Vinodh Jeevanantham

Adult Bone Marrow Cell Therapy Improves Survival and Induces Long-Term Improvement in Cardiac Parameters A Systematic Review and Meta-Analysis

Background— Despite rapid clinical translation and widespread enthusiasm, the therapeutic benefits of adult bone marrow cell (BMC) transplantation in patients with ischemic heart disease continue to remain controversial. A synthesis of the available data is critical to appreciate and underscore the true impact of this promising approach. Methods and Results— A total of 50 studies (enrolling 2625 patients) identified by database searches through January 2012 were included. Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were estimated with random-effects meta-analysis. Compared with control subjects, BMC-treated patients exhibited greater LV ejection fraction (3.96%; 95% confidence interval, 2.90–5.02; P<0.00001) and smaller infarct size (−4.03%, 95% confidence interval, −5.47 to −2.59; P<0.00001), LV end-systolic volume (−8.91 mL; 95% confidence interval, −11.57 to −6.25; P<0.00001), and LV end-diastolic volume (−5.23 mL; 95% confidence interval, −7.60 to −2.86; P<0.0001). These benefits were noted regardless of the study design (randomized controlled study versus cohort study) and the type of ischemic heart disease (acute myocardial infarction versus chronic ischemic heart disease) and persisted during long-term follow-up. Importantly, all-cause mortality, cardiac mortality, and the incidence of recurrent myocardial infarction and stent thrombosis were significantly lower in BMC-treated patients compared with control subjects. Conclusions— Transplantation of adult BMCs improves LV function, infarct size, and remodeling in patients with ischemic heart disease compared with standard therapy, and these benefits persist during long-term follow-up. BMC transplantation also reduces the incidence of death, recurrent myocardial infarction, and stent thrombosis in patients with ischemic heart disease.

Bisphosphonates and atrial fibrillation: systematic review and meta-analysis

Background: Bisphosphonates are widely used in osteoporosis, but there have been concerns about a potential link between bisphosphonate therapy and atrial fibrillation.Objective: We aimed to systematically evaluate the risk of atrial fibrillation associated with bisphosphonate use.Methods: We searched MEDLINE, regulatory authority websites, pharmaceutical company trial registers and product information sheets for randomized controlled trials (RCTs) and controlled observational studies published in English through to May 2008. We selected RCTs of bisphosphonates versus placebo for osteoporosis or fractures, with at least 3 months of follow-up, and data on atrial fibrillation. For the observational studies, we included case-control or cohort studies that evaluated the risk of atrial fibrillation in patients exposed to bisphosphonates compared with non-exposure. Data on atrial fibrillation as the primary outcome, and stroke and cardiovascular mortality as secondary outcomes, were extracted.Data Synthesis/Results: We calculated pooled odds ratio (OR) using random effects meta-analysis, and estimated statistical heterogeneity with the I2 statistic. Bisphosphonate exposure was significantly associated with risk of atrial fibrillation serious adverse events in a meta-analysis of four trial datasets (OR 1.47; 95% CI 1.01, 2.14; p = 0.04; I2 = 46%). However, meta-analysis of all atrial fibrillation events (serious and non-serious) from the same data-sets yielded a pooled OR of 1.14 (95% CI 0.96, 1.36; p = 0.15; I2 = 0%).We identified two case-control studies, one of which found an association between bisphosphonate exposure (ever users) and atrial fibrillation (adjusted OR 1.86; 95% CI 1.09, 3.15) while the other showed no association (adjusted OR 0.99; 95% CI 0.90, 1.10). Both studies failed to demonstrate a significant association in ‘current’ users.We did not find a significant increase in the risk of stroke (three trial datasets; OR 1.00; 95% CI 0.82, 1.22; p = 0.99; I2 = 0%) or cardiovascular mortality (three trial datasets; OR 0.86; 95% CI 0.66,1.13; p = 0.28; I2 = 31%).Conclusion: While there are some data linking bisphosphonates to serious atrial fibrillation, heterogeneity of the existing evidence, as well as paucity of information on some of the agents, precludes any definitive conclusions on the exact nature of the risk.

Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and Insights from Randomized Controlled Trials

RATIONALE Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. OBJECTIVE To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. METHODS AND RESULTS Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. CONCLUSIONS Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.Rationale: Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. Objective: To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. Methods and Results: Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91–3.92; P <0.00001), reduced infarct size (−2.25%; 95% confidence interval, −3.55 to −0.95; P =0.0007) and LV end-systolic volume (−6.37 mL; 95% confidence interval, −8.95 to −3.80; P <0.00001), and tended to reduce LV end-diastolic volume (−2.26 mL; 95% confidence interval, −4.59 to 0.07; P =0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. Conclusions: Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up. # Novelty and Significance {#article-title-77}

Physicians' Preferences and Attitudes About End-of-Life Care in Patients With an Implantable Cardioverter-Defibrillator

Clinical guidance is deficient regarding deactivation of implantable cardioverter-defibrillators (ICDs) in patients with terminal illnesses. We hypothesized that many physicians are apprehensive about discussing ICD deactivation with their dying patients. Thus, we conducted an anonymous survey of all the physicians in the Department of Medicine at Unity Health System in Rochester, NY. The survey collected information about the knowledge and preferences of these physicians regarding the medical, ethical, and legal issues involved in caring for patients with an ICD and terminal illness. Of the 204 surveys distributed, 87 (43%) were returned. Among the physicians who responded, 64 (74%) reported experience caring for a patient with an ICD and terminal illness. Forty physicians (46%) either thought it was illegal or were not sure if it was legal to deactivate an ICD in these circumstances. However, if reassured about the legality of discontinuing ICD therapy, 79 (91%) of these same respondents said that they would be willing to discuss voluntary ICD deactivation with their dying patients. With increased knowledge about managing the withdrawal of this potentially life-prolonging therapy, physicians are likely to become more skilled at caring for dying patients with an ICD.

Adult Bone Marrow Cell Therapy for Ischemic Heart DiseaseNovelty and Significance: Evidence and Insights From Randomized Controlled Trials

RATIONALE Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. OBJECTIVE To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. METHODS AND RESULTS Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. CONCLUSIONS Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.Rationale: Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. Objective: To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. Methods and Results: Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91–3.92; P <0.00001), reduced infarct size (−2.25%; 95% confidence interval, −3.55 to −0.95; P =0.0007) and LV end-systolic volume (−6.37 mL; 95% confidence interval, −8.95 to −3.80; P <0.00001), and tended to reduce LV end-diastolic volume (−2.26 mL; 95% confidence interval, −4.59 to 0.07; P =0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. Conclusions: Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up. # Novelty and Significance {#article-title-77}

No consistent evidence of differential cardiovascular risk amongst proton-pump inhibitors when used with clopidogrel: Meta-analysis

BACKGROUND Data from pharmacokinetic and pharmacodynamic studies indicate that the adverse clopidogrel-proton pump inhibitor (PPI) interaction may vary between PPIs, with pantoprazole considered relatively less problematic. We aimed to evaluate systematically whether individual PPIs differ in their risk for cardiovascular events when concomitantly administered with clopidogrel. METHODS We searched MEDLINE, EMBASE and Cochrane Trials Register up to December 2011 for randomized and non-randomized studies that reported adverse cardiovascular events with exposure to specific PPIs in patients receiving clopidogrel. We performed random effects meta-analysis, and assessed heterogeneity using the I(2) statistic. RESULTS A total of 23 studies with 222,311 participants were included. Meta-analysis of major adverse cardiovascular events was mostly limited by moderate-substantial heterogeneity. Pooled estimates of cardiovascular risk were significantly elevated for individual PPIs such as omeprazole, esomeprazole, lansoprazole, and pantoprazole when used with clopidogrel. However, meta-analysis of adverse cardiovascular risk in seven observational studies reporting on PPI therapy alone (without concomitant clopidogrel) also found an elevated odds ratio of 1.28 (95% CI 1.14-1.44) compared with no clopidogrel/no PPI exposure. Meta-analysis of two randomized controlled trials did not show significant adverse cardiovascular effect from omeprazole or esomeprazole. CONCLUSIONS The absence of consistent evidence on differential cardiovascular risk amongst PPIs (particularly regarding safety of pantoprazole) is in direct opposition to the platelet function and pharmacokinetic data. Our findings of increased cardiovascular risk with PPIs in the absence of clopidogrel suggest that confounding and bias are strong possibilities. The clinical validity or relevance of the hypothesized PPI-clopidogrel interaction remains questionable.

Variation in left atrial transmural wall thickness at sites commonly targeted for ablation of atrial fibrillation

BackgroundThe number of catheter ablations performed for atrial fibrillation (AF) has increased dramatically over the past several years. Regional variation in left atrial (LA) wall thickness is known to exist but have not been described in detail. AF ablation success and complication rates may be related to regional differences in LA wall thickness.ObjectiveTo evaluate differences in transmural wall thickness in five pre-defined anatomic areas within the LA which are commonly targeted for AF ablation.Materials and methodsWe measured LA wall transmural thickness in 34 human heart specimens using calipers in five anatomic areas frequently targeted during AF ablation (anterior wall, septum, mitral isthmus, posterior wall and roof).ResultsThe autopsied individuals were 53% female, 67.7% had CAD, 14.7% had atrial fibrillation, 61.8% had hypertension, and 21.6% had congestive heart failure. The roof was the thinnest region with mean thickness measuring significantly less than each other area (p 0.005 for the posterior wall and <0.001 for all other areas). The septum was the thickest region with mean thickness measuring significantly greater than each other area (p = 0.05, 0.001, <0.001, <0.001 measured against the anterior wall, isthmus, posterior wall and roof, respectively).ConclusionsSignificant regional differences exist for mean left atrial wall thickness among the different anatomic areas within the left atrium which are often targeted during catheter ablation of AF. These differences may have significant implications in determining the ideal intensity and total duration of radiofrequency energy required to achieve a safe and successful ablation.

Referral patterns of primary care physicians for chronic kidney disease in general population and geriatric patients.

BACKGROUND Late referral of patients with chronic kidney disease (CKD) by primary care physicians (PCPs) is associated with poor outcomes. We sought to assess factors influencing PCPs referral patterns in the general population and in geriatric patients, and compared their perceptions to the referral patterns. METHODS We retrospectively reviewed 268 patients with Stage 3 CKD (early referral) and 280 with Stage 4 CKD (appropriate referral) seen in renal clinic and compared them to 268 randomly selected non-referred Stage 4 CKD patients from primary care physicians office records. We also surveyed 400 regional PCPs on factors influencing their referral for CKD. RESULTS Non-referred patients were significantly (p < 0.05) more likely to be over 65 years (OR: 3.5; 95% CI: 2.3 - 5.2), females (OR: 1.4; 95% CI: 1.0 - 2.0) and of non-white race (OR: 2.6; 95% CI: 1.5 - 4.5) after adjusting for relevant confounding variables. Charlson comorbidity index greater than 4 was associated with non-referral when the non-referral group was compared to the early referral group. Among geriatric patients, women and a higher comorbidity index were associated with non-referral. 25% of PCPs completed the survey and 62% PCPs were unfamiliar with K/DOQI referral guidelines. Age > 75 years, limited life expectancy, patient noncompliance or refusal to consider dialysis influenced PCPs decision to refer. CONCLUSIONS Our study shows that elderly women, minorities and patients with multiple comorbidities are at risk for non-referral for CKD care. Educating PCPs on the appropriate referral of CKD patients, especially those at risk for late or non-referral to a nephrologist is warranted, as are trials assessing different educational strategies.

Referral to Nephrologists for Chronic Kidney Disease Care: Is Non-Diabetic Kidney Disease Ignored?

Background: Late referral to nephrologists is common and associated with increased morbidity and mortality. We aimed to analyze the prevalence rates, predictors and consequences of late referral to nephrologists by primary care physicians for chronic kidney disease (CKD) care. Methods: A retrospective analysis of 204 patients started on dialysis for CKD in two community hospitals between March 2003 and March 2005 was conducted. Relevant clinical and laboratory data were obtained from the patient records of the nephrology clinics and dialysis units. Patients referred in CKD stage 5 (estimated glomerular filtration rate <15 ml/min) were defined as late referral and patients in CKD stage 1–4 (estimated glomerular filtration rate >15 ml/min) as early referral. Results: Forty-five (22%) of the 204 patients were referred late. In the multivariate analysis, non-diabetic kidney disease (odds ratio = 2.46, p = 0.02) and Charlson comorbidity index (odds ratio = 1.17, p = 0.009) were significantly associated with late referral. The late referral group had lower hematocrit and serum calcium levels, and higher serum phosphorus and parathyroid hormone levels than the early referral group (p ≤0.05) at the time of referral. Late referral resulted in less permanent vascular access for initiation of dialysis (p = 0.03). Even though there was twice the number of deaths in the late referral group in 1 year (18 vs. 9%), this was not statistically significant (p = 0.07). Conclusion: Referring physicians should pay special attention to patients with non-diabetic kidney disease and patients with multiple comorbidities since delayed referral to nephrologists may result in poorer patient-related outcomes. Larger and long-term prospective studies analyzing the long-term consequences of late referral to nephrologists are needed.

Correlation of High Sensitivity C-Reactive Protein and Calcific Aortic Valve Disease

OBJECTIVE To determine whether a difference exists in the levels of high sensitivity C-reactive protein (Hs-CRP) in patients with and without calcific aortic valve disease (CAVD). PATIENTS AND METHODS This cross-sectional study consisted of 110 patients who had undergone echocardiographic examination from January 2005 to February 2006 at our institution. Information on demographic variables, coronary risk factors, and medications was obtained. More than 200 patients were excluded on the basis of any evidence of infection, active connective tissue disorder, rheumatoid arthritis, recent episodes of bleeding, acute fractures, bowel obstruction, or acute coronary syndrome or use of corticosteroids, nonsteroidal anti-inflammatory drugs, or antibiotic treatment. The values of Hs-CRP, total cholesterol, and erythrocyte sedimentation rate were included. RESULTS Of the 110 study subjects, 38 patients had aortic sclerosis, 36 patients had aortic stenosis, and 36 were controls. The mean Hs-CRP level in the control group was significantly lower (4.84 +/- 6.9 mg/L) compared with the levels in the groups with aortic sclerosis (14.9 +/- 19.6 mg/L) and aortic stenosis (13.6 +/- 17.3 mg/L) (P = -.01). No statistically significant difference was found between the patients in the aortic sclerosis and aortic stenosis groups. Among the patients with aortic stenosis, no significant correlation existed between Hs-CRP levels and aortic stenosis severity. CONCLUSIONS The Hs-CRP seems to have a significant association with CAVD during its early stage. The study findings did not have sufficient evidence to suggest the use of Hs-CRP as a marker of progression of calcific aortic stenosis. The Hs-CRP may have a role in identifying patients in the early stages of CAVD and in whom medical treatment may be beneficial to halt the progression to irreversible aortic valvular calcification and stenosis.