Disease-modifying treatments for primary autoimmune haemolytic anaemia
The Cochrane database of systematic reviews. 2021;3:Cd012493
BACKGROUND Primary autoimmune haemolytic anaemia (AIHA) is an autoantibody mediated condition characterised by a variable disease course. A myriad of immunomodulatory agents have been employed but there is a paucity of evidence to support their use or compare their effectiveness. OBJECTIVES To determine the effects of various disease-modifying treatment modalities in people with AHIHA. SEARCH METHODS We searched MEDLINE (Ovid) (1946 to 2021), Embase (Ovid) (1974 to 2021), Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to 2021), and the Cochrane Library (CENTRAL). Clinical trial registries and relevant conference proceedings were also reviewed. Records were included as of 7 March 2021. We did not impose any language restrictions. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing immunosuppressive or immunomodulatory treatments against no treatment, placebo, or another immunosuppressive or immunomodulatory treatment, for people of all age with idiopathic AIHA. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. The prioritised pre-defined outcomes included complete haematological response at 12 months, frequency of adverse events at two, six and 12 months, partial haematological response at 12 months, overall survival at six and 12 months, relapse-free survival (RFS) at six and 12 months, red blood cel (RBC) transfusion requirement after treatment at 12 months, and quality of life (QOL) as measured by validated instruments at 12 months. Based on data availability, we were only able to perform meta-analysis on frequency of complete haematological response. MAIN RESULTS Two trials were included, enrolling a total of 104 adult participants (96 randomised) with warm AIHA in the setting of tertiary referral centres, both comparing the effectiveness between rituximab (375 mg/m(2) weekly for four weeks, or 1000 mg for two doses two weeks apart) plus glucocorticoid (prednisolone 1.5 or 1mg/kg/day with taper) and glucocorticoid monotherapy. The average age of participants in the two trials were 67 and 71, respectively. One of the included studies had good methodological quality with low risk of bias, whereas the other study had high risk of performance and detection bias due to lack of blinding. Compared with glucocorticoid alone, adding rituximab may result in a large increase of complete response at 12 months (n = 96, risk ratio (RR) 2.13, 95% confidence interval (CI) 1.34 to 3.40, GRADE low-certainty evidence). Rates of adverse effects at prespecified time-points were not reported. Limited data on partial haematological response were reported. The evidence is very uncertain about the effect of adding rituximab to glucocorticoids on partial haematological response at 12 months (n = 32; study = 1; RR 3.00, 95% CI 0.13 to 68.57; GRADE very low-certainty evidence). RBC transfusion need at 12 months was reported in one study, with four participants (mean number of packed red cell units 4.0 ± 2.82) from the rituximab group and five participants from the placebo (corticosteroid only) (mean number of packed red cell units 5.6 ± 4.15) group requiring transfusion, indicating very uncertain evidence about the effect of adding rituximab to glucocorticoids (n = 32, RR 0.80, 95% CI 0.26 to 2.45, GRADE very low-certainty evidence). The other study did not report transfusion requirement at prespecified time points but reported no difference in transfusion requirement between the two groups when comparing responders from enrolment to end of response or to the end of study follow-up (34 units versus 30 units, median [range]: 0 [1 to 6] versus 0 [1 to 5], P = 0·81). Overall survival and RFS rates at prespecified time-points were not explicitly reported in either study. Data on QOL were not available. AUTHORS' CONCLUSIONS Available literature on the effectiveness of immunomodulatory therapy for primary AIHA is restricted to comparison between rituximab plus glucocorticoid and glucocorticoid alone, in patients with newly diagnosed warm AIHA, calling for need for additional studies. The current result suggests that combinatory therapy with rituximab and glucocorticoid may increase the rate of complete haematological response over glucocorticoid monotherapy.
Primary autoimmune haemolytic anaemia (AIHA) patients (2 studies, n= 104).
Rituximab plus glucocorticoid.
Compared with glucocorticoid alone, adding rituximab may result in a large increase of complete response at 12 months. Rates of adverse effects at pre-specified time-points were not reported. The evidence is very uncertain about the effect of adding rituximab to glucocorticoids on partial haematological response at 12 months. Red blood cell transfusion need at 12 months was reported in one study. The other study did not report transfusion requirement at pre-specified time points but reported no difference in transfusion requirement between the two groups.
Effectiveness of ankle fusion in patients with hemophilia, advanced ankle degeneration, and unbearable pain for whom nonsurgical and surgical treatments have been ineffective
Expert review of hematology. 2021
INTRODUCTION In underdeveloped countries, patients with hemophilia often experience repetitive ankle joint hemorrhages due to a shortage of coagulation factors (factor VIII [FVIII] and factor IX [FIX] for hemophilia A and B, respectively). AREAS COVERED This is a narrative literature review in which we searched the Cochrane Library and MEDLINE for articles related to ankle arthrodesis in patients with hemophilia. The searches covered the period from the databases´ inception to February 28, 2021. In the event of unsuccessful hematologic prophylaxis and conservative measures (e.g., analgesics, cyclooxygenase-2 inhibitors, taping, intra-articular injections of hyaluronic acid and corticosteroids, physical and rehabilitation medicine, orthoses, radiosynovectomy, and joint-preserving surgery (e.g., removal of the distal tibia by open surgery or by arthroscopic surgery, joint debridement by arthroscopic surgery), the only surgical solution is ankle arthrodesis, which does not preserve the ankle joint. EXPERT OPINION Ankle pain is reduced after ankle arthrodesis (75% of patients experience no pain). Approximately 5% of patients require reoperation due to lack of fusion, and deep infection occurs in 2.5%. After tibiotalar fusion, a self-reported activity scale shows that approximately 12% of patients improve, 9% worsen, and 79% show no improvement. The results of ankle arthrodesis therefore appear to be poor.
Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis
Blood advances. 2021;5(8):2137-2141
The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317.
Clinical hemocompatibility of double filtration lipoprotein apheresis comparing polyethersulfone and ethylene-vinyl alcohol copolymer membranes
Artificial organs. 2021
INTRODUCTION Activation of the complement system and leukocytes by blood-membrane interactions may further promote arteriosclerosis typically present in patients on lipoprotein apheresis. As clinical data on the hemocompatibility of lipoprotein apheresis are scarce, a controlled clinical study comparing two different types of plasma separation and fractionation membranes used in double filtration lipoprotein apheresis was urgently needed, as its outcome may influence clinical decision-making. METHODS In a prospective, randomized, crossover controlled trial, eight patients on double filtration lipoprotein apheresis were subjected to one treatment with recent polyethersulfone (PES) plasma separation and fractionation membranes and one control treatment using a set of ethylene-vinyl alcohol copolymer (EVAL) membranes. White blood cell (WBC) and platelet (PC) counts, complement factor C5a and thrombin-anti-thrombin III (TAT) concentrations were determined in samples drawn at defined times from different sites of the extracorporeal blood and plasma circuit. RESULTS With a nadir at 25 min, WBC in EVAL decreased to 33.5 ± 10.7 % of baseline compared to 63.8 ± 22.0 % at 20 min in PES (P < 0.001). The maximum C5a levels in venous blood re-entering the patients were measured at 30 min, being 30.0 ± 11.2 µg/L with EVAL and 12.3 ± 9.0 µg/L with PES (P < 0.05). The highest C5a concentrations were found in plasma after the plasma filters (EVAL 56.1 ± 22.0 µg/L at 15 min vs. PES 23.3 ± 15.2 µg/L at 10 min; P < 0.001). PC did not significantly decrease over time with both membrane types, while TAT levels did not rise until the end of the treatment without differences between membranes. Regarding lipoprotein(a) and LDL cholesterol removal, both membrane sets performed equally. CONCLUSION Compared to EVAL, PES membranes cause less leukocyte and complement system activation, the classical parameters of hemocompatibility of extracorporeal treatment procedures, at identical treatment efficacy. Better hemocompatibility may avoid inflammation-promoting effects through blood-material interactions in patients requiring double-filtration lipoprotein apheresis.
Treatment of Chronic Aplastic Anemia with Chinese Patent Medicine Pai-Neng-Da Capsule () for Replacing Androgen Partially: A Clinical Multi-Center Study
Chinese journal of integrative medicine. 2021
OBJECTIVE To evaluate the efficacy and safety of Pai-Neng-Da Capsule (, panaxadiol saponins component, PNDC) in combination with the cyclosporine and androgen for patients with chronic aplastic anemia (CAA). METHODS A total of 79 CAA patients was randomly divided into 2 groups by a random number table, including PCA group [43 cases, orally PNDC 320 mg/d plus cyclosporine 5 mg/(kg·d) plus andriol 80 mg/d] and CA group [36 cases, orally cyclosporine 5 mg/(kg·d) plus andriol 160 mg/d]. All patients were treated and followed-up for 6 treatment courses over 24 weeks. The complete blood counts, score of Chinese medical (CM) symptoms were assessed and urine routine, electrocardiogram, hepatic and renal function were observed for safety evaluation. Female masculinization rating scale was established according to the actual clinical manifestations to evaluate the accurate degree of masculinization in female CAA patients treated by andriol. RESULTS The effective rates were 88.1% (37/42) in the PCA group and 77.8% (28/36) in the CA group based on the standard for the therapeutic efficacy evaluation of hematopathy. There was no significant difference in the white blood cell (WBC) counts, platelet counts and hemoglobin concentration of peripheral blood between two groups after 6 months treatment. The masculinization score of female patient in the PCA group was significantly lower than the CA group (P<0.05). The mild abdominal distention was observed in 1 cases in the PCA group. In CA group, the abnormalities in the hepatic function developed in 2 cases and the renal disfunction was found in 1 case. CONCLUSION The PNDC possesses certain curative effects in the treatment of CAA without obvious side-effects and can partially replace andriol thereby to reduce the degree of masculinization [Registried at Chinese Clinical Trial Registry (ChicTR1900028153)].
Evaluation of fixed versus variable dosing of 4-factor prothrombin complex concentrate for emergent warfarin reversal
The American journal of emergency medicine. 2021;48:282-287
STUDY OBJECTIVE This study compares the safety and efficacy of a fixed dose of 4-factor prothrombin complex concentrate (4FPCC) to the FDA-approved variable dosing for reversal of warfarin-induced anticoagulation. METHODS This was a single-center, prospective, open-label, randomized controlled trial with subjects randomized to 4FPCC at a fixed dose of 1500 IU or the FDA-approved variable dosing regimen. The primary efficacy outcome (reversal success) was defined as a post-intervention international normalized ratio (INR) of less than or equal to 1.5. Given that 4FPCC is the standard of care for reversal of warfarin-induced anticoagulation an active-controlled approach was employed with the two dosing regimens compared based on efficacy, cost, and safety outcomes. RESULTS 71 subjects (34 in the fixed dose group and 37 in the variable dose group) completed the study. There were no significant differences in age, gender, weight, initial INR, or indication for 4FPCC administration between the two treatment groups. Reversal success in the fixed-dose group was 61.8%, while in the variable dose group reversal success was 89.2%. Reversal success in the fixed-dose group was significantly lower than the rate of reversal success in the variable dose group (27.4% lower, p = 0.011). CONCLUSION The results of this study provide evidence that fixed dosing results in lower reversal success rates as compared to variable dosing of 4FPCC for warfarin-induced anticoagulation.
Factor VIII concentrate dosing with lean body mass, ideal body weight and total body weight in overweight and obesity: A randomized, controlled, open-label, 3 × 3 crossover trial
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
INTRODUCTION Obesity alters the pharmacokinetic (PK) properties of drugs making it difficult to determine the appropriate dose when administering weight-based medications. Alternative descriptors of body weight, such as lean body mass (LBM) and ideal body weight (IBW), are sometimes used in these situations. METHODS We performed a single-centre, randomized, controlled, open-label, 3 × 3 crossover trial to determine whether recombinant factor VIII (rFVIII) dosing based on LBM and IBW achieves a targeted FVIII recovery with better precision than based on total body weight (TBW) in overweight and obese, adult males with haemophilia A. Participants were randomized to 1 of 6 possible FVIII concentrate dosing sequence scenarios (TBW, LBM and IBW). Recombinant FVIII was administered on 3 separate weeks following a washout period of at least 72 hours. RESULTS A total of 19 participants were randomized and completed the study. FVIII recovery was lower at 30 minutes post-rFVIII infusion in LBM vs TBW and IBW vs TBW-based dosing, mean difference -0.38 (95% CI: -0.56, -0.20) and -0.28 (95% CI: -0.47, -0.10) IU/dL per IU/kg, respectively. In LBM vs TBW and IBW vs TBW-based dosing, there was a non-significant increase in the proportion of participants with a targeted FVIII recovery of 2.00 ± 0.20 IU/dl per IU/kg, OR = 1.93 (95% CI: 0.44, 8.55) and OR = 3.65 (0.80, 16.72), respectively. DISCUSSION Based on our study's findings, overweight and obese patients with haemophilia A may benefit from an individualized PK analysis using LBM and IBW to determine the most accurate, and potentially cost-effective, method of achieving targeted FVIII recovery.
Outcomes for studies assessing the efficacy of hemostatic therapies in persons with congenital bleeding disorders
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
INTRODUCTION Management strategies and hemostatic treatments to achieve control of bleeding are relevant across many disease areas. Identification of primary outcomes for studies assessing hemostatic intervention was the objective of a National Heart, Lung and Blood Institute (NHLBI) sponsored multidisciplinary initiative. The aim of this report is to summarize the evidence reviewed, and the outcomes identified by the subgroup tasked to assess outcomes for inherited bleeding disorders. METHODS The subgroup decided to focus on haemophilia, the prototypal congenital bleeding disorder and the one with the largest available body of evidence. MEDLINE, EMBASE and PsycINFO, The Cochrane Review, CINAHL, and Web of Science were searched for systematic and narrative reviews on outcomes used in haemophilia clinical trials. Three different clinical goals were identified as typical objectives of future research. RESULTS Out of 1322 unique citations, 24 reviews published in the period 2002-2019 were included. We identified 113 outcome measures, categorized in 6 domains: health-related quality of life (HRQoL), comorbidities and mortality, overall physical functioning and participation, bleeding and hemostasis, joint health, and costs and resource use. Three different clinical goals were identified as typical objectives of future research: Episodic 'on demand' replacement therapy, prevention of bleeding (Prophylaxis), and long-term and overall impact of bleeding. For each of these scenarios, specific outcomes were recommended. CONCLUSIONS Primary outcomes for clinical trials assessing the efficacy of hemostatic treatment in achieving control, prevention and limiting long-term consequences of bleeding in inherited bleeding disorders are suggested, and their strength and limitations discussed.
Biological stratification of clinical disease courses in childhood immune thrombocytopenia
Journal of thrombosis and haemostasis : JTH. 2021
BACKGROUND In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes. OBJECTIVE To predict the response to intravenous Immunoglobulins (IVIg) and ITP disease course using genetic and immune markers. METHODS Children aged below seven years with newly diagnosed ITP (N = 147) from the TIKI study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies. RESULTS In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 x 10(9) /L) that lasted for at least one month (complete sustained response; CSR) and 32 exhibited no or a temporary response (absence of a sustained response; ASR). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: 1) hemoglobin; 2) platelet count; 3) genetic polymorphisms of FcγRIIc; 4) the presence of IgG anti-platelet antibodies; and 5) preceding vaccination. The ASR sensitivity was 0.91 (95% CI, 0.80 - 1.00) and specificity was 0.67 (95% CI, 0.53 - 0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during one-year follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses. CONCLUSIONS The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
Procedure-related bleeding risk in patients with cirrhosis and severe thrombocytopenia
European journal of clinical investigation. 2021;:e13508
BACKGROUND Gaps of knowledge still exist about the potential association between severe thrombocytopenia and increased risk of procedure-associated bleeding in patients with liver disease. METHODS In this narrative review we aimed at examining the association between procedure-related bleeding risk and platelet count in patients with cirrhosis and severe thrombocytopenia in various settings. We updated to 2020 a previously conducted literature search using MEDLINE/PubMed and EMBASE. The search string included clinical studies, adult patients with chronic liver disease and thrombocytopenia undergoing invasive procedures, any interventions and comparators, and haemorrhagic events of any severity as outcome. RESULTS The literature search identified 1,276 unique publications, 15 studies met the inclusion criteria and were analysed together with those identified by the previously search. Most of the new studies included in our analysis did not assess the association between post-procedural bleeding risk and platelet count alone in patients with chronic liver disease. Furthermore, some results could have been biased by prophylactic platelet transfusions. A few studies found that severe thrombocytopenia may be predictive of bleeding following percutaneous liver biopsy, dental extractions, percutaneous ablation of liver tumours, and endoscopic polypectomy. CONCLUSIONS Currently available literature cannot support definitive conclusions about the appropriate target platelet counts to improve the risk of bleeding in cirrhotic patients who underwent invasive procedures; moreover, it showed enormous variability in the use of prophylactic platelet transfusions.