Klein 2009.

Methods	Randomized controlled trial
Participants	The study location was University Hospital Mainz, Langenbeckstrasse, Mainz, Germany 26 participants were randomized to the intervention group and 24 participants were randomized to the control group The inclusion criteria were 18 years of age or over, first organ transplant, follow‐up care at University Hospital Mainz for the first year after transplantation, and administration of oral immunosuppressive therapy as a capsule or tablet
Interventions	Intervention: PHARMACEUTICAL CARE In addition to routine clinical care, patients in the intervention group received pharmaceutical care services provided by a dedicated hospital pharmacist. The pharmaceutical care program usually started about 1 week before discharge from the transplant surgery unit. The hospital pharmacist met with the patient 3 to 4 times and educated him on different issues regarding immunosuppressive medication, for example, action of the drugs, side effects, interactions, vital signs, laboratory data, and discharge medication. On discharge, the hospital pharmacist handed out and explained written information, including a discharge medication plan, information regarding the immunosuppressive therapy, and a diary for documenting vital signs and laboratory data. During the first year after transplantation, the patient met the pharmacist at least once per quarter year and at maximum once per month. During these meetings the pharmacist discussed with the patient changes in medication, laboratory values, and drug‐related problems. Preferably, family members were involved. In addition, the hospital pharmacist reviewed the patients' drug therapy, to minimize drug‐related problems, and simplify drug regimens Control: CONTROL Patients in the control group did not receive pharmaceutical care but they received routine clinical care from the same hospital pharmacist as the intervention group
Outcomes	The measures of adherence were medication event monitoring systems (MEMS), pill count, immunosuppressant drug concentrations, Morisky score, and self reported adherence questionnaires. Compliance with the immunosuppressive therapy was measured by MEMS. Compliance was defined as dosing compliance (DC), which describes the percentage of days with the correct number of bottle openings. For patients of both groups the immunosuppressive drug was distributed in MEMS bottles. The bottles were filled in the pharmacy department of the University Hospital Mainz. During each visit, remaining capsules/tablets were counted. During hospital stays electronic monitoring was discontinued. All data collected during the study were analyzed after the study was closed. If the patient's overall DC was less than 80%, the patient was characterized as noncompliant. To get the pill counts, tablets/capsules remaining in MEMS bottles were counted during each visit of the patient. These data were used to calculate the compliance rate at each visit for each patient. Blood samples were routinely collected from all liver transplant patients for immunosuppressant drug monitoring. Serum concentrations were assayed in house by the department of clinical chemistry. Results were used for assessment of compliance. Serum drug concentrations were classified into 2 categories, "target" or "not target". The Morisky score was determined by evaluating the answers to 4 questions concerning medication taking behavior. The Morisky score questionnaire was given to the patient upon discharge, at 6 and 12 months after transplantation. In the self report questionnaire, patients were asked how often they forgot to take a dose of their immunosuppressant during the last 4 weeks. This questionnaire was monitored at 6 and 12 months after transplantation The patient outcome was rejection episodes assessed by histologic diagnosis based on percutaneous liver biopsy. The number of biopsy‐proven rejection episodes were documented during the entire study period and compared for both groups
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on randomization procedure. (pg 840) "...this study was designed as a prospective randomized controlled trial..."
Allocation concealment (selection bias)	Unclear risk	No information on allocation concealment. (pg 840) "...this study was designed as a prospective randomized controlled trial..."
Selective reporting (reporting bias)	Unclear risk	No protocol available
Other bias	Unclear risk	The authors noted several limitations: "Although the prospective, randomized, controlled study design was chosen according to research standards in clinical trials, blinding is still a problem in intervention studies. Patients who participate in clinical studies benefit regardless of the treatment and whether they are assigned to the control or intervention group. This is probably because they receive special attention. This makes it more difficult to demonstrate the effect of an intervention, such as pharmaceutical care, because patients belonging to the control group are more likely to have better outcomes than the overall population. However, even in a small study population, results showing a statistical significance probably resulted from the pharmaceutical care provided. Because of the randomized design, patients of the intervention and control group visited the outpatient clinic at the same time and were able to exchange written and oral information. Moreover, patients in the control group received the basic immunosuppressant from the same hospital pharmacist as the intervention group. If those patients had questions or problems, not caring for them would have been unethical. Finally, it has to be discussed if it is necessary and justifiable not to tell the patients that we will be examining their compliance? Apart from the ethical problem, the high dropout rate caused by using pill boxes results from not informing the patients how the MEMS system works. However, this method is essential to receive valid data. Otherwise, patients could easily manipulate the results. To protect the patients' privacy, all data were coded and documented anonymously. Physicians and staff who cared for the patients had no access to the data, and the study design was approved by the ethical committee. Pill counts proved to be unfeasible, especially during the first weeks following transplantation, when the dose of the immunosuppressive drug was changed frequently. Therefore, documentation was time consuming and probably incomplete. However, this method was helpful for confirming the electronic data. Results of serum concentration measures also confirmed the MEMS results, especially because this method is a direct method of measuring compliance and proves ingestion of the drug. The questionnaire designed by Morisky was easy to administer and analyze. The biggest disadvantage is that the results are subjective. The number of patients assessed as compliant was much higher with the survey than with electronic compliance measurement. However, the questionnaire might be helpful in detecting compliance problems in daily clinical practice. Patients reporting to have forgotten their drug intake, or to have stopped their drug intake when feeling better, can be instructed especially on these issues. We were not surprised that only few patients reported to have forgotten to take their immunosuppressants. Our study reaffirms the previously reported findings that self reports are not reliable measures of compliance." (pg 846)
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ No blinding mentioned but outcome unlikely to be affected by outcome assessor
Blinding of outcome assessment (detection bias) Patient outcome	Low risk	(PRIMARY) REJECTION EPISODES ‐ Objective outcome. Rejection episodes: histologic diagnosis of rejection episodes was based on percutaneous liver biopsy. "The number of biopsy‐proven rejection episodes were documented during the entire study period and compared for both groups." (pg 842)
Blinding of participants (performance bias) Adherence measure	High risk	(PRIMARY) MEMS ‐ No mention of patient blinding
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) REJECTION EPISODES ‐ Objective outcome. Rejection episodes: histologic diagnosis of rejection episodes was based on percutaneous liver biopsy. "The number of biopsy‐proven rejection episodes were documented during the entire study period and compared for both groups." (pg 842)
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Insufficient information about who the key personnel are but outcome unlikely to be affected
Blinding of personnel (performance bias) Patient outcome	Low risk	(PRIMARY) REJECTION EPISODES ‐ Objective outcome. Rejection episodes: histologic diagnosis of rejection episodes was based on percutaneous liver biopsy. "The number of biopsy‐proven rejection episodes were documented during the entire study period and compared for both groups." (pg 842)
Incomplete outcome data (attrition bias) Adherence measure	Low risk	(PRIMARY) MEMS ‐ Low risk of bias: "Two patients in the intervention group died before compliance data could be downloaded for the first time. Four patients in the intervention group and three patients in the control group used additional pill containers besides MEMS. Excluding these nine patients, the intervention group consisted of 20 patients and the control group of 21 patients." (pg 843)
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) REJECTION EPISODES ‐ No incomplete data for this outcome are identified, but from the MEMS data it seems that "Two patients in the intervention group died before compliance data could be downloaded for the first time." Thus, probably no data were collected from these 2 patients