Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). We examined the cross-sectional association between novel risk factors and coronary artery calcium (CAC) measured by electron-beam computed tomography or multidetector computed tomography among 2,018 patients with CKD. Based on total Agatston scores, participants were classified as no (0), moderate (>0–100) or high (>100) CAC. After adjustment for age, sex, race, study sites, cigarette smoking, prior cardiovascular disease, hypertension, and diabetes, use of lipid-lowering drugs, body-mass index, waist circumference, and cystatin C, several novel risk factors were significantly associated with high CAC. For example, odds ratios (95% confidence interval) of high CAC associated with one standard deviation higher levels of risk factors were 1.20 (1.04, 1.38) for serum calcium, 1.21 (1.04, 1.41) for serum phosphate, 0.83 (0.71, 0.97) for log (total parathyroid hormone), 1.21 (1.03, 1.43) for log (HOMA-insulin resistance), and 1.23 (1.04, 1.45) for hemoglobin A1c. Additionally, the multivariable-adjusted odds ratio for one standard deviation higher level of cystatin C was 1.31 (1.14, 1.50). Serum high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-α, and homocysteine were not statistically significantly associated with high CAC. In conclusion, these data indicate that abnormal calcium and phosphate metabolism, insulin resistance, and declined kidney function were associated with the prevalence of high CAC independent of traditional risk factors in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on CAC in CKD patients.
calcium; chronic kidney disease; coronary artery calcium; cystatin C; insulin-resistance; phosphate; total parathyroid hormone
Despite the large burden of chronic kidney disease (CKD) in Hispanics, this population has been underrepresented in research studies. We describe the recruitment strategies employed by the Hispanic Chronic Renal Insufficiency Cohort Study, which led to the successful enrollment of a large population of Hispanic adults with CKD into a prospective observational cohort study. Recruitment efforts by bilingual staff focused on community clinics with Hispanic providers in high-density Hispanic neighborhoods in Chicago, academic medical centers, and private nephrology practices. Methods of publicizing the study included church meetings, local Hispanic print media, Spanish television and radio stations, and local health fairs. From October 2005 to July 2008, we recruited 327 Hispanics aged 21–74 years with mild-to-moderate CKD as determined by age-specific estimated glomerular filtration rate (eGFR). Of 716 individuals completing a screening visit, 49% did not meet eGFR inclusion criteria and 46% completed a baseline visit. The mean age at enrollment was 57.1 and 67.1% of participants were male. Approximately 75% of enrolled individuals were Mexican American, 15% Puerto Rican, and 10% had other Latin American ancestry. Eighty two percent of participants were Spanish-speakers. Community-based and academic primary care clinics yielded the highest percentage of participants screened (45.9% and 22.4%) and enrolled (38.2% and 24.5%). However, academic and community-based specialty clinics achieved the highest enrollment yield from individuals screened (61.9% to 71.4%). A strategy focused on primary care and nephrology clinics and the use of bilingual recruiters allowed us to overcome barriers to the recruitment of Hispanics with CKD.
There are limited data regarding national patterns of pharmacotherapy for atrial fibrillation (AF) among older patients. Drug exposure data are now captured for Medicare beneficiaries enrolled in prescription drug plans.
To describe pharmacotherapy for AF among Medicare beneficiaries.
Using a 5% national sample of Medicare claims data, we compared demographic characteristics, comorbidity, and treatment patterns according to Medicare Part D status among patients with prevalent AF in 2006 and 2007.
In 2006, 27,174 patients (29.3%) with prevalent AF were enrolled in Medicare Part D. In 2007, enrollment increased to 45,711 (49.1%). Most enrollees were taking rate control agents (74.0% in 2007). β-Blocker use was higher in those with concomitant AF and heart failure and increased with higher CHADS2 scores (P < .001). Antiarrhythmic use was 18.7% in 2006 and 19.1% in 2007, with amiodarone accounting for more than 50%. Class Ic drugs were used in 3.2% of patients in 2007. Warfarin use was less than 60% and declined with increasing stroke risk (P < .001).
Pharmacotherapy for AF varied according to comorbidity and underlying risk. Amiodarone was the most commonly prescribed antiarrhythmic agent. Postmarketing surveillance using Medicare Part D claims data linked to clinical data may help inform comparative safety, effectiveness, and net clinical benefit of drug therapy for AF in older patients in real-world settings.
Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Calcium Channel Blockers; Drug Therapy
Randomized trials of implantable cardioverter defibrillators (ICDs) for primary prevention predominantly employed single chamber devices. In clinical practice, patients often receive dual chamber ICDs, even without clear indications for pacing. The outcomes of dual versus single chamber devices are uncertain.
Compare outcomes of single and dual chamber ICDs for primary prevention of sudden cardiac death.
Design, Setting, and Participants
Retrospective cohort study. Admissions in the National Cardiovascular Data Registry’s (NCDR®) ICD Registry™ from 2006–2009 that could be linked to CMS fee for service Medicare claims data were identified. Patients were included if they received an ICD for primary prevention and did not have a documented indication for pacing.
Main Outcome Measures
Adjusted risks of 1-year mortality, all-cause readmission, HF readmission and device-related complications within 90 days were estimated with propensity-score matching based on patient, clinician and hospital factors.
Among 32,034 patients, 38% (n=12,246) received a single chamber device and 62% (n=19,788) received a dual chamber device. In a propensity-matched cohort, rates of complications were lower for single chamber devices (3.5% vs. 4.7%; p<0.001; risk difference −1.20; 95% CI −1.72, −0.69), but device type was not significantly associated with mortality or hospitalization outcomes (unadjusted rate 9.9% vs. 9.8%; HR 0.99, 95% CI 0.91–1.07; p=0.792 for 1-year mortality; unadjusted rate 43.9% vs. 44.8%; HR 1.00, 95% CI 0.97–1.04; p=0.821 for 1-year all-cause hospitalization; unadjusted rate 14.7% vs. 15.4%; HR 1.05, 95% CI 0.99–1.12; p=0.189 for 1-year HF hospitalization).
Conclusions and Relevance
Among patients receiving an ICD for primary prevention without indications for pacing, the use of a dual chamber device compared with a single chamber device was associated with a higher risk of device-related complications but not with different risks for mortality or hospitalization. Further studies should be performed to determine if other benefits of dual chamber devices exist, such as reduced device therapy or improved quality of life, to justify their use in this context.
Retinal vascular and anatomic abnormalities caused by diabetes, hypertension, and other conditions can be observed directly in the ocular fundus and may reflect severity of chronic renal insufficiency. The purpose of this study was to investigate the association between retinopathy and chronic kidney disease (CKD).
In this observational, cross-sectional study, 2605 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, a multi-center study of CKD, were offered participation. Non-mydriatic fundus photographs of the disc and macula in both eyes were obtained in 1936 of these subjects.
Photographs were reviewed in a masked fashion at a central photograph reading center using standard protocols. Presence and severity of retinopathy (diabetic, hypertensive or other) and vessel diameter caliber were assessed by trained graders and a retinal specialist using protocols developed for large epidemiologic studies. Kidney function measurements and information on traditional and non-traditional risk factors for decreased kidney function were obtained from the CRIC study.
Greater severity of retinopathy was associated with lower estimated glomerular filtration rate (eGFR) after adjustment for traditional and non-traditional risk factors. Presence of vascular abnormalities usually associated with hypertension was also associated with lower eGFR. We found no strong direct relationship between eGFR and average arteriolar or venular calibers.
Our findings show a strong association between severity of retinopathy and its features and level of kidney function after adjustment for traditional and non-traditional risk factors for CKD, suggesting that retinovascular pathology reflects renal disease.
Retinopathy; Retinal Vascular Diameter; Chronic Kidney Disease
Prescribing warfarin for atrial fibrillation depends in large part on the expected reduction in ischemic stroke risk versus the expected increased risk of intracranial hemorrhage (ICH). However, the anticoagulation decision also depends on the relative severity of such events. We assessed the impact of anticoagulation on 30-day mortality from ischemic stroke vs. ICH in a large community-based cohort of patients with atrial fibrillation.
We followed 13,559 patients with atrial fibrillation enrolled in an integrated healthcare delivery system for a median 6 years. Incident ischemic strokes and ICHs were identified from computerized databases and validated through medical record review. The association of warfarin and international normalized ratio (INR) at presentation with 30-day mortality was modeled using multivariable logistic regression, adjusting for clinical factors.
We identified 1025 incident ischemic strokes and 299 ICHs during follow-up. Compared with no antithrombotic therapy, warfarin was associated with reduced Rankin score and lower 30-day mortality from ischemic stroke (adjusted odds ratio and 95% confidence interval [OR] = 0.64 [0.45, 0.91]), but a higher mortality from ICH (OR = 1.62 [0.88, 2.98]). Therapeutic INRs (2-3) were associated with an especially low ischemic stroke mortality (OR = 0.38 [0.20, 0.70]) while INRs > 3 increased the odds of dying of ICH by 2.66 fold (95% confidence interval: 1.21, 5.86).
Warfarin reduces 30-day mortality from ischemic stroke, but increases ICH-related mortality. Both effects on event severity as well as on event rates need to be incorporated into rational decision-making about anticoagulants for atrial fibrillation.
Acute stroke; Intracranial hemorrhage; Anticoagulants; Warfarin; Atrial fibrillation
Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD). However, the long-term impact of development of AF on the risk of adverse renal outcomes in patients with CKD is unknown. In this study, we determined the association between incident AF and risk of end-stage renal disease (ESRD) among adults with CKD.
Methods and Results
We studied adults with CKD (defined as persistent glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 by the CKD-EPI equation) enrolled in Kaiser Permanente Northern California who were identified between 2002–2010 and who did not have prior ESRD or previously documented AF. Incident AF was identified using primary hospital discharge diagnoses and/or two or more outpatient visits for AF. Incident ESRD was ascertained from a comprehensive health plan registry for dialysis and renal transplant. Among 206,229 adults with CKD, 16,463 developed incident AF. During a mean follow-up of 5.1± 2.5 years, there were 345 cases of ESRD that occurred after development of incident AF (74 per 1000 person-years) compared with 6505 cases of ESRD during periods without AF (64 per 1000 person-years, P<0.001). After adjustment for potential confounders, incident AF was associated with a 67% increase in rate of ESRD (hazard ratio 1.67, 95% confidence interval: 1.46–1.91).
Incident AF is independently associated with increased risk of developing ESRD in adults with CKD. Further study is needed to identify potentially modifiable pathways through which AF leads to a higher risk of progression to ESRD.
arrhythmia; fibrillation; kidney
More accurate and reliable stroke risk prediction tools are needed to optimize anticoagulation decision making in patients with atrial fibrillation (AF). We developed a new AF stroke prediction model using the original Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) AF cohort and externally validated the score in a separate, contemporary, community‐based inception AF cohort, ATRIA–Cardiovascular Research Network (CVRN) cohort.
Methods and Results
The derivation ATRIA cohort consisted of 10 927 patients with nonvalvular AF contributing 32 609 person‐years off warfarin and 685 thromboembolic events (TEs). The external validation ATRIA‐CVRN cohort included 25 306 AF patients contributing 26 263 person‐years off warfarin and 496 TEs. Cox models identified 8 variables, age, prior stroke, female sex, diabetes mellitus, heart failure, hypertension, proteinuria, and eGFR<45 mL/min per 1.73 m2 or end‐stage renal disease, plus an age×prior stroke interaction term for the final model. Point scores were assigned proportional to model coefficients. The c‐index in the ATRIA cohort was 0.73 (95% CI, 0.71 to 0.75), increasing to 0.76 (95% CI, 0.74 to 0.79) when only severe events were considered. In the ATRIA‐CVRN, c‐indexes were 0.70 (95% CI, 0.67 to 0.72) and 0.75 (95% CI, 0.72 to 0.78) for all events and severe events, respectively. The C‐index was greater and net reclassification improvement positive comparing the ATRIA score with the CHADS2 or CHA2DS2‐VASc scores.
The ATRIA stroke risk score performed better than existing risk scores, was validated successfully, and showed improvement in predicting severe events, which is of greatest concern. The ATRIA score should improve the antithrombotic decision for patients with AF and should provide a secure foundation for the addition of biomarkers in future prognostic models.
anticoagulants; atrial fibrillation; risk score; stroke
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.
Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.
We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.
We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.
The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
Evaluate the reliability and validity of the Kidney Disease Quality of Life Short Form 36 (KDQOL-36™) in Hispanics with mild-to-moderate chronic kidney disease (CKD).
Chronic Renal Insufficiency Cohort Study
420 Hispanic (150 English- and 270 Spanish-speakers), and 409 non-Hispanic White individuals, matched by age (mean 57 years), sex (60% male), kidney function (mean estimated glomerular filtration rate 36ml/min/1.73m2), and diabetes (70%).
To measure construct validity, we selected instruments, comorbidities, and laboratory tests related to at least one KDQOL-36™ subscale. Reliability was determined by calculating Cronbach’s alpha.
Reliability of each KDQOL-36™ subscale [SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS), Symptoms/Problems, Burden of Kidney Disease and Effects of Kidney Disease] was very good (Cronbach’s alpha >0.8). Construct validity was supported by expected negative correlation between MCS scores and the Beck Depression Inventory in all three subgroups (r= −0.56 to −0.61, P<.0001). There was inverse correlation between the Symptoms/Problems subscale and the Patient Symptom Form (r= −0.70 to −0.77, P<.0001). We also found significant, positive correlation between the PCS score and a physical activity survey (r= +0.29 to +0.38, P≤.003); and between the PCS and MCS scores and the Kansas City Questionnaire (r= +0.31 to +0.64, P<.0001). Reliability and validity were similar across all racial/ethnic groups analyzed separately.
Our findings support the use of the KDQOL-36™ as a measure of HRQOL in this cohort of US Hispanics with CKD.
Validation; Quality of Life; Hispanics
Hispanics are the fastest growing minority group in the United States. The incidence of end-stage renal disease (ESRD) in Hispanics is higher than non-Hispanic Whites and Hispanics with chronic kidney disease (CKD) are at increased risk for kidney failure. Likely contributing factors to this burden of disease include diabetes and metabolic syndrome, both are common among Hispanics. Access to health care, quality of care, and barriers due to language, health literacy and acculturation may also play a role. Despite the importance of this public health problem, only limited data exist about Hispanics with CKD. We review the epidemiology of CKD in US Hispanics, identify the factors that may be responsible for this growing health problem, and suggest gaps in our understanding which are suitable for future investigation.
Chronic Kidney Disease; Hispanics; Health Care Disparities
Little is known regarding chronic kidney disease (CKD) in Hispanics. We compared baseline characteristics of Hispanic participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies with non-Hispanic CRIC participants.
Setting and Participants
Participants were aged 21–74 years with CKD using age-based glomerular filtration rate (eGFR) at enrollment into the CRIC/H-CRIC Studies. H-CRIC included Hispanics recruited at the University of Illinois from 2005–2008 while CRIC included Hispanics and non-Hispanics recruited at seven clinical centers from 2003–2007.
Blood pressure, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) use, CKD-associated complications
Demographic characteristics, laboratory data, blood pressure, and medications were assessed using standard techniques and protocols
Among H-CRIC/ CRIC participants, 497 were Hispanic, 1650 non-Hispanic Black, and 1638 non-Hispanic White. Low income and educational attainment were nearly twice as prevalent in Hispanics compared with non-Hispanics (p<0.01). Hispanics had self-reported diabetes (67%) more frequently than non-Hispanic Blacks (51%) and Whites (40%) (p<0.01). Blood pressure > 130/80 mmHg was more common in Hispanics (62%) compared with Blacks (57%) and Whites (35%) (p<0.05), and abnormalities in hematologic, metabolic, and bone metabolism parameters were more prevalent in Hispanics (p<0.05), even after stratifying by entry eGFR. Hispanics had the lowest receipt of ACE inhibitor/ARB among high-risk subgroups, including participants with diabetes, proteinuria, and blood pressure > 130/80 mmHg. Mean eGFR (ml/min/m2) was lower in Hispanics (39.6) than in Blacks (43.7) and Whites (46.2), while median proteinuria was higher in Hispanics (0.72 g/d) than in Blacks (0.24 g/d) and Whites (0.12 g/d) (p<0.01).
Generalizability; observed associations limited by residual bias and confounding
Hispanics with CKD in CRIC/H-CRIC Studies are disproportionately burdened with lower socioeconomic status, more frequent diabetes mellitus, less ACE inhibitor/ARB use, worse blood pressure control, and more severe CKD and associated complications than their non-Hispanic counterparts.
chronic kidney disease; Hispanics; epidemiology
Atrial fibrillation (AF) and heart failure (HF) are 2 of the most common cardiovascular conditions nationally and AF frequently complicates HF. We examined how AF has impacts on adverse outcomes in HF‐PEF versus HF‐REF within a large, contemporary cohort.
Methods and Results
We identified all adults diagnosed with HF‐PEF or HF‐REF based on hospital discharge and ambulatory visit diagnoses and relevant imaging results for 2005–2008 from 4 health plans in the Cardiovascular Research Network. Data on demographic features, diagnoses, procedures, outpatient pharmacy use, and laboratory results were ascertained from health plan databases. Hospitalizations for HF, stroke, and any reason were identified from hospital discharge and billing claims databases. Deaths were ascertained from health plan and state death files. Among 23 644 patients with HF, 11 429 (48.3%) had documented AF (9081 preexisting, 2348 incident). Compared with patients who did not have AF, patients with AF had higher adjusted rates of ischemic stroke (hazard ratio [HR] 2.47 for incident AF; HR 1.57 for preexisting AF), hospitalization for HF (HR 2.00 for incident AF; HR 1.22 for preexisting AF), all‐cause hospitalization (HR 1.45 for incident AF; HR 1.15 for preexisting AF), and death (incident AF HR 1.67; preexisting AF HR 1.13). The associations of AF with these outcomes were similar for HF‐PEF and HF‐REF, with the exception of ischemic stroke.
AF is a potent risk factor for adverse outcomes in patients with HF‐PEF or HF‐REF. Effective interventions are needed to improve the prognosis of these high‐risk patients.
atrial fibrillation; heart failure; hospitalization; mortality; systolic function
To determine whether ethnic differences in the incidence of albuminuria are present in patients with diabetes, and to identify social, behavioral, and provider factors that explain ethnic differences.
Survey follow-up design with a race-stratified baseline survey (2005–2006) in diabetic patients from a nonprofit, fully integrated healthcare system in Northern California. We followed the 10,596 respondents (30% whites, 20% blacks, 23% Hispanics, 14% Asians, and 13% Filipinos) without evidence of prevalent albuminuria at baseline.
Incident albuminuria was defined by positive dipstick urinalysis (≥1) or urine albumin to creatinine level (≥30 mg/g), and confirmed with repeat testing at least 3 months later.
The 27,292 person-years of observation yielded 981 incident albuminuria events. Age-standardized rates of albuminuria (per 1000 person-years) ranged from 13.6 (95% confidence interval [CI] 10.5–17.0) in whites to 27.8 (CI 18.2–38.3) in blacks. In fully adjusted Cox models, the hazard ratio for blacks (1.22, 95% CI 1.09–1.38), Asians (1.35, 95% CI 1.13–1.61), and Filipinos (1.93, 95% CI 1.61–2.32), but not Hispanics, was significantly greater than it was for whites. In some cases, point estimates changed markedly from the base model when fully adjusted for potential confounders. Moreover, adjustment for an array of potentially mediating factors explained only a small proportion of the observed ethnic disparities.
Despite uniform medical care coverage, Filipinos, blacks, and Asians with diabetes developed albuminuria at higher rates than white and Hispanic adults.
To assess whether older age is independently associated with hemorrhage risk in patients with atrial fibrillation, whether or not they are taking warfarin therapy.
Integrated healthcare delivery system.
Thirteen thousand five hundred fifty-nine adults with nonvalvular atrial fibrillation.
Patient data were collected from automated clinical and administrative databases using previously validated search algorithms. Medical charts were reviewed from patients hospitalized were for major hemorrhage (intracranial, fatal, requiring ≥2 units of transfused blood, or involving a critical anatomic site). Age was categorized into four categories (<60, 60–69, 70–79, and ≥80), and multivariable Poisson regression was used to assess whether major hemorrhage rates increased with age, stratified by warfarin use and adjusted for other clinical risk factors for hemorrhage.
A total of 170 major hemorrhages were identified during 15,300 person-years of warfarin therapy and 162 major hemorrhages during 15,530 person-years off warfarin therapy. Hemorrhage rates rose with older age, with an average increase in hemorrhage rate of 1.2 (95% confidence interval (CI) 1.0–1.4) per older age category in patients taking warfarin and 1.5 (95% CI=1.3–1.8) in those not taking warfarin. Intracranial hemorrhage rates were significantly higher in those aged 80 and older (adjusted rate ratio=1.8, 95% CI=1.1–3.1 for those taking warfarin, adjusted rate ratio=4.7, 95% CI=2.4–9.2 for those not taking warfarin) than in those younger than 80.
Older age increases the risk of major hemorrhage, particularly intracranial hemorrhage, in patients with atrial fibrillation, whether or not they are taking warfarin. Hemorrhage rates were generally comparable with those reported in previous randomized trials, indicating that carefully monitored warfarin therapy can be used with reasonable safety in older patients.
aging; anticoagulation; hemorrhage; atrial fibrillation
We assessed 5 risk stratification schemes for their ability to predict atrial fibrillation (AF)–related thromboembolism in a large community-based cohort.
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, CHADS2 (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack) index, Framingham score, and the 7th American College of Chest Physicians Guidelines.
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.
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%.
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.
Little is known about the outcomes of patients who have hemorrhagic complications while receiving warfarin therapy. We examined the rates of death and disability resulting from warfarin-associated intracranial and extracranial hemorrhages in a large cohort of patients with atrial fibrillation.
We assembled a cohort of 13,559 adults with nonvalvular atrial fibrillation and identified patients hospitalized for warfarin-associated intracranial and major extracranial hemorrhage. Data on functional disability at discharge and 30-day mortality were obtained from a review of medical charts and state death certificates. The relative odds of 30-day mortality by hemorrhage type were calculated using multivariable logistic regression.
We identified 72 intracranial and 98 major extracranial hemorrhages occurring in more than 15,300 person-years of warfarin exposure. At hospital discharge, 76% of patients with intracranial hemorrhage had severe disability or died, compared with only 3% of those with major extracranial hemorrhage. Of the 40 deaths from warfarin-associated hemorrhage that occurred within 30 days, 35 (88%) were from intracranial hemorrhage. Compared with extracranial hemorrhages, intracranial events were strongly associated with 30-day mortality (odds ratio 20.8 [95% confidence interval, 6.0–72]) even after adjusting for age, sex, anticoagulation intensity on admission, and other coexisting illnesses.
Among anticoagulated patients with atrial fibrillation, intracranial hemorrhages caused approximately 90% of the deaths from warfarin-associated hemorrhage and the majority of disability among survivors. When considering anticoagulation, patients and clinicians need to weigh the risk of intracranial hemorrhage far more than the risk of all major hemorrhages.
Atrial fibrillation; Death; Disability; Hemorrhage; Intracranial hemorrhage; warfarin
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).
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.
anticoagulants; atrial fibrillation; risk factors; stroke; women
To examine whether kidney dysfunction is associated with the type of clinical presentation of coronary heart disease (CHD).
Reduced kidney function increases risk of developing CHD, but it is not known whether it also influences the acuity of clinical presentation, which has important prognostic implications.
We conducted a case-control study of subjects whose first clinical presentation of CHD was either acute myocardial infarction or stable exertional angina between October 2001-December 2003. Glomerular filtration rate (eGFR) before the incident event was estimated using calibrated serum creatinine and the abbreviated MDRD equation. Patient characteristics and use of medications were ascertained from self-report and health plan databases. We used multivariable logistic regression to examine the association of reduced eGFR and CHD presentation.
We studied 803 adults with incident acute myocardial infarction and 419 adults with incident stable exertional angina who had a baseline eGFR ≤130 ml/min/1.73 m2. Mean eGFR was lower among subjects with acute myocardial infarction compared with stable angina. Compared with eGFR 90–130 ml/min/1.73 m2, we found a strong, graded independent association between reduced eGFR and presenting with acute myocardial infarction: adjusted odds ratio (OR) 1.36 (95% CI: 0.99 to 1.86) for eGFR 60–89 ml/min/1.73 m2, OR 1.55 (0.92 to 2.62) for eGFR 45–59 ml/min/1.73 m2 and OR 3.82 (1.55 to 9.46) for eGFR <45 ml/min/1.73 m2 (P<0.001 for trend).
eGFR less than 45 ml/min/1.73 m2 is a strong, independent predictor of presenting with acute myocardial infarction versus stable angina as the initial manifestation of CHD.
angina; myocardial infarction; renal failure; chronic kidney disease; risk factor
AHA Scientific Statements; atrial fibrillation; atrium; epidemiology; prevention; risk factors
To develop a risk stratification score to predict warfarin-associated hemorrhage
Optimal decision-making regarding warfarin use for atrial fibrillation requires estimation of hemorrhage risk.
We followed 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 via split-sample testing and compared to six published hemorrhage risk schemes.
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% in the low risk group (0-3 points), 2.6% in intermediate risk (4 points), and 5.8% in high risk (5-10 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 six comparators (from 27% to 56%).
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.
anticoagulants; atrial fibrillation; hemorrhage; risk prediction; warfarin
More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention deficit hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure, raising concerns about their cardiovascular safety.
Examine whether current use of medications used primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults.
Retrospective, population-based cohort study
Computerized health records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at one site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data.
Adults aged 25–64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n=150,359) was matched to two non-users on study site, birth year, sex, and calendar year (total users and non-users=443,198).
Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke. Comparison between current or new users and remote users to account for potential healthy user bias.
During 806,182 person-years of follow-up (median 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person-years of current use (median 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14–1.57) for MI, 0.30 (95% CI, 0.20–0.42) for SCD, and 0.56 (95% CI, 0.43–0.72) for stroke. The multivariable adjusted rate ratio (RR) of serious cardiovascular events for current use vs non-use of ADHD medications was 0.83 (95% CI 0.72–0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI 0.63–0.94). The adjusted RR was 1.03 (95% CI, 0.86–1.24) for current use vs remote use, and was 1.02 (95% CI, 0.82–1.28) for new use vs remote use.
Among young and middle-aged adults, current or new use of ADHD medications, compared with non-use or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy user bias.
Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD.
We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately.
The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
Cardiovascular disease; Chronic kidney disease; Chronic Renal Insufficiency Cohort (CRIC) Study; Metabolic syndrome
Epidemiological studies typically diagnose heart failure (HF) at the time of hospitalization, and have not evaluated the prevalence of HF symptoms in CKD patients without a prior HF diagnosis.
Methods and Results
We modified the Kansas City Cardiomyopathy Questionnaire (KCCQ) to detect and quantify symptoms characteristic of HF (dyspnea, edema, and fatigue) among 2,883 CKD patients without diagnosed heart failure in the Chronic Renal Insufficiency Cohort (CRIC). The KCCQ is a 23-item instrument that quantifies the impact of dyspnea, fatigue and edema on physical, social, and emotional functions (scored 0–100). The median KCCQ score was 92, and 25% had KCCQ scores < 75. Compared with cystatin C-based eGFR >50ml/min/1.73m2 (reference), eGFR 40–50, 30–40, and <30 were independently associated with lower KCCQ scores (<75); adjusted odds ratios and (95% CI): 1.38 (1.06–1.78), 1.39 (1.09–1.82), and 2.15 (1.54–3.00), respectively. Lower hemoglobin (Hb) levels also had independent associations with KCCQ <75: Hb > 14 g/dL (reference), Hb 13–14 g/dL (1.03; 0.76–1.40), Hb 12–13 g/dL (1.41; 1.04–1.91), Hb 11–12 g/dL (1.56; 1.12–2.16); and Hb<11 g/dL (1.65; 1.15–2.37).
CKD patients without diagnosed HF have a substantial burden of symptoms characteristic of HF, particularly among those with lower eGFR and hemoglobin levels.
hemoglobin; glomerular filtration rate
Background. Elderly women with breast cancer are considered underdiagnosed and undertreated, and this adversely affects their overall survival. Methods. A total of 393 female breast cancer patients aged 70 years and older, diagnosed within the years 1989–1999, were identified from the tumor registry of The Brooklyn Hospital Center. Comparisons between the 3 different subgroups 70–74, 75–79, and 80 years and older were made using the Pearson Chi Square test. Results. Lumpectomy was performed in 42% of all patients, while mastectomy was done in 46% of patients. Adjuvant therapy such as chemotherapy, radiation therapy, and hormonal therapy were done in 12%, 25%, and 38%, respectively. Forty-seven percent of patients with positive lymph nodes received chemotherapy. Eighty-six percent of patients who were estrogen receptor-positive received adjuvant hormonal therapy. Overall five-year survival was only 14% for the ≥80 age group, compared to that of 32% and 35% for the 70–74 and the 75–79 age groups, respectively. Conclusions. Surgery was performed in majority of these patients, about half received lumpectomy, the other half mastectomy. Adjuvant therapies were frequently excluded, with only hormonal therapy being the most commonly used. Overall five-year survival is significantly worse in patients ≥80 years with breast cancer.