Patient preferences regarding atrial fibrillation stroke prophylaxis in patients at potential risk of atrial fibrillation.

Background With an increasing number of options for atrial fibrillation (AF) stroke prophylaxis, there are several medication-related factors to consider. This study aimed to gain a better understanding of which preference factors influence patient decisions when selecting AF stroke prophylaxis. Objective To determine the factors that influence patient stroke prophylaxis decisions and preferred therapeutic options. Methods A questionnaire about AF stroke prophylaxis medication options was distributed to participants at risk of AF. Preferences were elicited through ranking and rating medication preference factor statements, then selecting most and least preferred treatment options. Results Reduced stroke risk and lowest risk of an intracranial haemorrhage (ICH) had the highest median preference factor ranking of 2 (IQR, 1-3.5 for stroke reduction; 2-4 for ICH risk). Reducing stroke risk, availability of a lab test to assess drug effect, and availability of an antidote were the preference factors with the highest ratings. Apixaban was the most preferred treatment option (44% blinded to drug name, 37% unblinded) while 'No treatment' was the least preferred option (48% blinded, 52% unblinded). Conclusions Reducing stroke risk and limiting ICH risk were the most important medication factors to participants. High inter-participant preference variability suggests the importance of including the patient in decision-making when selecting AF stroke prophylaxis.

Lacosamide as adjunctive therapy in refractory epilepsy in adults: a systematic review.

PURPOSE: To review the evidence for efficacy and safety of lacosamide in adult patients with refractory epilepsy and refractory status epilepticus (RSE). METHODS: A systematic literature search of MEDLINE, PubMed, EMBASE, IPA, Google and Google Scholar (through October 2014) was performed. RESULTS: Fourteen studies assessing lacosamide in 3509 refractory epilepsy patients were included. In 3 RCTs, more patients had at least 50% reduction in seizure frequency with lacosamide compared to placebo with 38.3-41.1%, 38.1-41.2%, and 18.3-25.8%, in the 400 mg/day, 600 mg/day, and placebo groups, respectively. In non-comparative trials, 18-69% of patients achieved at least 50% reduction in seizure frequency, and 1.7-26.2% achieved seizure freedom. Non-responders were documented in two trials, with 26.2-34% having no response. Thirteen studies assessing lacosamide in 390 RSE patients were included. When assessing lacosamide's ability to terminate RSE, one comparative cohort study found no improvement in SE duration or seizure control with addition of lacosamide. Another study documented no difference compared to use of phenytoin. Eleven descriptive studies using lacosamide as add-on RSE therapy revealed seizure termination rates of 0-100% (median 64.7%). In all patients receiving lacosamide, dizziness (21.8%), vision disturbances (10.4%), drowsiness (7.4%), headache (7.0%), nausea (6.5%), and coordination problems (5.8%) were the most common adverse effects. CONCLUSION: Based on evidence to date, adjunctive lacosamide is a treatment option to reduce seizure frequency in patients with refractory epilepsy and terminate seizures in patients with RSE. The safety information summary can be used to advise patients of potential adverse effects.

Assessing medication adherence in solid-organ transplant recipients.

OBJECTIVES: We sought to determine and compare the prevalence of nonadherence in lung, kidney, and liver transplant recipients, and identify potential risk factors for nonadherence. MATERIALS AND METHODS: This cross-sectional, single-center, retrospective cohort study, evaluated 225 outpatient lung, kidney, and liver transplant recipients' adherence to immunosuppressant medication. Based on immunosuppressant dosages and dispensing records, medication possession ratio (days of medication supplied/actual days) and gaps in prescription refills (> 30-day lapse between expected depletion of supply and next refill) were used as surrogate markers in assessing adherence for 2 years. Patients were adherent to their immunosuppressant medication regimens if their medication possession ratio was ≥ 80%. RESULTS: The mean age of the subjects was slightly greater than 50 years of age, and they were a median of 2.0, 1.3, and 1.1 years posttransplant at the start of data collection for lung, kidney, and liver recipients. Overall medication possession ratios were 95.4% ± 7.5%, 95.9% ± 7.6%, and 92.7% ± 12.3% in our lung, kidney, and liver recipients. Only 7.1% of patients had a medication possession ratio lower than 80%, which was the cutoff for nonadherence. No statistical analyses were performed to identify potential factors for nonadherence because of the small number of nonadherent patients. CONCLUSIONS: Immunosuppressant medication adherence at our center was high for all 3 organ cohorts, as measured by a medication possession ratio of 80% or better. Further study is needed to evaluate immunosuppressant adherence over time after transplant, and confirm the clinical factors that optimize adherence in high-risk patients.

First successful treatment of post-liver transplant hepatitis C fibrosing cholestatic hepatitis with boceprevir, peginterferon and ribavirin in a pre-transplant null responder.

Fibrosing cholestatic hepatitis (FCH) is a less common but well-recognized severe complication of recurrent hepatitis C virus (HCV) infection post-liver transplant. This condition is fatal without successful treatment and to date; post-transplant antiviral interferon-based antiviral therapy has been associated with guarded success. The new era of protease inhibitors in the treatment of chronic HCV infection may alter the dismal outcome of this condition. To date, however, the experience with protease inhibitors in this condition is unreported. We report a post-liver transplant recipient with HCV associated FCH treated successfully with boceprevir, peginteferon and ribavirin for severe FCH. The patient was young woman who was a null responder pre-transplant to peginterferon and ribavirin. The peak serum bilirubin 391 µmol/L normalized to 15 µmol/L by week 8 of therapy. The pre-treatment HCV viral load of > 78 million IU/mL, decreased to 78 IU/mL at week 8 of therapy and was undetectable by week 12 and at the end of 48 week of treatment. 12 weeks post treatment, the HCV viral load remains undetectable. Significant anemia and neutropenia were encountered. Tacrolimus dosage titrated to trough levels, required marked reduction to 0.5 mg three times weekly. Despite the suboptimal peginterferon and ribavirin dosing, limited by adverse effects, full boceprevir dosing was maintained, with resolution of liver dysfunction. Boceprevir was obtained on compassionate grounds from the manufacturer before its licensure in Canada and this was the first use of boceprevir in the world for post-transplant FCH.

Review of boceprevir and telaprevir for the treatment of chronic hepatitis C.

OBJECTIVE: To summarize and evaluate the published literature pertaining to boceprevir and telaprevir, and to provide clinicians with suggestions for use in patients with chronic hepatitis C infection. METHODS: A standardized search strategy was performed using the MEDLINE, EMBASE, Google Scholar and International Pharmaceuticals Abstracts databases using the search terms "boceprevir", "telaprevir", "boceprevir and hepatitis C", and "telaprevir and hepatitis C". A manual search of references was performed to identify articles missed by the electronic search. Studies were included in the review if they assessed either boceprevir or telaprevir in comparison with standard of care in chronic hepatitis C patients. RESULTS: The studies identified assessed boceprevir and telaprevir in genotype-1 hepatitis C patients. In both treatment-naive and treatment-experienced patients, sustained virological response rates were achieved more often with boceprevir or telaprevir in combination with pegylated interferon and ribavirin compared with pegylated interferon and ribavirin alone. Both medications were well tolerated, with anemia presenting as the most treatment-limiting adverse effect. CONCLUSIONS: Boceprevir and telaprevir will revolutionize the management of hepatitis C genotype 1 patients and will most likely decrease the burden of end-stage disease worldwide. However, current clinical limitations include establishing appropriate and cost-effective treatment durations, and use in special populations such as transplant patients and patients coinfected with HIV. Future research will need to clarify these clinical obstacles to clearly define the role of these agents in hepatitis C management.

A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients.

PURPOSE: Chronic hepatitis C virus (HCV) is a major problem affecting up to 170 million people worldwide. Two protease inhibitors have recently been approved that will revolutionize treatment. Our objective was to summarize and evaluate the literature pertaining to the pharmacokinetics of boceprevir and telaprevir, in order to provide clinicians with insight into the management of actual and potential drug interactions. SUMMARY: A standardized search using MEDLINE (1948-November 2011), EMBASE (1980-November 2011), IPA (1970-November 2011), Google, and Google Scholar that combined the search terms boceprevir, telaprevir, pharmacokinetics, drug interaction, and drug metabolism was performed. Manual reference searches of chosen articles were completed. Monographs and articles, conference proceedings, and abstracts were evaluated. Boceprevir and telaprevir are both substrates and inhibitors of cytochrome P450 3A4 and telaprevir is a substrate of p-glycoprotein. Levels of boceprevir are decreased in patients taking efavirenz but effects with other antiretrovirals are minimal or unknown. Coadministration with efavirenz may compromise telaprevir levels and should be avoided. Telaprevir may increase levels of cyclosporine, tacrolimus, atorvastatin, and amlodipine, which may expose patients to increased adverse effects. Conclusions. Significant drug-drug interactions occur with both boceprevir and telaprevir. Until studies are reported and experience is gained with these agents, clinicians will need to be careful when administering in high-risk populations and those receiving chronic therapy with interacting agents. Studies are urgently needed in HIV patients taking antiretrovirals and patients taking chronic immunosuppression as these populations are at increased risk of experiencing clinically significant interactions.

Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen.

PURPOSE: The pharmacokinetics of both tacrolimus and mycophenolic acid in renal transplant recipients on a corticosteroid-free regimen was evaluated. METHODS: Upon administration of steady-state morning tacrolimus and mycophenolate mofetil doses, 28 patients for whom at least three months had passed after renal transplantation underwent serial blood sample collection over a 12-hour dosing period. Whole blood concentrations of tacrolimus were measured, as were mycophenolic acid, mycophenolic acid 7-0-glucuronide (MPAG), and acyl glucuronide MPAG (AcMPAG) concentrations. Pharmacokinetic parameters were then analyzed by conventional noncompartmental modeling. RESULTS: The mean ± S.D. pharmacokinetic parameters for tacrolimus, normalized to a dose of 1 mg, were as follows: area under the concentration-time curve (AUC), 52.6 ± 24.8 µg · hr/L/mg; maximum concentration (C(max)), 8.0 ± 3.3 µg/L/mg; time to C(max) (t(max)), 1.8 ± 1.0 hr; and minimum concentration (C(min)), 2.6 ± 1.4 µg/L/mg. The mean ± S.D. pharmacokinetic parameters for mycophenolic acid, normalized to a mycophenolate mofetil dose of 1 g, were AUC, 26.9 ± 13.2 µg ·hr/mL/g; C(max), 17.5 ± 5.4 µg/mL/g; t(max), 0.9 ± 0.6 hr; and C(min), 1.5 ± 1.1 µg/mL/g. The free fraction of mycophenolic acid was 1.8% ± 0.7%. AUC ratios of MPAG:mycophenolic acid and AcMPAG:mycophenolic acid were 13.0 ± 5.8 and 0.1 ± 0.2, respectively. CONCLUSION: Overall exposure and C(min) values for tacrolimus were similar but C(max) values were higher than those documented in renal transplant patients treated with corticosteroid-based regimens. This may have clinical implications in corticosteroid-free patients experiencing symptoms of tacrolimus toxicity despite trough levels within target ranges. Mycophenolic acid exposure increased with time, but AUC values fell within the range expected for patients receiving concurrent corticosteroids.

The role of hepatitis B immunoglobulin in hepatitis B related liver transplantation: Canadian Transplant Centre Position Paper.

INTRODUCTION: Hepatitis B virus (HBV) related liver transplant (LT) recipients face a high risk of HBV reinfection in the absence of continuous post-operative HBV prophylaxis. Combination HBV prophylaxis with hepatitis B immune globulin (HBIg) and nucleos(t)ide anti-viral agents prevents HBV recurrence in 90 to 100% of patients who undergo transplantation for hepatitis B and is considered the standard of care in Canada. Post liver transplant HBV prophylaxis protocols vary with regard to the dosing, duration and routes of HBIg administration. All Canadian transplant centres managing liver transplant patients were surveyed as to their HBV transplant protocols. RESULTS: Results of the survey showed that the majority of the Canadian transplant centres use an oral antiviral in combination with long term or indefinite HBIg for prevention of HBV recurrence post liver transplantation. Studies were done to test new protocols using lower HBIg doses given intramuscularly or subcutaneously alone or in combination with antiviral agents.
Conclusion. Long term HBIg administration post transplantation in combination with antiviral agents is an integral part of Canadian HBV related liver transplant protocol.

Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review.

OBJECTIVE: To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens. DATA SOURCES: PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes. DATA SYNTHESIS: Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30-40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation. CONCLUSIONS: Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.

Development and validation of limited sampling strategies for tacrolimus and mycophenolate in steroid-free renal transplant regimens.

PURPOSE: 1) To develop and validate limited sampling strategies (LSSs) for tacrolimus (TAC) and mycophenolic acid (MPA) in renal transplant recipients not receiving corticosteroids; and 2) to evaluate predictive performance of published LSSs (for steroid-based regimens) in a steroid-free population. METHODS: On administration of steady-state morning TAC and mycophenolate mofetil doses, 12-hour serial blood samples from 28 stable renal transplant recipients were collected and measured by validated high-performance liquid chromatography methods and area under the curve (AUC) by trapezoidal rule. TAC LSSs were developed and validated by multiple regression analysis by a two-group method (index n = 18; validation n = 10) and MPA LSSs by the jackknife method (n = 28). Potential LSSs were those with r ≥ .8 (TAC) or r ≥ 0.7 (MPA) and < 3 time points within 2 hours (TAC) or 4 hours (MPA) postdose. Predictive performance was calculated and other published TAC and MPA LSSs tested using preset criteria for bias and precision of within ± 15%. RESULTS: For TAC, three three-concentration, one two-concentration, and one one-concentration model met preset criteria. The best equations were: TAC AUC = 10.338 + 7.739C0 + 3.589C2 (r = 0.956, bias = -3.4%, precision = 4.7%) and TAC AUC = 29.479 + 5.016C2 (r = 0.862, bias = 3.2%, precision = 9.7%). For MPA, only one model was identified: MPA AUC = 9.328 + 1.311C1 + 1.455C2 + 2.901C4 (r = 0.838, bias = -3.8%, precision = 14.9%). One published TAC (and no MPA) LSS in renal transplant recipients on steroid-based regimens met criteria. CONCLUSIONS: To the authors' knowledge, these LSSs are the first to be developed and validated in steroid-free renal transplant recipients and can be used to accurately predict TAC and MPA AUCs for steroid-free regimens. Because the commonly used MPA LSS is based on a steroid regimen and not predictive for steroid-free patients, the newly derived MPA LSS is being applied at the authors' institution. Other renal transplant centers may also wish to validate this equation in their own patients.

Methadone maintenance therapy in liver transplantation.

Cirrhosis due to chronic infection with hepatitis C virus remains by far the most common reason for liver transplantation in North America. Currently, parenteral use of street drugs is the most common means of acquiring hepatitis C. Methadone maintenance therapy is an accepted form of treatment for chronic opiate (eg, heroin) addiction and, not surprisingly, a significant proportion of methadone-treated patients have chronic hepatitis C. The feasibility of liver transplant candidacy in hepatitis patients who require methadone maintenance therapy is controversial, and some transplant centers require patients to withdraw from such therapy in order for the transplant process to move forward. Thus stable patients with end-stage cirrhosis who are receiving methadone maintenance are left in a most difficult situation: discontinue methadone and accept the side effects of withdrawal with the risk of recidivism to use of street opiates, an absolute contraindication for transplantation, or continue methadone therapy and risk exclusion from the transplant process. The issue of methadone replacement therapy in end-stage cirrhosis and the posttransplant literature on the subject are explored in this paper.

Efficacy of maintenance subcutaneous hepatitis B immune globulin (HBIG) post-transplant for prophylaxis against hepatitis B recurrence.

BACKGROUND: Patients who receive liver transplantation for chronic hepatitis B infection require long-term combination therapy with hepatitis B immunoglobulin (HBIG) and oral antiviral medication to prophylax against graft re-infection. This study examines the efficacy and patient preference of subcutaneous (SC) administration of HBIG in maintaining anti HBs titres > 100 IU/L. MATERIALS AND METHODS: 12 patients who were stable while receiving our standard IM HBIG protocol received an alternate formulation by SC injection, consisting of 10 mL (3120 IU) HBIG as 4 x 2.5 mL SC injections. SC injection were repeated as soon as titres reached 100-150 IU/mL during the 3 month study period. A questionnaire was administered upon study entry and exit to subjectively assess patient preference. RESULTS: Anti- HBs Cmax after first injection was 441.6 IU/L +/- 81.5, and Tmax was 7.1 +/- 3.2 days. SC injections were required every 56 days, which compared well to the frequency of required IM injections prior to study enrollment of 45 days. The patients mean ratings of pain on a 0-10 scale were 5 for the IM route and 1.6 for the SC route. All patients preferred the SC injections to the IM. CONCLUSION: SC administration of HBIG can effectively maintain anti HBs levels above the requisite 100 IU/L while substantially decreasing patient discomfort and improving patient satisfaction, and therefore becomes a very attractive alternative to IM HBIG injections. Further studies and wider use of SC HBIG based on this study may alter the standard practice of transplantation centers

Spontaneous clearance of hepatitis C infection post-liver transplant: A rare but real phenomenon? A case report and review of the literature.

Recurrent hepatitis C virus (HCV) infection after liver transplantation is a significant cause of morbidity, mortality and graft loss. Spontaneous clearance of recurrent HCV after liver transplant is a rarely reported phenomenon. We report a case of a 66-year-old woman who underwent liver transplantation for HCV cirrhosis (treatment- naive genotype 2) under immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and short-term corticosteroids. The patient developed histologically proved severe cholestatic recurrence of HCV hepatitis. Immunosuppression was reduced to tacrolimus monotherapy because of cytopenia. She subsequently became RNA negative at week 44 post- transplant while on tacrolimus and MMF despite no antiviral therapy. A spontaneous sustained virologic clearance was confirmed with subsequent HCV nucleotide testing. Only a few similar cases have been reported in the literature with uninterrupted immunosuppression and subsequent spontaneous clearance. Our experience, and the few other published cases in the literature, suggests that spontaneous clearance of HCV after liver transplantation is a rare but real phenomenon. Better understanding of this phenomenon may help to manage recurrent HCV disease after transplantation.

The use of sildenafil to treat portopulmonary hypertension prior to liver transplantation.

Portopulmonary hypertension (PPH) is an infrequent, but well-recognized complication of liver cirrhosis. PPH in those with end-stage liver disease has a significant impact on per-operative and intra-operative mortality, with liver transplantation being contraindicated in those individuals with mean pulmonary artery pressure exceeding 50 mmHg. Vasodilatory therapy is the mainstay of pharmacotherapy for PPH, although the evidence of benefit is largely extrapolated from the pulmonary hypertension literature. We report the use of the phosphodiesterase inhibitor, sildenafil, in a patient with end stage liver disease and PPH, with a pulmonary artery pressure before transplantation of 75 mmHg, to reduce pulmonary artery pressure prior to a successful liver transplant.

Mycophenolate mofetil in liver transplant patients with calcineurin-inhibitor-induced renal impairment.

BACKGROUND: Calcineurin inhibitors (CNIs) provide effective immunosuppression after orthotopic liver transplantation (OLTx), but the associated nephrotoxicity can cause substantial morbidity and mortality among transplant patients. In this study, we retrospectively investigated the efficacy and safety of mycophenolate mofetil (MMF) in OLTx patients with CNI-induced renal impairment. PATIENTS & METHODS: A chart review was undertaken of all liver transplant recipients followed at the Vancouver General Hospital. Twenty-one (12 male) patients were converted to either MMF monotherapy (n = 18) or MMF with corticosteroids (n = 3) for CNI-induced renal dysfunction. Six were excluded because of other factors contributing to renal dysfunction. Mean time from OLTx to conversion was 11.3 years and mean age was 60. Non-parametric Wilcoxon's signed rank testing was used to determine whether there was a difference between the serum creatinine (SCr) before conversion, and 3 or 6 months after conversion. RESULTS: Median follow-up was 294 days, ranging from 35 to 1103 days. The median SCr was significantly reduced from 144 micromol/L before conversion to 129 micromol/L and 139 micromol/L at 3 and 6 months follow-up (p = 0.001 and 0.008, respectively). MMF was well tolerated. Only one patient (6.7%) had elevated liver enzymes and required addition of sirolimus while two (13.4%) experienced gastrointestinal intolerance. CONCLUSIONS: MMF appears to be safe for stable OLTx recipients with CNI-induced nephrotoxicity. Serious side effects were uncommon as only one patient required discontinuation of the medication. However, longer follow-up and larger study populations are needed in the future to better determine its efficacy and safety.

The role of the cytomegalovirus antigenemia assay in the detection and prevention of cytomegalovirus syndrome and disease in solid organ transplant recipients: A review of the British Columbia experience.

BACKGROUND: The pp65 cytomegalovirus (CMV) antigenemia assay has been used as a means of guiding the pre-emptive therapy of CMV disease in solid organ transplant (SOT) recipients. Recently, concerns have been raised regarding the utility of the test to accurately and precisely detect viral activity early enough to reduce the morbidity and mortality associated with CMV OBJECTIVE: To determine the performance characteristics of the method of antigenemia testing of SOT recipients used at Vancouver General Hospital, Vancouver, British Columbia. METHODS: All SOT recipients between January 1, 1999, and June 30, 2000, were retrospectively reviewed for six months following transplantation. Physical examination results, laboratory parameters, antigenemia results and treatment information were reviewed. RESULTS: A total of 134 kidney, liver, lung and kidney-pancreas transplant recipients were included in the analysis. The overall performance characteristics of the antigenemia assay in predicting CMV disease included a sensitivity of 64%, a specificity of 81%, a positive predictive value of 76% and a negative predictive value of 71%. A mean of 18 days passed between the onset of signs and symptoms of CMV disease/syndrome and the first recorded positive antigenemia result, and only 26% of patients had a positive test result before the onset of symptoms. It was found that an antigenemia test breakpoint of at least one positive cell for defining a positive test provided the most sensitive and specific prediction, with increased odds of developing CMV disease. CONCLUSIONS: Based on performance characteristics, the Vancouver General Hospital's current method of antigenemia testing to guide pre-emptive ganciclovir therapy in SOT patients is not optimal for the early detection of disease. Further study is needed on new molecular testing methods to determine if our ability to predict CMV disease can be improved.