Ganesan Karthikeyan

American Association of Orthopedic Surgeons and American College of Chest Physicians Guidelines for Venous Thromboembolism Prevention in Hip and Knee Arthroplasty Differ: What Are the Implications for Clinicians and Patients?

The recently published American Association of Orthopedic Surgeons (AAOS) guidelines for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee surgery conflict with long-established and widely used American College of Chest Physicians (ACCP) guidelines. Both guidelines accepted that the most important goal of thromboprophylaxis in patients undergoing hip or knee replacement is to prevent pulmonary embolism (PE). The ACCP guidelines included asymptomatic (and symptomatic) deep vein thrombosis (DVT) detected by venography as a measure of the efficacy of thromboprophylaxis, whereas the AAOS rejected DVT as a valid outcome because the panelists considered the link between DVT and PE to be unproven. The AAOS position is inconsistent with evidence from imaging studies linking DVT with PE and from clinical studies demonstrating a parallel reduction of DVT and PE when antithrombotic agents are compared with placebo or untreated controls. The AAOS panel ignored the randomized data demonstrating that thromboprophylaxis reduces both DVT and PE, and many of their recommendations are based on expert opinion and lack a scientific basis. We recommend the ACCP guidelines because the methodology is explicit and rigorous and the treatment recommendations reflect all of the evidence from the randomized trials. Adoption of the ACCP guideline will ensure that patients undergoing hip and knee arthroplasty receive the best available therapies for prevention of VTE and reduce disability and death due to this common and potentially preventable condition.

Is a pre-operative brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement an independent predictor of adverse cardiovascular outcomes within 30 days of noncardiac surgery? A systematic review and meta-analysis of observational studies.

OBJECTIVES We conducted a systematic review and meta-analysis to determine if pre-operative brain natriuretic peptide (BNP) (i.e., BNP or N-terminal pro-B-type natriuretic peptide [NT-proBNP]) is an independent predictor of 30-day adverse cardiovascular outcomes after noncardiac surgery. BACKGROUND Pre-operative clinical cardiac risk indices have only modest predictive power. BNP predicts adverse cardiovascular outcomes in a variety of nonsurgical settings and may similarly predict these outcomes in the perioperative setting. METHODS We employed 5 search strategies (e.g., searching bibliographic databases), and we included all studies that assessed the independent prognostic value of pre-operative BNP measurement as a predictor of cardiovascular complications after noncardiac surgery. We determined study eligibility and conducted data abstraction independently and in duplicate. We calculated a pooled odds ratio using a random effects model. RESULTS Nine studies met eligibility criteria, and included a total of 3,281 patients, among whom 314 experienced 1 or more perioperative cardiovascular complications. The average proportion of patients with elevated BNP was 24.8% (95% confidence interval [CI]: 20.1 to 30.4%; I(2) = 89%). All studies showed a statistically significant association between an elevated pre-operative BNP level and various cardiovascular outcomes (e.g., a composite of cardiac death and nonfatal myocardial infarction; atrial fibrillation). Data pooled from 7 studies demonstrated an odds ratio (OR) of 19.3 (95% CI: 8.5 to 43.7; I(2) = 58%). The pre-operative BNP measurement was an independent predictor of perioperative cardiovascular events among studies that only considered the outcomes of death, cardiovascular death, or myocardial infarction (OR: 44.2, 95% CI: 7.6 to 257.0, I(2) = 51.6%), and those that included other outcomes (OR: 14.7, 95% CI: 5.7 to 38.2, I(2) = 62.2%); the p value for interaction was 0.28. CONCLUSIONS These results suggest that an elevated pre-operative BNP or NT-proBNP measurement is a powerful, independent predictor of cardiovascular events in the first 30 days after noncardiac surgery.

Detection of altered global DNA methylation in coronary artery disease patients.

Epigenetic modifications, especially alteration in DNA methylation, are increasingly being recognized as a key factor in the pathogenesis of complex disorders, including atherosclerosis. However, there are limited data on the epigenetic changes in the coronary artery disease (CAD) patients. In the present study we evaluated the methylation status of genomic DNA from peripheral lymphocytes in a cohort of 287 individuals: 137 angiographically confirmed CAD patients and 150 controls. The differential susceptibility of genomic DNA to methylation-sensitive restriction enzymes was utilized to assess the methylation status of the genome. We observed that the genomic DNA methylation in CAD patients is significantly higher than in controls (p < 0.05). Since elevated homocysteine levels are known to be an independent risk factor for CAD and a key modulator of macromolecular methylation, we investigated the probable correlation between plasma homocysteine levels and global DNA methylation. We observed a significant positive correlation of global DNA methylation with plasma homocysteine levels in CAD patients (p = 0.001). Further, within a higher range of serum homocysteine levels (>/=12-50 muM), global DNA methylation was significantly higher in CAD patients than in controls. The alteration in genomic DNA methylation associated with cardiovascular disease per se appears to be further accentuated by higher homocysteine levels.

The CHADS2 score for stroke risk stratification in atrial fibrillation – friend or foe?

The risk of stroke in patients with non-valvular atrial fibrillation (NVAF) varies widely depending on patient age and the presence of other risk factors such as hypertension, diabetes mellitus, congestive heart failure or prior stroke or transient ischaemic attack (TIA) (1, 2). Warfarin reduces the risk of stroke by about twothirds when compared to placebo or no treatment, and by about two-fifths when compared to aspirin, but substantially increases major bleeding (2, 3). The most feared complication of warfarin is intracranial bleeding which occurs at the rate of 2–5 per 1,000 patients per year and often results in disability or death (3). Consequently, the decision to use warfarin must balance the benefits of warfarin for stroke prevention against the risk of major bleeding. The goal of stroke prediction models is to help clinicians and patients select the most appropriate antithrombotic therapy for stroke prevention. Because the absolute benefit of warfarin for stroke prevention increases with increasing baseline stroke risk whereas the absolute risk of major bleeding is more constant (3, 4), the balance between benefits and risks of warfarin in individual patients is determined primarily by their baseline untreated stroke risk. In this paper we critically examine the value of the CHADS2 (acronym for recent Congestive heart failure, history of Hypertension, Age≥75 years, Diabetes mellitus, and past history of Stroke or TIA) risk index to estimate stroke risk in patients with NVAF.

Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study)

AIMS Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contemporary information on presentation, complications, and treatment. METHODS AND RESULTS This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%). One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1% of children had dilated LVs. Fifty-five percent (n = 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-coagulants were prescribed in 69.5% (n = 946) of patients with mechanical valves (n = 501), AF (n = 397), and high-risk mitral stenosis in sinus rhythm (n = 48). However, only 28.3% (n = 269) had a therapeutic international normalized ratio. Among 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. The utilization of valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries. CONCLUSION Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contraception, and variations in the use of percutaneous and surgical interventions by country income level.

Lipid Profile, Plasma Apolipoproteins, and Risk of a First Myocardial Infarction Among Asians : An Analysis From the INTERHEART Study

OBJECTIVES This study sought to determine the prevalence of lipid and lipoprotein abnormalities and their association with the risk of a first acute myocardial infarction (AMI) among Asians. BACKGROUND Patterns of lipid abnormalities among Asians and their relative impact on cardiovascular risk have not been well characterized. METHODS In a case-control study, 65 centers in Asia recruited 5,731 cases of a first AMI and 6,459 control subjects. Plasma levels of lipids and apolipoproteins in the different Asian subgroups (South Asians, Chinese, Southeast Asians, and Japanese) were determined and correlated with the risk of AMI. RESULTS Among both cases and controls, mean low-density lipoprotein cholesterol (LDL-C) levels were about 10 mg/dl lower in Asians compared with non-Asians. A greater proportion of Asian cases and controls had LDL-C </=100 mg/dl (25.5% and 32.3% in Asians vs. 19.4% and 25.3% in non-Asians, respectively). High-density lipoprotein cholesterol (HDL-C) levels were slightly lower among Asians compared with non-Asians. There was a preponderance of people with low HDL-C among South Asians (South Asia vs. rest of Asia: cases 82.3% vs. 57.4%; controls 81% vs. 51.6%; p < 0.0001 for both comparisons). However, despite these differences in absolute levels, the risk of AMI associated with increases in LDL-C and decreases in HDL-C was similar for Asians and non-Asians. Among South Asians, changes in apolipoprotein (Apo)A1 predicted risk better than HDL-C. ApoB/ApoA1 showed the strongest association with the risk of AMI. CONCLUSIONS The preserved association of LDL-C with risk of AMI among Asians, despite the lower baseline levels, suggests the need to rethink treatment thresholds and targets in this population. The low HDL-C level among South Asians requires further study and targeted intervention.

Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial

BACKGROUND Cardiopulmonary bypass initiates a systemic inflammatory response syndrome that is associated with postoperative morbidity and mortality. Steroids suppress inflammatory responses and might improve outcomes in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. We aimed to assess the effects of steroids in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. METHODS The Steroids In caRdiac Surgery (SIRS) study is a double-blind, randomised, controlled trial. We used a central computerised phone or interactive web system to randomly assign (1:1) patients at high risk of morbidity and mortality from 80 hospital or cardiac surgery centres in 18 countries undergoing cardiac surgery with the use of cardiopulmonary bypass to receive either methylprednisolone (250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients were assigned with block randomisation with random block sizes of 2, 4, or 6 and stratified by centre. Patients aged 18 years or older were eligible if they had a European System for Cardiac Operative Risk Evaluation of at least 6. Patients were excluded if they were taking or expected to receive systemic steroids in the immediate postoperative period or had a history of bacterial or fungal infection in the preceding 30 days. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcomes were 30-day mortality and a composite of death and major morbidity (ie, myocardial injury, stroke, renal failure, or respiratory failure) within 30 days, both analysed by intention to treat. Safety outcomes were also analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00427388. FINDINGS Patients were recruited between June 21, 2007, and Dec 19, 2013. Complete 30-day data was available for all 7507 patients randomly assigned to methylprednisolone (n=3755) and to placebo (n=3752). Methylprednisolone, compared with placebo, did not reduce the risk of death at 30 days (154 [4%] vs 177 [5%] patients; relative risk [RR] 0·87, 95% CI 0·70-1·07, p=0·19) or the risk of death or major morbidity (909 [24%] vs 885 [24%]; RR 1·03, 95% CI 0·95-1·11, p=0·52). The most common safety outcomes in the methylprednisolone and placebo group were infection (465 [12%] vs 493 [13%]), surgical site infection (151 [4%] vs 151 [4%]), and delirium (295 [8%] vs 289 [8%]). INTERPRETATION Methylprednisolone did not have a significant effect on mortality or major morbidity after cardiac surgery with cardiopulmonary bypass. The SIRS trial does not support the routine use of methylprednisolone for patients undergoing cardiopulmonary bypass. FUNDING Canadian Institutes of Health Research.

Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population.

AbstractAn elevated level of homocysteine is an independent risk factor for cardiovascular diseases and is associated with other complex disorders. Homocysteine levels can be elevated due to dietary and/or genetic factors. A majority of Indian population have a low level of vitamin B12 (presumably due to vegetarian diet)—a critical nutritional factor, deficiency of which results in hyperhomocysteinemia. Hence, polymorphisms in the genes responsible for homocysteine metabolism can be perceived to have a greater impact in relation to hyperhomocysteinemia in Indian population. For this reason, the effects of diet and/or methylenetetrahydrofolate reductase (MTHFR) polymorphism were assessed in 200 individuals having varying homocysteine levels. Homocysteine levels were significantly elevated in individuals adhering to a vegetarian diet (P=0.019) or having MTHFR A1298C polymorphism (P=0.006). The minor allele frequency (MAF) of MTHFR C677T and A1298C was 0.15 and 0.44 respectively in this cohort. Since the MAF of these polymorphisms differed considerably from Caucasian and other Asian populations, frequencies of these polymorphisms were also determined in more than 400 individuals from different ethnic populations, selected from the entire country based on their geographical location and linguistic lineage, and was found to be similar to that of our cohort. The fact that MTHFR A1298C polymorphism is significantly associated with homocysteine levels, and that the CC genotype is present at a higher frequency in the Indian population, makes it extremely relevant in terms of its potential impact on hyperhomocysteinemia.

Current worldwide nuclear cardiology practices and radiation exposure: results from the 65 country IAEA Nuclear Cardiology Protocols Cross-Sectional Study (INCAPS)

Aims To characterize patient radiation doses from nuclear myocardial perfusion imaging (MPI) and the use of radiation-optimizing ‘best practices’ worldwide, and to evaluate the relationship between laboratory use of best practices and patient radiation dose. Methods and results We conducted an observational cross-sectional study of protocols used for all 7911 MPI studies performed in 308 nuclear cardiology laboratories in 65 countries for a single week in March–April 2013. Eight ‘best practices’ relating to radiation exposure were identified a priori by an expert committee, and a radiation-related quality index (QI) devised indicating the number of best practices used by a laboratory. Patient radiation effective dose (ED) ranged between 0.8 and 35.6 mSv (median 10.0 mSv). Average laboratory ED ranged from 2.2 to 24.4 mSv (median 10.4 mSv); only 91 (30%) laboratories achieved the median ED ≤ 9 mSv recommended by guidelines. Laboratory QIs ranged from 2 to 8 (median 5). Both ED and QI differed significantly between laboratories, countries, and world regions. The lowest median ED (8.0 mSv), in Europe, coincided with high best-practice adherence (mean laboratory QI 6.2). The highest doses (median 12.1 mSv) and low QI (4.9) occurred in Latin America. In hierarchical regression modelling, patients undergoing MPI at laboratories following more ‘best practices’ had lower EDs. Conclusion Marked worldwide variation exists in radiation safety practices pertaining to MPI, with targeted EDs currently achieved in a minority of laboratories. The significant relationship between best-practice implementation and lower doses indicates numerous opportunities to reduce radiation exposure from MPI globally.

Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015.

BACKGROUND Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low‐income and middle‐income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study. METHODS We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod‐MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty. RESULTS We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age‐standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age‐standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub‐Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability‐adjusted life‐years due to rheumatic heart disease globally. CONCLUSIONS We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25‐year period. The health‐related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.)