Anne Holbrook

Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Interactions of Warfarin with Drugs and Food

Warfarin is the most widely used oral anticoagulant drug in North America, in part because of its relatively predictable onset and duration of action and its excellent bioavailability [1-3]. Warfarin, a racemic compound with a more potent S enantiomer and a less potent R enantiomer, achieves its anticoagulant effect by inhibiting the activation of vitamin Kdependent clotting factors. Oral anticoagulants are effective in the prevention and treatment of deep venous thrombosis and also in the prevention of thromboembolic events in patients with atrial fibrillation [4-8], prosthetic heart valves [9-12], and indwelling central venous catheters [13], as well as in patients who have had myocardial infarction [14-20]. Despite excellent evidence [21] for its clinical value, warfarin may be underused because of the inconvenience of monitoring and the concern about potential complications, primarily bleeding [22-24]. The risk for complications may be increased when concomitant drug therapy is required [25, 26]. The potential for warfarin to interact with other drugs, resulting in changes in its anticoagulant effect, is widely recognized among health professionals and informed patients. Many published reviews [3, 27-35] and extensive lists in standard medical textbooks (110 interacting drugs listed in the United States Pharmacopeia Dispensing Information [USP DI]) [36] attest to the widely held belief that drug interactions with warfarin are common and potentially harmful. However, reports on drug interactions are replete with small case series, single case reports, and extrapolation of in vitro or animal data. This evidence, when judged by the usual evaluative scales for therapy, is of lower quality [21, 37, 38]. Given that expensive clinical trial resources are unlikely to be used to address the fine points of therapy such as drug interactions, it is essential to evaluate the quality of these studies. Thus, we evaluated the quality of reports about drug and food interactions with warfarin. We prospectively applied explicit, reproducible criteria for determining the strength of inferred causation. We recognized that a yes, did cause or a no, did not cause conclusion might not be possible and used an estimate of the probability of causation (level of evidence) by adapting previously described principles of causality assessment [39-42]. Methods Relevant studies were identified by searching the MEDLINE and TOXLINE databases from 1966 to the end of October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only. Articles were considered eligible for evaluation if they contained original data about drug and food interactions with warfarin in humans. Bibliographies were also checked for additional pertinent studies. Reports on drugs not available in the United States or Canada were excluded. Eligible studies were evaluated independently by two authors according to three main categories: participants, description of interaction, and level of evidence. Participants We separated reports into those describing 1) patients who received the interacting drug during usual warfarin therapy and 2) healthy volunteers or patients prospectively entered into an experiment while receiving warfarin. Description of Interaction We noted the drug or food affected by the interaction, the type of interaction (potentiation, inhibition, or no effect), and the proposed or documented mechanism of interaction. Level of Evidence (Assurance) Each article was evaluated, with yes or no responses given according to seven criteria previously approved by a panel of experts in the fields of thromboembolism, clinical pharmacology, and clinical epidemiology (Appendix 1). Appendix 1. Criteria for Establishing a Drug or Food Interaction with Warfarin Responses to four criteria (A to D) required additional guidelines in order to be specific to the evaluation of drug interactions with warfarin. To meet criterion A, for patient-based studies, before the potentially interactive substance was started, the warfarin dose and intensity of anticoagulation must have been stable. Further, the potentially interacting substance had to be used in usual doses for enough time to attain a substantial plasma level. For volunteer-based studies, participants had to have received warfarin alone and with the interacting drug for similar periods. For criterion B, in patient-based studies, the coagulation variable had to be outside the therapeutic range, whereas for volunteer studies, a change of at least 20% in coagulation variables was required. To satisfy criterion C, we required some indication that medical conditions, especially liver disease, as well as other drug therapy and diet (notably dietary vitamin K intake) were constant. However, for healthy volunteers we assumed that these confounders were absent, even if not explicitly stated. For criterion D, other objective evidence refers to changes in plasma levels of warfarin or of vitamin Kdependent factors II, VII, IX, or X. The level of evidence (assurance) that a drug or food interaction with warfarin could occur was then determined as outlined in Appendix 1 (Table 3). Level 1 evidence obtained from patient-based and volunteer-based reports was considered definitive evidence of an interaction. Inter-rater agreement was assessed using a weighted statistic [43]. Wherever reported, we considered data from individual participants rather than relying on summary results. If individual data were not available, the summary statistics were used. If several studies assessed the same drug, the interaction supported by the highest level of evidence was considered the final warfarin interaction. If a study in volunteers showed a different type of interaction than did a study with the same level of evidence in a patient-based report, the latter was considered to be the final warfarin interaction. Level 1 studies were further reviewed with regard to the severity of effect of the interaction. Two thresholds were established: The first was clinically evident hemorrhage or thrombosis and the second was a doubling or halving [for inhibition] of coagulation measurements. Articles were also appraised for any description of the mechanism of interaction. Pharmacokinetic data suggesting altered drug clearance or changes in pharmacodynamic data, such as clotting factor or vitamin K levels, were considered adequate evidence. Because warfarin is a racemic compound, we classified the interaction as 1) being stereoselective if a differential change was noted in enantiomer concentrations, 2) being nonstereoselective if both enantiomers changed substantially but by a similar proportion, or 3) affecting clearance by an unknown mechanism if only plasma warfarin levels without its enantiomers were measured. Results Of 793 citations retrieved, 120 contained original data on 186 interactions. The weighted statistic for the level of evidence evaluation was 0.67, representing substantial agreement [43]. Disagreement about the scores of 38 articles was resolved by repeat review and discussion until a consensus was reached. Forty-three of 86 different drug and food interactions appraised were judged highly probable (level 1 evidence): Sixteen had a potentiating effect, 10 had an inhibiting effect, and 17 had no effect. These drugs were classified into the following six categories: antibiotics, anti-inflammatory agents or analgesics, cardiac drugs, gastrointestinal drugs, drugs active on the central nervous system, and miscellaneous drugs or foods (Table 1). The reported interactions for another 18 drugs were judged probable (level 2 evidence): 14 potentiating, 1 inhibiting, and 3 with no effect. Of the remaining 25 interacting medications, 16 were considered possible (level 3 evidence) and 9 were doubtful (level 4 evidence). All reports described interactions leading to some effect on warfarin therapy (as opposed to altering the effect of the other drug). Our summary of results listing the type of interaction by level of evidence according to drug categories is presented in Appendix 2. Table 1. Level 1 Evidence of Drug and Food Interactions with Warfarin* Appendix 2. Drug and Food Interactions with Warfarin by Level of Supporting Evidence and Type of Interaction* Drugs Potentiating the Effect of Warfarin Many antibiotics are reported to potentiate the effect of warfarin. The evidence was considered highly probable (level 1) for cotrimoxazole, erythromycin, isoniazid, fluconazole, miconazole, and metronidazole [44-50] and was probable (level 2) for ciprofloxacin, itraconazole, and tetracycline [51-58]. The evidence was much weaker for six other antibiotics [59-63]. Several cardiac drugs had highly probable evidence [64-73] that they potentiated the effect of warfarin: These included amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone. Sulfinpyrazones effect was biphasic, which means that an initial potentiation of the warfarin anticoagulant effect was noted, followed by inhibition of the effect. Quinidine, simvastatin, and acetylsalicylic acid had probable evidence that they potentiated warfarin [74-76]. Possible and doubtful evidence were reported for five other drugs [77-81]. Among the anti-inflammatory or analgesic drugs, phenylbutazone, piroxicam, acetylsalicylic acid, acetaminophen, and dextropropoxyphene had highly probable or probable evidence [74, 82-89]. The other medications with highly probable or probable evidence were cimetidine, omeprazole, alcohol (only if concomitant liver disease was present), chloral hydrate, disulfiram, phenytoin (late effect of inhibition), tamoxifen, anabolic steroids, and influenza vaccines [74, 90-105]. Drugs Inhibiting the Effect of Warfarin Fewer drugs inhibited the effect of warfarin, but the proportion with level 1 evidence was higher. Highly probable evidence was reported for nafcillin, rifampin, griseofulvin, cholestyramine, barbiturates, carbamazepine, chlordiazepoxide, sucra

Individualized electronic decision support and reminders to improve diabetes care in the community: COMPETE II randomized trial

Background: Diabetes mellitus is a complex disease with serious complications. Electronic decision support, providing information that is shared and discussed by both patient and physician, encourages timely interventions and may improve the management of this chronic disease. However, it has rarely been tested in community-based primary care. Methods: In this pragmatic randomized trial, we randomly assigned adult primary care patients with type 2 diabetes to receive the intervention or usual care. The intervention involved shared access by the primary care provider and the patient to a Web-based, colour-coded diabetes tracker, which provided sequential monitoring values for 13 diabetes risk factors, their respective targets and brief, prioritized messages of advice. The primary outcome measure was a process composite score. Secondary outcomes included clinical composite scores, quality of life, continuity of care and usability. The outcome assessors were blinded to each patient’s intervention status. Results: We recruited sequentially 46 primary care providers and then 511 of their patients (mean age 60.7 [standard deviation 12.5] years). Mean follow-up was 5.9 months. The process composite score was significantly better for patients in the intervention group than for control patients (difference 1.27, 95% confidence interval [CI] 0.79–1.75, p < 0.001); 61.7% (156/253) of patients in the intervention group, compared with 42.6% (110/258) of control patients, showed improvement (difference 19.1%, p < 0.001). The clinical composite score also had significantly more variables with improvement for the intervention group (0.59, 95% CI 0.09–1.10, p = 0.02), including significantly greater declines in blood pressure (−3.95 mm Hg systolic and −2.38 mm Hg diastolic) and glycated hemoglobin (−0.2%). Patients in the intervention group reported greater satisfaction with their diabetes care. Interpretation: A shared electronic decision-support system to support the primary care of diabetes improved the process of care and some clinical markers of the quality of diabetes care. (ClinicalTrials.gov trial register no. NCT00813085.)

Rates of hemorrhage during warfarin therapy for atrial fibrillation

Background: Although warfarin has been extensively studied in clinical trials, little is known about rates of hemorrhage attributable to its use in routine clinical practice. Our objective was to examine incident hemorrhagic events in a large population-based cohort of patients with atrial fibrillation who were starting treatment with warfarin. Methods: We conducted a population-based cohort study involving residents of Ontario (age ≥ 66 yr) with atrial fibrillation who started taking warfarin between Apr. 1, 1997, and Mar. 31, 2008. We defined a major hemorrhage as any visit to hospital for hemorrage. We determined crude rates of hemorrhage during warfarin treatment, overall and stratified by CHADS2 score (congestive heart failure, hypertension, age ≥ 75 yr, diabetes mellitus and prior stroke, transient ischemic attack or thromboembolism). Results: We included 125 195 patients with atrial fibrillation who started treatment with warfarin during the study period. Overall, the rate of hemorrhage was 3.8% (95% confidence interval [CI] 3.8%–3.9%) per person-year. The risk of major hemorrhage was highest during the first 30 days of treatment. During this period, rates of hemorrhage were 11.8% (95% CI 11.1%–12.5%) per person-year in all patients and 16.7% (95% CI 14.3%–19.4%) per person-year among patients with a CHADS2 scores of 4 or greater. Over the 5-year follow-up, 10 840 patients (8.7%) visited the hospital for hemorrhage; of these patients, 1963 (18.1%) died in hospital or within 7 days of being discharged. Interpretation: In this large cohort of older patients with atrial fibrillation, we found that rates of hemorrhage are highest within the first 30 days of warfarin therapy. These rates are considerably higher than the rates of 1%–3% reported in randomized controlled trials of warfarin therapy. Our study provides timely estimates of warfarin-related adverse events that may be useful to clinicians, patients and policy-makers as new options for treatment become available.

Views on health information sharing and privacy from primary care practices using electronic medical records.

OBJECTIVE To determine how patients and physicians balance the perceived benefits and harms of sharing electronic health data for patient care and for secondary purposes. DESIGN Before-after survey of patients and providers in practices using electronic medical records (EMRs) enrolled in a clinical trial in Ontario, Canada. MEASUREMENTS Outcomes were measured using the Health Information Privacy Questionnaire (HIPQ) at baseline and end of study. Thirteen questions in 4 general domains investigated attitudes towards the privacy of EMRs, outsiders use of patients health information, the sharing of patients information within the health care system, and the overall perception of benefits versus harms of computerization in health care. RESULTS 511 patients (mean age 60.3 years, 49.6% female) and 46 physicians (mean age 47.2 years, 37.0% female) participated. Most (>90%) supported the computerized sharing of the patients health records among their health care professionals and to provide clinical advice. Fewer agreed that the patients de-identified information should be shared outside of the health care circle (<70%). Only a minority of either group supported the notion that computerized records can be keep more private than paper records (38-50%). Overall, a majority (58% patients, 70% physicians) believed that the benefits of computerization were greater than the risks of confidentiality loss. This was especially true for patients who were frequent computer users. DISCUSSION While these primary care physicians and their patients valued the clinical features of EMRs, a substantial minority have concerns about the secondary use of de-identified information.

Features predicting the success of computerized decision support for prescribing: a systematic review of randomized controlled trials.

BackgroundComputerized decision support systems (CDSS) are believed to have the potential to improve the quality of health care delivery, although results from high quality studies have been mixed. We conducted a systematic review to evaluate whether certain features of prescribing decision support systems (RxCDSS) predict successful implementation, change in provider behaviour, and change in patient outcomes.MethodsA literature search of Medline, EMBASE, CINAHL and INSPEC databases (earliest entry to June 2008) was conducted to identify randomized controlled trials involving RxCDSS. Each citation was independently assessed by two reviewers for outcomes and 28 predefined system features. Statistical analysis of associations between system features and success of outcomes was planned.ResultsOf 4534 citations returned by the search, 41 met the inclusion criteria. Of these, 37 reported successful system implementations, 25 reported success at changing health care provider behaviour, and 5 noted improvements in patient outcomes. A mean of 17 features per study were mentioned. The statistical analysis could not be completed due primarily to the small number of studies and lack of diversity of outcomes. Descriptive analysis did not confirm any feature to be more prevalent in successful trials relative to unsuccessful ones for implementation, provider behaviour or patient outcomes.ConclusionWhile RxCDSSs have the potential to change health care provider behaviour, very few high quality studies show improvement in patient outcomes. Furthermore, the features of the RxCDSS associated with success (or failure) are poorly described, thus making it difficult for system design and implementation to improve.

Interventions to Improve Medication Reconciliation in Primary Care

Objective: To systematically review all primary care intervention studies designed to implement medication reconciliation for effects on medication discrepancies, clinical outcomes, and patient knowledge of their medications. Data Sources: We searched MEDLINE (1988–March 2008); Healthstar (1966–March 2008): CINAHL (1982–March 2008); EMBASE (1980–March 2008); Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Cochrane Methodology Register, and Health Technology Assessments; and unpublished material. No language restrictions were applied. Search terms included medication reconciliation, medication errors, prescribing error, medication systems, adverse drug events, drug utilization review, medication list, medication record, and medications management. Study Selection And Data Abstraction: Randomized controlled trials or before-and-after studies that examined the effect of various interventions on medication discrepancies either in ambulatory settings or at hospital discharge among community-dwelling adults were included. Two reviewers independently assessed studies to determine inclusion. Level of agreement between the reviewers was good, with unweighted Cohens κ of 0.71. Two of 3 independent reviewers abstracted data and evaluated validity from included studies. Disagreements between reviewers were resolved by consensus. Data Synthesis: Four trials met the inclusion criteria. Two before-and-after studies (n = 275) in ambulatory care examining systematic medication reconciliation at each visit produced conflicting results. One study showed a reduction in the proportion of medication discrepancies from 88.5% to 49.1% (OR 0.13; 95% CI 0.07 to 0.21); the other showed no benefit. One randomized controlled trial and one before-and-after study (n = 202) evaluated pharmacist medication review at hospital discharge. Neither showed a benefit. Heterogeneity precluded pooling of studies. All included studies had significant design flaws. Conclusions: There is no good quality evidence demonstrating the effectiveness of medication reconciliation in the primary care setting. Further research is needed.

Evidence-based management of anticoagulant therapy. Antithrombotic therapy and prevention of thrombosis, 9th ed

BACKGROUND High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Computerized clinical decision support systems for drug prescribing and management: A decision-maker-researcher partnership systematic review

BackgroundComputerized clinical decision support systems (CCDSSs) for drug therapy management are designed to promote safe and effective medication use. Evidence documenting the effectiveness of CCDSSs for improving drug therapy is necessary for informed adoption decisions. The objective of this review was to systematically review randomized controlled trials assessing the effects of CCDSSs for drug therapy management on process of care and patient outcomes. We also sought to identify system and study characteristics that predicted benefit.MethodsWe conducted a decision-maker-researcher partnership systematic review. We updated our earlier reviews (1998, 2005) by searching MEDLINE, EMBASE, EBM Reviews, Inspec, and other databases, and consulting reference lists through January 2010. Authors of 82% of included studies confirmed or supplemented extracted data. We included only randomized controlled trials that evaluated the effect on process of care or patient outcomes of a CCDSS for drug therapy management compared to care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive.ResultsSixty-five studies met our inclusion criteria, including 41 new studies since our previous review. Methodological quality was generally high and unchanged with time. CCDSSs improved process of care performance in 37 of the 59 studies assessing this type of outcome (64%, 57% of all studies). Twenty-nine trials assessed patient outcomes, of which six trials (21%, 9% of all trials) reported improvements.ConclusionsCCDSSs inconsistently improved process of care measures and seldomly improved patient outcomes. Lack of clear patient benefit and lack of data on harms and costs preclude a recommendation to adopt CCDSSs for drug therapy management.

Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis

BACKGROUND The clinical armamentarium for anticoagulation has expanded substantially since the recent approval of dabigatran, rivaroxaban and apixaban for the prevention of stroke in atrial fibrillation. However, patients in the general population often differ from participants in clinical trials. In this study, we assessed the uptake of these novel oral anticoagulants in Ontario, Canada, within the first 2 years after dabigatrans approval for this indication. METHODS Using data on province-wide prescription volumes, we conducted a time-series analysis of prescription trends between October 2010 and September 2012 for all orally administered anticoagulants (warfarin, dabigatran and rivaroxaban) that were available in this period. We stratified dabigatran prescription rates by age group (20-39, 40-59, 60-64, 65-84 and ≥ 85 yr). We compared the proportion of dabigatran prescriptions to patients aged 65 or older with similar data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. RESULTS Over the 24-month study period, we found that prescriptions for the novel anticoagulants rose more than 20-fold, to represent 21.1% of all prescriptions of oral anticoagulants by September 2012. The rise in prescriptions was due primarily to an increase in dabigatran use. Prescription rates of dabigatran were highest among people aged 85 years or more, a group at increased risk of bleeding who are markedly older than the average participant in the clinical trial in which the drug was tested (71 yr). In September 2012, most of the dabigatran prescriptions were for the lower-dose formulation (110 mg) in the older groups (58.8% of dabigatran prescriptions in the 65-84 age group and 93.6% in the oldest group). INTERPRETATION We observed rapid growth in the uptake of the novel oral anticoagulants since their approval for use in patients with atrial fibrillation, especially among those aged 85 years or more. This increase in use in the oldest group, a population at high risk of bleeding, signals the need to evaluate outcomes of use of novel oral anticoagulants in the clinical setting.