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1.  Adoption and Effectiveness of Internal Mammary Artery Grafting in Coronary Artery Bypass Surgery Among Medicare Beneficiaries 
To assess the pattern of the adoption of internal mammary artery (IMA) grafting in the United States, test its association with clinical outcomes, and assess whether its effectiveness differs in key clinical subgroups.
The effect of IMA grafting on major clinical outcomes has never been tested in a large randomized trial, yet it is now a quality standard for coronary artery bypass graft (CABG) surgery.
We identified Medicare beneficiaries aged ≥66 years who underwent isolated multivessel CABG between 1988 and 2008, and documented patterns of IMA use over time. We used a multivariable propensity score to match patients with and without an IMA, and compared rates of death, myocardial infarction (MI), and repeat revascularization. We tested for variations in IMA effectiveness using treatment by covariate interaction tests.
IMA use in CABG rose slowly from 31% in 1988 to 91% in 2008, with persistent wide geographic variations. Among 60,896 propensity score matched patients over a median 6.8 year follow-up, IMA use was associated with lower all-cause mortality (adjusted hazard ratio 0.77, p<0.001), lower death or MI (adjusted hazard ratio 0.77, p<0.001), and fewer repeat revascularization over five years (8% vs. 9%, p<0.001). The association between IMA use and lower mortality was significantly weaker (p≤0.008) for older patients, women, and for patients with diabetes or peripheral arterial disease.
IMA grafting was adopted slowly and still shows substantial geographic variation. IMA use is associated with lower rates of death, MI and repeat coronary revascularization.
PMCID: PMC3947230  PMID: 24080110
Internal Mammary-Coronary Artery Anastomosis; Outcomes Research; Comparative Effectiveness Research
2.  Economic Return From the Women’s Health Initiative Estrogen Plus Progestin Clinical Trial 
Annals of internal medicine  2014;160(9):594-602.
The findings of the Women’s Health Initiative (WHI) estrogen plus progestin (E+P) trial led to a substantial reduction in use of combined hormone therapy (cHT) among postmenopausal women in the United States. The economic effect of this shift has not been evaluated relative to the trial’s $260 million cost (2012 U.S. dollars).
To estimate the economic return from the WHI E+P trial.
Decision model to simulate health outcomes for a “WHI scenario” with observed cHT use and a “no-WHI scenario” with cHT use extrapolated from the pretrial period.
Data Sources
Primary analyses of WHI outcomes, peer-reviewed literature, and government sources.
Target Population
Postmenopausal women in the United States, aged 50 to 79 years, who did not have a hysterectomy.
Time Horizon
2003 to 2012.
Combined hormone therapy.
Outcome Measures
Disease incidence, expenditure, quality-adjusted life-years, and net economic return.
Results of Base-Case Analysis
The WHI scenario resulted in 4.3 million fewer cHT users, 126 000 fewer breast cancer cases, 76 000 fewer cardiovascular disease cases, 263 000 more fractures, 145 000 more quality-adjusted life-years, and expenditure savings of $35.2 billion. The corresponding net economic return of the trial was $37.1 billion ($140 per dollar invested in the trial) at a willingness-to-pay level of $100 000 per quality-adjusted life-year.
Results of Sensitivity Analysis
The 95% CI for the net economic return of the trial was $23.1 to $51.2 billion.
No evaluation of indirect costs or outcomes beyond 2012.
The WHI E+P trial made high-value use of public funds with a substantial return on investment. These results can contribute to discussions about the role of public funding for large, prospective trials with high potential for public health effects.
Primary Funding Source
National Heart, Lung, and Blood Institute.
PMCID: PMC4157355  PMID: 24798522
3.  Rheumatoid Arthritis and Cardiovascular Disease 
American heart journal  2013;166(4):622-628.e1.
Rheumatic disease and heart disease share common underpinnings involving inflammation. The high levels of inflammation that characterize rheumatic diseases provide a “natural experiment” to help elucidate the mechanisms by which inflammation accelerates heart disease. Rheumatoid arthritis (RA) is the most common of the rheumatic diseases and has the best studied relationships with heart disease.
Review of current literature on heart disease and rheumatoid arthritis
Patients with RA have an increased risk of developing heart disease that is not fully explained by traditional cardiovascular risk factors. Therapies used to treat RA may also affect the development of heart disease; by suppressing inflammation, they may also reduce the risk of heart disease. However, their other effects, as in the case of steroids, may increase heart disease risk.
Investigations of the innate and adaptive immune responses occurring in RA may delineate novel mechanisms in the pathogenesis of heart disease, and help identify novel therapeutic targets for the prevention and treatment of heart disease.
PMCID: PMC3890244  PMID: 24093840
4.  Effectiveness of β-Blockers in Heart Failure With Left Ventricular Systolic Dysfunction and Chronic Kidney Disease 
Journal of cardiac failure  2013;19(3):176-182.
Establishing medication effectiveness outside of a randomized trial requires careful study design to mitigate selection bias. Previous observational studies of β-blockers in patients with chronic kidney disease and heart failure have had methodologic limitations that may have introduced bias. We examined whether initiation of β-blocker therapy was associated with better outcomes among patients with chronic kidney disease and newly diagnosed heart failure with left ventricular systolic dysfunction.
Methods and Results
We identified 668 adults in the Kaiser Permanente Northern California system from 2006 to 2008 with chronic kidney disease, incident heart failure, left ventricular systolic dysfunction, and no previous β-blocker use. We defined chronic kidney disease as estimated glomerular filtration rate <60 mL min−1 1.73 m−2 or proteinuria, and we excluded patients receiving dialysis. We used extended Cox regression to assess the association of treatment with death and the combined end point of death or heart failure hospitalization. Initiation of β-blocker therapy was associated with a significantly lower crude risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.35–0.63), but this association was attenuated and no longer significant after multivariable adjustment (HR 0.75, CI 0.51–1.12). β-Blocker therapy was significantly associated with a lower risk of death or heart failure hospitalization even after adjustment for potential confounders (HR 0.67, CI 0.51–0.88).
β-Blocker therapy is associated with lower risk of death or heart failure hospitalization among patients with chronic kidney disease, incident heart failure, and left ventricular systolic dysfunction.
PMCID: PMC4126798  PMID: 23482078
Heart failure; renal dysfunction; chronic kidney disease; beta-blockers; death; hospitalizations; cardiovascular disease; epidemiology
5.  Comparative effectiveness of coronary artery bypass grafting and percutaneous coronary intervention for multivessel coronary disease in a community-based population with chronic kidney disease 
American heart journal  2013;165(5):800-808.e2.
Randomized clinical trials comparing coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) have largely excluded patients with chronic kidney disease (CKD), leading to uncertainty about the optimal coronary revascularization strategy. We sought to test the hypothesis that an initial strategy of CABG would be associated with lower risks of long-term mortality and cardiovascular morbidity compared with PCI for the treatment of multivessel coronary heart disease in the setting of CKD.
We created a propensity score–matched cohort of patients aged ≥30 years with no prior dialysis or renal transplant who received multivessel coronary revascularization between 1996 and 2008 within a large integrated health care delivery system in northern California. We used extended Cox regression to examine death from any cause, acute coronary syndrome, and repeat revascularization.
Coronary artery bypass grafting was associated with a significantly lower adjusted rate of death than PCI across all strata of estimated glomerular filtration rate (eGFR) (in mL/min per 1.73 m2): the adjusted hazard ratio (HR) was 0.81, 95% CI 0.68 to 1.00 for patients with eGFR ≥60; HR 0.73 (CI 0.56–0.95) for eGFR of 45 to 59; and HR 0.87 (CI 0.67–1.14) for eGFR <45. Coronary artery bypass grafting was also associated with significantly lower rates of acute coronary syndrome and repeat revascularization at all levels of eGFR compared with PCI.
Among adults with and without CKD, multivessel CABG was associated with lower risks of death and coronary events compared with multivessel PCI.
PMCID: PMC4125571  PMID: 23622918
6.  Temporal Trends in Mortality after Coronary Artery Revascularization in Patients with End-Stage Renal Disease 
The Permanente Journal  2014;18(3):11-16.
Recent studies that have assessed the comparative effectiveness between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with end-stage renal disease (ESRD) that have included analyses of temporal trends in mortality have noted mixed results.
We conducted an observational longitudinal cohort study of all adults with ESRD undergoing CABG or PCI within Kaiser Permanente Northern California. The primary predictor, index period of revascularization, was categorized into 3 periods: 1996–1999 (reference), 2000–2003, and 2004–2008, with the primary outcome being 3-year all-cause mortality. A multivariable Cox regression model with the assumption of independent censoring was used to determine the adjusted relative risk of the primary predictor.
Among 1015 ESRD patients, 3-year mortality showed no significant change in the 2000–2003 period but was lower during the 2004–2008 period with an adjusted hazard ratio of 0.66 (95% confidence interval: 0.49–0.88; trend test p = 0.01). No change in 30-day mortality was noted. Further adjustment for receipt of medications at baseline and after revascularization did not materially affect risk estimates. No significant interactions were observed between the type of revascularization (CABG or PCI) and the period of the index revascularization.
Among a high-risk cohort of patients with ESRD and coronary artery disease within Kaiser Permanente Northern California who were referred for coronary revascularization by either CABG or PCI, the relative risk of mortality in the 2004–2008 period decreased by 34% compared with the 1996–1999 period, with the benefit primarily in the decrease in late mortality.
PMCID: PMC4116259  PMID: 25102514
7.  Obesity, Physical Activity, and Their Interaction in Incident Atrial Fibrillation in Postmenopausal Women 
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased risk of stroke and death. Obesity is an independent risk factor for AF, but modifiers of this risk are not well known. We studied the roles of obesity, physical activity, and their interaction in conferring risk of incident AF.
Methods and Results
The Women's Health Initiative (WHI) Observational Study was a prospective observational study of 93 676 postmenopausal women followed for an average of 11.5 years. Incident AF was identified using WHI‐ascertained hospitalization records and diagnostic codes from Medicare claims. A multivariate Cox's hazard regression model adjusted for demographic and clinical risk factors was used to evaluate the interaction between obesity and physical activity and its association with incident AF. After exclusion of women with prevalent AF, incomplete data, or underweight body mass index (BMI), 9792 of the remaining 81 317 women developed AF. Women were, on average, 63.4 years old, 7.8% were African American, and 3.6% were Hispanic. Increased BMI (hazard ratio [HR], 1.12 per 5‐kg/m2 increase; 95% confidence interval [CI], 1.10 to 1.14) and reduced physical activity (>9 vs. 0 metabolic equivalent task hours per week; HR, 0.90; 95% CI, 0.85 to 0.96) were independently associated with higher rates of AF after multivariate adjustment. Higher levels of physical activity reduced the AF risk conferred by obesity (interaction P=0.033).
Greater physical activity is associated with lower rates of incident AF and modifies the association between obesity and incident AF.
PMCID: PMC4310412  PMID: 25142057
atrial fibrillation; electrophysiology; epidemiology; exercise; obesity
8.  Comparative Effectiveness of Multivessel Coronary Bypass Surgery and Multivessel Percutaneous Coronary Intervention 
Annals of internal medicine  2013;158(10):727-734.
Randomized trials of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) suggest that patient characteristics modify the effect of treatment on mortality.
To assess whether clinical characteristics modify the comparative effectiveness of CABG versus PCI in an unselected, general patient population.
Observational treatment comparison using propensity score matching and Cox proportional hazards models.
United States, 1992 to 2008.
Medicare beneficiaries aged 66 years or older.
Multivessel CABG or multivessel PCI.
The CABG–PCI hazard ratio (HR) for all-cause mortality, with prespecified treatment-by-covariate interaction tests, and the absolute difference in life-years of survival in clinical subgroups after CABG or PCI, both over 5 years of follow-up.
Among 105 156 propensity score–matched patients, CABG was associated with lower mortality than PCI (HR, 0.92 [95% CI, 0.90 to 0.95]; P < 0.001). Association of CABG with lower mortality was significantly greater (interaction P ≤ 0.002 for each) among patients with diabetes (HR, 0.88), a history of tobacco use (HR, 0.82), heart failure (HR, 0.84), and peripheral arterial disease (HR, 0.85). The overall predicted difference in survival between CABG and PCI treatment over 5 years was 0.053 life-years (range, −0.017 to 0.579 life-years). Patients with diabetes, heart failure, peripheral arterial disease, or tobacco use had the largest predicted differences in survival after CABG, whereas those with none of these factors had slightly better survival after PCI.
Treatments were chosen by patients and physicians rather than being randomly assigned.
Multivessel CABG is associated with lower long-term mortality than multivessel PCI in the community setting. This association is substantially modified by patient characteristics, with improvement in survival concentrated among patients with diabetes, tobacco use, heart failure, or peripheral arterial disease.
Primary Funding Source
National Heart, Lung, and Blood Institute.
PMCID: PMC4117804  PMID: 23609014
9.  Incremental prognostic information from kidney function in patients with new onset coronary heart disease 
American heart journal  2013;167(1):86-92.
Prognostic factors are usually evaluated by their statistical significance rather than by their clinical utility. Risk reclassification measures the extent to which a novel marker adds useful information to a prognostic model. The extent to which estimated glomerular filtration rate (eGFR) adds information about prognosis among patients with coronary heart disease is uncertain.
We studied patients in an integrated health care delivery system with newly diagnosed coronary heart disease. We developed a model of the risk of death over 2 years of follow-up and then added eGFR to the model and measured changes in C-index, net reclassification improvement, and integrated discrimination improvement.
Almost half of the 31,533 study patients had reduced eGFR (<60 mL/min per 1.73 m2). Mortality was significantly higher among patients who had lower levels of eGFR, even after adjustment for baseline characteristics (P < .0001). The addition of eGFR to the prognostic model increased the C-index from 0.837 to 0.843, the net reclassification improvement by 3.2% (P < .0001), and integrated discrimination improvement by 1.3% (P = .007).
Estimated glomerular filtration rate is an informative prognostic factor among patients with incident coronary heart disease, independent of other clinical characteristics.
PMCID: PMC4088948  PMID: 24332146
10.  Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction 
American heart journal  2007;154(6):1052-1058.
Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis.
We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina.
An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively).
Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.
PMCID: PMC4031914  PMID: 18035074
11.  Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease 
Human genetics  2008;123(4):399-408.
Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
PMCID: PMC4023692  PMID: 18369664
12.  Effectiveness of preoperative beta-blockade on intra-operative heart rate in vascular surgery cases conducted under regional or local anesthesia 
SpringerPlus  2014;3:227.
Preoperative β-blockade has been posited to result in better outcomes for vascular surgery patients by attenuating acute hemodynamic changes associated with stress. However, the incremental effectiveness, if any, of β-blocker usage in blunting heart rate responsiveness for vascular surgery patients who avoid general anesthesia remains unknown.
We reviewed an existing database and identified 213 consecutive vascular surgery cases from 2005–2011 conducted without general anesthesia (i.e., under monitored anesthesia care or regional anesthesia) at a tertiary care Veterans Administration medical center and categorized patients based on presence or absence of preoperative β-blocker prescription. For this series of patients, with the primary outcome of maximum heart rate during the interval between operating room entry to surgical incision, we examined the association of maximal heart rate and preoperative β-blocker usage by performing crude and multivariate linear regression, adjusting for relevant patient factors.
Of 213 eligible cases, 137 were prescribed preoperative β-blockers, and 76 were not. The two groups were comparable across baseline patient factors and intraoperative medication doses. The β-blocker group experienced lower maximal heart rates during the period of evaluation compared to the non-β-blocker group (85 ± 22 bpm vs. 98 ± 36 bpm, respectively; p = 0.002). Adjusted linear regression confirmed a statistically-significant association between lower maximal heart rate and the use of β-blockers (Beta = -11.5; 95% CI [-3.7, -19.3] p = 0.004).
The addition of preoperative β-blockers, even when general anesthesia is avoided, may be beneficial in further attenuating stress-induced hemodynamic changes for vascular surgery patients.
PMCID: PMC4024108  PMID: 24855591
Perioperative medicine; Vascular surgery; β-blockers; Heart rate; General anesthesia; Regional anesthesia; Monitored anesthesia care; Effectiveness
13.  Duke Activity Status Index for Cardiovascular Diseases: Validation of the Portuguese Translation 
Arquivos Brasileiros de Cardiologia  2014;102(4):383-390.
The Duke Activity Status Index (DASI) assesses the functional capacity of patients with cardiovascular disease (CVD), but there is no Portuguese version validated for CVD.
To translate and adapt cross-culturally the DASI for the Portuguese-Brazil language, and to verify its psychometric properties in the assessment of functional capacity of patients with CVD.
The DASI was translated into Portuguese, then checked by back-translation into English and evaluated by an expert committee. The pre-test version was first evaluated in 30 subjects. The psychometric properties and correlation with exercise testing was performed in a second group of 67 subjects. An exploratory factor analyses was performed in all 97 subjects to verify the construct validity of the DASI.
The intraclass correlation coefficient for test-retest reliability was 0.87 and for the inter-rater reliability was 0.84. Cronbach's α for internal consistency was 0.93. The concurrent validity was verified by significant positive correlations of DASI scores with the VO2max (r = 0.51, p < 0.001). The factor analysis yielded two factors, which explained 54% of the total variance, with factor 1 accounting for 40% of the variance. Application of the DASI required between one and three and a half minutes per patient.
The Brazilian version of the DASI appears to be a valid, reliable, fast and easy to administer tool to assess functional capacity among patients with CVD.
PMCID: PMC4028943  PMID: 24652056
Cardiovascular diseases; Work capacity evaluation; Practice guidelines; Exercise test; Questionnaires; Validation studies
14.  Epidemiologic and Statistical Methods for Comparative Effectiveness Research 
Heart failure clinics  2012;9(1):29-36.
PMCID: PMC3589582  PMID: 23168315
Comparative effectiveness research; Randomized trials; Observational data; Statistical methods; Epidemiologic methods
Circulation  2012;126(19):2293-2301.
One sixth of U.S. dialysis patients older than 65 years have been diagnosed with atrial fibrillation/flutter (AF) and the prevalence is increasing. Little is known, however, about the incidence of AF in this population.
Methods and Results
From the U.S. Renal Data System, we identified 258,605 older patients (≥67 years) with fee-for-service Medicare initiating dialysis between 1995 and 2007, who had not been diagnosed with AF within the previous 2 years. Patients were followed for newly diagnosed AF, which was ascertained from 1 inpatient or 2 outpatient claims containing an AF code. Multivariable proportional hazards regression was used to examine temporal trends and associations of race and ethnicity with incident AF. We also studied temporal trends in the mortality and risk of ischemic stroke after new AF. Over 514,395 person years of follow-up, 76,252 patients experienced incident AF for a crude AF incidence rate of 148/1,000 person years. Incidence of AF increased by 11% (95%CI: 5%-16%) from 1995-2007. Compared with non-Hispanic whites, African Americans (−30%), Asians (−19%), Native Americans (−42%), and Hispanics (−29%) all had lower rates of incident AF. Mortality after incident AF decreased by 22% from 1995-2008. Even more pronounced reductions were seen for incident ischemic stroke during these years.
The incidence of AF is high in older patients initiating dialysis in the U.S. and has been increasing over the 13 years of study. Mortality declined during that time, but remained >50% during the first year after newly diagnosed AF. Since data on warfarin use were not available, we were unable to understand whether trends towards better outcomes could be explained by higher rates of oral anticoagulation in more recent years.
PMCID: PMC3640842  PMID: 23032326
end-stage renal disease; atrial fibrillation; disparities; outcomes; cardiovascular; mortality
17.  Future Directions for Cardiovascular Disease Comparative Effectiveness Research 
Comparative effectiveness research (CER) aims to provide decision-makers the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart Lung and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address eight clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.
PMCID: PMC3416944  PMID: 22796257
comparative effectiveness; research methods; clinical trials
18.  Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden 
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.
PMCID: PMC3653306  PMID: 23352782
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
19.  Chronic Kidney Disease and Risk of Presenting with Acute Myocardial Infarction versus Stable Exertional Angina in Adults with Coronary Heart Disease 
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.
PMCID: PMC3184235  PMID: 21958887
angina; myocardial infarction; renal failure; chronic kidney disease; risk factor
20.  The effect of age on clinical outcomes and health status in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial (BARI 2D) 
The objective was to determine the extent to which effectiveness of cardiac and diabetes treatment strategies varies by patient age.
The impact of age on the effectiveness of revascularization and hyperglycemia treatments has not been thoroughly investigated.
In BARI 2D, 2368 patients with documented stable heart disease and type 2 diabetes were randomized to receive prompt revascularization versus initial medical therapy with deferred revascularization and insulin-sensitization versus insulin-provision for hyperglycemia treatment. Patients were followed for an average of 5.3 years. Cox regression and mixed models were used to investigate the effect of age and randomized treatment assignment on clinical and health status outcomes.
The effect of prompt revascularization versus medical therapy did not differ by age for death (interaction p=0.99), major cardiovascular events (interaction p=0.081), angina (interaction p=0.98) or health status outcomes. After intervention, participants of all ages had significant angina and health status improvement. Younger participants experienced a smaller decline in health status during follow-up than older participants (age by time interaction p<0.01). The effect of the randomized glycemia treatment on clinical and health status outcomes was similar for patients of different ages.
Among patients with stable heart disease and type 2 diabetes, relative beneficial effects of a strategy of prompt revascularization versus initial medical therapy, and insulin-sensitizing versus insulin-providing therapy on clinical endpoints, symptom relief, and perceived health status outcomes do not vary by age. Health status improved significantly after treatment for all ages, and this improvement was sustained longer among younger patients.
PMCID: PMC3164969  PMID: 21835316
age; coronary heart disease; diabetes mellitus; revascularization; health status
21.  Economic Outcomes of Treatment Strategies for Type 2 Diabetes and Coronary Artery Disease in the BARI 2D Trial 
Circulation  2009;120(25):2550-2558.
The economic outcomes of clinical management strategies are important in assessing their value to patients.
Methods and Results
BARI 2D randomized patients with Type 2 diabetes and angiographically documented, stable coronary disease to strategies of 1) prompt revascularization vs. medical therapy with delayed revascularization as needed to relieve symptoms, and 2) insulin sensitization vs. insulin provision. Prior to randomization, the physician declared whether CABG or PCI would be used if the patient were assigned to revascularization. We followed 2005 patients for medical utilization and costs, and assessed the cost-effectiveness of these management strategies.
Medical costs were higher for revascularization than medical therapy, with a significant interaction with the intended method of revascularization (p<0.0001). In the CABG stratum, four-year costs were $80,900 for revascularization vs. $60,600 for medical therapy (p<0.0001). In the PCI stratum, costs were $73,400 for revascularization vs. $67,800 for medical therapy (p<0.02). Costs also were higher for insulin sensitization ($71,300) vs. insulin provision ($70,200). Other factors that significantly (p<0.05) and independently increased cost included insulin use and dose at baseline, female sex, white race, body mass index ≥30, and albuminuria.
Cost-effectiveness based on four-year data favored the strategy of medical therapy over prompt revascularization and the strategy of insulin provision over insulin sensitization. Lifetime projections of cost-effectiveness showed that medical therapy was cost-effective compared with revascularization in the PCI stratum ($600 per life-year added) with high confidence. Lifetime projections suggest revascularization may be cost-effective in the CABG stratum ($47,000 per life-year added), but with lower confidence.
Prompt coronary revascularization significantly increases costs among patients with Type 2 diabetes and stable coronary disease. The strategy of medical therapy (with delayed revascularization as needed) appears to be cost-effective compared with the strategy of prompt coronary revascularization among patients identified a priori as suitable for PCI.
PMCID: PMC3403834  PMID: 19920002
cost-benefit analysis; revascularization; angioplasty; surgery; diabetes mellitus
23.  BMI and Health Status in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial (BARI 2D) 
American heart journal  2011;162(1):184-192.e3.
The longitudinal association between obesity, weight variability and health status outcomes is important for patients with coronary disease and diabetes.
The Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (BARI 2D) was a multi-center randomized clinical trial to evaluate the best treatment strategy for patients with both documented stable ischemic heart disease and type 2 diabetes. We examined BARI 2D participants for four years to study how BMI was associated with health status outcomes. Health status was evaluated by the Duke Activity Status Index (DASI), RAND Energy/fatigue, Health Distress, and Self-rated health. BMI was measured quarterly throughout follow-up years, and health status was assessed at each annual follow-up visit. Variation in BMI measures was separated into between-person and within-person change in longitudinal analysis.
Higher mean BMI over follow-up years (the between-person BMI) was associated with poorer health status outcomes. Decreasing BMI (the within-person BMI change) was associated with better Self-rated health. The relationships between BMI variability and DASI or Energy appeared to be curvilinear, and differed by baseline obesity status. Decreasing BMI was associated with better outcomes if patients were obese at baseline, but was associated with poorer DASI and Energy outcomes if patients were non-obese at baseline.
For patients with stable ischemic heart disease and diabetes, weight gain was associated with poorer health status outcomes, independent of obesity-related comobidities. Weight reduction is associated with better functional capacity and perceived energy for obese patients but not for non-obese patients at baseline.
PMCID: PMC3141323  PMID: 21742107
BMI; obesity; coronary disease; diabetes mellitus; health status
24.  Persistent racial disparities in survival following heart transplantation 
Circulation  2011;123(15):1642-1649.
Racial and ethnic disparities are well-documented in many areas of health care but have not been comprehensively evaluated among recipients of heart transplantation.
Methods and results
We performed a retrospective cohort study of 39,075 adult primary heart transplant recipients from 1987-2009 using national data from the United Network of Organ Sharing, and compared mortality for non-white and white patients using the Cox proportional hazards model. During the study period, 8,082 non-white and 30,993 white patients underwent heart transplantation. Non-white heart transplant recipients increased over time, comprising nearly 30% of transplants since 2005. Non-white recipients had a higher clinical risk profile than white recipients at the time of transplantation but had significantly higher post-transplant mortality even after adjustment for baseline risk. Among the non-white group, only black recipients had an increased risk of death when compared with white recipients after multivariable adjustment for recipient, transplant, and socioeconomic factors (hazard ratio [HR] 1.34; 95% confidence interval [CI], 1.21-1.47; p<0.001). Five-year mortality was 35.7% (CI, 35.2%-38.3%) among black and 26.5% (CI, 26.0%-27.0%) among white recipients. Black patients were more likely to die from graft failure or a cardiovascular cause than white patients, but less likely to die from infection or malignancy. Although mortality decreased over time for all transplant recipients, the disparity in mortality between blacks and whites remained essentially unchanged.
Black heart transplant recipients have had persistently higher mortality than whites recipients over the past two decades, perhaps due to a higher rate of graft failure.
PMCID: PMC3125110  PMID: 21464049
Transplantation; Survival; Race; Treatment disparities; Trends
25.  Strengthening the Reporting of Genetic Risk Prediction Studies (GRIPS): Explanation and Elaboration 
European journal of epidemiology  2011;26(4):313-337.
The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice.The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality.Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction.A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines.These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.
PMCID: PMC3088812  PMID: 21424820

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