Modeling the Clinical Implications of Andexanet Alfa in Factor Xa Inhibitor–Associated Intracerebral Hemorrhage

Background and Objectives:Andexanet alfa was recently approved as a reversal agent for the Factor Xa inhibitors (FXai) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. We aimed to explore potential clinical implications of andexanet alfa in FXai-associated ICH in this simulation study.Methods:We simulated potential downstream implications of andexanet alfa across a range of possible hemostatic effects using data from a single center that treats FXai-associated ICH with prothrombin complex concentrate (PCC). We determined baseline probabilities of inadequate hemostasis across FXai and non-FXai patients via multivariable regression models, then determined probabilities of unfavorable 3-month outcome (modified Rankin Scale 4-6) using models comprising established predictors and each patient’s calculated probability of inadequate hemostasis. We applied bootstrapping with model parameters from this derivation cohort to simulate a range of hemostatic improvements and corresponding outcomes, then calculated absolute risk reduction (relative to PCC) and projected number needed to treat (NNT) to prevent one unfavorable outcome.Results:Training models using real-world patients (n=603 total; 55 FXai) had good accuracy in predicting inadequate hemostasis (AUC 0.78) and unfavorable outcome (AUC 0.78). Inadequate hemostasis was strongly associated with unfavorable outcome (OR 4.5, 95% CI 2.0-9.9) and occurred in 11.4% of FXai patients. Across simulated FXai patients comparable to those in the ANNEXA-4 study, predicted absolute risk reduction of unfavorable outcome was 4.9% (95% CI 1.3%-7.8%) when the probability of inadequate hemostasis was reduced by 33%, and 7.4% (95% CI 2.0%-11.9%) at 50% reduction, translating to projected NNTs of 21 (cumulative cost $519,750) and 14 ($346,500), respectively.Discussion:Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered. Placebo-controlled randomized trials are needed before its use can definitively be recommended.

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Abstract MP39: Modeling the Clinical Implications of Andexanet Alfa in Factor Xa Inhibitor-Associated Intracerebral Hemorrhage

Stroke ◽

10.1161/str.52.suppl_1.mp39 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Carlin Chuck ◽

Daniel Kim ◽

Roshini Kalagara ◽

Nathaniel Rex ◽

Tracy Madsen ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Absolute Risk ◽

Factor Xa ◽

Unfavorable Outcome ◽

Model Parameters ◽

Clinical Implications ◽

Number Needed To Treat ◽

Derivation Cohort ◽

Andexanet Alfa ◽

Hemostatic Effects

Background: Andexanet alfa was recently approved as a reversal agent for the Factor Xa inhibitors (FXai) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. Methods: We performed a simulation study to determine the potential clinical implications of andexanet alfa across a range of possible hemostatic effects using data from a single-center cohort of ICH patients who did not receive the drug. We used this data to determine the baseline probability of insufficient hemostatic efficacy (IHE) across patients with and without FXai use via k-fold cross-validated multivariable regression models, which we aggregated into an IHE propensity score. We then determined the probability of unfavorable 3-month outcome (modified Rankin Scale 4-6) using a model comprised of established clinical predictors and IHE propensity. We applied model parameters from this derivation cohort to simulate a range of IHE reductions and corresponding outcomes, which we used to calculate absolute risk reduction (ARR) and projected number needed to treat (NNT) to prevent one unfavorable outcome. Results: Training models using a real-world ICH cohort (n=604 total; 55 FXai patients) had good accuracy in predicting IHE (AUC 0.78) and unfavorable outcome (AUC 0.82). IHE was strongly associated with unfavorable outcome (OR 6.7, 95% CI 3.8-11.8) and occurred in 11.4% of FXai patients. Predicted ARR of unfavorable outcome was 5% (95% CI 3-8%) at one-third reduction of IHE and 8% (95% CI = 4-13%) at 50% IHE reduction, translating to a projected NNT of 20 (cumulative treatment cost $495,000) and 13 ($321,750), respectively. Conclusion: Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered, and placebo-controlled randomized trials are needed before its use can definitively be recommended.

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Non–Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Atrial Fibrillation Patients With Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.118.023797 ◽

2019 ◽

Vol 50 (4) ◽

pp. 939-946 ◽

Cited By ~ 7

Author(s):

Peter Brønnum Nielsen ◽

Flemming Skjøth ◽

Mette Søgaard ◽

Jette Nordstrøm Kjældgaard ◽

Gregory Y.H. Lip ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Risk Reduction ◽

Vitamin K ◽

Risk Ratio ◽

Absolute Risk ◽

Oral Anticoagulants ◽

Absolute Risk Reduction ◽

Vitamin K Antagonist

Background and Purpose— Recurrent bleeding associated with oral anticoagulants (OACs) causes a dilemma in patients with atrial fibrillation (AF) sustaining an intracerebral hemorrhage. Treatment recommendations guiding clinical practice on optimal OAC agent selection in this population are lacking. This study aimed to investigate the comparative effectiveness and safety of non–vitamin K antagonist OAC (NOAC) versus warfarin in patients with AF sustaining an intracerebral hemorrhage. Methods— We conducted a nationwide observational cohort study including patients with AF sustaining an intracerebral hemorrhage and who subsequently claimed an OAC prescription. Contrasts of 1-year risks for ischemic stroke and intracerebral hemorrhage risks were obtained and evaluated by inverse probability treatment weighted absolute risk reduction and risk ratios. Results— Among 622 AF patients with intracerebral hemorrhage, 274 claimed a warfarin prescription and 348 a NOAC prescription. Mean age was 76 years (39% females); 72% had an index nonsevere event and 28% moderate to severe index event according to the Scandinavian Stroke Severity scale. The 1-year ischemic stroke risk was 7.85% for warfarin and 4.01% for NOACs, with a weighted absolute risk reduction of 3.78% (95% CI, −0.15% to 7.71%); the weighted risk ratio was 0.52 (0.27–1.00). For recurrent intracerebral hemorrhage, the risk was 7.00% for warfarin and 5.07% for NOACs. The absolute risk reduction was 1.93% (−2.02% to 5.87%), with an a weighted risk ratio of 0.72 (0.38–1.38). Conclusions— NOACs were associated with a nonsignificant lower risk of ischemic stroke and recurrent intracerebral hemorrhage compared with warfarin. The results add to current recommendations of selecting a NOAC agent for stroke prophylaxis treatment in patients with AF, including those with sustaining an intracerebral hemorrhage.

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Use of pre-operative calcium and vitamin D supplementation to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy: a systematic review

The Journal of Laryngology & Otology ◽

10.1017/s0022215121001523 ◽

2021 ◽

pp. 1-6

Author(s):

A S Khatiwada ◽

A S Harris

Keyword(s):

Systematic Review ◽

Vitamin D ◽

Clinical Trials ◽

Total Thyroidectomy ◽

Risk Reduction ◽

Operative Treatment ◽

Absolute Risk ◽

Absolute Risk Reduction ◽

Vitamin D Supplementation ◽

Absolute Reduction

Abstract Objective This systematic review aimed to establish the evidence behind the use of pre-operative calcium, vitamin D or both calcium and vitamin D to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy. Method This review included prospective clinical trials on adult human patients that were published in English and which studied the effects of pre-operative supplementation with calcium, vitamin D or both calcium and vitamin D on the rate of post-operative hypocalcaemia following total thyroidectomy. Results Seven out of the nine trials included reported statistically significantly reduced rates of post-operative laboratory hypocalcaemia (absolute risk reduction, 13–59 per cent) and symptomatic hypocalcaemia (absolute reduction, 11–40 per cent) following pre-operative supplementation. Conclusion Pre-operative treatment with calcium, vitamin D or both calcium and vitamin D reduces the risk of post-operative hypocalcaemia and should be considered in patients undergoing total thyroidectomy.

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Amblyopia screening effectiveness at 3–4 years old: a cohort study

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2020-000599 ◽

2021 ◽

Vol 6 (1) ◽

pp. e000599

Author(s):

Sandra Guimaraes ◽

Andreia Soares ◽

Cristina Freitas ◽

Pedro Barros ◽

Ricardo Dourado Leite ◽

...

Keyword(s):

Risk Reduction ◽

Treatment Effectiveness ◽

Absolute Risk ◽

Absolute Risk Reduction ◽

Number Needed To Screen ◽

History Of ◽

Disease Study ◽

New Diagnosis ◽

Screening Effectiveness ◽

Timely Referral

ObjectiveTo study the effectiveness of amblyopia screening at ages 3–4.Methods and AnalysisFrom a population with no previous screening, a cohort of 2300 children with 3–4 years old attending school (91% of children this age attend school in Portugal), were submitted to a complete ophthalmological evaluation. Amblyopia was diagnosed, treated and followed. Amblyopia prevalence, treatment effectiveness, absolute risk reduction (ARR), number needed to screen (NNS) and relative risk reduction (RRR) were estimated.ResultsPast/present history of amblyopia was higher than 3.1%–4.2%, depending on amblyopia definition normatives. Screening at age 3–4, had estimated ARR=2.09% (95% CI 1.50% to 2.68%) with a reduced risk of amblyopia in adulthood of 87% (RRR). NNS was 47.8 (95% CI 37.3 to 66.7). Treatment effectiveness of new diagnosis was 88% (83% if we include children already followed). 91% of new amblyopia diagnoses were refractive (of which 100% surpassed amblyopia Multi-Ethnic Pediatric Eye Disease Study criteria after treatment), while most strabismic amblyopias were already treated or undertreatment. Only 30% of children with refractive amblyopia risk factors that were not followed by an ophthalmologist, ended up having amblyopia at age 3–4. Eye patch was needed equally in new-diagnosis versus treated-earlier refractive amblyopia.ConclusionsScreening amblyopia in a whole-population setting at age 3–4 is highly effective. For each 48 children screened at age 3–4, one amblyopia is estimated to be prevented in the future (NNS). Screening earlier may lead to overdiagnosis and overtreatments: Treating all new diagnosis before age 3–4 would have a maximal difference in ARR of 0.3%, with the possible burden of as much as 70% children being unnecessary treated before age 3–4.Involving primary care, with policies for timely referral of suspicious/high-risk preverbal children, plus whole screening at age 3–4 seems a rational/effective way of controlling amblyopia.

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Abstract P297: Long-Term Benefit Comparison of Absolute Risk Reduction versus Absolute Risk to Prioritize Statin Therapy

Circulation ◽

10.1161/circ.137.suppl_1.p297 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Ciaran N Kohli-Lynch ◽

Andrew E Moran ◽

George Thanassoulis ◽

Allan D Sniderman ◽

Yiyi Zhang ◽

...

Keyword(s):

Risk Factor ◽

Statin Therapy ◽

Risk Reduction ◽

Treatment Initiation ◽

Absolute Risk ◽

Treatment Strategies ◽

Absolute Risk Reduction ◽

Statin Treatment ◽

Policy Model

Introduction: Individuals with no established cardiovascular disease (CVD) are currently recommended preventive statin therapy based on 10-year absolute risk (AR) of CVD, and individuals with a 10-year AR ≥7.5% are recommended statins. However, individuals with elevated LDL cholesterol experience greater absolute CVD absolute risk reduction (ARR) from statin therapy compared with those with the same 10-year AR but with lower LDL. A previous study showed that ARR-based statin treatment would prevent more CVD events than AR-based treatment in the 10 years following treatment initiation. Objective: This study aimed to quantify the long-term benefits of treating patients based on ARR rather than AR. Methods: A microsimulation version of the CVD Policy Model, a decision-analytic state transition model, simulated intermediate-strength statin therapy in 40,000 CVD-free US adults (50% female) under a variety of treatment strategies. The model predicts health outcomes for individuals based on their age, sex, and risk factor profile, accounting for the competing risk of non-CVD mortality. Individuals entered the model aged 40 years, and a time horizon of 40 years was employed. Life year gains and CVD events prevented compared to no treatment were estimated for a range of 10-year ARR and AR treatment initiation thresholds. Results: At the same numbers of patient-years of treatment (PYoT), ARR consistently produced more life year gains than AR (Figure). A 10-year ARR threshold of ≥2.62% would lead to approximately the same PYoT as standard of care (10-year AR ≥7.5%) while preventing 60 additional CVD events and producing 421 additional life year gains in the cohort. Conclusion: Treating patients with statins based on ARR would yield significant health gains in the U.S. population compared to standard AR-based treatment strategies. The ARR strategy may also achieve greater adherence and uptake as it focuses on individuals with elevated levels of a modifiable risk factor.

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Abstract TP352: Safety and Efficacy of Andexanet Alfa in Patients With Life Threatening Intracerebral Hemorrhage: A Single Center Experience

Stroke ◽

10.1161/str.51.suppl_1.tp352 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Syed Daniyal Asad ◽

Stephanie R Lombardi ◽

Ilene Staff ◽

Amre M Nouh ◽

Mark J Alberts

Keyword(s):

Intracerebral Hemorrhage ◽

Factor Xa ◽

Hospital Length ◽

Factor Xa Inhibitors ◽

Hematoma Expansion ◽

Amyloid Angiopathy ◽

Single Center ◽

Discharge Disposition ◽

Ischemic Complications ◽

Andexanet Alfa

Background: Intracerebral hemorrhage (ICH) is a devastating condition with high 30- day mortality. Up to a third of patients experience hematoma expansion within the first 24 hours; anticoagulation with factor Xa inhibitors may increase the risk of expansion and poor outcomes. Objective: We assessed our experience using Andexanet alfa (Aα) by evaluating stabilization of the hematoma and ischemic complications. Methods: We conducted a single center prospective observational study on all patients receiving Aα for reversal of anticoagulation in the setting of an ICH and use of Factor Xa inhibitors. The degree of hematoma expansion within 12 hours of drug administration on non-contrast head CT was categorized as 'excellent' (<20% increase in hematoma size), ‘good' ( > 20-<35%), and 'poor' ( > 35%). Secondary outcomes included dosage, median length of stay, mortality, modified Rankin score (mRS), discharge disposition, and ischemic complications. Results: Fifteen patients received Aα (5=lobar, 5=deep, 5= multicompartment). One patient with a presumed deep hemorrhage was excluded because subsequent imaging showed chronic mineralization. The predominant etiologies were hypertension (40%), amyloid angiopathy (26.6%) and trauma (13.3%). The median age was 86 years (IQR 19) and median ICH score on arrival was 2 (IQR 2), and median hematoma size was 14.3 mL (IQR 34.5). Most patients (71.4%) received the low dose formulation. Based on hematoma expansion, 64.3%, 14.3% and 21.4% of patients achieved excellent, good and poor hemostasis, respectively. Reduction in hematoma size was seen in 20% (n=3) while 13.3% (n=2) patients had no expansion. Median ICU and hospital length of stays were 2.0 days (IQR 2.2) and 6.6 days (IQR 9.78) respectively. Mortality was 28.6% and median mRS upon discharge was 4 (IQR 2), with most patients discharged to rehabilitation facilities (60%). There were no ischemic complications. Conclusion: Our experience is consistent with the results of the ANNEXA 4 study with 78.6% of patients showing excellent or good hemostasis. These results led to improved clinical outcomes, with 60% of patients being discharged to rehabilitation. These data support the efficacy of this treatment paradigm in a real-world setting.

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Folic Acid and Folinic Acid for Reducing Side Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.130738 ◽

2014 ◽

Vol 41 (6) ◽

pp. 1049-1060 ◽

Cited By ~ 60

Author(s):

Beverley Shea ◽

Michael V. Swinden ◽

Elizabeth Tanjong Ghogomu ◽

Zulma Ortiz ◽

Wanruchada Katchamart ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Trials ◽

Folic Acid ◽

Side Effects ◽

Folinic Acid ◽

Risk Reduction ◽

Absolute Risk ◽

Absolute Risk Reduction ◽

Risk Of Bias ◽

Serum Transaminase

Objective.To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit.Methods.We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.Results.Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as “moderate” for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as “low.” There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001].Conclusion.The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.

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