Effects of Influenza Vaccine on Mortality and Cardiovascular Outcomes in Patients With Cardiovascular Disease: A Systematic Review and Meta-Analysis.

Background Influenza infection causes considerable morbidity and mortality in patients with cardiovascular disease. We assessed the effects of the influenza vaccine on mortality and cardiovascular outcomes in patients with cardiovascular disease. Methods and Results We searched PubMed, Embase, and the Cochrane Library through January 2020 for randomized controlled trials and observational studies assessing the effects of influenza vaccine on mortality and cardiovascular outcomes in patients with cardiovascular disease. Estimates were reported as random effects risk ratios (RRs) with 95% CIs. Analyses were stratified by study design into randomized controlled trials and observational studies. A total of 16 studies (n=237 058), including 4 randomized controlled trials (n=1667) and 12 observational studies (n=235 391), were identified. Participants' mean age was 69.2±7.01 years, 36.6% were women, 65.1% had hypertension, 31.1% had diabetes mellitus, and 23.4% were smokers. At a median follow-up duration of 19.5 months, influenza vaccine was associated with a lower risk of all-cause mortality (RR, 0.75; 95% CI, 0.60-0.93 [P=0.01]), cardiovascular mortality (RR, 0.82; 95% CI, 0.80-0.84 [P<0.001]), and major adverse cardiovascular events (RR, 0.87; 95% CI, 0.80-0.94 [P<0.001]) compared with control. The use of the influenza vaccine was not associated with a statistically significant reduction of myocardial infarction (RR, 0.73; 95% CI, 0.49-1.09 [P=0.12]) compared with control. Conclusions Data from both randomized controlled trials and observational studies support the use of the influenza vaccine in adults with cardiovascular disease to reduce mortality and cardiovascular events, as currently supported by clinical guidelines. Clinicians and health systems should continue to promote the influenza vaccine as part of comprehensive secondary prevention.

Review of Bone Modifying Agents in Metastatic Breast Cancer.

Bone is the most common site for distant metastases in breast cancer and can cause significant morbidity and mortality. Bone modifying agents (BMAs) that include bisphosphonates (BPAs) and denosumab help in decreasing and delaying skeletal-related events (SREs) associated with metastatic breast cancer. BPAs approved for use by the Food and Drug Administration (FDA) in bone metastases (BM) in the United States are pamidronate and zolendronic acid, while clodronate and ibandronate are licensed for use in other countries. Current American Society of Clinical Oncology (ASCO) guidelines recommend denosumab 120 mg subcutaneously every four weeks, or zolendronic acid 4 mg every four weeks or every 12 weeks, or intravenous pamidronate 90 mg every four weeks. Current guidelines do not recommend one BMA over another, however, zolendronic acid and denosumab were the most commonly used BMAs in population-based studies. Side effects of BMAs include acute phase reactions, hypocalcemia, nephrotoxicity, osteonecrosis of jaw, etc. While other side effects are common with both BPAs and denosumab, the latter has less nephrotoxic potential and is preferred for use in patients with renal failure. Current ASCO guidelines recommend continuing BMAs indefinitely, however, in clinical practice, this decision needs to be individualized, especially since there is no data on the impact of long-term use of BMAs. Further studies would need to be developed to develop an algorithm of SRE risk assessment and to determine which patients would benefit from BMAs.

Representation of women, older patients, ethnic, and racial minorities in trials of atrial fibrillation.

BACKGROUND: Representation trends of women, older adults, and ethnic/racial minorities in randomized controlled trials (RCTs) of atrial fibrillation (AF) are uncertain. METHODS: We systematically reviewed 134 AF related RCTs (phase II and III) encompassing 149,162 participants using Medline and ClinicalTrials.gov through April 2019 to determine representation trends of women, older patients (≥75 years), and ethnic/racial minorities. Weighted data on the prevalence of AF from epidemiological studies were used to compare the representation of the studied groups of interest in AF RCTs to their expected burden of the disease. RESULTS: Only 18.7% of the RCTs reported proportion of older patients, and 12.7% RCTs reported ethnic/racial minorities. The proportions of women in RCTs versus general population were 35.2% and 35.1%, of Hispanics were 11.9% and 5.2%, of Blacks were 1.2% and 5.7%, of American Indian/Alaskans were 0.2% and 0.2%, of Asians were 14.2% and 2.4%, of native Hawaiian/Pacific Islanders were 0.05% and 0.1% and of non-Whites were 19.5% and 22.5%, respectively. The weighted mean age (SD) across the trials was 65.3 (3.2) years which was less than the corresponding weighted mean age of 71.1 (4.5) years in the comparative epidemiological data. CONCLUSION: The reporting of older patients and ethnic/racial minorities was poor in RCTs of AF. The representation of women and American Indian/Alaskan natives matched their expected population share of disease burden. Hispanics and Asians were over-represented and Blacks, native Hawaiian/Pacific Islanders and non-Whites were under-represented in RCTs of AF.

Bilateral Primary Marginal Zone Lymphoma of the Breast - A Rare Breast Malignancy.

Extranodal marginal zone lymphoma (EMZL) presents only rarely within the breast, although the incidence of breast EMZL has increased in the past decade for unclear reasons. Due to its rarity, the etiology, course, and treatment response of this cancer are less studied. Case Report: We present the case of a 64-year-old female who had bilateral diffuse irregularity in a trabecular pattern on screening mammogram. Random ultrasound-guided breast biopsy of the right breast demonstrated an extra-nodal marginal zone B-cell lymphoma. She also had approximately 25% marrow involvement by mucosa-associated lymphoid tissue-type marginal zone lymphoma and splenomegaly. Clinically she remained asymptomatic during a 1-year follow-up. Although she presented with advanced-stage disease involving both breasts, spleen and bone marrow, given her lack of associated symptoms, she was observed with active surveillance. Conclusion: Asymptomatic cases of breast EMZL can be managed with close observation as exemplified by our case.

Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in Patients With Multiple Comorbidities: Long-Term Safety and Efficacy Results From a Tertiary Care Community Hospital.

BACKGROUND: Cure rates of Clostridium difficile infection (CDI) with fecal microbiota transplant (FMT) have been promising. However, there is debate regarding success of FMT in patients with comorbidities. METHODS: Electronic chart review was done to collect data on patients who underwent FMT from January 2015 to August 2017. Charts were analyzed in November 2018 with a median follow-up of 25.4 months (interquartile range 20 - 31 months). RESULTS: Twenty patients underwent FMT. The primary success rate at our institution was 90% and overall success rate was 100%. Six patients (43%) had FMT failure (two early and four late). CONCLUSIONS: This case series is a description of our center's initial experience with FMT for treatment of recurrent CDI. Our high success rate reiterates the efficacy and safety of FMT in this population including patients with comorbidities.

Aspirin for primary prevention of cardiovascular outcomes in diabetes mellitus: An updated systematic review and meta-analysis.

BACKGROUND: The safety and efficacy of aspirin for the primary prevention of cardiovascular disease in patients with diabetes mellitus remains controversial. DESIGN: A meta-analysis to investigate the effects of aspirin for the prevention of cardiovascular disease in diabetes mellitus. METHODS: Ten randomized controlled trials were selected using MEDLINE, EMBASE and CENTRAL databases until 27 September 2018. Risk ratios (RRs) with 95% confidence intervals (CIs) and risk differences (RDs) reported as incident events per 1000 person-years were calculated. RESULTS: In 33,679 patients, aspirin did not significantly reduce the risk of major adverse cardiovascular outcomes (RR 0.93, 95% CI 0.87-1.00, P = 0.06; RD -0.68 incident cases per 1000 person-years (95% CI -1.54, 0.17)), cardiovascular mortality (RR 0.95, 95% CI 0.83-1.09, P = 0.49; RD 0.11 incident cases per 1000 person-years (95% CI -0.80, 1.02)), myocardial infarction (RR 0.91, 95% CI 0.75-1.11, P = 0.36; RD -0.66 incident cases per 1000 person-years (95% CI -2.07, 0.75)), or stroke (RR 0.91, 95% C, 0.76-1.10, P = 0.33; RD -0.55 incident cases per 1000 person-years (95% CI -1.57, 0.47)). There was a significantly higher risk of total bleeding associated with aspirin (RR 1.29, 95% CI 1.07-1.55, P = 0.01; RD 1.49 incident cases per 1000 person-years (95% CI 0.36, 2.61)). CONCLUSION: The use of aspirin for primary prevention of cardiovascular disease in patients with diabetes mellitus increases the risk of total bleeding without reducing the risk of major adverse cardiovascular outcomes.

Residual inflammatory risk after contemporary lipid lowering therapy.

BACKGROUND: Recently, there has been an increasing interest in targeting inflammation to reduce major adverse cardiovascular events (MACE) in patients with cardiovascular risk. Statins, PCSK9 inhibitors, and ezetimibe have been shown to reduce MACE owing to reduction in low-density lipoproteins cholesterol (LDL-c). Herein, we investigate whether the intensity of these agents is associated with (i) discernible reduction in inflammation measured by the levels of high-sensitivity C-reactive protein (hsCRP); (ii) reduction in MACE; (iii) if there is an association between the baseline hsCRP and MACE. METHODS AND RESULTS: Electronic databases were searched for randomized controlled trials (RCTs) that compared statins, ezetimibe, PCSK9 inhibitors with placebos/active controls and reported MACEs and hsCRP (mg/L). Studies were stratified based on baseline hsCRP (<2, 2-3, >3) with subgroup analysis conducted across each stratum. Fourteen RCTs including 133 109 patients randomized into more intensive therapy (MIT) and less intensive therapy were selected. Meta-analysis did not demonstrate any significant differences between use of MIT and hsCRP levels (mean difference, -0.02; CI, -0.06, 0.02; P = 0.31). The MIT significantly reduced the risk of MACE (RR, 0.82; CI, 0.75, 0.91; P < 0.001). The relative risk and absolute risk remained consistent across the strata. However, there was a 0.5% statistically significant absolute risk reduction in all-cause mortality in patients with higher hsCRP (RD, -0.005; CI, -0.009, -0.001; P = 0.01). CONCLUSION: Overall, LDL-c lowering therapies reduce relative risk of MACEs particularly in patients with higher baseline hsCRP. However, there appears to be a residual inflammatory risk despite the use of contemporary lipid lowering agents.

Implantable cardioverter defibrillator in nonischemic cardiomyopathy: A systematic review and meta-analysis.

The evidence to support implantable cardioverter defibrillator (ICD) in subjects with nonischemic cardiomyopathy (NICM) for primary prevention of sudden cardiac death (SCD) is not robust. This meta-analysis intends to assess the impact of routine ICD implantation for primary prevention of mortality due to SCD in NICM based on all the published randomized clinical trials (RCTs). Six RCTs were selected using PubMed/Medline, EMBASE, and CENTRAL from inception to December 2016. Outcomes were calculated as random-effects relative risk (RR) and risk difference (RD) with 95% confidence interval (CI). Patients were randomized to ICD arm and control arm (usual care, medical treatment, and anti-arrhythmic drugs). ICD significantly reduced all-cause mortality in NICM patients (RR, 0.74, 95% CI, 0.56-0.97, P = .03, I2 = 40). Mortality benefit was achieved due to a significant reduction in sudden cardiac death (SCD) (RR, 0.47, 95% CI, 0.30-0.73, P < .001, I2 = 0). There were no statistical differences between two groups with regard to risk of noncardiac mortality, non-SCD, cardiac arrest, cardiac transplant, sustained ventricular tachycardia (VT), and VT requiring medical treatment. Our results support efficacy of ICDs at reducing all-cause mortality due to a reduction in SCD.

The Clinical Benefits and Mortality Reduction Associated With Catheter Ablation in Subjects With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

OBJECTIVES: This study sought to compare the efficacy and safety of catheter ablation (CA) with those of medical therapy (MT) for the treatment of atrial fibrillation (AF). BACKGROUND: The preferred therapeutic strategy for subjects with AF remains unclear. METHODS: A total of 17 randomized controlled trials were selected using Medline, EMBASE, and CENTRAL (September 1998 to 2 February 2018). The analysis was stratified at the trial level according to the following: 1) patients with AF and heart failure (HF); and 2) patients with AF without HF. RESULTS: A total of 2,272 patients with AF (775 patients with HF and 1,497 patients without HF) participated in this analysis. In patients with HF, CA was associated with significant relative risk reduction in all-cause mortality (risk ratio [RR]: 0.52; 95% confidence interval [CI]: 0.36 to 0.76; p < 0.001; I2 = 0), recurrent atrial arrhythmia (RR: 0.44; 95% CI: 0.31 to 0.61; p <0.001; I2 = 56), and cardiac hospitalization (RR: 0.63; 95% CI: 0.46 to 0.87; p = 0.01; I2 = 43) compared with MT. Conversely, in patients without HF, CA had no beneficial effect on the risk of all-cause mortality compared with MT (RR: 0.88, 95% CI: 0.29 to 2.61; p = 0.81; I2 = 0). However, CA reduced the risk of recurrent atrial arrhythmia (RR: 0.40; 95% CI: 0.31 to 0.52; p < 0.001; I2 = 73) and cardiac hospitalization (RR: 0.32; 95% CI: 0.23 to 0.45; p < 0.001; I2 = 0) in patients without HF. CONCLUSIONS: This meta-analysis suggests that although CA reduced the risk of cardiac hospitalization and recurrent atrial arrhythmia both in subjects with HF and in subjects without HF, the reduction in all-cause mortality was limited to subjects with HF only.

Efficacy and safety of mechanical versus manual compression in cardiac arrest - A Bayesian network meta-analysis.

AIM: To compare relative efficacy and safety of mechanical compression devices (AutoPulse and LUCAS) with manual compression in patients with cardiac arrest undergoing cardiopulmonary resuscitation (CPR). METHODS: For this Bayesian network meta-analysis, seven randomized controlled trials (RCTs) were selected using PubMed/Medline, EMBASE, and CENTRAL (Inception- 31 October 2017). For all the outcomes, median estimate of odds ratio (OR) from the posterior distribution with corresponding 95% credible interval (Cr I) was calculated. Markov chain Monte Carlo (MCMC) modeling was used to estimate the relative ranking probability of each intervention based on surface under the cumulative ranking curve (SUCRA). RESULTS: In analysis of 12, 908 patients with cardiac arrest [AutoPulse (2, 608 patients); LUCAS (3, 308 patients) and manual compression (6, 992 patients)], manual compression improved survival at 30 days or hospital discharge (OR, 1.40, 95% Cr I, 1.09-1.94), and neurological recovery (OR, 1.51, 95% Cr I, 1.06-2.39) compared to AutoPulse. There were no differences between LUCAS and AutoPulse with regards to survival to hospital admission, neurological recovery or return of spontaneous circulation (ROSC). Manual compression reduced the risk of pneumothorax (OR, 0.56, 95% Cr I, 0.33-0.97); while, both manual compression (OR, 0.15, 95% Cr I, 0.01-0.73) and LUCAS (OR, 0.07, 95% Cr I, 0.00-0.43) reduced the risk of hematoma formation compared to AutoPulse. Probability analysis ranked manual compression as the most effective treatment for improving survival at 30 days or hospital discharge (SUCRA, 84%). CONCLUSIONS: Manual compression is more effective than AutoPulse and comparable to LUCAS in improving survival at 30 days or hospital discharge and neurological recovery. Manual compression had lesser risk of pneumothorax or hematoma formation compared to AutoPulse.

A Bayesian network meta-analysis of PCSK9 inhibitors, statins and ezetimibe with or without statins for cardiovascular outcomes.

Background The comparative effects of statins, ezetimibe with or without statins and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors remain unassessed. Design Bayesian network meta-analysis was conducted to compare treatment groups. Methods Thirty-nine randomized controlled trials were selected using MEDLINE, EMBASE, and CENTRAL (inception - September 2017). Results In network meta-analysis of 189,116 patients, PCSK9 inhibitors were ranked as the best treatment for prevention of major adverse cardiovascular events (Surface Under Cumulative Ranking Curve (SUCRA), 85%), myocardial infarction (SUCRA, 84%) and stroke (SUCRA, 80%). PCSK9 inhibitors reduced the risk of major adverse cardiovascular events compared with ezetimibe + statin (odds ratio (OR): 0.72; 95% credible interval (CrI), 0.55-0.95; Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria: moderate), statin (OR: 0.78; 95% CrI: 0.62-0.97; GRADE: moderate) and placebo (OR: 0.63; 95% CrI: 0.49-0.79; GRADE: high). The PCSK9 inhibitors were consistently superior to groups for major adverse cardiovascular event reduction in secondary prevention trials (SUCRA, 95%). Statins had the highest probability of having lowest rates of all-cause mortality (SUCRA, 82%) and cardiovascular mortality (SUCRA, 84%). Compared with placebo, statins reduced the risk of all-cause mortality (OR: 0.88; 95% CrI: 0.83-0.94; GRADE: moderate) and cardiovascular mortality (OR: 0.84; 95% CrI: 0.77-0.90; GRADE: high). For cardiovascular mortality, PCSK9 inhibitors were ranked as the second best treatment (SUCRA, 78%) followed by ezetimibe + statin (SUCRA, 50%). Conclusion PCSK9 inhibitors were ranked as the most effective treatment for reducing major adverse cardiovascular events, myocardial infarction and stroke, without having major safety concerns. Statins were ranked as the most effective therapy for reducing mortality.

Meta-Analysis of the Safety and Efficacy of the Oral Anticoagulant Agents (Apixaban, Rivaroxaban, Dabigatran) in Patients With Acute Coronary Syndrome.

The significance of adding new oral anticoagulants (NOACs) to antiplatelet therapy in patients with acute coronary syndrome (ACS) is unclear. We conducted a meta-analysis to assess the safety and efficacy of adding NOACs (apixaban, rivaroxaban, and dabigatran) to single antiplatelet agent (SAP) or dual antiplatelet therapy (DAPT) in patients with ACS. Seven randomized controlled trials were selected using PubMed or MEDLINE, Scopus, and Cochrane library (inception to August 2017). The summary measure was random effects hazard ratio (HR) with 95% confidence interval (CI). The primary safety outcome was clinically significant bleeding. The secondary efficacy outcome was major adverse cardiovascular events (MACE; composite of myocardial infarction, stroke, and all-cause mortality). In 31,574 patients, addition of NOAC to SAP did not increase the risk of clinically significant bleeding (HR 0.82, 95% CI 0.56 to 1.20, p = 0.31); however, the risk of clinically significant bleeding was significantly increased with NOAC plus DAPT (HR 2.24, 95% CI 1.75 to 2.87, p < 0.001). NOACs had no statistically beneficial effect on MACE when used with SAP (HR 0.82, 95% CI 0.66 to 1.04, p = 0.10); however, a modest reduction in MACE was observed when NOACs were combined with DAPT (HR 0.86, 95% CI 0.78 to 0.93, p < 0.001). In conclusion, in patients with ACS, the addition of NOAC to DAPT resulted in increased risk of clinically significant bleeding, whereas only a modest reduction in MACE was achieved. The addition of NOACs to SAP did not result in significant reduction of MACE or increase in clinically significant bleeding.

Atypical presentation of central pontine myelinolysis in hyperglycemia.

Central pontine myelinolysis (CPM) usually occurs with rapid correction of severe chronic hyponatremia. Despite the pronounced fluctuations in serum osmolality, CPM is rarely seen in diabetics. This is a case report of CPM associated with hyperglycemia. A 45-year-old non-smoking and non-alcoholic African American male with past medical history of type 2 diabetes, hypertension, stage V chronic kidney disease and hypothyroidism presented with a two-week history of intermittent episodes of gait imbalance, slurred speech and inappropriate laughter. Physical examination including complete neurological assessment and fundoscopic examination were unremarkable. Laboratory evaluation was significant for serum sodium: 140 mmol/L, potassium: 3.9 mmol/L, serum glucose: 178 mg/dL and serum osmolality: 317 mosmol/kg. His ambulatory blood sugars fluctuated between 100 and 600 mg/dL in the six weeks prior to presentation, without any significant or rapid changes in his corrected serum sodium or other electrolyte levels. MRI brain demonstrated a symmetric lesion in the central pons with increased signal intensity on T2- and diffusion-weighted images. After neurological consultation and MRI confirmation, the patient was diagnosed with CPM secondary to hyperosmolar hyperglycemia. Eight-week follow-up with neurology was notable for near-complete resolution of symptoms. This case report highlights the importance of adequate blood glucose control in diabetics. Physicians should be aware of complications like CPM, which can present atypically in diabetics and is only diagnosed in the presence of a high index of clinical suspicion. LEARNING POINTS: Despite the pronounced fluctuations in serum osmolality, central pontine myelinolysis (CPM) is rarely seen in diabetics. This case report of CPM associated with hyperglycemia highlights the importance of adequate blood glucose control in diabetics.Physicians should be aware of complications like CPM in diabetics.CPM can present atypically in diabetics and is only diagnosed in the presence of a high index of clinical suspicion.