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Biomedical subjects

Brian F Gage

Publications and source records attributed to Brian F Gage.

At least 19 recordsLinked to original sources
PubMed2006

Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation.

BACKGROUND AND PURPOSE: More than 2 million Americans have atrial fibrillation, and without antithrombotic therapy, their stroke rate is increased 5-fold. In randomized controlled trials, warfarin prevented 65% of ischemic strokes (hazard ratio [HR], 0.35; 95% CI, 0.26 to 0.48) compared with no antithrombotic therapy. However, the effectiveness of warfarin therapy outside of clinical trials is unknown, especially in black and Hispanic populations. Our goal was to quantify use of warfarin therapy, frequency of International Normalized Ratio monitoring, and effectiveness for stroke prophylaxis in Medicare beneficiaries with atrial fibrillation. METHODS: This was a cohort study of Medicare beneficiaries with atrial fibrillation who were hospitalized between March 1998 and April 1999 in all 50 US states. The primary outcome was incident hospitalizations for ischemic stroke based on validated International Classification of Diseases, 9th Revision, Clinical Modification codes. RESULTS: Two thirds of ideal anticoagulation candidates were prescribed warfarin on hospital discharge. In unadjusted analyses, the stroke rates per 100 patient years of warfarin therapy were 5.2 in (non-Hispanic) white Medicare beneficiaries, 10.6 in black beneficiaries, and 12.2 in Hispanic beneficiaries. After adjusting for comorbid conditions, warfarin prescription was more frequent and monitoring more regular in white Medicare beneficiaries than in black or Hispanic beneficiaries (P<0.0001). Warfarin use was associated with 35% fewer ischemic strokes (HR, 0.65; 95% CI, 0.55 to 0.76) compared with no antithrombotic therapy but was less effective in black and Hispanic beneficiaries (P for interaction=0.048). CONCLUSIONS: The use, monitoring, and effectiveness of warfarin therapy are suboptimal in Medicare beneficiaries, especially in black and Hispanic beneficiaries.

Aged↗
PubMed2006

Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2.

BACKGROUND: Vitamin K allows for gamma-carboxylation of glutamyl residues, a conversion that activates clotting factors and bone proteins. Vitamin K antagonists such as warfarin inhibit this process. Our goal was to quantify the association between warfarin and osteoporotic fractures in patients with atrial fibrillation. METHODS: This was a retrospective cohort study of Medicare beneficiaries with atrial fibrillation who were hospitalized between March 1998 and April 1999 in all 50 US states. The study outcome was osteoporotic fractures, identified by an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for a fracture of the hip, spine, or wrist. RESULTS: Compared with 7587 patients who were not prescribed warfarin, the adjusted odds ratio (OR) of fracture was 1.25 (95% confidence interval [CI], 1.06-1.48) in 4461 patients prescribed long-term warfarin therapy (> or = 1 year). The association between osteoporotic fracture and long-term warfarin use was significant in men (OR, 1.63; 95% CI, 1.26-2.10) but nonsignificant in women (OR, 1.05; 95% CI, 0.88-1.26). In 1833 patients prescribed warfarin for less than a year, the risk of osteoporotic fracture was not increased significantly (OR, 1.03). Odds ratios (95% CIs) of independent predictors of osteoporotic fractures were as follows: increasing age, 1.63 (1.47-1.80) per decade; high fall risk, 1.78 (1.42-2.21); hyperthyroidism, 1.77 (1.16-2.70); neuropsychiatric disease, 1.51 (1.28-1.78); and alcoholism, 1.50 (1.01-2.24). Factors with a reduced OR (95% CI) included African American race, 0.30 (0.18-0.51); male sex, 0.54 (0.46-0.62); and use of beta-adrenergic antagonists, 0.84 (0.70-1.00). CONCLUSIONS: Long-term use of warfarin was associated with osteoporotic fractures, at least in men with atrial fibrillation. Beta-adrenergic antagonists may protect against osteoporotic fractures.

Age Distribution↗
PubMed2006

Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF).

BACKGROUND: Although warfarin and other anticoagulants can prevent ischemic events, they can cause hemorrhage. Quantifying the rate of hemorrhage is crucial for determining the risks and net benefits of prescribing antithrombotic therapy. Our objective was to find a bleeding classification scheme that could quantify the risk of hemorrhage in elderly patients with atrial fibrillation. METHODS: We combined bleeding risk factors from existing classification schemes into a new scheme, HEMORR2HAGES, and validated all bleeding classification schemes. We scored HEMORR2HAGES by adding 2 points for a prior bleed and 1 point for each of the other risk factors: hepatic or renal disease, ethanol abuse, malignancy, older (age > 75 years), reduced platelet count or function, hypertension (uncontrolled), anemia, genetic factors, excessive fall risk, and stroke. We used data from quality improvement organizations representing 7 states to assemble a registry of 3791 Medicare beneficiaries with atrial fibrillation. RESULTS: There were 162 hospital admissions with an International Classification of Diseases, Ninth Revision, Clinical Modification code for hemorrhage. With each additional point, the rate of bleeding per 100 patient-years of warfarin increased: 1.9 for 0, 2.5 for 1, 5.3 for 2, 8.4 for 3, 10.4 for 4, and 12.3 for > or =5 points. In patients prescribed warfarin, HEMORR2HAGES had greater predictive accuracy (c statistic 0.67) than other bleed prediction schemes (P < .001). CONCLUSIONS: Adaptations of existing classification schemes, especially a new bleeding risk scheme, HEMORR2HAGES, can quantify the risk of hemorrhage and aid in the management of antithrombotic therapy.

Aged↗
PubMed2006

Pharmacogenetics-based coumarin therapy.

To reduce the risk of hemorrhage, experts advocate prescribing the anticipated therapeutic dose to patients who are beginning coumarin therapy, but until now there was no accurate way to estimate that dose. Using pharmacogenetics-based coumarin therapy, clinicians can now estimate the therapeutic dose by genotyping their patients for single nucleotide polymorphisms (SNPs) that affect coumarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect coumarin metabolism. Patients with either of two common variants, CYP2C9*2 or CYP2C9*3, metabolize coumarins slowly and are twice as likely to have a laboratory or clinical adverse event, unless their initial coumarin doses are reduced. SNPs in vitamin K epoxide reductase (VKORC1) correlate with coumarin sensitivity. Patients known to be homozygous for a common VKORC1 promoter polymorphism, -1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), should be started on lower coumarin doses than genotype GG patients. By providing an estimate of the therapeutic coumarin dose, pharmacogenetics-based therapy may improve the safety and effectiveness of coumarin therapy.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

Anticoagulants↗
PubMed2005

Costs and effectiveness of ximelagatran for stroke prophylaxis in chronic atrial fibrillation.

CONTEXT: Recent trials have found that ximelagatran and warfarin are equally effective in stroke prevention for patients with atrial fibrillation. Because ximelagatran can be taken in a fixed, oral dose without international normalized ratio monitoring and may have a lower risk of hemorrhage, it might improve quality-adjusted survival compared with dose-adjusted warfarin. OBJECTIVE: To compare quality-adjusted survival and cost among 3 alternative therapies for patients with chronic atrial fibrillation: ximelagatran, warfarin, and aspirin. DESIGN: Semi-Markov decision model. PATIENTS: Hypothetical cohort of 70-year-old patients with chronic atrial fibrillation, varying risk of stroke, and no contraindications to anticoagulation therapy. MAIN OUTCOME MEASURES: Quality-adjusted life-years (QALYs) and costs in US dollars. RESULTS: For patients with atrial fibrillation but no additional risk factors for stroke, both ximelagatran and warfarin cost more than 50,000 dollars per QALY compared with aspirin. For patients with additional stroke risk factors and low hemorrhage risk, ximelagatran modestly increased quality-adjusted survival (0.12 QALY) at a substantial cost (116,000 dollars per QALY) compared with warfarin. For ximelagatran to cost less than 50,000 dollars per QALY it would have to cost less than 1100 dollars per year or be prescribed to patients who have an elevated risk of intracranial hemorrhage (>1.0% per year of warfarin) or a low quality of life with warfarin therapy. CONCLUSION: Assuming equal effectiveness in stroke prevention and decreased hemorrhage risk, ximelagatran is not likely to be cost-effective in patients with atrial fibrillation unless they have a high risk of intracranial hemorrhage or a low quality of life with warfarin.

Aged↗
PubMed2005

Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall.

PURPOSE: Patients at high risk for falls are presumed to be at increased risk for intracranial hemorrhage, and high risk for falls is cited as a contraindication to antithrombotic therapy. Data substantiating this concern are lacking. METHODS: Quality improvement organizations identified 1245 Medicare beneficiaries who were documented in the medical record to be at high risk of falls and 18261 other patients with atrial fibrillation. The patients were elderly (mean 80 years), and 48% were prescribed warfarin at hospital discharge. The primary endpoint was subsequent hospitalization for an intracranial hemorrhage, based on ICD-9 codes. RESULTS: Rates (95% confidence interval [CI]) of intracranial hemorrhage per 100 patient-years were 2.8 (1.9-4.1) in patients at high risk for falls and 1.1 (1.0-1.3) in other patients. Rates (95% CI) of traumatic intracranial hemorrhage were 2.0 (1.3-3.1) in patients at high risk for falls and 0.34 (0.27-0.45) in other patients. Hazard ratios (95% CI) of other independent risk factors for intracranial hemorrhage were 1.4 (1.0-3.1) for neuropsychiatric disease, 2.1 (1.6-2.7) for prior stroke, and 1.9 (1.4-2.4) for prior major bleeding. Warfarin prescription was associated with intracranial hemorrhage mortality but not with intracranial hemorrhage occurrence. Ischemic stroke rates per 100 patient-years were 13.7 in patients at high risk for falls and 6.9 in other patients. Warfarin prescription in patients prone to fall who had atrial fibrillation and multiple additional stroke risk factors appeared to protect against a composite endpoint of stroke, intracranial hemorrhage, myocardial infarction, and death. CONCLUSION: Patients at high risk for falls with atrial fibrillation are at substantially increased risk of intracranial hemorrhage, especially traumatic intracranial hemorrhage. However, because of their high stroke rate, they appear to benefit from anticoagulant therapy if they have multiple stroke risk factors.

Accidental Falls↗
PubMed2005

Reliability for grading acute rejection and airway inflammation after lung transplantation.

BACKGROUND: The Lung Rejection Study Group (LRSG) created a scheme for grading acute allograft rejection in 1990 and then revised it in 1996, but virtually no studies have evaluated the reliability of this formulation. This investigation assessed the reliability of the current LRSG system by determining inter- and intrareader agreement for grading transbronchial biopsy samples from lung transplant recipients. METHODS: Biopsy samples from a cohort of 204 recipients were reviewed and classified by a single pathologist who was blinded to original interpretations. The "A" and "B" rejection grades from this contemporary review were compared with original grades by the kappa statistic. RESULTS: For "A" grading, weighted kappa was 0.65 (95% confidence interval [CI] 0.60-0.70) for interreader agreement (n = 529 specimens) and 0.65 (95% CI 0.53-0.76) for intrareader agreement (n = 97 specimens). For "B" grading, weighted kappa was 0.26 (95% CI 0.14-0.39) for interreader agreement (n = 164 specimens) and 0.33 (95% CI 0.15-0.51) for intrareader agreement (n = 58 specimens). CONCLUSIONS: On the basis of the analysis of the LRSG scheme, "A" grades exhibit very good reliability, but "B" grades have only fair reliability, and steps to improve this shortcoming should be taken.

Acute Disease↗
PubMed2005

Implantable cardioverter-defibrillator therapy improves long-term survival in patients with unexplained syncope, cardiomyopathy, and a negative electrophysiologic study.

OBJECTIVES: The purpose of this study was to evaluate the long-term outcomes of patients with unexplained syncope, ischemic or nonischemic cardiomyopathy, and a negative electrophysiologic study (EPS). BACKGROUND: EPS is frequently performed to evaluate syncope in patients with left ventricular dysfunction. Limited long-term data evaluating all-cause mortality in patients with no inducible arrhythmia or examining the potential benefits from implantable cardioverter-defibrillator (ICD) therapy are available. METHODS: We evaluated 102 consecutive patients with unexplained syncope, cardiomyopathy, and a negative EPS from September 1996 to December 2000. A blinded matched case-control analysis utilized 51 of these patients (19 treated with an ICD and 32 matched controls treated with conventional therapy). We compared primary endpoint of death and documented cardiac arrest of patients treated with ICD therapy to matched controls. RESULTS: Baseline characteristics were similar between groups. There were 14 primary events among the study population during a follow-up period of 44.3 +/- 20 months: 2 in the ICD group and 12 in the conventional therapy group. The hazard ratio for the risk of event in the ICD group compared with the conventional therapy group was 0.18 (95% confidence interval, 0.04-0.85; P = .04). Other comorbid conditions, including age, sex, ischemic etiology of heart failure, ejection fraction, and antiarrhythmic use, did not predict outcome. Appropriate ICD shocks occurred in 26% of patients at 2 years. CONCLUSIONS: This study suggests that empiric ICD therapy improves long-term outcomes in patients with unexplained syncope, ischemic or nonischemic cardiomyopathy, and negative EPS.

Aged↗
PubMed2005

Use of EPO in critically ill patients with acute renal failure requiring renal replacement therapy.

BACKGROUND: Recombinant human erythropoietin (EPO) is used widely to treat anemia in patients with chronic kidney disease, but the benefits of EPO use in patients with acute renal failure (ARF) are unclear. In vitro and animal studies suggest that EPO may promote renal recovery and decrease mortality in ARF. METHODS: We conducted a retrospective cohort study at a tertiary-care center to evaluate the use of EPO in 187 critically ill patients with ARF requiring renal replacement therapy. RESULTS: Compared with patients not administered EPO (n = 116), patients administered EPO (n = 71) were significantly more likely to have baseline chronic kidney disease, have undergone vascular surgery, and have received intermittent hemodialysis, rather than continuous renal replacement therapy. In a propensity-adjusted analysis that controlled for differences between the 2 cohorts and baseline hemoglobin level, EPO use did not decrease the transfusion of packed red blood cells. Renal recovery was not more common in patients administered EPO: the odds ratio for renal recovery in the propensity-adjusted analysis was 0.63 (95% confidence interval, 0.30 to 1.3) with EPO use. In-hospital survival was more common in the EPO-treated group, but this potential benefit was not significant in propensity-adjusted analyses. CONCLUSION: Although EPO use was not associated with a decrease in transfusion requirements or with renal recovery in our retrospective study, 37% of critically ill patients with ARF were treated with EPO at varying doses. A randomized controlled trial is needed to evaluate the potential benefits of EPO use in patients with ARF.

APACHE↗
PubMed2005

Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors.

OBJECTIVES: We sought to determine which ICD-9-CM codes in Medicare Part A data identify cardiovascular and stroke risk factors. DESIGN AND PARTICIPANTS: This was a cross-sectional study comparing ICD-9-CM data to structured medical record review from 23,657 Medicare beneficiaries aged 20 to 105 years who had atrial fibrillation. MEASUREMENTS: Quality improvement organizations used standardized abstraction instruments to determine the presence of 9 cardiovascular and stroke risk factors. Using the chart abstractions as the gold standard, we assessed the accuracy of ICD-9-CM codes to identify these risk factors. MAIN RESULTS: ICD-9-CM codes for all risk factors had high specificity (>0.95) and low sensitivity (< or =0.76). The positive predictive values were greater than 0.95 for 5 common, chronic risk factors-coronary artery disease, stroke/transient ischemic attack, heart failure, diabetes, and hypertension. The sixth common risk factor, valvular heart disease, had a positive predictive value of 0.93. For all 6 common risk factors, negative predictive values ranged from 0.52 to 0.91. The rare risk factors-arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis-had high negative predictive value (> or =0.98) but moderate positive predictive values (range, 0.54-0.77) in this population. CONCLUSIONS: Using ICD-9-CM codes alone, heart failure, coronary artery disease, diabetes, hypertension, and stroke can be ruled in but not necessarily ruled out. Where feasible, review of additional data (eg, physician notes or imaging studies) should be used to confirm the diagnosis of valvular disease, arterial peripheral embolus, intracranial hemorrhage, and deep venous thrombosis.

Adult↗
PubMed2005

Comorbidity indices to predict mortality from Medicare data: results from the national registry of atrial fibrillation.

BACKGROUND: By accounting for level of comorbidity, risk-adjustment models should quantify the risk of death. How accurately comorbidity indices predict risk of death in Medicare beneficiaries with atrial fibrillation is unclear. OBJECTIVES: We sought to quantify how well 3 administrative-data based comorbidity indices (Deyo, Romano, and Elixhauser) predict mortality compared with a chart-review index. DESIGN: We undertook a retrospective cohort study using Medicare claim data (1995-1999) and medical record review. SUBJECTS: We studied Medicare beneficiaries (n = 2728; mean age = 77) with a common cardiac dysrhythmia, atrial fibrillation. MEASURES: The outcome was time to death with the accuracy of the comorbidity indices measured by the c-statistic. RESULTS: Correlation between Deyo and Romano indices was strong, but weak between them and the other indices. Prevalence of many comorbidity conditions varied with different indices. Compared with demographic data alone (c = 0.64), all comorbidity indices predicted death significantly (P < 0.001) better: the c index was 0.76 for Deyo, 0.78 for Romano, 0.76 for Elixhauser, and 0.75 for medical record review. The 95% confidence intervals of the c-statistic for the 4 indices overlapped with one another. Key comorbidity conditions for death included metastatic cancer, neuropsychiatric disease, heart failure, and liver disease. CONCLUSION: The predictive accuracy of 3 administrative-data based indices was similar and comparable with chart-review.

Aged↗
PubMed2005

Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype.

Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4-9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R(2) = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.

Adult↗
PubMed2005

The pharmacogenetics of coumarin therapy.

Vitamin K antagonists (coumarins) are widely-used oral anticoagulants for the prevention of venous thromboembolism and strokes. Wide inter-individual variation in dose response and frequent bleeds characterize the initiation of coumarin therapy. Over the past 10 years both genetic and nongenetic determinants of coumarin dose response have been identified. A comprehensive pharmacogenetics approach to warfarin therapy has the potential to improve the safety and efficiency of warfarin initiation.

Anticoagulants↗