Changchun Xie

Adverse Impact of Bleeding on Prognosis in Patients With Acute Coronary Syndromes

Background— The use of multiple antithrombotic drugs and aggressive invasive strategies has increased the risk of major bleeding in acute coronary syndrome (ACS) patients. It is not known to what extent bleeding determines clinical outcome. Methods and Results— Using Cox proportional-hazards modeling, we examined the association between bleeding and death or ischemic events in 34 146 patients with ACS enrolled in the Organization to Assess Ischemic Syndromes and the Clopidogrel in Unstable Angina to Prevent Recurrent Events studies. Patients with major bleeding were older, more often had diabetes or a history of stroke, had a lower blood pressure and higher serum creatinine, more often had ST-segment changes on the presenting ECG, and had a 5-fold-higher incidence of death during the first 30 days (12.8% versus 2.5%; P<0.0001) and a 1.5-fold-higher incidence of death between 30 days and 6 months (4.6% versus 2.9%; P=0.002). Major bleeding was independently associated with an increased hazard of death during the first 30 days (hazard ratio, 5.37; 95% CI, 3.97 to 7.26; P<0.0001), but the hazard was much weaker after 30 days (hazard ratio, 1.54; 95% CI, 1.01 to 2.36; P=0.047). The association was consistent across subgroups according to cointerventions during hospitalization, and there was an increasing risk of death with increasing severity of bleeding (minor less than major less than life-threatening; P for trend=0.0009). A similar association was evident between major bleeding and ischemic events, including myocardial infarction and stroke. Conclusions— In ACS patients without persistent ST-segment elevation, there is a strong, consistent, temporal, and dose-related association between bleeding and death. These data should lead to greater awareness of the prognostic importance of bleeding in ACS and should prompt evaluation of strategies to reduce bleeding and thereby improve clinical outcomes.

Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data

BACKGROUND India has the highest burden of acute coronary syndromes in the world, yet little is known about the treatments and outcomes of these diseases. We aimed to document the characteristics, treatments, and outcomes of patients with acute coronary syndromes who were admitted to hospitals in India. METHODS We did a prospective registry study in 89 centres from 10 regions and 50 cities in India. Eligible patients had suspected acute myocardial infarction with definite electrocardiograph changes (whether elevated ST [STEMI] or non-STEMI or unstable angina), or had suspected myocardial infarction without ECG changes but with prior evidence of ischaemic heart disease. We recorded a range of clinical outcomes, and all-cause mortality at 30 days. FINDINGS We enrolled 20,937 patients. Of the 20,468 patients who were given a definite diagnosis, 12,405 (60.6%) had STEMI. The mean age of these patients was 57.5 (SD 12.1) years; patients with STEMI were younger (56.3 [12.1] years) than were those with non-STEMI or unstable angina (59.3 [11.8] years). Most patients were from lower middle 10,737 (52.5%) and poor 3999 (19.6%) social classes. The median time from symptoms to hospital was 360 (IQR 123-1317) min, with 50 (25-68) min from hospital to thrombolysis. 6226 (30.4%) patients had diabetes; 7720 (37.7%) had hypertension; and 8242 (40.2%) were smokers. Treatments for STEMI differed from those for non-STEMI or unstable angina. More patients with STEMI than with non-STEMI were given anti-platelet drugs (98.2%vs 97.4%); angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) (60.5%vs 51.2%); and percutaneous coronary interventions (8.0%vs 6.7%, p<0.0001 for all comparisons). Thrombolytics (96.3% streptokinase) were used for 58.5% of patients with STEMI. Conversely, fewer patients with STEMI than those with non-STEMI or unstable angina were given beta blockers (57.5%vs 61.9%); lipid-lowering drugs (50.8%vs 53.9%); and coronary bypass graft surgery (1.9%vs 4.4%, p<0.0001 for all comparisons). The 30-day outcomes for patients with STEMI were death (8.6%), reinfarction (2.3%), and stroke (0.7%). Outcomes for those with non-STEMI or unstable angina were better: death (3.7%), reinfarction (1.2%), and stroke (0.3%, p<0.0001 for all comparisons). Use of key treatments also differed by socioeconomic status: more rich patients than poor patients were given thrombolytics (60.6%vs 52.3%), beta blockers (58.8%vs 49.6%), lipid-lowering drugs (61.2%vs 36.0%), ACE inhibitors or ARB (63.2%vs 54.1%), percutaneous coronary intervention (15.3%vs 2.0%), and coronary artery bypass graft surgery (7.5%vs 0.7%, p<0.0001 for all comparisons). Mortality was higher for poor patients than for rich patients (8.2%vs 5.5%, p<0.0001). Adjustment for treatments (but not risk factors and baseline characteristics) eliminated this difference in mortality. INTERPRETATION Patients in India who have acute coronary syndromes have a higher rate of STEMI than do patients in developed countries. Since most of these patients were poor, less likely to get evidence-based treatments, and had greater 30-day mortality, reduction of delays in access to hospital and provision of affordable treatments could reduce morbidity and mortality.

Radial Artery Access as a Predictor of Increased Radiation Exposure During a Diagnostic Cardiac Catheterization Procedure

OBJECTIVES We sought to determine whether radial artery access is associated with increased radiation exposure during cardiac catheterization and whether this relationship differs between operators, after adjustment for clinical and patient characteristics associated with greater radiation exposure. BACKGROUND Although previous studies have demonstrated a relationship between radial access and increased radiation exposure to the patient during fluoroscopy-guided cardiac procedures, such studies did not account for differences in operator technique or clustering of patients, procedure complexity, or patient size. Those studies included data from few operators. METHODS Data were collected prospectively on 5,954 diagnostic cardiac catheterizations performed at a tertiary cardiac center. A multilevel regression analysis was used to determine the relationship between radial artery access and radiation exposure. RESULTS After adjustment for multiple factors, radial access was associated with increased exposure (beta = 0.22, p < 0.0001) when compared with the use of femoral access, as measured using the logarithmically transformed air kerma (LogAK). On average, radial access accounted for a 23% increase in measured AK. This was consistent between operators. There were observed differences in the mean LogAK between operators (p = 0.0158), as well as substantial variation in measured LogAK between patients within each operators practice (p < 0.001). CONCLUSIONS Radial artery access cardiac catheterization was associated with increased radiation exposure to the patient when compared with femoral access. The measured AK was still far below the threshold for deterministic effects in most patients studied. Observed variations in AK between and within operators may point to better opportunities to reduce exposure.

Parental History and Myocardial Infarction Risk Across the World The INTERHEART Study

A parental history (PH) of coronary heart disease (CHD) is consistently associated with a higher risk of the development of CHD in several studies ([1–9][1]). It is generally accepted that this association is explained by a combination of predominantly known risk factors and genetic variants ([10

The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study

Ron Do and colleagues find that a prudent diet high in raw vegetables may modify the increased genetic risk of cardiovascular disease conferred by the chromosome 9p21 SNP.

Genetic variants associated with myocardial infarction risk factors in over 8000 individuals from five ethnic groups: The INTERHEART Genetics Study.

Background—Myocardial infarction (MI) is a leading cause of death globally, but specific genetic variants that influence MI and MI risk factors have not been assessed on a global basis. Methods and Results—We included 8795 individuals of European, South Asian, Arab, Iranian, and Nepalese origin from the INTERHEART case-control study that genotyped 1536 single-nucleotide polymorphisms (SNPs) from 103 genes. One hundred and two SNPs were nominally associated with MI, but the statistical significance did not remain after adjustment for multiple testing. A subset of 940 SNPs from 69 genes were tested against MI risk factors. One hundred and sixty-three SNPs were nominally associated with a MI risk factor and 13 remained significant after adjusting for multiple testing. Of these 13, 11 were associated with apolipoprotein (Apo) B/A1 levels: 8 SNPs from 3 genes were associated with Apo B, and 3 cholesteryl ester transfer protein SNPs were associated with Apo A1. Seven of 8 of the SNPs associated with Apo B levels were nominally associated with MI (P<0.05), whereas none of the 3 cholesteryl ester transfer protein SNPs were associated with MI (P≥0.17). Of the 3 SNPs most significantly associated with MI, rs7412, which defines the Apo E2 isoform, was associated with both a lower Apo B/A1 ratio (P=1.0×10−7) and lower MI risk (P=0.0004). Two low-density lipoprotein receptor variants, 1 intronic (rs6511720) and 1 in the 3′ untranslated region (rs1433099) were both associated with a lower Apo B/A1 ratio (P<1.0×10−5) and a lower risk of MI (P=0.004 and P=0.003, respectively). Conclusions—Thirteen common SNPs were associated with MI risk factors. Importantly, SNPs associated with Apo B levels were associated with MI, whereas SNPs associated with Apo A1 levels were not. The Apo E isoform, and 2 common low-density lipoprotein receptor variants (rs1433099 and rs6511720) influence MI risk in this multiethnic sample.

The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression

Candidate gene and genome-wide association studies have not identified common variants, which are reliably associated with depression. The recent identification of obesity predisposing genes that are highly expressed in the brain raises the possibility of their genetic contribution to depression. As variation in the intron 1 of the fat mass- and obesity-associated (FTO) gene contributes to polygenic obesity, we assessed the possibility that FTO gene may contribute to depression in a cross-sectional multi-ethnic sample of 6561 depression cases and 21 932 controls selected from the EpiDREAM, INTERHEART, DeCC (depression case–control study) and Cohorte Lausannoise (CoLaus) studies. Major depression was defined according to DSM IV diagnostic criteria. Association analyses were performed under the additive genetic model. A meta-analysis of the four studies showed a significant inverse association between the obesity risk FTO rs9939609 A variant and depression (odds ratio=0.92 (0.89, 0.97), P=3 × 10−4) adjusted for age, sex, ethnicity/population structure and body-mass index (BMI) with no significant between-study heterogeneity (I2=0%, P=0.63). The FTO rs9939609 A variant was also associated with increased BMI in the four studies (β 0.30 (0.08, 0.51), P=0.0064) adjusted for age, sex and ethnicity/population structure. In conclusion, we provide the first evidence that the FTO rs9939609 A variant may be associated with a lower risk of depression independently of its effect on BMI. This study highlights the potential importance of obesity predisposing genes on depression.

Challenges in the conduct of large simple trials of important generic questions in resource-poor settings: the CREATE and ECLA trial program evaluating GIK (glucose, insulin and potassium) and low-molecular-weight heparin in acute myocardial infarction.

Abstract Background Approximately 15.5 million deaths from cardiovascular diseases occur every year. About half are due to acute myocardial infarction (AMI), and 80% occur in low- and middle-income countries. Therefore, low-cost therapies would be invaluable. Although glucose-insulin-potassium (GIK) infusion and low-molecular-weight heparin (LMWH) appear to be promising in AMI, the available trials are inconclusive and these treatments require rigorous evaluation. Methods The Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation-Estudios Clínicos Latino America (CREATE-ECLA) study is a randomized controlled trial in ST-elevation AMI patients evaluating a 24-hour infusion of Glucose-Insulin-Potassium (GIK) intravenous vs usual care (control) on 30-day mortality in 20 000 patients from 21 countries. Patients from India and China (n = 15 000) are also randomized using a factorial design to receive low-molecular-weight heparin (Reviparin) or placebo injection twice daily for 7 days to assess the impact on the composite outcomes of death, reinfarction or stroke (first co-primary outcome) or the composite + refractory ischemia (second co-primary outcome). Results Twenty thousand two hundred and one (20,201) GIK/control patients and 15,570 Reviparin/placebo patients have been included, with results expected in November 2004. Conclusions The CREATE-ECLA trial will provide definitive answers to the role of 2 practical, promising and low-cost therapies, LMWH and GIK, in AMI patients. If effective, these therapies could be used in small medical centers in low- and middle- income countries. The experiences in this trial indicate that large trials of important questions can be successfully conducted in resource-poor settings, by academic groups without industry involvement.

Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study

OBJECTIVE Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure—outcomes that may have a genetic etiology. RESEARCH DESIGN AND METHODS We genotyped 4,197 participants of the multiethnic DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965). RESULTS One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47–2.42]; P = 5.32 × 10−7, corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10−4) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10−3). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05). CONCLUSIONS Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone.

Predictors of increased radiation dose during percutaneous coronary intervention.

Radiation-induced injury is a potential unintended outcome of fluoroscopy-supported cardiology procedures (e.g., percutaneous coronary intervention [PCI]). The injury might be deterministic in nature. Air kerma (AK) is considered an indicator of skin dose, and thus, an indicator for deterministic effects. Few studies have investigated the factors that contribute to an increased radiation dose, and none have used AK as a dependent variable. We studied the registry data of 967 consecutive patients (derivation model) undergoing ad hoc PCI. Linear and multiple regression analyses were performed to investigate which clinical, technical, and anatomic factors were associated with an increased AK. Multiple regression analyses were performed on an additional sample of 1,082 consecutive patients (validation model) to confirm the results. The variables found significant (multiple regression analyses) were radial access (mean increase in AK 253 mGy, 95% confidence interval [CI] 104 to 418, p = 0.0006), number of lesions treated (547 mGy, 95% CI 332 to 789, p < 0.0001), Type C lesions (132 mGy, 95% CI, 26 to 246, p = 0.014), bifurcation lesions (280 mGy, 95% CI 104 to 477, p = 0.0013), and chronic total occlusions (453 mGy, 95% CI 76 to 923, p = 0.016). The validation model (n = 1,082) confirmed all but type C lesions (p = 0.065). In conclusion, the present study has described factors that might contribute to an increased AK during PCI. In revealing a priori known factors associated with an increased radiation dose during PCI, physicians and patients might be more able to evaluate the risks and benefits of such a procedure.