Weekly epistaxis duration as an indicator of epistaxis severity in hereditary hemorrhagic telangiectasia-Preliminary results from a randomized controlled trial
Laryngoscope investigative otolaryngology. 2021;6(3):370-375
OBJECTIVES There is great interest in developing and studying novel therapies for epistaxis in hereditary hemorrhagic telangiectasia (HHT) given its associated morbidity and impact on patients' quality of life. Several recent randomized controlled trials (RCTs) have been negative, likely attributed to poorly characterized outcome measures. This study reported on and evaluated an epistaxis outcome measure, weekly epistaxis duration (WED) in an ongoing RCT, with the aim of better characterizing the measurement of epistaxis for clinical trials. MATERIALS AND METHODS Patients were recruited to an ongoing phase II, double-blind, cross-over RCTs of oral doxycycline for HHT-associated epistaxis. Patients were included for the epistaxis measures analysis if they had already completed the initial 3-month run-in period, and had received treatment of either study drug doxycycline or placebo for a minimum of 6 months. The primary measure of interest was patient-reported outcome (PRO)-WED, captured from prospective daily diaries. Epistaxis severity score (ESS) was collected as a secondary outcome. RESULTS Seven patients were included for analysis, with 98% completion of the daily diary. The average PRO-WED across all patients was 85.0 minutes, SD 93.2 at baseline, and 65.6 minutes, SD 59.5 during treatment/placebo. Coefficient of variance for PRO-WED at baseline and during treatment/placebo was 0.49, SD 0.1 and 0.58, SD 0.2, respectively. Statistically significant changes in the mean PRO-WED from baseline to treatment/placebo was noted in six patients (86%). Only two patients (29%) had a significant change in ESS, with both reporting decreased (improved) scores after treatment/placebo as compared to baseline. CONCLUSIONS PRO-WED was a feasible clinical trials measure, was reasonably stable during baseline measurement, and appeared to be variable with treatment state, suggesting it may provide a sensitive clinical trials PRO in HHT.
The Pancreatic changes affecting glucose homeostasis in transfusion dependent β- thalassemia (TDT): a short review
Acta bio-medica : Atenei Parmensis. 2021;92(3):e2021232
BACKGROUND The natural history of the glycometabolic state in transfusion-dependent β-thalassemia (TDT) patients is characterized by a deterioration of glucose tolerance over time. AIMS This review depicts our current knowledges on the complex and multifacet pathophysiologic mechanisms implicated in the development of alteration of glucose homeostasis in patients with TDT. SEARCH STRATEGY A systematic search was done on December 2020 including Web of Science (ISI), Scopus, PubMed, Embase, and Scholar for papers published in the last 20 years. Moreover, we checked the reference lists of the relevant articles and previously performed reviews for additional pertinent studies. The personal experience on the care of patients with thalassemias is also reported. CONCLUSION A regular packed red blood cells (PRBCs) transfusion program, optimization of chelation therapy, and prevention and treatment of liver infections are critical to achieve adequate glucometabolic control in TDT patients. Many exciting opportunities remain for further research and therapeutic development.
Hydroxyurea Adherence Strategies for Persons with Sickle Cell Disease: A Systematic Review
Journal of health care for the poor and underserved. 2021;32(1):99-118
INTRODUCTION Adherence to hydroxyurea is essential to modify the pathology of sickle cell disease. OBJECTIVE To identify best strategies to support adherence to hydroxyurea in persons with sickle cell disease. METHODS A systematic review was conducted. PubMed, Cumulative Index of Nursing and Allied Health Literature, PsycArticles, PsycInfo, Embase databases and Cochrane Library were searched for studies between 1998 to 2018. RESULTS Six studies met inclusion criteria: two randomized controlled trials, three prospective studies, and one retrospective chart review. DISCUSSION Few studies addressed strategies that tested adherence interventions primarily composed of behavioral change resulting in medication adherence. More studies on hydroxyurea adherence are needed.
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.
Orthopedic surgery in hemophilic patients with musculoskeletal disorders: A systematic review
Experimental and therapeutic medicine. 2021;22(3):995
Hemophilia is a hereditary coagulopathy caused by factor VIII (hemophilia type A) or by coagulation factor IX (hemophilia type B) dysfunction, characterized by an increased bleeding predisposition, which is either spontaneous or secondary to minimal trauma. Currently, hemophilia may also be considered an 'orthopedic' condition, due to the fact that it affects the musculoskeletal system of most hemophilic patients. In recent years, constant prophylaxis using coagulation factors has led to a significant improvement in the hemophilic patient's quality of life, by reducing both life-threatening hemorrhagic phenomena, as well as the occurrence of chronic complications. Nevertheless, progressive joint bleeding remains unavoidable in this category of patients, and the onset of chronic arthropathy with secondary motor deficiency remains the main complication with an invalidating character. In such cases, orthopedic management is imperative; osteoarticular complications being managed most often with the help of conservative or surgical techniques. The purpose of this review is to provide an overview of modern orthopedic practices which are useful in the management of hemophilic patients suffering from osteoarticular disorders.
Efficacy and Safety of Avatrombopag in Patients with Chronic Immune Thrombocytopenia: A Systematic Literature Review and Network Meta-Analysis
Advances in therapy. 2021
INTRODUCTION A network meta-analysis (NMA) was performed to assess the efficacy and safety of avatrombopag, relative to eltrombopag, romiplostim, and fostamatinib, for patients with chronic immune thrombocytopenia (ITP) not responding adequately to corticosteroids. METHODS A systematic search of publication and clinical trial databases was conducted to identify relevant randomized controlled trials (RCTs) and observational studies. Data from eligible studies were extracted and analyzed in a Bayesian framework using relative effect sizes vs placebo. Outcomes included durable platelet response; need for rescue therapy; reduction in use of concomitant ITP medication; incidence of any or World Health Organization (WHO) grade 2-4 bleeding events, and any adverse events. Results were reported as odds ratios or incidence rate ratios (IRR) with 95% credible intervals (CrIs). RESULTS The NMA included seven phase 3 RCTs. Compared with placebo, avatrombopag was associated with statistically significant improvements in durable platelet response, reduction in use of concomitant ITP medication, and incidence of any bleeding events. Statistically significant differences vs placebo were also observed for durable platelet response and need for rescue therapy (eltrombopag, romiplostim, and fostamatinib); reduction in use of concomitant ITP medication (eltrombopag and romiplostim); incidence of any bleeding events (fostamatinib); and incidence of WHO grade 2-4 bleeding events (romiplostim and fostamatinib). No statistically significant differences were observed for any adverse events. Avatrombopag was associated with a statistically significant lower incidence of any bleeding events vs eltrombopag (IRR 0.38 [95% CrI 0.19, 0.75]) and romiplostim (IRR 0.38 [95% Crl 0.17, 0.86]); no other between-treatment differences were observed. CONCLUSION In this NMA, avatrombopag significantly increased the chance of achieving durable platelet response and reducing the use of concomitant ITP medication vs placebo, and significantly reduced the incidence of any bleeding events compared with placebo, eltrombopag, and romiplostim. The study aims to help guide clinicians managing patients with chronic ITP and insufficient response to previous treatment.
Patients with chronic immune thrombocytopenia (ITP), not responding to corticosteroids (7 studies).
Eltrombopag, romiplostim, fostamatinib therapy or placebo.
Compared with placebo, avatrombopag was associated with statistically significant improvements in durable platelet response, reduction in use of concomitant ITP medication, and incidence of any bleeding events. Statistically significant differences vs. placebo were also observed for durable platelet response and need for rescue therapy (eltrombopag, romiplostim, and fostamatinib); reduction in use of concomitant ITP medication (eltrombopag and romiplostim); incidence of any bleeding events (fostamatinib); and incidence of WHO grade 2-4 bleeding events (romiplostim and fostamatinib). No statistically significant differences were observed for any adverse events. Avatrombopag was associated with a statistically significant lower incidence of any bleeding events vs. eltrombopag (IRR 0.38) and romiplostim (IRR 0.38); no other between-treatment differences were observed.
Pre-procedural use of thrombopoietin-receptor agonists in cirrhosis and severe thrombocytopenia: A systematic review and meta-analysis
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2021
BACKGROUND Severe thrombocytopenia in cirrhosis can preclude invasive procedures. Platelet transfusion is recommended if platelet count pre-procedure is potential alternative to platelet transfusion is thrombopoietin-receptor (TPO) agonists. AIM: Evaluate TPO-agonist efficacy and safety in cirrhotic patients with severe thrombocytopenia undergoing invasive procedures. METHODS Randomized control trials (RCT) from electronic reference databases were searched from inception till December 2019. PRISMA guidelines were followed. Primary outcome was platelet transfusion avoidance. Secondary outcomes were weighted mean difference (WMD) in platelet count from baseline to pre-procedure and rates of major adverse events (AE). Pooled Odds Ratio (OR) were estimated using a random-effects model. RESULTS Six RCTs with 1,229 patients were included. All studies had low risk of bias. Compared with placebo, those treated with TPO-agonists had a pooled OR of 0.12(0.08-0.17), P<0.01 for platelet transfusion avoidance, and WMD in platelet count (x10 3 /µL) of 35.6(28.6-42.7), P<0.01. Major AE did not differ between groups [Pooled OR: 0.87(0.47-1.62), P=0.66]. CONCLUSION Compared to placebo, TPO-agonists used in cirrhotic patients with severe thrombocytopenia prior to elective invasive procedures had 88% reduced odds of requiring peri-procedural platelet transfusion and increased platelet count pre-procedure, with no difference in AE rates.
Acquired von Willebrand syndrome in monoclonal gammopathy - A scoping review on hemostatic management
Research and practice in thrombosis and haemostasis. 2021;5(2):356-365
BACKGROUND Acquired von Willebrand syndrome (AVWS) has been associated with monoclonal gammopathy of undetermined significance (MGUS), with limited data on its management. METHODS We conducted a systematic literature search in Medline (Ovid), Embase, and Scopus up to September 11, 2019, for studies reporting on the management of AVWS associated with MGUS (AVWS-MGUS). Data on patient characteristics, laboratory parameters at presentation, and clinical and laboratory outcomes were extracted. OBJECTIVES To describe the clinical presentation and outcomes of different therapeutic approaches. RESULTS Seventy-five studies were included in the final review, for a total of 137 patients. Most patients had von Willebrand factor ristocetin cofactor activity <30 IU/dL (86.6%) and factor VIII levels <50 IU/dL (91.8%). Bleeding severity ranged from no bleeding (16.1%) to minor bleeding (46.4%) and major bleeding (37.5%). The overall clinical success rates for 1-deamino-8-D-arginine vasopressin (DDAVP), factor replacement therapy, and intravenous immunoglobulin (IVIG) were 43.8%, 33.3%, and 85.4%, respectively. The laboratory response rates for DDAVP, factor replacement therapy, and IVIG were 39.0%, 62.9%, and 88.6%, respectively. Several other treatments were also reported in small numbers, out of which myeloma-directed therapies, plasma exchange, recombinant factor VIIa, and antifibrinolytics appeared most successful, while immunosuppressive agents were largely ineffective. CONCLUSION IVIG appears to be an effective treatment for AVWS-MGUS bleeding, conferring a high clinical success rate with measurable laboratory outcomes; albeit temporary. DDAVP and factor replacement therapy may be partially successful in controlling minor bleeds, but not major bleeds. Other less commonly used agents may be effective in certain cases, although data are limited.
Inhibitor in Congenital Factor VII Deficiency; a Rare but Serious Therapeutic Challenge-A Systematic Literature Review
Journal of clinical medicine. 2021;10(2)
BACKGROUND Congenital factor (F) VII deficiency is a rare coagulation factor deficiency with an estimated incidence of 1 per 500,000 individuals. Patients with severe FVII deficiency present a broad range of clinical presentations. Alloimmunization against exogenous FVII, as the main challenge of replacement therapy, is an extremely rare phenomenon that is accompanied by a high rate of life-threatening bleeding, that renders replacement therapy less effective. Due to the importance of the issue, we performed a systematic literature review in order to assess incidence, molecular basis, clinical presentations, and therapeutic challenge and management of inhibitor in congenital FVII deficiency. Strategy of search: This systematic review was performed in accordance with PRISMA guidelines. We performed an English-language literature review in the PubMed, EMBASE, Scopus, and Google Scholar databases, using the following keywords: "factor VII inhibitor", "factor VII inhibitors", "FVII inhibitors", "congenital FVII deficiency", "recombinant factor VII", "anti rFVIIa", "replacement therapy", and "alloantibody". RESULTS Out of 380 patients in the 13 studies, 27 had inhibitor against FVII; 18 were male, 7 were female, while the sex of 2 was not stated. The majority (92%) developed a high-titer inhibitor (Bethesda Unit > 5). All patients had severe FVII deficiency (FVII:C < 10%), and the majority received recombinant FVII prior to inhibitor development (N: 24, 89%). Among ten patients with a detected mutation, three subjects had a common non-sense (30%), and two had a deletion (20%). CONCLUSIONS Inhibitor development is a relatively rare phenomenon seen only in severe FVII deficiency, where it is associated with severe and life-threatening presentations, treatment challenge, and economic burden on the patients and their families.
Serum or plasma ferritin concentration as an index of iron deficiency and overload
The Cochrane database of systematic reviews. 2021;5(5):Cd011817
BACKGROUND Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice. OBJECTIVES To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes. SEARCH METHODS We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies. SELECTION CRITERIA We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies. We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions. MAIN RESULTS Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification. We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults. Iron deficiency We included 72 studies (75 records) involving 6059 participants. Apparently healthy populations Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people. People presenting for medical care There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50. Among non-healthy adults using a fixed threshold of 30 μg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test. Iron overload We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women. Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8. AUTHORS' CONCLUSIONS At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload.