Cardiac troponin is associated with cardiac outcomes in men and women with atrial fibrillation, insights from the ARISTOTLE trial.

BACKGROUND: Cardiac troponin T (cTnT) and I (cTnI) concentrations provide strong prognostic information in anticoagulated patients with atrial fibrillation (AF). Whether the associations between cardiac troponin concentrations and mortality and morbidity differ by sex is not known. OBJECTIVES: To assess whether men and women have different concentrations and prognostic value of cTnT and cTnI measurements in anticoagulated patients with AF. METHODS: cTnT and cTnI concentrations were measured with high-sensitivity (hs) assays in EDTA plasma samples obtained from the multicentre ARISTOTLE trial, which randomized patients with AF and at least one risk factor for stroke or systemic embolic event to warfarin or apixaban. Patients were stratified according to sex and the associations between hs-troponin concentrations, and all-cause death, cardiac death, myocardial infarction, stroke or systemic embolic event and major bleeding were assessed in multivariable regression models. RESULTS: We found higher cardiac troponin concentrations in men (n = 9649) compared to women (n = 5331), both for hs-cTnT (median 11.8 [Q1-3 8.1-18.0] vs. 9.6 [6.7-14.3] ng L-1 , P < 0.001) and hs-cTnI (5.8 [3.4-10.8] vs. 4.9 [3.1-8.8] ng L-1 , P < 0.001). Adjusting for baseline demographics, comorbidities and medications, men still had significantly higher hs-troponin concentrations than women. C-reactive protein and N-terminal pro-B-type natriuretic peptide concentrations were higher in female patients. Both hs-cTnT and hs-cTnI concentrations were associated with all clinical outcomes similarly in men and women (p-value for interaction >0.05 for all end-points). CONCLUSION: Men have higher hs-troponin concentrations than women in AF. Regardless of sex, hs-troponin concentrations remain similarly associated with adverse clinical outcomes in anticoagulated patients with AF.

Global public awareness of venous thromboembolism.

BACKGROUND: Data on public awareness about thrombosis in general and venous thromboembolism (VTE) in particular are limited. We aimed to measure the global awareness of thrombosis to address this gap. METHODS: With Ipsos-Reid, from 22 July to 5 August 2014, we surveyed 800 respondents in their native language from each of Argentina, Australia, Canada, Germany, Japan, Thailand, the Netherlands, the United Kingdom and the United States to measure general awareness about thrombosis, including deep vein thrombosis (DVT) and pulmonary embolism (PE). In each country, respondents were distributed among three age groups: 18-39 years, 40-64 years, and over 65 years of age. Proportions and 95% confidence intervals (CIs) were calculated. RESULTS: Overall, the proportion of respondents that were aware of thrombosis, DVT and PE (68%, 44% and 54%, respectively) was lower than the proportion that was aware of other thrombotic disorders, such as heart attack and stroke (88% and 85%, respectively), and health conditions such as hypertension, breast cancer, prostate cancer and AIDS (90%, 85%, 82% and 87%, respectively). Although there was variation across countries, lower awareness was associated with younger age and being male. Only 45% (95% CI, 43.9-46.5) of respondents were aware that blood clots were preventable, and awareness of cancer, hospitalization and surgery as risk factors was low (16%, 25%, and 36%, respectively). CONCLUSIONS: On a global level, public awareness about thrombosis overall, and VTE in particular, is low. Campaigns to increase public awareness about VTE are needed to reduce the burden from this largely preventable thrombotic disorder.

Thrombosis: a major contributor to global disease burden.

BACKGROUND: Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. OBJECTIVE: To review the literature on the global burden of disease caused by VTE. APPROACH AND RESULTS: We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. CONCLUSIONS: VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden.

D-dimer and risk of thromboembolic and bleeding events in patients with atrial fibrillation--observations from the ARISTOTLE trial.

BACKGROUND: D-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases. OBJECTIVES: To evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin. METHODS: In the ARISTOTLE trial, 18 201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14 878 patients at randomization. The cohort was separated into two groups; not receiving vitamin K antagonist (VKA) treatment and receiving VKA treatment at randomization. RESULTS: Higher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR] [Q4 vs. Q1] 1.72, 95% confidence interval [CI] 1.14-2.59, P = 0.003), death (HR [Q4 vs. Q1] 4.04, 95% CI 3.06-5.33) and major bleeding (HR [Q4 vs. Q1] 2.47, 95% CI 1.77-3.45, P < 0.0001) in the no-VKA group. Similar results were obtained in the on-VKA group. Adding D-dimer level to the CHADS2 score improved the C-index from 0.646 to 0.655 for stroke or systemic embolism, and from 0.598 to 0.662 for death, in the no-VKA group. D-dimer level improved the HAS-BLED score for prediction of major bleeds, with an increase in the C-index from 0.610 to 0.641. There were no significant interactions between efficacy and safety of study treatment and D-dimer level. CONCLUSION: In anticoagulated patients with AF, the level of D-dimer is related to the risk of stroke, death, and bleeding, and adds to the predictive value of clinical risk scores. The benefits of apixaban were consistent, regardless of the baseline D-dimer level.

Female sex as an independent risk factor for stroke in atrial fibrillation: possible mechanisms.

Atrial fibrillation (AF) is an independent risk factor for thromboembolism and stroke. Women with AF are at a higher overall risk for thromboembolic stroke when compared to men with AF. Recent evidence suggests that female sex, after adjusting for stroke risk profile and sex differences in utilisation of anticoagulation, is an independent stroke risk factor in AF. The inclusion of female sex has improved the accuracy of the CHADS2 stroke risk stratification schema (Congestive heart failure, Hypertension, Age 75 years or greater, Diabetes mellitus, and prior Stroke or TIA). The newly revised and validated schema, CHA2DS2-VASc, dichotomises age and incorporates female sex and vascular disease history. The pathophysiological mechanisms to explain this increased risk in women are not well understood. According to Virchow's triad, thrombosis that leads to stroke in AF should arise from three co-existing phenomena: structural abnormalities, blood stasis, and a hypercoagulable state. Herein, we explore the sex differences in the biological processes that lead to thrombus formation as applied to Virchow's Triad. The objective of this review is to describe the potential mechanisms behind the increased risk of stroke in AF associated with female sex.

INR targets and site-level anticoagulation control: results from the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).

BACKGROUND: Not all clinicians target the same International Normalized Ratio (INR) for patients with a guideline-recommended target range of 2-3. A patient's mean INR value suggests the INR that was actually targeted. We hypothesized that sites would vary by mean INR, and that sites of care with mean values nearest to 2.5 would achieve better anticoagulation control, as measured by per cent time in therapeutic range (TTR). OBJECTIVES: To examine variations among sites in mean INR and the relationship with anticoagulation control in an integrated system of care. PATIENTS/METHODS: We studied 103,897 patients receiving oral anticoagulation with an expected INR target between 2 and 3 at 100 Veterans Health Administration (VA) sites from 1 October 2006 to 30 September 2008. Key site-level variables were: proportion near 2.5 (that is, percentage of patients with mean INR between 2.3 and 2.7) and mean risk-adjusted TTR. RESULTS: Site mean INR ranged from 2.22 to 2.89; proportion near 2.5, from 30 to 64%. Sites' proportions of patients near 2.5, below 2.3 and above 2.7 were consistent from year to year. A 10 percentage point increase in the proportion near 2.5 predicted a 3.8 percentage point increase in risk-adjusted TTR (P < 0.001). CONCLUSIONS: Proportion of patients with mean INR near 2.5 is a site-level 'signature' of care and an implicit measure of targeted INR. This proportion varies by site and is strongly associated with site-level TTR. Our study suggests that sites wishing to improve TTR, and thereby improve patient outcomes, should avoid the explicit or implicit pursuit of non-standard INR targets.

Future directions of stroke prevention in atrial fibrillation: the potential impact of novel anticoagulants and stroke risk stratification.

Stroke prevention in atrial fibrillation is of paramount importance given its associated morbidity and mortality. The many challenges of warfarin limit its effective use in real-world clinical practice. We are entering an exciting therapeutic era as new classes of anticoagulants, including direct thrombin inhibitors, factor Xa inhibitors and novel vitamin K antagonists, are being evaluated for possible use in this patient population. If proven to be as efficacious as warfarin and safer, expanded use of these novel agents to lower risk subgroups may be justified. It is imperative that providers be aware of the many advantages and potential challenges posed by use of these novel agents in routine clinical care. An understanding of individual pharmacokinetic profiles and potential drug-drug and drug-disease interactions will translate into improved effectiveness in real-world practice.

Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).

BACKGROUND: In patients receiving oral anticoagulation, improved control can reduce adverse outcomes such as stroke and major hemorrhage. However, little is known about patient-level predictors of anticoagulation control. OBJECTIVES: To identify patient-level predictors of oral anticoagulation control in the outpatient setting. PATIENTS/METHODS: We studied 124,619 patients who received oral anticoagulation from the Veterans Health Administration from October 2006 to September 2008. The outcome was anticoagulation control, summarized using percentage of time in therapeutic International Normalized Ratio range (TTR). Data were divided into inception (first 6 months of therapy; 39,447 patients) and experienced (any time thereafter; 104,505 patients). Patient-level predictors of TTR were examined by multivariable regression. RESULTS: Mean TTRs were 48% for inception management and 61% for experienced management. During inception, important predictors of TTR included hospitalizations (the expected TTR was 7.3% lower for those with two or more hospitalizations than for the non-hospitalized), receipt of more medications (16 or more medications predicted a 4.3% lower than for patients with 0-7 medications), alcohol abuse (-4.6%), cancer (-3.1%), and bipolar disorder (-2.9%). During the experienced period, important predictors of TTR included hospitalizations (four or more hospitalizations predicted 9.4% lower TTR), more medications (16 or more medications predicted 5.1% lower TTR), alcohol abuse (-5.4%), female sex (- 2.9%), cancer (-2.7%), dementia (-2.6%), non-alcohol substance abuse (-2.4%), and chronic liver disease (-2.3%). CONCLUSIONS: Some patients receiving oral anticoagulation therapy are more challenging to maintain within the therapeutic range than others. Our findings can be used to identify patients who require closer attention or innovative management strategies to maximize benefit and minimize harm from oral anticoagulation therapy.

Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users.

BACKGROUND: For patients on warfarin therapy an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. For patients whose INR values are nearly always therapeutic, less frequent INR monitoring may be feasible. OBJECTIVE: To identify patients with stable INRs (INR values exclusively within the INR range) and comparator patients (at least one INR outside the INR range), compare occurrences of thromboembolism, bleeding and death between groups, and identify independent predictors of stable INR control. METHODS: The study was a retrospective, longitudinal cohort study using data extracted from electronic databases. Patient characteristics and risk factors were entered into multivariate logistic regression models to identify variables that independently predict stable INR status. RESULTS: There were 533 stable and 2555 comparator patients. Bleeding and thromboembolic complications were significantly lower in stable vs. comparator patients (2.1% vs. 4.1% and 0.2% vs. 1.3%, respectively; P < 0.05). Independent predictors of stable INR control were age >70 years, male gender and the absence of heart failure. Stable patients were significantly less likely to have target INR > or =3.0 or chronic diseases. CONCLUSION: A group of patients with exclusively therapeutic INR values over 12 months is identifiable. In general, these patients are older, have a target INR <3.0, and do not have heart failure and/or other chronic diseases. Our findings suggest that many patients whose INR values remain within the therapeutic range over time could be safely treated with INR recall intervals >4 weeks.

Anticoagulation for valvular heart disease in community-based practice.

Little is known about patients who receive oral anticoagulation for valvular heart disease (VHD) in community-based practice. It was this study's objective to describe the characteristics, management, and outcomes of patients anticoagulated for VHD, compared to patients anticoagulated for atrial fibrillation (AF). We used a nationally-representative cohort of community-based anticoagulation care in the United States. Data collected included indications for therapy, demographics, selected comorbid conditions, international normalised ratio (INR) target ranges, INR control, and clinical outcomes. We identified 1,057 patients anticoagulated for VHD (15.6% of the overall cohort) and 3,396 patients anticoagulated for AF (50.2%). INR variability was similar between the two groups (0.64 vs. 0.69, p = 0.80). Among patients with aortic VHD, for whom a standard (2-3) target INR range is recommended, 461 (84%) had a high target range (2.5-3.5), while 95 (16%) had a standard target range. VHD patients had a higher rate of major haemorrhage compared to AF patients (3.57 vs. 1.78 events per 100 patient-years, incidence rate ratio 2.02, 95% CI 1.33 - 3.06). The rate of stroke/systemic embolus was similar between groups (0.67 vs. 0.97 events per 100 patient-years, incidence rate ratio 0.71, 95% CI 0.32 - 1.57). In our community-based study, approximately 15.6% of patients receiving warfarin were anticoagulated for VHD. VHD patients achieved similar anticoagulation control to patients with AF, as measured by INR variability. Nevertheless, the rate of major haemorrhage was elevated among VHD patients compared to AF patients; this finding requires further investigation.

Incidence and predictors of bleeding or thrombosis after polypectomy in patients receiving and not receiving anticoagulation therapy.

BACKGROUND AND AIMS: To assess the effect of warfarin anticoagulation therapy (AC) on the incidence of colon bleeding after elective colonoscopy with polypectomy and to identify independent predictors of post-polypectomy colon bleeding. METHODS: This was a retrospective cohort analysis. Patients interrupting warfarin AC therapy for polypectomy (AC group) were matched on age (+/- 3 years) with up to two patients who underwent polypectomy but were not receiving AC (non-AC group). Data were extracted from electronic medical, pharmacy and laboratory claims and records and manual medical chart review. Incidence rates of colon bleeding requiring hospitalization, other gastrointestinal bleeding, thrombosis and death in the 30 days post-polypectomy were compared between groups. Multivariate regression techniques were used to identify independent predictors of post-polypectomy colon bleeding. RESULTS: A total of 425 AC group patients were matched to 800 non-AC group patients. Post-polypectomy colon bleeding occurred more often in AC group patients (2.6% vs. 0.2%, P = 0.005). There were no differences in the rates of other outcomes (P > 0.05). Independent predictors of colon bleeding included AC group status [adjusted odds ratio (AOR) = 11.6; 95% confidence interval (CI) = 2.3-57.3], number of polyps removed (AOR = 1.2; 95% CI = 1.1-1.4) and male gender (AOR = 9.2, 95% CI = 1.1-74.9). CONCLUSIONS: The incidence of post-polypectomy colon bleeding was higher in patients receiving AC even although warfarin was interrupted for the procedure. Independent predictors of colon bleeding were identified as: receiving AC, removal of multiple polyps and male gender. Our findings suggest that additional methods to reduce the likelihood of post-polypectomy colon bleeding in AC patients should be investigated.

Warfarin dose management affects INR control.

BACKGROUND: Little is known about how patterns of warfarin dose management contribute to percentage time in the therapeutic International Normalized Ratio (INR) range (TTR). OBJECTIVES: To quantify the contribution of warfarin dose management to TTR and to define an optimal dose management strategy. PATIENTS/METHODS: We enrolled 3961 patients receiving warfarin from 94 community-based clinics. We derived and validated a model for the probability of a warfarin dose change under various conditions. For each patient, we computed an observed minus expected (O - E) score, comparing the number of dose changes predicted by our model to the number of changes observed. We examined the ability of O - E scores to predict TTR, and simulated various dose management strategies in the context of our model. RESULTS: Patients were observed for a mean of 15.2 months. Patients who deviated the least from the predicted number of dose changes achieved the best INR control (mean TTR 70.1% unadjusted); patients with greater deviations had lower TTR (65.8% and 62.0% for fewer and more dose changes respectively, Bonferroni-adjusted P < 0.05/3 for both comparisons). On average, clinicians in our study changed the dose when the INR was 1.8 or lower/3.2 or higher (mean TTR: 68%); optimal management would have been to change the dose when the INR was 1.7 or lower/3.3 or higher (predicted TTR: 74%). CONCLUSIONS: Our observational study suggests that INR control could be improved considerably by changing the warfarin dose only when the INR is 1.7 or lower/3.3 or higher. This should be confirmed in a randomized trial.

Warfarin for atrial fibrillation in community-based practise.

BACKGROUND: Previous studies of anticoagulation for atrial fibrillation (AF) have predominantly occurred in academic settings or randomized trials, limiting their generalizability. OBJECTIVE: To describe the management of patients with AF anticoagulated with warfarin in community-based practise. METHODS: We enrolled 3396 patients from 101 community-based practises in 38 states. Data included demographics, comorbidities, and International Normalized Ratio (INR) values. Outcomes included time in therapeutic INR range (TTR), stroke, and major hemorrhage. RESULTS: The mean TTR was 66.5%, but varied widely among patients: 37% had TTR above 75%, while 34% had TTR below 60%. The yearly rates of major hemorrhage and stroke were 1.90 per 100 person-years and 1.00 per 100 person-years. Four percent of patients (n = 127) were intentionally targeted to a lower INR, and spent 42.7% of time with an INR below 2.0, compared to 18.8% for patients with a 2.0-3.0 range (P < 0.001). Mean TTR for new warfarin users (57.5%) remained below that of prevalent users through the first six months. Patients with interruptions of warfarin therapy had lower TTR than all others (61.6% vs. 67.2%, P < 0.001), which corrected after deleting low peri-procedural INR values (67.0% vs. 67.4%, P = 0.73). CONCLUSIONS: Anticoagulation control varies widely among patients taking warfarin for AF. TTR is affected by new warfarin use, procedural interruptions, and INR target range. In this community-based cohort of predominantly prevalent warfarin users, rates of hemorrhage and stroke were low. The risk versus benefit of a lower INR target range to offset bleeding risk remains uncertain.

Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke.

BACKGROUND AND OBJECTIVES: Prior ischemic stroke is a risk factor for intracerebral hemorrhage (ICH) in patients taking warfarin, but the mechanism is not known. This study investigates radiographic and clinical characteristics of patients with warfarin-related ICH following ischemic stroke. METHODS: In this case-control study, the authors selected all patients with warfarin-related ICH and previous symptomatic ischemic stroke from a prospective cohort of consecutive patients with ICH. Control subjects were similarly aged patients with history of symptomatic stroke randomly chosen from an anticoagulant therapy unit. The 26 eligible ICH cases and 56 controls were compared for vascular risk factors, stroke characteristics, and extent of leukoaraiosis (graded in anterior and posterior brain regions on a validated scale of 0 to 4). RESULTS: The presence and severity of leukoaraiosis on CT scan correlated strongly with the occurrence of ICH. Leukoaraiosis was seen in 24 of 26 cases (92%) compared with 27 of 56 controls (48%), yielding an odds ratio of 12.9 (95% CI 2.8 to 59.8). Other clinical factors associated with ICH included an international normalized ratio >3.0, history of multiple previous strokes, and the presence of carotid artery stenosis. The relationship between leukoaraiosis and ICH persisted in multivariable analyses controlling for these risk factors as well as hypertension and diabetes mellitus. CONCLUSIONS: Leukoaraiosis is an independent risk factor for warfarin-related ICH in survivors of ischemic stroke, including those in the commonly employed range of anticoagulation.

Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin.

BACKGROUND: An elevated international normalized ratio (INR) increases the risk for major hemorrhage during warfarin therapy. Optimal management of patients with asymptomatic elevations in INR is hampered by the lack of understanding of the time course of INR decay after cessation of warfarin therapy. OBJECTIVE: To identify predictors of the rate of INR normalization after excessive anticoagulation. DESIGN: Retrospective cohort study. SETTING: Outpatient anticoagulant therapy unit. PATIENTS: Outpatients with an INR greater than 6.0 were identified from August 1993 to September 1998. Patients in whom two doses of warfarin were withheld and a follow-up INR was obtained on the second calendar day were enrolled. No patient received vitamin K(1). MEASUREMENTS: The INR was measured 2 days after an INR greater than 6.0 was recorded. RESULTS: Of 633 study patients with an initial INR greater than 6.0, 232 (37%) still had an INR of 4.0 or greater after two doses of warfarin were withheld. Patients who required larger weekly maintenance doses of warfarin were less likely to have an INR of 4.0 or greater on day 2 (adjusted odds ratio per 10 mg of warfarin, 0.87 [95% CI, 0.79 to 0.97]). Other risk factors for having an INR of 4.0 or greater on day 2 included age (odds ratio per decade of life, 1.18 [CI, 1.01 to 1.38]), index INR (odds ratio per unit, 1.25 [CI, 1.14 to 1.37]), decompensated congestive heart failure (odds ratio, 2.79 [CI, 1.30 to 5.98]), and active cancer (odds ratio, 2.48 [CI, 1.11 to 5.57]). CONCLUSIONS: Steady-state warfarin dose, advanced age, and extreme elevation in INR are risk factors for prolonged delay in return of the INR to within the therapeutic range. Decompensated congestive heart failure and active cancer greatly increase this risk.

Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.

CONTEXT: Atrial fibrillation is the most common arrhythmia in elderly persons and a potent risk factor for stroke. However, recent prevalence and projected future numbers of persons with atrial fibrillation are not well described. OBJECTIVE: To estimate prevalence of atrial fibrillation and US national projections of the numbers of persons with atrial fibrillation through the year 2050. DESIGN, SETTING, AND PATIENTS: Cross-sectional study of adults aged 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997. MAIN OUTCOME MEASURES: Prevalence of atrial fibrillation in the study population of 1.89 million; projected number of persons in the United States with atrial fibrillation between 1995-2050. RESULTS: A total of 17 974 adults with diagnosed atrial fibrillation were identified during the study period; 45% were aged 75 years or older. The prevalence of atrial fibrillation was 0.95% (95% confidence interval, 0.94%-0.96%). Atrial fibrillation was more common in men than in women (1.1% vs 0.8%; P<.001). Prevalence increased from 0.1% among adults younger than 55 years to 9.0% in persons aged 80 years or older. Among persons aged 50 years or older, prevalence of atrial fibrillation was higher in whites than in blacks (2.2% vs 1.5%; P<.001). We estimate approximately 2.3 million US adults currently have atrial fibrillation. We project that this will increase to more than 5.6 million (lower bound, 5.0; upper bound, 6.3) by the year 2050, with more than 50% of affected individuals aged 80 years or older. CONCLUSIONS: Our study confirms that atrial fibrillation is common among older adults and provides a contemporary basis for estimates of prevalence in the United States. The number of patients with atrial fibrillation is likely to increase 2.5-fold during the next 50 years, reflecting the growing proportion of elderly individuals. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with atrial fibrillation.

Oral anticoagulants. Pharmacologic issues for use in the elderly.

There has been a marked expansion of the indications for oral anticoagulant therapy, particularly among the elderly. Despite the documented benefits, the use of warfarin remains strikingly low among patients 80 years of age and older. Elderly patients often exhibit an enhanced dose response to warfarin. On average, steady-state warfarin doses decrease by 11% per decade of age. Pharmacokinetic changes in the elderly are negligible. Pharmacodynamic differences have not been well characterized. Initiating warfarin dosing in the elderly should be done cautiously, with doses of 5 mg or less. Doses should be adjusted downward in the presence of congestive heart failure, advanced obstructive lung disease, liver disease, malignancy, protracted diarrhea, enteral feedings, or concurrent potentiating medications. Numerous medications interfere with the anticoagulant response of warfarin. The most powerful potentiating drugs are those that interfere with the metabolism of (S)-warfarin. Examples include amiodarone, trimethoprim-sulfamethoxazole, and metronidazole. These drugs should be prescribed with caution in the elderly and mandate frequent INR monitoring during the induction period. An extensive assessment of patient-specific factors that might increase the hazards related to warfarin therapy needs to be conducted and documented before initiating oral anticoagulant therapy. Patients and their caregivers need to understand the risks and benefits, and to recognize signs of abnormal bleeding and the need for frequent monitoring. Patients should be encouraged to maintain consistency in their vitamin K intake and should strive to meet the recommended dietary allowance for vitamin K. To improve anticoagulation control, physicians and other health care providers need to be aware of the many warfarin drug interactions and be cognizant of the increased dose response of warfarin seen in the elderly. Concurrent prescription of multiple drugs known to affect warfarin's anticoagulant response should be minimized and use of nonselective nonsteroidal anti-inflammatory drugs should be limited given their deleterious effects on the gastric mucosa. Transitions from inpatient care to subacute care and back to outpatient care are particularly vulnerable periods for patients' anticoagulation control. Enhanced provider communication and more seamless transitions help to ensure optimal INR follow-up and timely warfarin dose adjustment if indicated.

Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most feared complication of warfarin therapy. The pathogenesis of this often-fatal complication remains obscure. Cerebral amyloid angiopathy (CAA) is a major cause of spontaneous lobar hemorrhage in the elderly and is associated with specific alleles of the APOE gene. OBJECTIVE: To assess the role of CAA in warfarin-associated ICH. METHODS: Clinical characteristics and APOE genotype were compared between 41 patients with warfarin-related ICH (from a cohort of 59 consecutive patients aged > or = 65 years with supratentorial ICH on warfarin) and 66 randomly selected individuals aged > or = 65 years without ICH taking warfarin. In addition, all neuropathologic specimens from ICH patients were reviewed for the presence and severity of CAA. RESULTS: Hemorrhages tended to be in the lobar regions of the brain, and most (76%) occurred with an international normalized ratio of < or = 3.0. The APOE epsilon2 allele was overrepresented among patients with warfarin-associated lobar hemorrhage (allele frequency 0.13 versus 0.04 in control subjects; p = 0.031). After controlling for other variables associated with ICH, carriers of the epsilon2 allele had an OR of 3.8 (95% CI, 1.0 to 14.6) for lobar ICH. CAA was pathologically diagnosed as the cause of lobar hemorrhage in 7 of 11 patients with available tissue samples. CONCLUSIONS: CAA is an important cause of warfarin-associated lobar ICH in the elderly. Although diagnosis of CAA before hemorrhage is not yet possible, these data offer hope that future patients at high risk for hemorrhage may be identified before initiation of warfarin therapy.

Implications of stroke risk criteria on the anticoagulation decision in nonvalvular atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study.

BACKGROUND: Warfarin dramatically reduces the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) but increases the likelihood of bleeding. Accurately identifying patients who need anticoagulation is critical. We assessed the potential impact of prominent stroke risk classification schemes on this decision in a large sample of patients with NVAF. METHODS AND RESULTS: We used clinical and electrocardiographic databases to identify 13 559 ambulatory patients with NVAF from July 1996 through December 1997. We compared the proportion of patients classified as having a low enough stroke risk to receive aspirin using published criteria from the Atrial Fibrillation Investigators (AFI), American College of Chest Physicians (ACCP), and the Stroke Prevention in Atrial Fibrillation Investigators (SPAF). In this cohort, AFI criteria classified 11% as having a low stroke risk, compared with 23% for ACCP and 29% for SPAF (kappa range, 0.44 to 0.85). This 2- to-3-fold increase in low stroke risk patients by ACCP and SPAF criteria primarily resulted from the inclusion of many older subjects (65 to 75 years+/-men >75 years) with no additional clinical stroke risk factors. CONCLUSIONS: The age threshold for assigning an increased stroke risk has a dramatic impact on whether to recommend warfarin in populations of patients with NVAF. Large, prospective studies with many stroke events are needed to precisely determine the relationship of age to stroke risk in AF and to identify which AF subgroups are at a sufficiently low stroke risk to forego anticoagulation.

Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation.

BACKGROUND: Warfarin sodium therapy is highly effective in preventing thromboembolism. Its major toxic effect is hemorrhage, the risk of which increases with the international normalized ratio (INR). Data on the rate of major hemorrhage and the rate of INR decay after an episode of excessive anticoagulation therapy would help guide management of elevated INRs in the outpatient setting. METHODS: We prospectively followed up outpatients in an anticoagulant therapy unit from April 24, 1995, through March 1, 1996. Study patients had to be taking warfarin for longer than 1 month and have an INR target range of 2.0 to 3.0. Consecutive outpatients with an INR greater than 6.0 were identified and compared with a randomly selected concurrent set of patients whose INR was in the target range. Major hemorrhage was defined as fatal, intracranial, or requiring hospitalization and transfusion of at least 2 U of blood. RESULTS: One hundred fourteen patients with INRs greater than 6.0 were identified and compared with 268 patients with INRs in the target range. None of the patients had clinically apparent bleeding at the time of the INR measurement, and none received phytonadione (vitamin K1). Patients did not differ significantly in age, sex, indication, or duration of warfarin therapy. Ten patients with an INR greater than 6.0 (8.8%; 95% confidence interval, 4.3%-15.5%) sought medical attention for abnormal bleeding, and 5 of these experienced a major hemorrhage during 14-day follow-up (4.4%; 95% confidence interval, 1.4%-9.9%) compared with none of the patients with an in-range INR (P<.001). Thirty-three percent of patients with INRs greater than 6.0 had INRs less than 4.0 within 24 hours, 55% within 48 hours, 73% within 72 hours, and nearly 90% within 96 hours of temporary discontinuation of warfarin therapy. CONCLUSIONS: Outpatients with INRs greater than 6.0 face a significant short-term risk of major hemorrhage. Randomized trials are needed to determine the net benefit of preventive treatment with phytonadione.