Scott M. Stevens

Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation

Background— Pharmacogenetic-guided dosing of warfarin is a promising application of “personalized medicine” but has not been adequately tested in randomized trials. Methods and Results— Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic=30.7%, standard=33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic=29%, standard=39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of ≥4 (P=0.03). Conclusions— An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.

A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

BACKGROUND The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

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

BACKGROUND Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults. 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. RESULTS We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B). CONCLUSIONS Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.

A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

Background— Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. Methods and Results— A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ⩽1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. Conclusions— These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.

Risk of Symptomatic DVT Associated With Peripherally Inserted Central Catheters

BACKGROUND Previous studies undertaken to identify risk factors for peripherally inserted central catheter (PICC)-associated DVT have yielded conflicting results. PICC insertion teams and other health-care providers need to understand the risk factors so that they can develop methods to prevent DVT. METHODS A 1-year prospective observational study of PICC insertions was conducted at a 456-bed, level I trauma center and tertiary referral hospital affiliated with a medical school. All patients with one or more PICC insertions were included to identify the incidence and risk factors for symptomatic DVT associated with catheters inserted by a facility-certified PICC team using a consistent and replicated approach for vein selection and insertion. RESULTS A total of 2,014 PICCs were inserted during 1,879 distinct hospitalizations in 1,728 distinct patients for a total of 15,115 days of PICC placement. Most PICCs were placed in the right arm (76.9%) and basilic vein (74%) and were double-lumen 5F (75.3%). Of the 2,014 PICC insertions, 60 (3.0%) in 57 distinct patients developed DVT in the cannulated or adjacent veins. The best-performing predictive model for DVT (area under the curve, 0.83) was prior DVT (odds ratio [OR], 9.92; P < .001), use of double-lumen 5F (OR, 7.54; P < .05) or triple-lumen 6F (OR, 19.50; P < .01) PICCs, and prior surgery duration of > 1 h (OR, 1.66; P = .10). CONCLUSIONS Prior DVT and surgery lasting > 1 h identify patients at increased risk for PICC-associated DVT. More importantly, increasing catheter size also is significantly associated with increased risk. Rates of PICC-associated DVT may be reduced by improved selection of patients and catheter size.

Physician Alerts to Prevent Symptomatic Venous Thromboembolism in Hospitalized Patients

Background— Venous thromboembolism (VTE) prophylaxis remains underused among hospitalized patients. We designed and carried out a large, multicenter, randomized controlled trial to test the hypothesis that an alert from a hospital staff member to the attending physician will reduce the rate of symptomatic VTE among high-risk patients not receiving prophylaxis. Methods and Results— We enrolled patients using a validated point score system to detect hospitalized patients at high risk for symptomatic VTE who were not receiving prophylaxis. We randomized 2493 patients (82% on Medical Services) from 25 study sites to the intervention group (n=1238), in which the responsible physician was alerted by another hospital staff member, or the control group (n=1255), in which no alert was issued. The primary end point was symptomatic, objectively confirmed VTE within 90 days. Patients whose physicians were alerted were more than twice as likely to receive VTE prophylaxis as control subjects (46.0% versus 20.6%; P<0.0001). The symptomatic VTE rate was lower in the intervention group (2.7% versus 3.4%; hazard ratio, 0.79; 95% CI, 0.50 to 1.25), but the difference did not achieve statistical significance. The rate of major bleeding at 30 days in the alert group was similar to that in the control group (2.1% versus 2.3%; P=0.68). Conclusions— A strategy of direct notification of the physician by a staff member increases prophylaxis use and leads to a reduction in the rate of symptomatic VTE in hospitalized patients. However, VTE prophylaxis continues to be underused even after physician notification, especially among Medical Service patients.

Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis

Objective To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. Design Meta-analysis of individual patient data. Data sources Authors of 13 studies (n=10 002) provided their datasets, and these individual patient data were merged into one dataset. Eligibility criteria Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. Main outcome measures Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. Results Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. Conclusion Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.

Radiation and Chest CT Scan Examinations: What Do We Know?

In the past 3 decades, the total number of CT scans performed has grown exponentially. In 2007, > 70 million CT scans were performed in the United States. CT scan studies of the chest comprise a large portion of the CT scans performed today because the technology has transformed the management of common chest diseases, including pulmonary embolism and coronary artery disease. As the number of studies performed yearly increases, a growing fraction of the population is exposed to low-dose ionizing radiation from CT scan. Data extrapolated from atomic bomb survivors and other populations exposed to low-dose ionizing radiation suggest that CT scan-associated radiation may increase an individuals lifetime risk of developing cancer. This finding, however, is not incontrovertible. Because this topic has recently attracted the attention of both the scientific community and the general public, it has become increasingly important for physicians to understand the cancer risk associated with CT scan and be capable of engaging in productive dialogue with patients. This article reviews the current literature on the public health debate surrounding CT scan and cancer risk, quantifies radiation doses associated with specific studies, and describes efforts to reduce population-wide CT scan-associated radiation exposure. CT scan examinations of the chest, including CT scan pulmonary and coronary angiography, high-resolution CT scan, low-dose lung cancer screening, and triple rule-out CT scan, are specifically considered.

Derivation and Validation of a Simple Model to Identify Venous Thromboembolism Risk in Medical Patients

BACKGROUND Fewer than half of eligible hospitalized medical patients receive appropriate venous thromboembolism (VTE) prophylaxis. One reason for this low rate is the complexity of existing risk assessment models. A simple set of easily identifiable risk factors that are highly predictive of VTE among hospitalized medical patients may enhance appropriate thromboprophylaxis. METHODS Electronic medical record interrogation was performed to identify medical admissions from January 1, 2000-December 31, 2007 (n=143,000), and those patients with objectively confirmed VTE during hospitalization or within 90 days following discharge. Putative risk factors most predictive of VTE were identified, and a risk assessment model (RAM) was derived; 46,000 medicine admissions from January 1, 2008-December 31, 2009 served as a validation cohort to test the predictive ability of the RAM. The newly derived RAM was compared with a published VTE assessment tool (Kucher Score). RESULTS Four risk factors: previous VTE; an order for bed rest; peripherally inserted central venous catheterization line; and a cancer diagnosis, were the minimal set most predictive of hospital-associated VTE (area under the receiver operating characteristic curve [AUC]=0.874; 95% confidence interval [CI], 0.869-0.880). These risk factors upon validation in a separate population (validation cohort) retained an AUC=0.843; 95% CI, 0.833-0.852. The ability of the 4-element RAM to identify patients at risk of developing VTE within 90 days was superior to the Kucher Score. CONCLUSIONS The 4-element RAM identified in this study may be used to identify patients at risk for VTE and improve rates of thromboprophylaxis. This simple and accurate RAM is an alternative to more complicated published VTE risk assessment tools that currently exist.

Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design.

The risk of venous thromboembolism (VTE) is higher after the total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The genetics-informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT) is a 2 × 2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) is a lower target international normalized ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR⩾4, and death.