010; Beex-Oosterhuis et al., 2013). As a consequence, physicians and pharmacists receive drug safety alerts directly during prescribing preventing for suboptimal doses, drug interactions and monitoring issues (e.g. the measurement of through levels for certain drugs).

Most frequently proposed interventions were dosage optimization, individualized recommendation regarding drug compliance and drug discontinuation. Interestingly, most ADRs and nonadherence issues in this cohort were due to complex medication schedules. Furthermore, the use of unnecessary drugs was approximately one fifth of the MRPs, which shows that a comprehensive review of medication is not regularly performed by the treating physician during the outpatient visit.

MRPs and especially nonadherence have been found to be correlated to multiple factors such as socioeconomic, therapy-related and healthcare organizational (Belaiche et al., 2017). Methods used to improve nonadherence are automated prescription refill assistance, patient’s self-reports or eHealth applications. However, MRPs in LTx recipients can only be solved by multi-faceted interventions targeting behavioral, educational and emotional factors and providing multidisciplinary care including a consultation with a CP.

Interventions proposed by the CP were in 93.6% followed by both the patient and the hepatologist. Other international studies show comparable acceptance rates of approximately 95%, whereas studies in the Netherlands show an acceptance rate of approximately 80% (Kopp et al., 2007; Bosma et al., 2008). Probably, at the Erasmus University Medical Center an acceptance rate in accordance with international studies is achieved by a recent change in the workflow. CPs are dedicated to specific wards causing intensive collaborations with all health care providers. During some consultations the number of interventions initiated for the MRPs were greater than the total number of MRPs. This is caused by the fact that for some MRPs multiple interventions are possible. For example, nonadherence could be improved by medication optimizations and medication compliance advises. Also, ADRs could be solved by a change in the dosage regimen and an advice on how to reduce or handle adverse drug reactions. Moreover, potential medication related complications were prevented in 68.3% of the patients.

This newly established consultation with the CP is performed during the annual check-up. Possibly a consultation more frequently over the year might be more beneficial, even for recently transplanted patients. A potential hurdle for this kind of involvement of the pharmacist is current absence of financial reimbursement for the CP in the Netherlands. With a reduction in patients experiencing compliance issues and patients using drugs with indication issues we show the clinical relevance of this program. The results of this study implicate that an intensive collaboration between liver transplant healthcare professionals and pharmacists is needed and should be evolved in the near future.

Strengths of our study are the real-life clinical setting, the fact that the MRPs were independently categorized and the good collaboration between the Department of Hepatology and the Department of Hospital Pharmacy. Furthermore, we did assess the severity of the MRPs and evaluated the MRPs and proposed interventions one year after the consultation. As far as we know, this is the first study that describes MRPs in the outpatient setting focusing on liver transplant recipients. Our study has some limitations. Due to the fact that the consultation with the CP was planned one afternoon per week, not every LTx recipient monitored at the outpatient clinic of the Erasmus University Medical Center has been consulted by the CP. As a consequence, we might under- or overestimate the actual prevalence of MRPs in our cohort. However, patients of all hepatologists working at the Erasmus University Medical Center are seen by the CP. Therefore, we assume that this cohort is a good reflection of all LTx recipients monitored at the outpatient clinic. Furthermore, patient satisfaction about the consultation of the CP was not monitored. Further research could focus on this topic, together with the prevention of unplanned hospital admissions of LTx recipients. In the future, a randomized controlled trial could be performed evaluating the effect of a consultation provided by a CP that combines several strategies to reduce MRPs in LTx recipients. In summary, LTx recipients in this cohort experience a median of 2 MRPs of which ADRs, nonadherence and unnecessary drugs are most frequently reported. The clinical relevance of this program is shown by a reduction in patients experiencing compliance issues and patients using drugs with indication issues. An outpatient monitoring program of a CP for LTx recipients can signal MRPs and lead to interventions that are accepted by both the patients and the hepatologists and hence result in optimization of medication safety in LTx recipients.