Yuchiao Chang

Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation

Context The appropriate level of warfarin anticoagulation in elderly patients with atrial fibrillation has been debated because of an age-associated increase in intracerebral hemorrhage. Contribution Patients with atrial fibrillation and intracerebral hemorrhage who were receiving anticoagulation were matched with similar patients who did not develop intracerebral hemorrhage. Although intracerebral hemorrhage was associated with increasing age (especially > 85 years) and increasing international normalized ratios (INRs) (especially > 3.5), the incidence of intracerebral hemorrhage was not statistically different in patients with INRs less than 2.0 and those with INRs between 2.0 and 3.0. This was true even among those older than 75 years of age. Implications Risk for intracerebral hemorrhage is not diminished in elderly patients with atrial fibrillation when anticoagulation is maintained below an INR of 2.0. The Editors Intracranial hemorrhage is the most dangerous complication of warfarin anticoagulant therapy because of its high short-term risk for death and severe neurologic deficit (1-5). Warfarin is extremely effective in reducing the risk for ischemic stroke associated with atrial fibrillation (6, 7). However, fear of hemorrhage may prompt some physicians to avoid prescribing anticoagulation (8), especially in elderly patients, who appear to have a higher risk for hemorrhage (8-13). Prominent recent guidelines recommend using lower-intensity anticoagulation for the primary prevention of stroke in patients older than 75 years of age who have atrial fibrillation (14) and suggest a target international normalized ratio (INR) range of 1.6 to 2.5, despite evidence that the risk for ischemic stroke increases sharply at INRs less than 2.0 (15, 16). Previous studies have not thoroughly addressed the relationship of age and anticoagulation intensity to the risk for intracranial hemorrhage among patients with atrial fibrillation (1, 2). A study of 121 patients with warfarin-associated intracranial hemorrhage used the now-outdated prothrombin time ratio as a measure of anticoagulation intensity and did not specifically address risk in patients with atrial fibrillation (1). Earlier studies also included patients receiving anticoagulation for mechanical valves, whose risk-to-benefit ratio is different from that of patients with atrial fibrillation (1, 2, 17). As the number of individuals with atrial fibrillation increases (18-21) and as a greater proportion of older adults receive anticoagulant therapy (22), more precise data are needed about the association of age, INR, and risk for intracranial hemorrhage. Intracranial hemorrhage, although critically important, is an uncommon complication among patients with atrial fibrillation who are receiving anticoagulation. As a result, randomized trials and cohort studies have difficulty accumulating enough hemorrhage events to powerfully assess risk factors. To address these limitations, we performed a large casecontrol study to evaluate the relationship of increasing age and INR to the risk for intracranial hemorrhage among patients with nonvalvular atrial fibrillation. Methods Case-Patients We performed a casecontrol study comparing 2 groups: 1) case-patients with nonvalvular atrial fibrillation who developed intracranial hemorrhage while taking warfarin and 2) controls who were receiving anticoagulation for nonvalvular atrial fibrillation but did not develop intracranial hemorrhage. We found potential case-patients using the Partners HealthCare System Research Patient Data Registry, which can identify patients with specific International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses by searching the Massachusetts General Hospital billing system. We searched for patients 18 years of age or older who had diagnoses of atrial fibrillation (ICD-9-CM code 427.31) and intracranial hemorrhage (ICD-9-CM codes 430, 431, 432.0, 432.1, 432.9) at any time from October 1993 to June 2002. By 1993, nearly all prothrombin time ratios at the hospital were reported as INRs. We reviewed medical records to confirm whether patients were eligible, that is, whether they had intracranial hemorrhage documented by computed tomography or magnetic resonance imaging and documentation of warfarin therapy for atrial fibrillation at the time of the event. We excluded patients who were not taking warfarin at the time of hemorrhage; those who were receiving anticoagulation for rheumatic heart disease, mitral stenosis, or mechanical valve placement; those whose event was an ischemic stroke with hemorrhagic conversion; or those in whom clinical factors may have led to hemorrhage independent of warfarin therapy. These factors included underlying anatomic brain abnormalities (such as tumors or aneurysms), antecedent major head trauma (skull fracture, trauma with loss of consciousness, motor vehicle injury, or neurosurgical procedures), or platelet count less than 50 109 cells/L. Starting in July 1994, consecutive patients with intracerebral hemorrhage have been enrolled through the Massachusetts General Hospital emergency department as part of a longitudinal cohort study (23). To validate our automated search strategy, we compared our case-patient list with the list of patients identified through the cohort study and found that our search strategy missed only 4 patients with intracerebral hemorrhage. We obtained data on patient date of birth, sex, and ethnicity from computerized records. The type of hemorrhage (intracerebral, subdural, subarachnoid, intraventricular, or epidural) was determined through review of radiology reports. Data on presenting symptoms, history of minor head trauma, concomitant aspirin use, and disposition status were obtained from review of the admission medical record and were recorded on a standardized data collection form. We recorded the INR measurement obtained closest to the onset of symptoms. If an INR was not available or fresh frozen plasma or vitamin K was administered before the measurement, we considered INR data missing. We reviewed medical charts for documentation of the following comorbid conditions: history of cerebrovascular disease (defined as previous ischemic stroke or carotid artery disease), hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, and cancer (excluding nonmelanoma skin cancer). Controls Controls were sampled from patients managed by the Massachusetts General Hospital Anticoagulation Management Services clinic, which followed approximately 1000 patients receiving anticoagulation for atrial fibrillation at any given time during the study period. All patients who were followed in the anticoagulation clinic, received anticoagulation for atrial fibrillation, and had an INR measurement obtained in the same month and year as the given case date were assigned a random number. Six controls per case-patient were then randomly selected. We matched case-patients to controls by INR date to account for any technical changes in INR testing that may have occurred over time. Because of this sampling method, an individual patient could potentially serve as a control for more than 1 case-patient (24). Like case-patients, controls were 18 years of age or older; were receiving anticoagulation for atrial fibrillation; and had no documented rheumatic heart disease, mitral stenosis, or valve replacement. We sought data on potential confounders of the association of age, INR, and risk for intracranial hemorrhage, focusing on relevant comorbid conditions and combined use of aspirin with warfarin. We reviewed available computerized discharge summaries, outpatient clinic notes, and medication lists from up to 2 years before the admission date. If combination warfarin and aspirin use was not documented, patients were considered to not be taking aspirin. Statistical Analysis Case-patients were categorized by type of hemorrhage: intracerebral, subdural, and other (subarachnoid, intraventricular, or epidural). Clinical differences between types of hemorrhage were compared by using the KruskalWallis test for continuous variables (age and INR) and chi-square tests for categorical variables. We compared case-patients with controls by using multivariable conditional logistic regression, matching on INR date. Patient age was divided into 5-year intervals that were coded as indicator variables, and the odds of intracranial hemorrhage for each interval were compared with the odds of hemorrhage at a referent age of 70 to 74 years. The INR was divided into a set of ordered intervals that were coded as indicator variables. The relative odds for intracranial hemorrhage at each interval were calculated by using an INR of 2.0 to 3.0 as the referent category. In addition to age, INR, sex, and ethnicity, the following variables were included in the multivariable models to control for potential confounding effects of clinical factors and aspirin use: cerebrovascular disease, hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, cancer, and concomitant aspirin use. If no records were available for review, comorbid conditions and aspirin use were coded as missing. We used multiple imputations for missing data on ethnicity, comorbid conditions, and aspirin use (25). We tested for interactions between age and INR and comorbid conditions using 2-way interactions. None of the interaction terms were included in the model if they were not statistically significant when tested collectively. We tested the models goodness of fit using the HosmerLemeshow method (26). Because the hospitals anticoagulation clinic did not follow some case-patients before the event, and since factors relating to differences in outpatient care and monitoring could have confounded our analyses, we repeated these analyses in the subgroup of case-patients managed by the anticoagulation clinic. These restricted analyses approximated

A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.

OBJECTIVES The purpose of this study was to develop a risk stratification score to predict warfarin-associated hemorrhage. BACKGROUND Optimal decision making regarding warfarin use for atrial fibrillation requires estimation of hemorrhage risk. METHODS We followed up 9,186 patients with atrial fibrillation contributing 32,888 person-years of follow-up on warfarin, obtaining data from clinical databases and validating hemorrhage events using medical record review. We used Cox regression models to develop a hemorrhage risk stratification score, selecting candidate variables using bootstrapping approaches. The final model was internally validated by split-sample testing and compared with 6 published hemorrhage risk schemes. RESULTS We observed 461 first major hemorrhages during follow-up (1.4% annually). Five independent variables were included in the final model and weighted by regression coefficients: anemia (3 points), severe renal disease (e.g., glomerular filtration rate <30 ml/min or dialysis-dependent, 3 points), age ≥75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Major hemorrhage rates ranged from 0.4% (0 points) to 17.3% per year (10 points). Collapsed into a 3-category risk score, major hemorrhage rates were 0.8% for low risk (0 to 3 points), 2.6% for intermediate risk (4 points), and 5.8% for high risk (5 to 10 points). The c-index for the continuous risk score was 0.74 and 0.69 for the 3-category score, higher than in the other risk schemes. There was net reclassification improvement versus all 6 comparators (from 27% to 56%). CONCLUSIONS A simple 5-variable risk score was effective in quantifying the risk of warfarin-associated hemorrhage in a large community-based cohort of patients with atrial fibrillation.

Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study.

Background—Previous studies provide conflicting results about whether women are at higher risk than men for thromboembolism in the setting of atrial fibrillation (AF). We examined data from a large contemporary cohort of AF patients to address this question. Methods and Results—We prospectively studied 13 559 adults with AF and recorded data on patients’ clinical characteristics and the occurrence of incident hospitalizations for ischemic stroke, peripheral embolism, and major hemorrhagic events through searching validated computerized databases and medical record review. We compared event rates by patient sex using multivariable log-linear regression, adjusting for clinical risk factors for stroke, and stratifying by warfarin use. We identified 394 ischemic stroke and peripheral embolic events during 15 494 person-years of follow-up off warfarin. After multivariable analysis, women had higher annual rates of thromboembolism off warfarin than did men (3.5% versus 1.8%; adjusted rate ratio [RR], 1.6; 95% CI, 1.3 to 1.9). There was no significant difference by sex in 30-day mortality after thromboembolism (23% for both). Warfarin use was associated with significantly lower adjusted thromboembolism rates for both women and men (RR, 0.4; 95% CI, 0.3 to 0.5; and RR, 0.6; 95% CI, 0.5 to 0.8, respectively), with similar annual rates of major hemorrhage (1.0% and 1.1%, respectively). Conclusions—Women are at higher risk than men for AF-related thromboembolism off warfarin. Warfarin therapy appears be as effective in women, if not more so, than in men, with similar rates of major hemorrhage. Female sex is an independent risk factor for thromboembolism and should influence the decision to use anticoagulant therapy in persons with AF.

Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease: The PRIMO Randomized Controlled Trial

CONTEXT Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking. OBJECTIVE To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2). DESIGN, SETTING, AND PARTICIPANTS Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010. INTERVENTION Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112). MAIN OUTCOME MEASURES Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function. RESULTS Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. CONCLUSION Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00497146.

Benign Prostatic Hyperplasia Specific Health Status Measures in Clinical Research: How Much Change in the American Urological Association Symptom Index and the Benign Prostatic Hyperplasia Impact Index is Perceptible to Patients?

PURPOSE We assessed the relationship between changes in scores for the American Urological Association (AUA) symptom index and benign prostatic hyperplasia (BPH) impact index with patient global ratings of improvement in a large Veterans Affairs trial comparing different pharmacological therapies for BPH. MATERIALS AND METHODS The primary analyses compared absolute score changes from baseline with global ratings of improvement at 13 weeks for 1,218 men. RESULTS Subjects who rated themselves as being slightly improved had a mean decrease in AUA symptom index and BPH impact index scores of 3.1 and 0.4 points, respectively. However, the baseline scores strongly influenced this relationship. CONCLUSIONS These data provide guidance for investigators using the AUA symptom index and BPH impact index as outcome measures.

Phosphorus Binders and Survival on Hemodialysis

Although hyperphosphatemia is a risk factor for mortality, there are limited data on whether therapy with phosphorus binders affects survival. We analyzed a prospective cohort study of 10,044 incident hemodialysis patients using Cox proportional hazards analyses to compare 1-yr all-cause mortality among patients who were or were not treated with phosphorus binders. We performed intention-to-treat analyses to compare patients who began treatment with phosphorus binders during the first 90 d after initiating hemodialysis (n = 3555) with those who remained untreated during that period (n = 5055). We also performed as-treated analyses that modeled phosphorus binder treatment as a time-dependent exposure. We compared survival in a subcohort of treated (n = 3186) and untreated (n = 3186) patients matched by their baseline serum phosphate levels and propensity score of receiving phosphorus binders during the first 90 d. One-year mortality was 191 deaths/1000 patient-years at risk. Treatment with phosphorus binders was independently associated with decreased mortality compared with no treatment in the intention-to-treat, as-treated, and matched analyses. The results were independent of baseline and follow-up serum phosphate levels and persisted in analyses that excluded deaths during the first 90 d of hemodialysis. In summary, treatment with phosphorus binders is independently associated with improved survival among incident hemodialysis patients. Although confirmatory studies are needed in the dialysis setting, future placebo-controlled, randomized trials of phosphorus binders might focus on predialysis patients with chronic kidney disease and normal serum phosphate levels.

Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study.

Recall of fear extinction, which is thought to aid in recovery from a psychologically traumatic event, is hypothesized to be deficient in post-traumatic stress disorder (PTSD), but this has not yet been demonstrated in the laboratory, nor has its origin been investigated. To address these two issues, 14 pairs of monozygotic twins discordant for combat exposure, in 7 of which the combat-exposed twin had PTSD, underwent a two-day fear conditioning and extinction procedure. On Day 1, subjects viewed colored light conditioned stimuli, some of which were paired with mild electric shock, followed by extinction of the conditioned responses. On Day 2, recall of Day 1 extinction learning (i.e., extinction retention) was assessed. Skin conductance response (SCR) was the dependent measure. There were no group differences during acquisition or extinction learning. However, a significant PTSD Diagnosis (in the exposed twin) x combat Exposure interaction emerged during extinction recall, with the PTSD combat veterans having larger SCRs than their own co-twins, and than the non-PTSD combat veterans and their co-twins. These results indicate that retention of extinction of conditioned fear is deficient in PTSD. Furthermore, they support the conclusion that this deficit is acquired as a result of combat trauma leading to PTSD, rather than being a predisposing factor to developing PTSD upon the stress of combat.

Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation.

OBJECTIVES We assessed 5 risk stratification schemes for their ability to predict atrial fibrillation (AF)-related thromboembolism in a large community-based cohort. BACKGROUND Risk schemes can help target anticoagulant therapy for patients at highest risk for AF-related thromboembolism. We tested the predictive ability of 5 risk schemes: the Atrial Fibrillation Investigators, Stroke Prevention in Atrial Fibrillation, CHADS(2) (Congestive heart failure, Hypertension, Age >or= 75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack) index, Framingham score, and the 7th American College of Chest Physicians Guidelines. METHODS We followed a cohort of 13,559 adults with AF for a median of 6.0 years. Among non-warfarin users, we identified incident thromboembolism (ischemic stroke or peripheral embolism) and risk factors from clinical databases. Each scheme was divided into low, intermediate, and high predicted risk categories and applied to the cohort. Annualized thromboembolism rates and c-statistics (to assess discrimination) were calculated for each risk scheme. RESULTS We identified 685 validated thromboembolic events that occurred during 32,721 person-years off warfarin therapy. The risk schemes had only fair discriminating ability, with c-statistics ranging from 0.56 to 0.62. The proportion of patients assigned to individual risk categories varied widely across the schemes. The proportion categorized as low risk ranged from 11.7% to 37.1% across schemes, and the proportion considered high risk ranged from 16.4% to 80.4%. CONCLUSIONS Current risk schemes have comparable, but only limited, overall ability to predict thromboembolism in persons with AF. Recommendations for antithrombotic therapy may vary widely depending on which scheme is applied for individual patients. Better risk stratification is crucially needed to improve selection of AF patients for anticoagulant therapy.

Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy).

Abstract CRPS‐I consists of post‐traumatic limb pain and autonomic abnormalities that continue despite apparent healing of inciting injuries. The cause of symptoms is unknown and objective findings are few, making diagnosis and treatment controversial, and research difficult. We tested the hypotheses that CRPS‐I is caused by persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small‐diameter axons. These subserve pain and autonomic function. We studied 18 adults with IASP‐defined CRPS‐I affecting their arms or legs. We studied three sites on subjects’ CRPS‐affected and matching contralateral limb; the CRPS‐affected site, and nearby unaffected ipsilateral and matching contralateral control sites. We performed quantitative mechanical and thermal sensory testing (QST) followed by quantitation of epidermal neurite densities within PGP9.5‐immunolabeled skin biopsies. Seven adults with chronic leg pain, edema, disuse, and prior surgeries from trauma or osteoarthritis provided symptom‐matched controls. CRPS‐I subjects had representative histories and symptoms. Medical procedures were unexpectedly frequently associated with CRPS onset. QST revealed mechanical allodynia (P < 0.03) and heat‐pain hyperalgesia (P < 0.04) at the CRPS‐affected site. Axonal densities were highly correlated between subjects’ ipsilateral and contralateral control sites (r = 0.97), but were diminished at the CRPS‐affected sites of 17/18 subjects, on average by 29% (P < 0.001). Overall, control subjects had no painful‐site neurite reductions (P = 1.00), suggesting that pain, disuse, or prior surgeries alone do not explain CRPS‐associated neurite losses. These results support the hypothesis that CRPS‐I is specifically associated with post‐traumatic focal MDNI affecting nociceptive small‐fibers. This type of nerve injury will remain undetected in most clinical settings.

Response to Letter Regarding Article, “Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation: Validation of the R2CHADS2 Index in the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study Cohorts”

Background —We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. Methods and Results —In ROCKET AF, 14,264 patients with nonvalvular AF and creatinine clearance (CrCl) ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system (CNS) embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA, an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 (4.0%) patients experienced primary endpoint events. Reduced CrCl was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack (TIA). Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, and vascular disease of the heart and limbs (C-index 0.635). A model including CrCl (R2CHADS2) improved net reclassification index (NRI) by 6.2% when compared with CHA2DS2VASc (C-statistic=0.578) and 8.2% when compared with CHADS2 (C-statistic=0.575). The inclusion of estimated glomerular filtration rate <60 and prior stroke or TIA in a model with no other covariates led to a C-statistic of 0.590. Validation of R2CHADS2 in an external, separate population improved NRI by 17.4% (95% CI 12.1-22.5%) relative to CHADS2. Conclusions —In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. Clinical Trial Registration Information —ClinicalTrials.gov; Unique identifier: [NCT00403767][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00403767&atom=%2Fcirculationaha%2Fearly%2F2012%2F12%2F03%2FCIRCULATIONAHA.112.107128.atom