Dilli Ram Poudel

Meta-Analysis on Risk of Bleeding With Apixaban in Patients With Renal Impairment

Apixaban is a novel oral anticoagulant which is approved for the management of atrial fibrillation and venous thromboembolism prophylaxis. There have been concerns regarding bleeding risks with apixaban in patients with renal impairment. We performed a systematic review and meta-analysis to evaluate the risk of bleeding with apixaban in these patients. Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane library, and clinicaltrials.gov (from inception to February 24, 2014). Phase III randomized controlled trials that compared apixaban with conventional agents (vitamin K antagonist and/or warfarin, low molecular weight heparin, aspirin, and placebo) were included. We defined mild renal impairment as creatinine clearance of 50 to 80 ml/min and moderate to severe renal impairment as creatinine clearance <50 ml/min. Study-specific risk ratios were calculated, and between-study heterogeneity was assessed using the I(2) statistics. In 6 trials involving 40,145 patients, the risk of bleeding with apixaban in patients with mild renal impairment was significantly less (risk ratio 0.80, 95% confidence interval 0.66 to 0.96, I(2) = 13%) compared with conventional anticoagulants. In patients with moderate to severe renal impairment, the risk of bleeding with was found to be similar (risk ratio 1.01, 95% confidence interval 0.49 to 2.10, I(2) = 72%). In conclusion, compared with the conventional agents, bleeding risk with apixaban in patients with mild and moderate to severe renal insufficiency is lower and similar, respectively.

Rituximab-induced serum sickness: A systematic review

OBJECTIVES To report a case of rituximab-induced serum sickness (RISS) and perform a systematic review and characterize RISS in autoimmune diseases and hematological malignancies. METHODS A comprehensive search of MEDLINE, EMBASE, ACR, and EULAR databases was performed for relevant articles of patients with RISS from inception to September 2014. Statistical analysis of demographic and clinical features was performed using Microsoft EXCEL 2007 and SPSS version 20.0. RESULTS In the 33 patients with RISS, the mean age of presentation was 39.1 ± 17.5yr with a female preponderance (n = 23, 76.67%). The majority of cases were associated with an underlying rheumatologic condition (n = 17, 51.5%), most commonly Sjögrens syndrome (n = 8, 44.4%). The classic triad of serum sickness (fever, rash, and arthralgia) was reported in 16 (48.5%) cases. Time from drug exposure to symptom onset was significantly greater with the first doses of rituximab compared to the second dose (mean time 10.00 vs. 4.05d, P = 0.002), and time to resolution was significantly greater for rheumatologic vs. hematological indications (mean time 2.50 vs. 1.00d, P = 0.035). Corticosteroids were the most commonly used treatment (n = 21), with all cases reporting a complete resolution of symptoms in 2.15 ± 1.34d. CONCLUSION It is important to recognize RISS clinically, as it may mimic exacerbation of various rheumatologic conditions. Although RISS is typically self-limited, further infusions of rituximab should be avoided, as it may provoke more severe symptoms.

Takotsubo cardiomyopathy associated with epinephrine use: A systematic review and meta-analysis

BACKGROUND Takotsubo cardiomyopathy is a syndrome of transient cardiac dysfunction that is frequently associated with sudden emotional or physical stress. Epinephrine use has been implicated in precipitating Takotsubo cardiomyopathy in multiple case reports and case series. We sought to systematically review the current English literature on this association. METHODS We searched relevant articles on Takotsubo cardiomyopathy associated with epinephrine administration and extracted data on demographic characteristics, clinical features, investigations and clinical outcomes. RESULTS We identified total of 41 cases from 36 articles. The mean age of presentation was (47.07±15.73years) with strong female preponderance (83%, P=0.0001). The most common symptom at presentation was chest pain (82%). Mean peak troponin I level was (7.12±11.22ng/ml). The most common EKG abnormality was ST elevation, seen in 40% of patients. The most common finding on echocardiography was apical hypokinesis, seen in 48.78% cases. Patients younger than 45 were less likely to have apical cardiomyopathy (n=5/20, 25%) compared to patients with age >45 (n=14/21, 66%, p value 0.001, OR 0.17). The most common route of administration of epinephrine was intravenous (65.85%). All patients except one survived with complete recovery of systolic function reported in most cases within an average of 14.7days. CONCLUSION Exposure to epinephrine in clinical practice can trigger Takotsubo cardiomyopathy, which is rapidly reversible with good prognosis in most cases. This review further supports the notion that both exogenous and endogenous catecholamines are associated with the pathogenesis of Takotsubo cardiomyopathy.

Burden of hospitalizations related to adverse drug events in the USA: a retrospective analysis from large inpatient database

Adverse drug events (ADEs) represent medication‐related patient harm, which is associated with significant patient morbidity and mortality. This study was conducted to determine the rate, specific causes, and outcomes of ADE‐related hospitalization in the USA.

Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review

Abstract Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year-old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 × 109/L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient’s serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4-dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 × 109/L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 × 109/L by POD45 and 199 × 109/L by POD79. The patient’s serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1–1.2 μg/mL, i.e., in vitro fondaparinux “cross-reactivity”). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT.

Meta-analysis on efficacy and safety of new oral anticoagulants for venous thromboembolism prophylaxis in overweight and obese postarthroplasty patients

Obesity is an independent risk factor for venous thromboembolism (VTE), and the risk rises further in the postarthroplasty period. Although medication doses often require adjustment for the altered pharmacokinetic profile in obese patients, the efficacy and safety of a fixed-dose regimen of new oral anticoagulants (NOACs) in overweight and obese patients remain unclear. Relevant studies were identified through searches of major databases. Phase III randomized controlled trials that compared NOACs against low-molecular-weight heparin (LMWH) in the prevention of VTE in postarthroplasty patients were included. Efficacy and safety outcomes with NOACs in overweight (BMI 25–29 kg/m2) and obese (BMI ≥ 30 kg/m2) patients were assessed. In five trials involving 16 674 patients, NOACs were found similar to LMWH in preventing VTE and VTE-related deaths after arthroplasty in both overweight and obese patients [odds ratio (OR) 0.64, P = 0.19 and OR 0.76, P = 0.43, respectively]. Similarly, the risk of major or clinically relevant bleeding was similar to LMWH in overweight patient with a trend toward lower bleeding in obese patients (OR 0.83, P = 0.54 and OR 0.44, P = 0.07 respectively). Apixaban was found to be more effective than LMWH in obese patients (OR 0.54, P = 0.01) with the lower dose of dabigatran (150 mg) being less effective (OR 1.81, P = 0.02). Our study suggests that a fixed-dose regimen of dabigatran might be ineffective in severe obesity. However, apixaban at the currently recommended dose seems to be superior to LMWH in obese patients with noninferior bleeding risk.

Acute myocardial infarction and antiphospholipid antibody syndrome: a systematic review.

Background Antiphospholipid antibody syndrome (APS) is a disorder associated with both arterial and venous thromboembolic disease, including acute myocardial infarction (AMI). Given that management with anticoagulants is critical and differs from usual AMI care, identification of key discriminators of patients with AMI with APS is important. Methods We performed an English-language systematic review of the literature of cases and case series of patients with AMI and APS from inception until 20 March 2016, collecting demographics, investigations, and outcomes. Results Forty cases of AMI because of APS were identified from 27 articles. Patients were younger than typical AMI patients (41.10±13.61 years) and 45% were women. STelevation myocardial infarction was the presentation in 45% (18/40) of cases. The average platelet count was 130 000±138 912 c/mm3 in the 10 cases reporting it and partial thromboplastin time was elevated in all four reporting it. Coronary arteries were described as normal or with acute thrombosis in 75%. Three died during hospitalization and six had recurrence of myocardial infarction within 3 months after admission. Conclusion APS should be considered in young patients with AMI, especially if previous unprovoked thromboses, lower platelet counts, high partial thromboplastin times, and normal coronary arteries or coronary thromboses are identified.

Meta-analysis on efficacy and safety of new oral anticoagulants for venous thromboembolism prophylaxis in elderly elective postarthroplasty patients.

The risk of venous thromboembolism (VTE) increases with age. New oral anticoagulants (NOACs) have been increasingly studied for VTE prophylaxis in patients with elective postarthroplasty. Although the elderly population accounts for a significant proportion of patients requiring VTE prophylaxis, safety and efficacy of NOACs in this subgroup for VTE prophylaxis has not been well studied. Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov (from inception to 12 August 2014). Phase III randomized controlled trials that compared NOACs against low-molecular-weight heparin (LMWH) in the prevention of VTE prophylaxis in patients with elective postarthroplasty were included. We defined our elderly population as adults of at least 75 years and assessed the reported safety and efficacy outcomes with NOACs in this population. Study-specific odds ratios (ORs) were calculated and between-study heterogeneity was assessed using the I2 statistic. In nine trials involving 29 403 patients, the risk of VTE or VTE-related deaths in elderly patients with elective postarthroplasty was similar with NOACs compared with LMWH (OR 0.62, 95% confidence interval 0.30–1.26; P = 0.18; I2 = 44%) but bleeding risk was significantly lower (OR 0.71, 95% confidence interval 0.53–0.94; P = 0.02; I2 = 0%). Analysis of individual NOACs showed superior efficacy but similar safety for apixaban when compared with LMWH. Efficacy and safety profiles of rivaroxaban and dabigatran were similar to LMWH. In elderly patients with elective postarthroplasty, NOACs have similar efficacy but superior safety when compared with enoxaparin for VTE prophylaxis.

Determinants of mortality in systemic sclerosis: a focused review

Scleroderma (systemic sclerosis) is an autoimmune rheumatic disorder that is characterized by fibrosis, vascular dysfunction, and autoantibody production that involves most visceral organs. It is characterized by a high morbidity and mortality rate, mainly due to disease-related complications. Epidemiological data describing mortality and survival in this population have been based on both population and observational studies. Multiple clinical and non-clinical factors have been found to predict higher likelihood of death among thepatients. Here, we do an extensive review of the available literature, utilizing the PubMed database, to describe scleroderma and non-scleroderma related determinants of mortality in this population. We found that even though the mortality among the general population has declined, scleroderma continues to carry a very high morbidity and mortality rate, however we have made some slow progress in improving the mortality among scleroderma patients over the last few decades.

Ischemic Stroke and Impact of Thyroid Profile at Presentation: A Systematic Review and Meta-analysis of Observational Studies

BACKGROUND Stroke is the fifth leading cause of mortality in the United States and a leading cause of disability. A complex relationship between thyroid hormone levels and severity of, and outcome after, stroke has been described. AIM Our objective is to identify the association between baseline thyroid function profile and outcome after acute ischemic stroke. METHODS Studies looking at the association between thyroid function and functional stroke outcomes were identified from available electronic databases from inception to December 16, 2016. Study-specific risk ratios were extracted and combined with a random effects model meta-analysis. RESULTS In the analysis of 12 studies with 5218 patients, we found that subclinical hypothyroidism was associated with better modified Rankin scale scores at 1 and 3 months (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.13-5.91, P = .03 and OR 2.28, 95% CI 1.13-3.91, P = .003, respectively) compared with the euthyroid cases. Likewise, patients with higher initial thyrotropin-releasing hormone (TSH) and fT3 or T3 levels had favorable outcomes at discharge (mean differences of TSH .12 [95% CI .03-.22, P = .009] and of fT3 .36 (CI .20-.53, P < .0001]) and at 3 months (mean differences of TSH .25 [95% CI .03-.47, P = .03] and of T3 8.60 [CI 4.58-12.61, P < .0001]). CONCLUSIONS Elevated initial TSH (clinical or subclinical hypothyroidism) may correspond to better functional outcomes, whereas low initial T3/fT3 might correlate with worse outcomes in acute ischemic stroke among clinically euthyroid patients. This complex relation merits further well-designed investigations. Whether correcting thyroid profile with hormone supplementation or antagonism may lead to improved outcomes will require large, prospective, interventional studies.