Four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fixed versus variable dosing
Research and practice in thrombosis and haemostasis. 2023;7(2):100107
BACKGROUND The optimal dosing strategy of four-factor prothrombin complex concentrate (4F-PCC) to treat oral factor Xa (FXa) inhibitor-associated bleeding has not been established. OBJECTIVES To evaluate the effectiveness and safety of fixed versus variable 4F-PCC dosing for the management of FXa inhibitor-associated bleeding. METHODS A systematic literature search and meta-analysis of clinical studies was performed using PubMed, Embase, and Cochrane databases from inception to January 2022. The primary outcomes included hemostatic effectiveness, mortality, and thromboembolic events. Secondary outcomes included 4F-PCC usage, total length of stay in hospital and in intensive care units, and time to 4F-PCC administration. The pooled incidence or mean was calculated using a random-effects model and compared between the 2 dosing strategies. RESULTS Twenty-five studies were included and data from 1,760 patients (fixed dosing, n = 228; variable dosing, n = 1,532) were analyzed. There were no significant differences in hemostatic effectiveness, thromboembolic events, or mortality rates between the dosing strategies. Hospital length of stay was significantly longer in the fixed-dosing group, with a mean stay of 7.4 days (95% CI: 3.6-11.1) compared to 5.9 days (95% CI: 5.5-6.3) in the variable-dosing group (P < 0.001). The mean initial 4F-PCC dose was significantly higher with variable dosing than fixed dosing (38 IU/kg; 95% CI: 32-44 vs. 27 IU/kg; 95% CI: 26-28, P < 0.001). CONCLUSIONS A fixed-dosing strategy appears to be a safe and effective alternative to variable weight-based dosing and was associated with lower 4F-PCC usage. However, direct comparative studies are needed to confirm these results.
Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial
Modern rheumatology. 2022
OBJECTIVES We conducted a Phase 3, multicentre randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of intravenous immunoglobulin (IVIg) in patients with glucocorticoid-refractory neuropathy associated with microscopic polyangiitis. METHODS Patients received immunoglobulin or placebo intravenously for five consecutive days at baseline and after four weeks. IVIg and placebo groups received placebo and IVIg, respectively, after eight weeks. The primary and major secondary endpoint were least squares mean (LS mean) of change in manual muscle test (MMT) sum score after eight and four weeks, respectively. RESULTS A total of 37 patients were randomised into two groups (IVIg 19, placebo 18). The LS mean for change in MMT sum score after eight weeks was 9.02 for IVIg and 6.71 for placebo (difference 2.32, 95% CI -2.60 to 7.23, p = .345) and after four weeks was 6.81 and 2.83 (difference 3.99, 95% CI -1.22 to 9.19, p = .129). There were no new safety concerns for IVIg. CONCLUSIONS MMT sum scores improved with IVIg compared with placebo after eight weeks of dosing and two courses of treatment, but the differences were not statistically significant, and the results showed no clear efficacy of IVIg in this patient population. No new safety concerns were raised.
Efficacy and safety of intravenous immunoglobulin for treating refractory livedoid vasculopathy: a systematic review
Therapeutic advances in chronic disease. 2022;13:20406223221097331
INTRODUCTION Intravenous immunoglobulin (IVIG) was reported to be the third most used monotherapy in livedoid vasculopathy (LV). There is currently a lack of randomized controlled clinical trials and no standardized therapeutic regimen for IVIG therapy in LV. METHODS We performed a systematic review of the efficacy and safety of IVIG in treating patients with LV using PubMed, Cochrane, and Embase databases. RESULTS Eighty LV patients from 17 articles were included, receiving IVIG therapy at a dose of 1-2.1 g/kg body weight every 4 weeks. The effective rate of IVIG therapy in LV patients was 95% (76/80) in published studies, showing a good clinical response for resolution of pain, skin ulcerations, and neurological symptoms, and reducing the dependence on glucocorticoids and immunosuppressive agents. IVIG therapy was well tolerated, and no severe adverse events were observed. CONCLUSION Overall, to a certain degree, IVIG is probably a safe and effective treatment alternative for refractory LV patients, which still need to be confirmed by large-scale randomized controlled clinical trials.
A systematic review and meta-analysis of randomized controlled trials evaluating pharmacologic therapies for acute and recurrent pericarditis
Trends in cardiovascular medicine. 2022
Acute idiopathic pericarditis (AIP) is a benign inflammatory condition associated with high recurrence rates. Non-steroidal anti-inflammatory drug (NSAIDs) and colchicine are the recommended therapies. Our objective was to systematically assess effects of pharmacological therapies on recurrences or treatment failure in patients with first and subsequent AIP episodes. PubMed, BioMedCentral, Cochrane, Clinicaltrials.gov, Google Scholar and EMBASE (Ovid) were searched up to April 2020 for randomized controlled trials (RCT) evaluating NSAIDs, indomethacin, colchicine, steroids, intravenous immunoglobulins, immunomodulators, or interleukin receptor antagonists in adult patients with acute episode of idiopathic pericarditis. Mantel-Haenzel random effects models were used for meta-analyses, and effects were reported as odds ratios (ORs) and their 95% confidence intervals (CI). Six RCTs of colchicine plus NSAIDs (n=914 patients) and one RCT of anakinra (n=21) were found. No RCTs testing NSAIDs or corticosteroids were identified. Colchicine plus NSAIDs and anakinra significantly reduced recurrence (OR 0.37; 95%CI 0.27-0.51; and OR 0.02; 95%CI, 0.00-0.32, respectively). Colchicine plus NSAIDs also reduced treatment failure (OR 0.29; 95%CI 0.21-0.41). No differences in adverse events between colchicine and placebo were found (OR 1.16; 95%CI 0.72 to 1.86). In conclusion, Colchicine plus NSAIDS and anakinra are efficacious for preventing AIP recurrences. Colchicine reduces treatment failure as well. Although its use is supported by clinical experience, no solid evidence is currently available for the role of NSAIDs or steroids in the treatment of AIP.
Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants
Journal of the American College of Cardiology. 2021;77(24):2987-3001
BACKGROUND Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding. OBJECTIVES The aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding. METHODS The investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model. RESULTS The investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used. CONCLUSIONS The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.
Patients with severe direct oral anticoagulant-related bleeding (60 studies, n= 4,735).
4-factor prothrombin complex concentrates (n= 2,688).
Idarucizumab (n= 1,111), or andexanet (n= 936).
Mortality rates, thromboembolic events, and haemostatic efficacy were meta-analyzed using a random effects model. The mortality rate was 17.7%; 95% CI [15.1%, 20.4%], and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial haemorrhages (15.4%). The thromboembolism rate was 4.6%; 95% CI [3.3%, 6.0%], being particularly high with andexanet (10.7%; 95% CI [6.5%, 15.7%]). The effective haemostasis rate was 78.5%; 95% CI [75.1%, 81.8%] and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2%; 95% CI [5.5%, 23.1%] and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective haemostasis (relative risk: 3.63; 95% CI [2.56, 5.16]). The results were robust regardless of the type of study or the haemostatic scale used.
A Randomized Double-Blind Placebo-Control Feasibility Trial of Immunoglobulin Treatment for Prevention of Recurrent Acute Exacerbations of COPD
International Journal of Chronic Obstructive Pulmonary Disease. 2021;16:3275-3284
BACKGROUND Observational studies suggest that immunoglobulin treatment may reduce the frequency of acute exacerbations of COPD (AECOPD). OBJECTIVE To inform the design of a future randomised control trial (RCT) of intravenous immunoglobulin (IVIG) treatment efficacy for AECOPD prevention. METHODS A pilot RCT was conducted. We recruited patients with COPD hospitalized for AECOPD, or from ambulatory clinics with one severe, or two moderate AECOPD in the previous year regardless of their serum IgG level. Patients were allocated in a 1:1 ratio with balanced randomisation to monthly IVIG or normal saline for 1 year. The primary outcome was feasibility defined as pre-specified accrual, adherence, and follow-up rates. Secondary outcomes included safety, tolerance, AECOPD rates, time to first AECOPD, quality of life, and healthcare costs. RESULTS Seventy patients were randomized (37 female; mean age 67.7; mean FEV1 35.1%). Recruitment averaged 4.5±0.9 patients per month (range 0-8), 34 (49%) adhered to at least 80% of planned treatments, and four (5.7%) were lost to follow-up. There were 35 serious adverse events including seven deaths and one thromboembolism. None was related to IVIG. There were 56 and 48 moderate and severe AECOPD in the IVIG vs control groups. In patients with at least 80% treatment adherence, median time to first moderate or severe AECOPD was 275 vs 114 days, favoring the IVIG group (HR 0.76, 95% CI 0.3-1.92). CONCLUSION The study met feasibility criteria for recruitment and retention, but adherence was low. A trend toward more robust treatment efficacy in adherent patients supports further study, but future trials must address treatment adherence. TRIAL REGISTRATION NUMBER NCT0290038, registered 24 February 2016, https://clinicaltrials.gov/ct2/show/NCT02690038 and NCT03018652, registered January 12, 2017, https://clinicaltrials.gov/ct2/show/NCT03018652.
Intravenous immunoglobulin for presumed viral myocarditis in children and adults
The Cochrane database of systematic reviews. 2020;8:Cd004370
BACKGROUND This is an update of a previous review. Case reports and case series have described dramatic responses to intravenous immunoglobulin (IVIG) in people with presumed viral myocarditis, and its administration has become commonplace. OBJECTIVES The primary objective of this review was to compare event-free (death, requirement for a cardiac transplant, or placement of a left ventricular assist device) or overall (death) survival of adults and children with presumed viral myocarditis treated with IVIG versus those who did not receive IVIG. A secondary objective was to determine if a group of patients with presumed viral myocarditis could be identified (on the basis of age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virological results, or the presence or absence of histological evidence of acute myocarditis on cardiac biopsy in patients in whom a biopsy was performed) who would be the most likely to benefit from IVIG. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, DARE, CINAHL, Web of Science Core Collection, and LILACS in July 2019, and two trial registries in November 2019. We contacted authors of trials and checked reference lists of relevant papers. We applied no language restrictions. SELECTION CRITERIA We included studies if (1) participants had a clinical diagnosis of acute myocarditis with a left ventricular ejection fraction (LVEF) ≤ 0.45, left ventricular end-diastolic diameter (LVEDD) > 2 standard deviations (SDs) above the norm, or a left ventricular shortening fraction (LVSF) > 2 SDs below the mean, with duration of cardiac symptoms < 6 months; (2) participants had no evidence of non-infectious or bacterial cardiac disease; and (3) participants were randomly assigned to receive at least 1 g/kg of IVIG versus no IVIG or placebo. We excluded studies if (1) participants had received immunosuppression before outcome assessment; or (2) onset of myocarditis was reported to have occurred < 6 months postpartum. DATA COLLECTION AND ANALYSIS Two review authors independently screened the search results and extracted data. We assessed risk of bias with the Cochrane 'Risk of bias' tool. We conducted meta-analysis for two outcomes (overall survival and improvement in LVEF) with two adult trials. Other meta-analyses were not possible because only three relevant trials were included, and researchers analysed markedly different populations and used different outcome measures. MAIN RESULTS In this update we added two trials to the two previously included trials. A quasi-randomised trial was previously included due to a paucity of evidence from randomised trials; however, with the addition of two new randomised trials, it was removed from this update. For two adult trials, the overall risk of bias was unclear with very low-certainty evidence for all outcomes. The first trial studied 62 adults with recent-onset dilated cardiomyopathy randomly assigned to receive IVIG or an equivalent volume of 0.1% albumin in a blinded fashion. The effect on event-free survival between groups was uncertain (risk ratio (RR) of any event 1.76, 95% confidence interval (CI) 0.48 to 6.40). The second trial studied 41 adults with acute myocarditis randomised to either high-dose IVIG (1 to 2 g/kg over two days) or no treatment. The IVIG group reported greater survival time after 60 days (no raw data, P < 0.01), but the evidence is uncertain. We pooled the reported number of deaths in both trials, with no evidence of a difference between groups (RR 0.91, 95% CI 0.23 to 3.62, I(2) = 31%, very low-certainty evidence). The evidence on the effect of IVIG treatment on LVEF (pooled mean difference (MD) -0.01, 95% CI -0.06 to 0.05) after 12 months and an unknown time frame is uncertain. The results for functional capacity, assessed by peak oxygen consumption at 12 months, were uncertain (MD -0.80, 95% CI -4.57 to 2.97). The results for infusion-related side effects were also uncertain due to a very large CI (RR 20.29, 95% CI 1.25 to 329.93). Lastly, there was uncertain evidence addressing failure to attain complete recovery (RR 0.46, 95% CI 0.19 to 1.14). Evidence for improvement in LVEDD, left ventricular shortening fraction, and hospitalisation status in adults was not reported. In the single included paediatric trial, the overall risk of bias was low with very low-certainty evidence for all outcomes. The trial included 86 children in Egypt presenting with acute myocarditis. Children were randomly assigned to 1 g/kg IVIG daily for two consecutive days or placebo followed by echocardiography one and six months post randomisation for recording of LVEDD and LVSF. The evidence for overall survival after six months was uncertain (risk of death RR 0.48, 95% CI 0.20 to 1.15). The evidence was also uncertain for improvement in LVEDD and LVSF after six months (LVEDD MD -4.00, 95% CI -9.52 to 1.52; LVSF no raw data). Evidence for improvement in LVEF, functional capacity, side effects, complete recovery, and hospitalisation status in children was not reported. AUTHORS' CONCLUSIONS Evidence from two trials of very low certainty and with unclear risk of bias provides contradictory evidence on the use of IVIG in the treatment of adults with presumed viral myocarditis. One trial reported that use of IVIG results in longer survival time after 60 days, whilst the other trial found that IVIG does not provide an appreciable benefit. The evidence of a difference in event-free or overall survival, LVEDD, or LVSF is of very low certainty in a single paediatric trial with a low risk of bias. Until higher-quality studies with low risk of bias and larger sample sizes have demonstrated benefit in a particular group of patients, the evidence for treatment with IVIG for presumed viral myocarditis is uncertain. Further studies of the pathophysiology of myocarditis would lead to improved diagnostic criteria, which would facilitate future research.
Intravenous Immunoglobulin Therapy in Adult Patients with Chronic Idiopathic Cardiomyopathy and Cardiac Parvovirus B19 persistence
European journal of heart failure. 2020
AIM: Previous uncontrolled studies indicated a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)-related dilated cardiomyopathy (DCM). This randomized, double-blind, placebo-controlled single-centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence (NCT00892112). METHODS AND RESULTS Fifty patients (39 men; mean(±SD) age 54±11years) with chronic (>6 months) idiopathic DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200copies/μgDNA were blindly randomized to either IVIg (n=26, 2g/kg over four days) or placebo (n=24). The primary outcome was change in LVEF at six months after randomization. Secondary outcomes were change in functional capacity assessed by 6-minute walking test (6mwt), quality of life (Minnesota Living with Heart Failure Questionnaire (MLHFQ), left ventricular end-diastolic volume (LVEDV), and EMB B19V load at six months after randomization. LVEF significantly improved in both IVIg and placebo group (absolute mean (±SD) increase 5±9%, P=0.011 and 6±10%, P=0.008, respectively), without a significant difference between both groups (P=0.609). Additionally, change in 6mwt (median [IQR] IVIg 36[13;82] vs placebo 32[5;80]m, P=0.573), MLHFQ (IVIg 0[-7;5] vs placebo -2[-6;6], P=0.904) and LVEDV (IVIg -16±49 vs placebo -29±40ml/m(2) , P=0.334) did not significantly differ between both groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups. CONCLUSION IVIg therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.
Role of intravenous immunoglobulin therapy in the survival rate of pediatric patients with acute myocarditis: A systematic review and meta-analysis
Scientific reports. 2019;9(1):10459
The treatment of pediatric myocarditis is controversial, and the benefits of intravenous immunoglobulin (IVIG) are inconclusive due to limited data. We searched studies from PubMed, MEDLINE, Embase, and Cochrane Library databases since establishment until October 1st, 2018. Thirteen studies met the inclusion criteria. We included a total of 812 patients with IVIG treatment and 592 patients without IVIG treatment. The meta-analysis showed that the survival rate in the IVIG group was higher than that in the non-IVIG group (odds ratio = 2.133, 95% confidence interval (CI): 1.32-3.43, p = 0.002). There was moderate statistical heterogeneity among the included studies (I(2) = 35%, p = 0.102). However, after adjustment using Duval and Tweedie's trim and fill method, the point estimate of the overall effect size was 1.40 (95% CI 0.83, 2.35), which became insignificant. Moreover, the meta-regression revealed that age (coefficient = -0.191, 95% CI (-0.398, 0.015), p = 0.069) and gender (coefficient = 0.347, 95% CI (-7.586, 8.279), p = 0.93) were not significantly related to the survival rate. This meta-analysis showed that IVIG treatment was not associated with better survival. The use of IVIG therapy in acute myocarditis in children cannot be routinely recommended based on current evidence. Further prospective and randomized controlled studies are needed to elucidate the effects of IVIG treatment.
Intravenous Immunoglobulin Therapy for Acute Myocarditis in Children and Adults
International heart journal. 2019
The efficacy of intravenous immunoglobulin (IVIG) in the treatment of acute myocarditis remains controversial. The aim of this study was to conduct a meta-analysis to assess the efficacy of IVIG in children and adults with acute myocarditis.We searched PubMed, Scopus, Embase, Medline, the Cochrane Library, Google Scholar, and the ClinicalTrials.gov website. Eligible studies were clinical trials of patients with acute myocarditis who received IVIG therapy. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the outcomes.Thirteen studies with 1534 cases were incorporated into our meta-analysis. Pooled results showed that IVIG therapy significantly reduced in-hospital mortality (OR: 0.44, 95% CI 0.17 to 0.71, P < 0.001) and improved the left ventricular ejection fraction (LVEF) (OR: 1.73, 95% CI 1.34 to 2.13, P < 0.001) in acute myocarditis patients. Furthermore, patients with acute fulminant myocarditis (AFM) exhibited a significantly higher survival rate (OR: 2.80, 95% CI 1.16 to 6.77, P = 0.022) in the IVIG group.IVIG therapy can not only result in lower in-hospital mortality and superior recovery of left ventricular function in patients with acute myocarditis, but also increase the survival rate of AFM patients. The present study provides some supportive evidence for IVIG therapy in acute myocarditis patients.