Malini Chandra

Population Trends in the Incidence and Outcomes of Acute Myocardial Infarction

BACKGROUND Few studies have characterized recent population trends in the incidence and outcomes of myocardial infarction. METHODS We identified patients 30 years of age or older in a large, diverse, community-based population who were hospitalized for incident myocardial infarction between 1999 and 2008. Age- and sex-adjusted incidence rates were calculated for myocardial infarction overall and separately for ST-segment elevation and non-ST-segment elevation myocardial infarction. Patient characteristics, outpatient medications, and cardiac biomarker levels during hospitalization were identified from health plan databases, and 30-day mortality was ascertained from administrative databases, state death data, and Social Security Administration files. RESULTS We identified 46,086 hospitalizations for myocardial infarctions during 18,691,131 person-years of follow-up from 1999 to 2008. The age- and sex-adjusted incidence of myocardial infarction increased from 274 cases per 100,000 person-years in 1999 to 287 cases per 100,000 person-years in 2000, and it decreased each year thereafter, to 208 cases per 100,000 person-years in 2008, representing a 24% relative decrease over the study period. The age- and sex-adjusted incidence of ST-segment elevation myocardial infarction decreased throughout the study period (from 133 cases per 100,000 person-years in 1999 to 50 cases per 100,000 person-years in 2008, P<0.001 for linear trend). Thirty-day mortality was significantly lower in 2008 than in 1999 (adjusted odds ratio, 0.76; 95% confidence interval, 0.65 to 0.89). CONCLUSIONS Within a large community-based population, the incidence of myocardial infarction decreased significantly after 2000, and the incidence of ST-segment elevation myocardial infarction decreased markedly after 1999. Reductions in short-term case fatality rates for myocardial infarction appear to be driven, in part, by a decrease in the incidence of ST-segment elevation myocardial infarction and a lower rate of death after non-ST-segment elevation myocardial infarction.

Prehypertension and Hypertension in Community-Based Pediatric Practice

OBJECTIVE: To examine the prevalence of prehypertension and hypertension among children receiving well-child care in community-based practices. METHODS: Children aged 3 to 17 years with measurements of height, weight, and blood pressure (BP) obtained at an initial (index) well-child visit between July 2007 and December 2009 were included in this retrospective cohort study across 3 large, integrated health care delivery systems. Index BP classification was based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents: normal BP, <90th percentile; prehypertension, 90th to 94th percentile; hypertension, 3 BP measurements ≥95th percentile (index and 2 subsequent consecutive visits). RESULTS: The cohort included 199 513 children (24.3% aged 3–5 years, 34.5% aged 6–11 years, and 41.2% aged 12–17 years) with substantial racial/ethnic diversity (35.9% white, 7.8% black, 17.6% Hispanic, 11.7% Asian/Pacific Islander, and 27.0% other/unknown race). At the index visit, 81.9% of participants were normotensive, 12.7% had prehypertension, and 5.4% had a BP in the hypertension range (≥95th percentile). Of the 10 848 children with an index hypertensive BP level, 3.8% of those with a follow-up BP measurement had confirmed hypertension (estimated 0.3% prevalence). Increasing age and BMI were significantly associated with prehypertension and confirmed hypertension (P < .001 for trend). Among racial/ethnic groups, blacks and Asians had the highest prevalence of hypertension. CONCLUSIONS: The prevalence of hypertension in this community-based study is lower than previously reported from school-based studies. With the size and diversity of this cohort, these results suggest the prevalence of hypertension in children may actually be lower than previously reported.

Statin and β-Blocker Therapy and the Initial Presentation of Coronary Heart Disease

Context We know little about factors that are associated with initial clinical presentations of coronary disease. Contribution This large casecontrol study compared characteristics of patients whose first clinical presentation of coronary disease was either acute myocardial infarction or stable exertional angina. Patients presenting with myocardial infarction rather than stable angina had received statins and -blockers less often; were more often men, smokers, and physically inactive; and more often had hypertension and diabetes. Cautions The study was observational and could not prove cause and effect. Implications Several factors, including statin and -blocker therapy, might protect against higher-risk presentations of coronary disease. The Editors Acute myocardial infarction is believed to result from the acute rupture of a lipid-laden coronary atherosclerotic plaque, which in turn leads to acute thrombosis, cardiac ischemia, and subsequent myocardial necrosis (1). While many epidemiologic risk factors have been established to predict the development of any clinical manifestation of coronary heart disease (that is, acute myocardial infarction, unstable angina, or angina pectoris), most studies have not attempted to differentiate between unstable presentations, such as acute coronary syndromes, and more stable presentations of coronary disease, such as exertional angina. Thus, predictors of the development of plaque rupture and acute coronary events have not been well delineated. Previous studies have identified relatively few risk factors for acute myocardial infarction in patients with underlying coronary atherosclerosis. Among patients hospitalized with an acute coronary syndrome, those with acute myocardial infarction were less likely to have been taking aspirin before admission than those with unstable angina (2). Other clinical predictors of having an acute myocardial infarction compared with unstable angina included current smoking and absence of a previous diagnosis of hypertension (3). In several randomized, placebo-controlled trials, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have substantially reduced the incidence of clinical coronary disease in both primary and secondary prevention populations (4, 5). In addition to their beneficial effects on cholesterol levels, statins may have important nonlipid-related effects, including reduction in inflammation (6, 7), alteration of plaque composition and stabilization of atherosclerotic plaques (8), and improvement in endothelial dysfunction (9, 10). -Adrenergic receptor antagonists (-blockers) have also been shown to reduce incident and recurrent major cardiovascular events compared with placebo (11-13). The favorable effects of -blockers may be due to reduced myocardial oxygen demand as a result of lower systemic blood pressure and heart rate (14, 15), improved endothelial function (16), and effects on atherosclerotic burden (17, 18). On the other hand, results have been somewhat mixed for the efficacy of angiotensin-converting enzyme (ACE) inhibitors (19-21), angiotensin-IIreceptor blockers (22-24), calcium-channel blockers (25, 26), and diuretics (21), depending on the study sample and the comparison treatment or placebo group. However, whether use of any of these pharmacologic agents is associated with the mode of clinical presentation of coronary disease (that is, acute coronary syndrome vs. stable coronary disease) is not known. If possible, shifting the mode of initial presentations of coronary disease from acute myocardial infarction to stable angina may reduce overall patient risk and permit intervention before irreversible complications occur. To address this question, we examined whether recent use of selected cardiovascular medications or patient characteristics were associated with the mode of initial clinical presentation in patients who developed initial symptoms of coronary disease in a large community sample of patients. We compared patients who developed an initial acute myocardial infarction with patients who developed stable exertional angina, since these syndromes are clinically distinct on the spectrum of unstable to stable symptoms of coronary atherosclerosis. We hypothesized that the recent use of statins, -blockers, and ACE inhibitors would be associated with a lower likelihood of presenting with an acute myocardial infarction as the first sign of clinical coronary disease. Methods Study Sample The study sample included adults who were enrolled in Kaiser Permanente of Northern California, a large integrated health care delivery system providing comprehensive care to more than 35% of insured adults in the greater San Francisco Bay area. The Kaiser Permanente membership is representative of the local surrounding and statewide insured adult population, with the exception of slightly lower proportions of persons at the extremes of age and income distribution (27). We identified all Kaiser Permanente members who first presented with symptoms of coronary disease between 28 October 2001 and 31 December 2003. Institutional review boards of the collaborating institutions approved the study. Cases of Incident Acute Myocardial Infarction We included men between 45 and 75 years of age and women between 55 and 75 years of age who presented with an acute myocardial infarction and who had no history of coronary disease. We searched automated laboratory and hospital discharge databases weekly to identify hospitalized patients with a serum troponin I level of 4.0 g/L or greater or a combination of an elevated creatine kinaseMB level of 5.6 g/L or greater and creatine kinaseMB index of 0.033 or greater, as well as a primary discharge diagnosis of myocardial infarction (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 410). We excluded patients who met any of the following criteria: evidence of previously diagnosed coronary disease in hospital discharge or ambulatory visit databases, previous prescriptions for nitroglycerin in the pharmacy database, previous hospitalizations with elevated serum troponin I levels, receipt of maintenance dialysis, previous organ or bone marrow transplantation, lack of a primary care provider, death before study contact, or serious cognitive impairment or uncontrolled psychiatric condition as assessed by the patients primary provider. Primary physicians of potential participants confirmed the occurrence of an acute myocardial infarction and approved patient contact. We then screened patients by a telephone interview to confirm the absence of previously diagnosed coronary disease, coronary revascularization, or ischemic symptoms more than 14 days before admission for acute myocardial infarction, as well as any exclusion criteria that health plan databases did not identify. We also searched for previous silent myocardial infarction in the 52% of patients who had available previous electrocardiograms and excluded 2 patients with evidence of a pathologic Q wave (28). The index date for enrolled participants was the date of admission for the index hospitalization. Cases of Incident Stable Exertional Angina We identified men and women between 18 and 75 years of age without a history of coronary disease who presented with stable exertional angina between 28 October 2001 and 31 December 2003. We performed weekly searches of automated ambulatory visit databases for new diagnoses of angina pectoris (ICD-9-CM code 413.x) and applied the same exclusion criteria as described previously, except that we also excluded patients who received a prescription for nitroglycerin more than 6 months before the index date. Primary physicians of potential participants confirmed the occurrence of exertional angina and approved patient contact. We then screened patients by a telephone interview to confirm the absence of previously diagnosed coronary disease, coronary revascularization, and any exclusion criteria that the health plan database did not identify. In addition, patients had to report a history of stable chest pain or chest pressure that 1) was reproduced by the same level of physical exertion, 2) lasted more than 1 minute and less than 15 minutes, and 3) responded to rest or nitroglycerin (29). Patients could have had qualifying symptoms for no more than 6 months before the outpatient angina diagnosis and could not have reported these symptoms to a health care provider before their index date. We also searched for evidence of previous silent myocardial infarction in the 81.3% of patients with angina with available electrocardiograms and excluded 5 patients with pathologic Q waves (28). We considered the index date to be the date of the first outpatient clinic visit for angina pectoris in confirmed cases. Cases of Incident Fatal Coronary Heart Disease In our sensitivity analysis, we also used electronic databases to identify patients who had either fatal myocardial infarction or sudden cardiac death as their initial presentation of coronary disease. We ascertained potential fatal myocardial infarction events by using 1) primary discharge diagnoses of acute myocardial infarction (ICD-9-CM codes 410.x) and a discharge status of death found in health plan hospitalization and billing claims databases or 2) outpatient deaths found in state death registry files that were assigned a group cause of 165 (ICD-10 codes I21 and I22). We identified potential sudden death events from 1) inpatient deaths with a primary discharge diagnosis of cardiac arrest (ICD-9-CM code 427.5) found in health plan hospitalization and billing claims databases or 2) outpatient deaths found in state death registry files that were assigned a group cause of 177. After excluding nonmembers, patients with previously diagnosed coronary disease, and those having less than 5 months of pharmacy benefit before the fatal event, we identified 2758 patients with possible incident fatal coronary disease. Medi

Antipsychotic Medication Use Among Children and Risk of Diabetes Mellitus

OBJECTIVE: To assess whether the risk of incident diabetes was increased with the use of second-generation antipsychotics (SGAs) in a large diverse cohort of children. METHODS: A retrospective study was conducted by using the administrative databases of 3 health plans participating in the Health Maintenance Organization Research Network. Children 5 to 18 years of age who initiated SGA therapy between January 2001 and December 2008 and 2 comparison groups, namely, nonusers of psychotropic drugs and users of antidepressant medications, were identified. Diagnoses from inpatient and outpatient records, pharmacy dispensings, and outpatient laboratory results were used to identify incident cases of diabetes. RESULTS: The crude incidence rate of diabetes for the SGA-exposed cohort was 3.23 cases per 1000 person-years (95% confidence interval [CI]: 1.67–5.65), compared with 0.76 cases per 1000 person-years (95% CI: 0.49–1.12) among nonusers of psychotropic medications and 1.86 cases per 1000 person-years (95% CI: 1.12–2.90) among antidepressant users. The risk of incident diabetes was significantly increased among SGA users (unadjusted incidence rate ratio: 4.24 [95% CI: 1.95–8.72]) in comparison with nonusers of psychotropic medications but was not significantly increased in comparison with antidepressant medication users (unadjusted incidence rate ratio: 1.74 [95% CI: 0.77–3.78]). CONCLUSIONS: Although we found a potentially fourfold increased rate of diabetes among children exposed to SGAs, the findings were inconsistent and depended on the comparison group and the outcome definition.

Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy

PURPOSE Atypical femur fractures represent a potential complication of chronic oral bisphosphonate therapy in women with osteoporosis, but the risk of atypical femur fractures among cancer patients receiving intravenous bisphosphonates at higher cumulative doses remains unclear. We examined femur fractures occurring in cancer patients treated with intravenous bisphosphonates (IVBP) to determine whether a subset may be atypical fractures. METHODS Between 2005 and 2010, we identified patients with known IVBP therapy for multiple myeloma or metastatic breast cancer, who subsequently sustained a femur fracture based on hospitalization, oncology, pharmacy and chemotherapy visit records. Radiographs were examined by an orthopedic surgeon to determine anatomic fracture site and pattern. An atypical fracture was defined as a transverse or short oblique fracture occurring below the lesser trochanter with evidence of focal hypertrophy of the lateral cortex and absence of biopsy-proven malignancy or radiation therapy at the fracture site. RESULTS A total of 62 patients with breast cancer (N=39) or multiple myeloma (N=23) with femur fracture and prior IVBP treatment for bone malignancy were identified. There were 30 proximal hip, 18 subtrochanteric and 14 femoral shaft fractures. Intraoperative bone samples were sent in 29 of 58 fracture cases undergoing operative repair, with 76% positive for malignancy. Six cases (4 breast cancer, 2 multiple myeloma) of atypical femur fracture were identified, two with negative intraoperative pathology and four with no bone biopsy samples sent. Five of the six patients with atypical fracture had bilateral femur findings, including two with transverse fracture in the contralateral femur and three with focal hypertrophy of the contralateral cortex. Two atypical fracture cases also experienced osteonecrosis of the jaw compared to 3 in the remaining cohort (33% vs. 5%, p=0.07). Patients with atypical fracture received more IVBP (median 55 vs. 15 doses) and zoledronic acid (32 vs. 12 doses) and had longer treatment duration (median 5.9 vs. 1.6 years) compared to patients without atypical fracture (all p≤0.01). CONCLUSIONS Among 62 patients who received IVBP for skeletal malignancy and experienced a femur fracture, we identified six cases of atypical fracture. While fractures in this population are often assumed to be pathologic, prospective studies investigating fracture pattern, microscopic bone pathology and pharmacologic exposures should be conducted to further examine the association of IVBP and atypical femur fractures.

Incidental Pulmonary Nodules on Cardiac Computed Tomography: Prognosis and Use

BACKGROUND Small asymptomatic lung nodules are found frequently in the course of cardiac computed tomography (CT) scanning. However, the utility of assessing and reporting incidental findings in healthy, asymptomatic subjects is unknown. METHODS The sample comprised 1023 60- to 69-year-old subjects free of clinical cardiovascular disease and cancer who participated in the Atherosclerotic Disease, VAscular functioN and genetiC Epidemiology Study. All subjects underwent cardiac CT for determination of coronary calcium between 2001 and 2004, and the first 459 subjects were assessed for incidental pulmonary findings. We used health plan clinical databases to ascertain 24-month health care use and clinical outcomes. RESULTS Noncalcified pulmonary nodules were reported in 81 of 459 subjects (18%). Chest CT was performed on 78% of participants in the 24 months after notification, compared with 2.5% in the previous 24 months. Chest x-ray use increased from 28% to 49%. The mean number of chest CT scans per subject was 1.3 (range, 0-5). Although no malignant lesions were diagnosed in the group who had pulmonary findings read, 1 lung cancer case was diagnosed in the group who did not have lung findings read. Among the 63 participants followed up by CT, the original lesion was not identified in 22 participants (35%), the lesion had decreased or remained stable in 39 participants (62%), and there was interval growth in 2 participants (3%). CONCLUSION Reporting noncalcified pulmonary nodules resulted in substantial rescanning that overwhelmingly revealed resolution or stability of pulmonary nodules, arguing for benign processes.

Prevalence of obesity and extreme obesity in children aged 3–5 years

The prevalence of obesity in the United States has increased dramatically over the past three decades. There is a growing spectrum of severe obesity among children and adolescents. Obesity trends and race/ethnic differences may be evident at a young age.

Chronic Kidney Disease and Risk for Presenting With Acute Myocardial Infarction Versus Stable Exertional Angina in Adults With Coronary Heart Disease

OBJECTIVES The aim of this study was to examine whether kidney dysfunction is associated with the type of clinical presentation of coronary heart disease (CHD). BACKGROUND Reduced kidney function increases the risk for developing CHD, but it is not known whether it also influences the acuity of clinical presentation, which has important prognostic implications. METHODS A case-control study was conducted of subjects whose first clinical presentation of CHD was either acute myocardial infarction or stable exertional angina between October 2001 and December 2003. Estimated glomerular filtration rate (eGFR) before the incident event was calculated using calibrated serum creatinine and the abbreviated MDRD (Modification of Diet in Renal Disease) equation. Patient characteristics and use of medications were ascertained from self-report and health plan databases. Multivariable logistic regression was used to examine the association of reduced eGFR and CHD presentation. RESULTS A total of 803 adults with incident acute myocardial infarctions and 419 adults with incident stable exertional angina who had baseline eGFRs ≤130 ml/min/1.73 m(2) were studied. Mean eGFR was lower in subjects with acute myocardial infarctions compared with those with stable angina. Compared with eGFR of 90 to 130 ml/min/1.73 m(2), a strong, graded, independent association was found between reduced eGFR and presenting with acute myocardial infarction, with adjusted odds ratios of 1.36 (95% confidence interval: 0.99 to 1.86) for eGFR 60 to 89 ml/min/1.73 m(2), 1.55 (95% confidence interval: 0.92 to 2.62) for eGFR 45 to 59 ml/min/1.73 m(2), and 3.82 (95% confidence interval: 1.55 to 9.46) for eGFR <45 ml/min/1.73 m(2) (p < 0.001 for trend). CONCLUSIONS An eGFR <45 ml/min/1.73 m(2) is a strong, independent predictor of presenting with acute myocardial infarction versus stable angina as the initial manifestation of CHD.

The association of race/ethnicity and risk of atypical femur fracture among older women receiving oral bisphosphonate therapy

PURPOSE Several epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women. METHODS Using data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age≥50years old who initiated oral bisphosphonate therapy during 2002-2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors. RESULTS Among 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9-14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7-11.5) after adjusting for bisphosphonate duration and current use. CONCLUSIONS Our study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk.

Methods for assessing fracture risk prediction models: experience with FRAX in a large integrated health care delivery system.

Area under the receiver operating characteristics (AUROC) curve is often used to evaluate risk models. However, reclassification tests provide an alternative assessment of model performance. We performed both evaluations on results from FRAX (World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK), a fracture risk tool, using Kaiser Permanente Northern California women older than 50yr with bone mineral density (BMD) measured during 1997-2003. We compared FRAX performance with and without BMD in the model. Among 94,489 women with mean follow-up of 6.6yr, 1579 (1.7%) sustained a hip fracture. Overall, AUROCs were 0.83 and 0.84 for FRAX without and with BMD, suggesting that BMD did not contribute to model performance. AUROC decreased with increasing age, and BMD contributed significantly to higher AUROC among those aged 70yr and older. Using an 81% sensitivity threshold (optimum level from receiver operating characteristic curve, corresponding to 1.2% cutoff), 35% of those categorized above were reassigned below when BMD was added. In contrast, only 10% of those categorized below were reassigned to the higher risk category when BMD was added. The net reclassification improvement was 5.5% (p<0.01). Two versions of this risk tool have similar AUROCs, but alternative assessments indicate that addition of BMD improves performance. Multiple methods should be used to evaluate risk tool performance with less reliance on AUROC alone.