A correlation of thrombin generation assay and clot waveform analysis in patients on warfarin.

OBJECTIVES: Thrombin generation assays and activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA), are some examples of global coagulation assays. Each modality evaluates different aspects of the clot forming process to globally define haemostasis with exclusive measurement parameters. Data on CWA are emerging, but its performance against other haemostatic assays is yet to be ascertained. This study evaluates the correlation between aPTT-based CWA and CAT parameters across a range of INR in warfarin-treated patients. PATIENTS/METHODS: A prospective study consisting of patients on warfarin anticoagulation with varying INR levels. CWA and CAT were performed for the study subjects. RESULTS: 54 samples were included covering an INR range from 1.33-6.89, with a mean of 4.31 +/- 1.13. For CAT parameters, endogenous thrombin potential (ETP) and peak thrombin were assessed. Both unadjusted and adjusted (adjusted for final plateau transmittance) aPTT-based CWA were evaluated for parameters min1 (maximum velocity), min2 (maximum acceleration) and max2 (maximum deceleration). Peak thrombin showed significant correlation with all CWA parameters (min1: r = 0.435, P<0.001; min2: r = 0.485, P<0.001; max2: r = 0.578, P<0.001; adjusted min1: r = 0.734, P<0.001, adjusted min2: r = 0.693, P<0.001; adjusted max2: r = 0.751, P<0.001). ETP correlated significantly with all CWA parameters except unadjusted min1 (min1: r = 0.235, P = 0.087; min2: r = 0.326, P = 0.016; max2: r = 0.437, P<0.001; adjusted min1: r = 0.610, P<0.001, adjusted min2: r = 0.563, P<0.001; adjusted max2: r = 0.642, P<0.001). CONCLUSION: We demonstrated a modest correlation between CAT and CWA parameters. Adjusted CWA improved this correlation. These findings provide additional understanding of CWA and it's role in the evaluation of global haemostatic function.

Evaluation of pharmacist satisfaction with simulation-based learning in Singapore.

BACKGROUND AND PURPOSE: High fidelity human patient simulation (HPS) has been incorporated in various United States doctor of pharmacy programs with favorable learning experiences, knowledge retention, and problem-solving skills reported. In Singapore, HPS is a novel learning technique as it has not been utilized in the Bachelor of Science (Pharmacy) curriculum or for continuing professional education (CPE). It is necessary to evaluate acceptance of HPS compared to asynchronous online learning (AOL). EDUCATIONAL ACTIVITY AND SETTING: Nineteen participants from two institutions completed the study in Singapore. This was an experimental study design with participants randomized into groups A and B. Group A completed AOL followed by HPS, whereas group B completed them in reverse order. Acceptance of teaching modalities was evaluated with a Likert scale survey and analyzed with Fisher's exact test. Educational content was congestive heart failure and was evaluated externally for equivalency. FINDINGS: All participants enjoyed the HPS activity compared to 13 (68.4%; p = 0.02) for AOL. Eighteen (94.7%) and 15 (78.9%; p = 0.34) participants felt that HPS activity and AOL improved their critical and decision-making skills respectively. Sixteen (84.2%) and 17 (89.5%) agreed that AOL and HPS activity improved their confidence (p = 1.00). DISCUSSION: Participants enjoyed HPS activity significantly more than AOL. HPS activity could be used to achieve improved critical and decision-making skills of learners as there was a trend of more learners perceiving improvement compare to AOL. SUMMARY: High fidelity HPS learning was well received by participants in Singapore and can be implemented in CPE.

Prospective study of the efficacy of a ketogenic diet in 20 patients with Dravet syndrome.

PURPOSE: We evaluated the efficacy and tolerability of the ketogenic diet (KD) on generalised convulsions and status epilepticus (SE) in patients with Dravet syndrome (DS). METHODS: Patients with DS having ≥2 generalised convulsions/month despite drug treatment were included in this study and placed on a KD for 6 months. From 3 months before (baseline) to 6 months after KD initiation, caregivers recorded patients' seizure activity, antiepileptic drug use, and adverse events. The KD efficacy was determined by examining the frequency and duration of seizures at 3 and 6 months vs. baseline. Responders were defined as individuals whose generalised convulsions decreased in frequency by ≥50% vs. baseline. Seizures lasting ≥5 min and SE were specifically evaluated. Patients' cognition was also assessed at 3 and 6 months via questionnaire. RESULTS: Twenty patients continued the KD for at least 3 months. Of the 17 responders identified at month 3, seizures decreased by 50-89% and 90-99% in nine and two patients, respectively; six patients were seizure free. The KD was ineffective in three patients, who discontinued the diet. By month 6, seizures decreased by 50-89% and 90-99% in six and one patient(s), respectively; 10 patients were seizure free. The frequency of other seizure types also improved. During all 6 months, neither generalised convulsions lasting ≥5 min nor SE was detected in the 17 responders. The KD also improved patients' cognition. CONCLUSION: The KD is a good treatment option for medically intractable epilepsy.

Clinicopathologic Features and Prognostic Impact of Lymph Node Involvement in Patients With Breast Implant-associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma that arises around breast implants. Most patients manifest with periprosthetic effusion, whereas a subset of patients develops a tumor mass or lymph node involvement (LNI). The aim of this study is to describe the pathologic features of lymph nodes from patients with BI-ALCL and assess the prognostic impact of LNI. Clinical findings and histopathologic features of lymph nodes were assessed in 70 patients with BI-ALCL. LNI was defined by the histologic demonstration of ALCL in lymph nodes. Fourteen (20%) patients with BI-ALCL had LNI, all lymph nodes involved were regional, the most frequent were axillary (93%). The pattern of involvement was sinusoidal in 13 (92.9%) cases, often associated with perifollicular, interfollicular, and diffuse patterns. Two cases had Hodgkin-like patterns. The 5-year overall survival was 75% for patients with LNI and 97.9% for patients without LNI at presentation (P=0.003). Six of 49 (12.2%) of patients with tumor confined by the capsule had LNI, compared with LNI in 8/21 (38%) patients with tumor beyond the capsule. Most patients with LNI achieved complete remission after various therapeutic approaches. Two of 14 (14.3%) patients with LNI died of disease compared with 0/56 (0%) patients without LNI. Twenty percent of patients with BI-ALCL had LNI by lymphoma, most often in a sinusoidal pattern. We conclude that BI-ALCL beyond capsule is associated with a higher risk of LNI. Involvement of lymph nodes was associated with decreased overall survival. Misdiagnosis as Hodgkin lymphoma is a pitfall.

Stability of a novel corticosteroid nasal irrigation solution: betamethasone 17-valerate added to extemporaneously prepared nasal irrigation solutions.

BACKGROUND: There are no commercially available nasal irrigation solutions containing corticosteroids. Instead, such preparations are extemporaneously prepared by adding existing corticosteroid formulations to nasal irrigation solutions. The stability of the corticosteroid betamethasone 17-valerate (B17V), in nasal irrigation solutions of different compositions and pH and stored under different temperatures, was studied to determine the optimal choice of solution and storage conditions. METHODS: Triplicate extemporaneous preparations made with B17V were prepared by adding a predetermined volume of B17V lotion to each nasal irrigation solution: normal saline (NS), sodium bicarbonate (NaHCO3 ) powder dissolved in tap water, and a commercially available powder mixture (FLO Sinus Care Powder), dissolved in tap water or pre-boiled tap water. Preparations were stored at 30°C and 4°C. Sampling was carried out at 0, 1, 2, 6, and 24 hours. The concentrations of B17V and its degradation compound, betamethasone 21-valerate (B21V), were determined by high-performance liquid chromatography. RESULTS: Preparations stored at 30°C contained a lower amount of B17V and higher amount of B21V than those stored at 4°C. B17V stability in nasal irrigation solutions decreased in the following order: NS, FLO in fresh tap water, FLO in pre-boiled tap water, and NaHCO3 . The degradation rate of B17V increased with higher storage temperature and higher pH. CONCLUSION: B17V is most stable when added to NS and least stable in NaHCO3 solution. FLO solution prepared with either cooled boiled water or tap water is an alternative if administered immediately. Storage at 4°C can better preserve stability of B17V, over a period of 24 hours.

Modelling the cost-effectiveness of pharmacist-managed anticoagulation service for older adults with atrial fibrillation in Singapore.

Background Oral anticoagulation with warfarin is the cornerstone therapy in atrial fibrillation (AF) for stroke prevention. Multi-disciplinary anticoagulation management services have been shown to be cost-effective in the United States, Hong Kong and Thailand, but the findings are not readily generalizable to Singapore's healthcare system. Objective This study aimed to evaluate the cost-effectiveness of pharmacist-managed anticoagulation clinic (ACC) compared with usual care (UC) for the management of older adults with AF receiving oral anticoagulation with warfarin. Setting Pharmacist-managed ACC in an academic medical centre. Method A Markov model with 3-month cycle length and 30-year time horizon compared costs and quality-adjusted life-years (QALYs) of ACC and UC from the patient's and healthcare provider's perspectives. Four pathways based on time in therapeutic range (TTR) were: ACC TTR < 70 %, ACC TTR ≥ 70 %, UC TTR < 70 % and UC TTR ≥ 70 %. A hypothetical cohort of 70-year-old Singaporean AF patients receiving warfarin was utilised. Local data from national disease registries, patient surveys and hospital databases were used. When local data was not available, published studies on Asian populations were utilized when available. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to account for uncertainties. Costs and QALYs were discounted annually by 3 %. Main outcome measure Costs and QALYs of ACC and UC. Results Pharmacist-managed ACC was found to dominate UC in all comparisons. It improved effectiveness by 0.19 and 0.13 QALYs at TTR < 70 % and TTR ≥ 70 % respectively compared with UC. From the patient's perspective, ACC reduced costs by SG$1222.67 (€1110.24) for TTR < 70 % and SG$1008.16 (€915.46) for TTR ≥ 70 %. Similar trends were observed from the healthcare provider's perspective, with ACC reducing costs by SG$1444.79 (€1311.94) for TTR < 70 % and SG$1269.17 (€1152.46) for TTR ≥ 70 % compared with UC. The results were robust to variations of the parameters over their plausible ranges in one-way sensitivity analyses. Probabilistic sensitivity analyses demonstrated that ACC was cost-effective more than 79 % of the time from both perspectives at a willingness-to-pay threshold of SG$69,050 (€62,701) per QALY. Conclusion Pharmacist-managed ACC is more effective and less costly compared with UC regardless of the quality of anticoagulation therapy. The findings support the current body of evidence demonstrating the cost-effectiveness of ACC.

Comparison of Medication Adherence and Treatment Persistence between New Oral Anticoagulant and Warfarin among Patients.

INTRODUCTION: This study aimed to compare medication adherence and treatment persistence of patients on warfarin versus rivaroxaban in Singapore. A secondary objective was to identify significant covariates influencing adherence. MATERIALS AND METHODS: A retrospective cohort study was conducted where data from September 2009 to October 2014 was retrieved from the hospital electronic databases. Prescription records of rivaroxaban patients with 3 months or more of continuous prescription were extracted and compared against those of patients on warfarin. Primary outcome of adherence was determined based on the medication possession ratio (MPR), while treatment persistence was determined by outpatient clinic appointment gaps. RESULTS: A total of 94 rivaroxaban and 137 warfarin users were analysed by complete case analysis. The MPR of warfarin patients was lower than rivaroxaban patients by 10% (95% CI, 6.4% to 13.6%; P <0.0001). Also, there were more warfarin patients who had gaps in treatment persistence compared to those prescribed rivaroxaban (8.0% vs 1.1%; P = 0.03). Significant factors affecting medication adherence were age and duration of anticoagulant use. For every 10-year increase in age, MPR increased by 1.7% (95% CI, 0.7% to 2.8%). Similarly, for every year increase in duration of use, MPR increased by 1.8% (95% CI, 0.6% to 3.0%). Race, gender, concomitant medication and type of residence were not found to be significant covariates in the multivariable analysis. CONCLUSION: Patients on rivaroxaban are likely to be more adherent to their prescribed oral anticoagulant with increasing age and duration of treatment influencing adherence.

Nonlinear mixed effects modelling for the analysis of longitudinal body core temperature data in healthy volunteers.

Many longitudinal studies have collected serial body core temperature (T c) data to understand thermal work strain of workers under various environmental and operational heat stress environments. This provides the opportunity for the development of mathematical models to analyse and forecast temporal T c changes across populations of subjects. Such models can reduce the need for invasive methods that continuously measure T c. This current work sought to develop a nonlinear mixed effects modelling framework to delineate the dynamic changes of T c and its association with a set of covariates of interest (e.g. heart rate, chest skin temperature), and the structure of the variability of T c in various longitudinal studies. Data to train and evaluate the model were derived from two laboratory investigations involving male soldiers who participated in either a 12 (N = 18) or 15 km (N = 16) foot march with varied clothing, load and heat acclimatisation status. Model qualification was conducted using nonparametric bootstrap and cross validation procedures. For cross validation, the trajectory of a new subject's T c was simulated via Bayesian maximum a posteriori estimation when using only the baseline T c or using the baseline T c as well as measured T c at the end of every work (march) phase. The final model described T c versus time profiles using a parametric function with its main parameters modelled as a sigmoid hyperbolic function of the load and/or chest skin temperature. Overall, T c predictions corresponded well with the measured data (root mean square deviation: 0.16 °C), and compared favourably with those provided by two recently published Kalman filter models.

Real-World Impact of Setting a Narrow International Normalized Ratio Target Range in the Management of Older Adult Patients on Warfarin.

INTRODUCTION: Elderly patients intrinsically have higher bleeding risks, deterring clinicians from prescribing them oral anticoagulants. Setting a narrow international normalized ratio (INR) target range might potentially mitigate some of these risks. This study sought to compare the outcomes of elderly patients who were assigned to either a narrow INR target range or the conventional INR target range in a real-world environment. METHODS: This was a retrospective cohort study with the primary and secondary outcomes being the mean percentage time above INR 3.0 and the mean percentage time below INR 2.0 and the incidents of bleeding and thromboembolism associated with oral anticoagulant therapy, respectively. Patients and health care workers managing them had no prior knowledge of this study. RESULTS: Data of 150 patients with a narrow INR target range (2.0-2.5) and 164 patients with a conventional INR target range (2.0-3.0) were collected and analyzed. The narrow INR group had significantly higher underlying risks of bleeding than the conventional INR group. Patients in the narrow INR group had a significantly lower percentage time above INR 3.0 but no significant difference in the percentage time below INR 2.0. Adjusted incidence rate ratio (IRR) for bleeding events was significantly lower for the narrow INR group, while the adjusted IRR for thromboembolic events between both groups was similar. CONCLUSION: Patients assigned to a narrow INR target range in real-world practice spent a significantly lower amount of time below an INR of 3.0 compared to conventional INR target range with lower incidents of bleeding complications and no increase in subtherapeutic INRs.

Impact of enhanced recovery after surgery program on postoperative recovery in patients undergoing lapa-roscopic colorectal resection / 临床麻醉学杂志

Objective To investigate the impact of enhanced recovery after surgery (ERAS) program on postoperative recovery in patients undergoing laparoscopic colorectal resection. Methods Eighty-four patients undergoing laparoscopic colorectal resection from March 201 5 to June 201 6 (55 males,29 females,aged 36-78 years,ASA physical status Ⅰ or Ⅱ),were randomly divid-ed into two groups (n = 38 each).Patients in group E were received epidural block combined with general anesthesia,and a series of perfect ERAS strategies,such as strengthen preoperative educa-tion, maintaining perioperative normothermia, perioperative goal-directed fluid therapy, intraoperative and postoperative analgesia.While the patients in group C received routine anesthetic management.The volume of fluid,the nasopharyngeal temperature,the time of recovery of bouel sound,first anal exhaust,eating fluid food,ambulation and remove of the catheter were recorded in two groups.Furthermore,time of PACU after surgery,the total days of hospitalization and total hos-pital costs were recorded.Results The volume of fluid [(1 328 ± 64)ml vs.(2 463 ± 135 )ml]in group E were significantly lower than group C (P <0.05),the nasopharyngeal temperature [(36.2± 0.2)℃ vs.(35.1±0.5)℃]was significantly higher in group E (P <0.05).Compared with group C,the time of recovery of bowel sound [(33.4 ± 12.5 )h vs.(42.8 ± 14.3 )h],first anal exhaust [(43.6±13.9)h vs.(60.7±1 5.4)h],eating fluid food [(26.8±4.1)h vs.(67.4±13.5)h],first ambulation [(7.4±1.6)h vs.(26.5±3.8)h]and remove of the catheter [(29.2±6.1)h vs.(5 1.8 ±7.6) h ], time of PACU [(26.4 ± 8.5 ) min vs.(37.2 ± 1 1.6 ) min ], the total days of hospitalization [(7.5±0.9)d vs.(9.7±1.2)d]were significantly shorter (P <0.05),and hospital costs [(2.1±0.6)ten thousand yuan vs.(2.6±0.8)ten thousand yuan]were significantly decreased (P <0.05).The incidence of adverse reactions such as nausea and vomiting (2.4% vs.21.4%),pru-ritus (7.1% vs.23.8%),agitation (4.8% vs.26.2%)and chills (0% vs.1 9.0%)were significantly lower in group E (P <0.05).Conclusion ERAS program applied to patients undergoing laparoscopic colorectal resection can reduce the intraoperative sufentanil consumption,avoid the occurrence of postoperative hypothermia, accelerate recovery of gastrointestinal function, which can obviously reduce the hospitalization costs and shorten the hospitalization time.

Comparison of Medication Adherence and Treatment Persistence between New Oral Anticoagulant and Warfarin among Patients

<p><b>INTRODUCTION</b>This study aimed to compare medication adherence and treatment persistence of patients on warfarin versus rivaroxaban in Singapore. A secondary objective was to identify significant covariates influencing adherence.</p><p><b>MATERIALS AND METHODS</b>A retrospective cohort study was conducted where data from September 2009 to October 2014 was retrieved from the hospital electronic databases. Prescription records of rivaroxaban patients with 3 months or more of continuous prescription were extracted and compared against those of patients on warfarin. Primary outcome of adherence was determined based on the medication possession ratio (MPR), while treatment persistence was determined by outpatient clinic appointment gaps.</p><p><b>RESULTS</b>A total of 94 rivaroxaban and 137 warfarin users were analysed by complete case analysis. The MPR of warfarin patients was lower than rivaroxaban patients by 10% (95% CI, 6.4% to 13.6%; P <0.0001). Also, there were more warfarin patients who had gaps in treatment persistence compared to those prescribed rivaroxaban (8.0% vs 1.1%; P = 0.03). Significant factors affecting medication adherence were age and duration of anticoagulant use. For every 10-year increase in age, MPR increased by 1.7% (95% CI, 0.7% to 2.8%). Similarly, for every year increase in duration of use, MPR increased by 1.8% (95% CI, 0.6% to 3.0%). Race, gender, concomitant medication and type of residence were not found to be significant covariates in the multivariable analysis.</p><p><b>CONCLUSION</b>Patients on rivaroxaban are likely to be more adherent to their prescribed oral anticoagulant with increasing age and duration of treatment influencing adherence.</p>

Patient-reported health preferences of anticoagulant-related outcomes.

Strokes can have a catastrophic impact on patients' health-related quality of life (HRQoL). In addition to warfarin, two novel oral anticoagulants, i.e., dabigatran and rivaroxaban, have been approved to prevent strokes. This study aimed to use direct measures to elicit patient-reported utilities (i.e., preferences) for anticoagulant-related outcomes. A cross-sectional survey was administered to 100 patients taking warfarin in an anticoagulation clinic. Utilities for six long-term and four short-term anticoagulant-related health states were elicited by the visual analogue scale (VAS) and standard gamble (SG) methods. Health states with the highest SG-derived mean utility values were "well on rivaroxaban" (mean ± SD = 0.90 ± 0.15), "well on warfarin" (0.86 ± 0.17), and "well on dabigatran" (0.83 ± 0.18). Approximately half of the patients considered major ischemic stroke (-1.57 ± 6.77) and intracranial hemorrhage (-1.99 ± 6.98) to be worse than death. The percentages of patients who considered a particular health state worse than death ranged from 0 to 55 % among various health states assessed. The VAS had similar findings. Good logical consistency was observed in both VAS- and SG-derived utility values. Ischemic stroke and intracranial hemorrhage had a significant impact on patients' HRQoL. Greater variation in patients' preferences was observed for more severely impaired health states, indicating the need for individualized medical decision-making. In this study, both long-term and short-term health states were included in the utility assessment. The findings of this study can be used in cost-utility analysis of future anticoagulation therapies.

Cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for stroke prevention in patients with atrial fibrillation.

PURPOSE: This study aimed to evaluate the cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for the prevention of stroke in patients with atrial fibrillation (AF) in Singapore. METHODS: A Markov model was constructed to compare the lifetime costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) of dabigatran 110 and 150 mg, rivaroxaban 20 mg and adjusted-dose warfarin from the perspective of the Singapore healthcare system, using clinical data from published studies, utilities from a patient-reported survey and costs from hospital databases. The target population was a hypothetical cohort of 65-year-old AF patients with no contraindications to anticoagulation. RESULTS: In the base-case analysis, the QALYs were 8.75 with warfarin, 8.73 with dabigatran 110 mg, 8.82 with dabigatran 150 mg, and 9.33 with rivaroxaban. The costs were Singapore dollar (SG$) 34,648 for warfarin, SG$54,919 for dabigatran 110 mg, SG$50,484 for dabigatran 150 mg and SG$51,975 for rivaroxaban. The ICER of rivaroxaban versus warfarin was SG$29,697 (US$26,727) per QALY. Rivaroxaban and warfarin had extended dominance over the high-dose dabigatran. The low-dose dabigatran was dominated by warfarin. Deterministic sensitivity analyses showed that the ICER of rivaroxaban versus warfarin was sensitive to cost of rivaroxaban and utilities for rivaroxaban and warfarin. Probability sensitivity analysis demonstrated that the probability of rivaroxaban being the optimal choice was 97.8% and 99.5% at a willingness-to-pay threshold of SG$65,000 (US$58,500) and SG$130,000 (US$117,000) per QALY, respectively. CONCLUSION: Rivaroxaban may be a cost-effective alternative to warfarin for the prevention of stroke in patients with AF in Singapore.

Knowledge, satisfaction, and concerns regarding warfarin therapy and their association with warfarin adherence and anticoagulation control.

INTRODUCTION: A better understanding of patients' knowledge, satisfaction and concerns can identify deficits and help develop targeted patient education. This study aimed to examine patients' knowledge, satisfaction and concerns regarding warfarin therapy and assess their association with warfarin adherence and international normalized ratio (INR) control. MATERIALS AND METHODS: A cross-sectional survey was conducted in a convenience sample of patients taking warfarin in an anticoagulation clinic. The questionnaire consisted of questions on patients' knowledge, satisfaction and concerns regarding warfarin treatment. Patients' warfarin refill records and time within the therapeutic INR range were retrieved from hospital databases. RESULTS: One hundred and eighty-three patients participated in the survey. Patients had inadequate knowledge of warfarin-diet and warfarin-drug interactions. Over 40% of the respondents were not satisfied with the waiting time to see a pharmacist. The most common concerns of taking warfarin were worries about warfarin-drug interactions (36.1%), forgetting to take warfarin (26.2%) and worries about side effects (25.7%). Higher satisfaction was associated with better knowledge (r=0.24, p=0.001) and fewer concerns (rs=-0.23, p=0.002). Better knowledge and higher satisfaction were associated with higher warfarin adherence (rs=0.21 and 0.16; p=0.01 and 0.046, respectively). Better knowledge, higher satisfaction, fewer concerns, and better warfarin adherence were associated with good INR control (p=0.003, 0.02, 0.03 and 0.003, respectively). CONCLUSIONS: This study highlighted patients' concerns and deficits in knowledge regarding warfarin treatment, and also demonstrated their association with warfarin adherence and INR control.

Comparison of three medication adherence measures in patients taking warfarin.

In order to improve warfarin adherence, we must first know the rate of non-adherence and the reasons for it. Assessment of warfarin adherence is important in improving patients' warfarin-taking behavior and International Normalized Ratio (INR) control. This study aimed to compare three medication adherence measures in patients taking warfarin: the 8-item Morisky Medication Adherence Scale (MMAS), the 100-point Visual Analogue Scale (VAS) and medication refill adherence (MRA). A cross-sectional observational study was conducted in a convenience sample of 174 patients taking warfarin at an anticoagulation clinic. A survey questionnaire that included the MMAS, VAS, and demographic and warfarin-related clinical questions was administered to patients in English or Chinese depending on their preferences. The MRA and INR values were retrieved from hospital electronic databases. Most participants were adherent to warfarin as indicated by the three measures. A weak association was found between the MMAS and the other two adherence measures. The MMAS and MRA were associated with the percentage of INRs within range in the past 2 weeks. Moreover, the MRA was weakly associated with time within the therapeutic INR range in the past 3 months and 2 weeks. The findings provide insights into the differences among three medication adherence measures and may assist healthcare providers to select the most suitable measure for the assessment of warfarin adherence.

A questionnaire survey of patient experience with the Rheumatology Monitoring Clinic in Singapore.

AIM: The concept of a pharmacist/advanced practice nurse (APN)-led Rheumatology Monitoring Clinic (RMC) is a novel service in Singapore; we therefore conducted a questionnaire survey of patient experience. METHODS: Patients attending the RMC were provided with a set of questionnaires. As a substudy, a separate questionnaire was given to the rheumatologists and therapists conducting the RMC. RESULTS: Of the 105 patients surveyed, a total of 97 (92.4%) patients were satisfied/strongly satisfied with the overall service, and none were dissatisfied; 96% felt that the pharmacists/APNs provided clear, detailed information about their disease and medication, while 92% of patients were confident they knew what side-effects were possible. Ninety-two percent and 93% of patients were more likely to adhere to treatment, and were willing to come back for follow-up at the RMC, respectively. There was no difference in patient satisfaction in the average Likert summed scores, between the pharmacists and APNs. Age, gender, ethnicity and underlying disease did not exert any influence on the responses. All the rheumatologists surveyed were satisfied with the patients' management and the professionalism of the therapists. They opined that the RMC freed up time for them to see more complex cases. All the pharmacists/APNs concurred that the referrals were appropriately selected. CONCLUSIONS: We established the acceptability of a non-physician-led clinic in our local setting and highlighted the usefulness of having a routine clinic for monitoring medication toxicity and patient education. The RMC received positive feedback from patients, rheumatologists and allied health therapists, with a high degree of satisfaction among the respondents.

Psychometric properties of the 8-item Morisky Medication Adherence Scale in patients taking warfarin.

There is no patient-reported medication adherence measure that has been validated in Singapore. This study aimed to validate the 8-item Morisky Medication Adherence Scale (MMAS) in patients taking warfarin in Singapore. A cross-sectional survey was conducted in a convenience sample of 151 patients taking warfarin at an anticoagulation clinic in 2011. Respondents completed the MMAS in English or Chinese depending on their preference. The MMAS had a Cronbach's alpha of 0.56 and good criterion-related validity as the scale scores were associated with warfarin refill rates (p = 0.04). Respondents with higher MMAS scores were found to have a higher percentage of International Normalised Ratios (INRs) within the therapeutic range (p = 0.01), higher adherence to diet recommendations (p = 0.02), and less perceived difficulty in taking all medications (p < 0.001); they were also more likely to take warfarin at the same time every day (p < 0.001). Confirmatory factor analysis showed that the eight items loaded onto one factor (RMSEA = 0.03). The sensitivity, specificity, positive predictive value and negative predictive value of the MMAS for identifying patients with poor INR control were 73.0%, 35.6%, 49.5% and 60.5%, respectively, using the time in the therapeutic INR range as the gold standard. This study shows that the 8-item MMAS has good validity and moderate reliability in patients taking warfarin. Future research is needed to investigate the scale's psychometric properties in other patient populations and clinical settings.

Validity of current recommendation for peri-operative interruption of warfarin in Asians.

Temporary interruption of anticoagulation therapy is usually recommended for anticoagulated patients undergoing invasive procedures to minimize their bleeding risks. We validated the current consensus recommendation on warfarin interruption which were based on Western population studies to determine if they could safely be applied to Asians. The international normalized ratios (INR) in twenty warfarinised patients with a stable INR of 2-3 were prospectively measured at days 0, 3 and 5 after stopping warfarin for procedures or at completion of treatment. The median INR at days 0, 3 and 5 were 2.30 (95% CI 2.16-2.43), 1.32 (95% CI 1.22-1.57) and 1.06 (95% CI 1.05-1.13) respectively (P < 0.001 for trend). All patients were below therapeutic INRs by day 3 with 14 patients (70%, 95% CI 49.92-90.08) achieving INR readings below 1.5. By day 5, all INRs were below 1.5 and only 2 patients (10%, 95% CI -3.15 to 23.15) had INRs above 1.2. There were no significant peri-procedure bleeding or thrombotic events in the 1 month following interruption of warfarin. Our results suggest that the current international recommendation of stopping warfarin for 5 days prior to procedure can safely be applied to Asians without compromising risk of bleeding or thrombosis.

VKORC1 diplotype-derived dosing model to explain variability in warfarin dose requirements in Asian patients.

SUMMARY: Warfarin-induced bleeding complications and high inter-patient variability are major hindrances to oral anticoagulant therapy. The present study identifies the influence of VKORC1 diplotypes, CYP2C9 and CYP2C19 variants on warfarin disposition and dose requirements in Chinese patients (n=107). The study subjects were genotyped for VKORC1, CYP2C9 and CYP2C19 polymorphic variants. Weekly warfarin dose requirements and S-warfarin clearance were stratified by VKORC1, CYP2C9 and CYP2C19 pharmacogenetics. The major VKORC1 diplotypes were H1-H1 (62%), H1-H7 (18%) and H1-H(*)(b) (10%). Warfarin dose requirements were significantly lower in patients with VKORC1 H1-H1 and H1-H(*)(a) diplotypes compared to patients harboring the H1-H7 and H1-H(*)(b) diplotypes (P<0.05). Hepatic tissues with H1-H1 diplotype had significantly lower expression of VKORC1 mRNA compared with liver tissues carrying the H1-H7 and H1-H(*)(b) diplotypes (P=0.006). The percent variability explained by VKORC1 diplotype status was 59.1% while the CYP2C9 genotype status accounted for 6.9% variability in warfarin dose requirements. Patient age and weight were significant covariates accounting for 29% and 8.6% of warfarin dose variability, respectively. The present study shows that VKORC1 diplotype status, CYP2C9 genotype, age and weight are significant covariates, accounting for 73.4% of interindividual variability in warfarin dose requirements among Chinese patients. Translation of these findings into clinical guidelines for warfarin dosing may be required to assess its impact on the safety and efficacy of warfarin.