Scott C. Woller

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.

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.

Diagnosis and management of upper extremity deep-vein thrombosis in adults

Upper extremity deep-vein thrombosis (UEDVT) is common and can cause important complications, including pulmonary embolism and post-thrombotic syndrome. An increase in the use of central venous catheters, particularly peripherally inserted central catheters has been associated with an increasing rate of disease. Accurate diagnosis is essential to guide management, but there are limitations to the available evidence for available diagnostic tests. Anticoagulation is the mainstay of therapy, but interventional treatments may be considered in select situations. The risk of UEDVT may be reduced by more careful selection of patients who receive central venous catheters and by use of smaller catheters. Herein we review the diagnosis, management and prevention of UEDVT. Due to paucity of research, some principles are drawn from studies of lower extremity DVT. We present a practical approach to diagnosing the patient with suspected deep-vein thrombosis of the upper extremity.

Reduction of Peripherally Inserted Central Catheter-Associated DVT

BACKGROUND As peripherally inserted central catheter (PICC) use has increased, so has the upper extremity DVT rate. PICC diameter may pose the most modifiable risk for PICC-associated DVT. METHODS A 3-year, prospective, observational study of all PICC insertions by a specially trained and certified team using a consistent and replicable approach was conducted at a 456-bed, level I trauma and tertiary referral hospital during January 1, 2008, through December 31, 2010. An intensified effort by the PICC team in 2010 was introduced to discuss and reach interdisciplinary consensus on the need for each lumen of the PICC and a change to smaller diameter 5F triple-lumen PICC. RESULTS Significantly more 4F single-lumen PICCs were used during 2010 (n = 470) compared with 2008 and 2009 (n = 338, 382; P < .0001). DVT rates were similar with the use of 5F triple-lumen PICCs in 2010 as 5F double-lumen PICCs and lower rates than 6F triple-lumen catheters used in 2008 and 2009. The PICC-associated DVT rate was significantly lower (1.9% vs 3.0%, P < .04) in 2010 compared with 2008 and 2009. The cost and length of stay attributable to PICC-associated DVT were

Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia

15,973 and 4.6 days. CONCLUSIONS A significant increase in the use of single-lumen PICCs in addition to the institutional adoption of smaller 5F triple-lumen PICCs was associated with a significant decrease in the rate of PICC-associated DVT.

Guidance for the evaluation and treatment of hereditary and acquired thrombophilia

BACKGROUND The mechanisms behind the association of atrial fibrillation (AF) and dementia are unknown. One possibility is that exposure to chronic microembolism or microbleeds results in repetitive cerebral injury that is manifest by cognitive decline. OBJECTIVE The purpose of this study was to test the hypothesis that AF patients with a low percentage of time in the therapeutic range (TTR) are at higher risk for dementia due to under- or overanticoagulation. METHODS Patients anticoagulated with warfarin (target international normalized ratio [INR] 2-3), managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service with no history of dementia or stroke/transient ischemic attack, were included in the study. The primary outcome was dementia incidence defined by ICD-9 codes. Percent time in TTR was calculated using the method of linear interpolation and stratified as >75%, 51%-75%, 26%-50%, and ≤25%. Multivariable Cox hazard regression was used to determine dementia incidence by percentage categories of TTR. RESULTS A total of 2605 patients (age 73.7 ± 10.8 years, 1408 [54.0%] male) were studied. The CHADS2 score distribution was 0: 216 (8.3%); 1: 579 (22.2%); 2: 859(33.0%); 3: 708 (27.2%); and ≥4: 243 (9.3%). The percent TTR averaged 63.1 ± 21.3, with percent INR <2.0: 25.6% ± 17.9% and percent INR >3.0: 16.2% ± 13.6%. Dementia was diagnosed in 109 patients (4.2%) (senile: 37 [1.4%]; vascular: 8 [0.3%]; Alzheimer: 64 (2.5%]). After adjustment, decreasing categories of percent TTR were associated with increased dementia risk (vs >75%): <25%: hazard ratio (HR) 5.34, P < .0001; 26%-50%: HR 4.10, P < .0001; and 51%-75%: HR = 2.57, P = .001. CONCLUSION Quality of anticoagulation management represented as percent TTR among AF patients without dementia was associated with dementia incidence. These data support the possibility of chronic cerebral injury as a mechanism that underlies the association of AF and dementia.