An update on reversal agents for Novel Anticoagulants.

• Novel anticoagulant are used in the prevention and treatment of thromboembolism. Inspite of their safety and efficacy, the lack of specific antidote to reverse its anticoagulation effects is an important limitation. 
• Idarucizumab and adexanet are new reversal agents approved by FDA for reversal of NOAC.

Idarucizumab

• It is highly selective and specific monoclonal antibody fragment (fab) which binds dabigatran with high affinity.

Dose and Administration

• Dose: 5gm infusion
  
  
  
• Availability : 2.5g/ vial
• Stability : 2-8 C

Recommendation : FDA has given full approval from 2018.

Adverse Effect

• Headache
• Constipation
• Nausea

Evidence

• RE-VERSE AD Trial( Pollack et al. NEJM. 2015) prospective cohort study was done to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding or required an urgent procedure. Study found that Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes.

• Further RE-VERSE AD Trial group published ( Pollack et al. NEJM. 2017) in his multicentric, prospective open label study done to determine whether 5gm of IV idarucizumab would be able to reverse anticoagulation effect patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B).The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B,the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals.

Andexanet

• Andexanet alfa is a modified recombinant inactive form of human factor Xa, which binds and sequesters factor Xa inhibitor molecules, rapidly reducing anti–factor Xa  activity and restoring thrombin generation.

Recommendation 

• Andexanet Alfa is approved by FDA from may 2018 to reverse apixaban and rivaraxaban in patients with life threatening or uncontrolled bleeding.

Dose & Administration 

• Dose : 
•  Low dose: 400mg @ 30mg/min followed by an infusion of 4mg/min for upto 2 hours.
• High dose: 800mg @ 30mg /min followed by 8 mg/min for upto 2 hours.

• Regimen is choosen based on time and size of the dose.

• If the last dose of rivaroxaban was 10 mg  apixaban less than 5mg or less and drug administration was less than 8 hours ago or unknown, give the low dose.

• If the last dose of rivaroxaban was more than 10 mg, apixaban more than 5mg  or of an unknown amount and drug administration was less than 8 hours ago or unknown, give the high dose.

• Route : IV
• Availability: 100mg lyophilised powder 
  
  
  
• Stability: 2-8 C
• Dilution: 100mg in 10ml sterile water

Adverse Effect

• Deep vein thrombosis,
• Arterial thrombosis,
• Pulmonary embolism, 
• Ischemic stroke, 
• Acute myocardial infarction, and death

Monitoring 

Drug effects are measurable by anti-Xa activity, free fraction of apixaban or rivaroxaban, and thrombin generation. Anti-Xa activity returns to placebo concentrations about 2 hours after a bolus or infusion, but tissue factor pathway inhibitors persist for about 22 hours after giving the drug.

• ANNEXA-I Connolly et (NEJM.2023) published a study on Andexanet for factor Xa inhibitor associated Acute ICH taken within 15h.Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P=0.003).Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P=0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke.

• ANNEXA-4 Connolly et al (NEJM.2019) published a  multicentric, prospective, open label study report (n=352)of andexanet alfa for bleeding associated with factor Xa inhibitors (Apixaban, Rivoraxaban). They  evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity 92%(baseline value 149.7 ng/ml was reduced to 11.1 ng/ml after adexanet bolus), and 82% (204 out of 249) of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria.

• ANNEXA-4 Miling et al (Circulation.2023) published a extended study(n=479) on Andexanet Alfa for major bleeding within 18 hours factor Xa inhibitors administration. Study found that in patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.

• ANNEXA A & ANNEXA R (Siegal at al. NEJM.2015) published a two part randomised, double blinded, placebo controlled study to assess the safety in older volunteers. Part 1: IV bolus alone. Part 2: IV bolus followed by continuous 120 minute infusion. ANNEX-A received apixaban 5mg BD for 3.5 days whereas ANNEXA-R received rivaroxaban 20mg OD for 4 days.On day 4 ANNEXA-A received Part 1 : 400mg bolus; Part 2: 400mg bolus followed by 4mg/min infusion for 120 minutes. ANNEXA-R recieved Part 1 : 800mg bolus; Part 2: 800mg bolus followed by 8mg/min infusion for 120 minutes. Among apixiban treated patients(n=24), anti-factor Xa activity was reduced by 94% those who received an adexanet bolus and thrombin generation was 100% restored .Among rivoraxaban treated patients(n=27), anti-factor Xa activity was reduced by 92% those who received an adexanet bolus and thrombin generation was 96% restored. These effects were sustained in bolus plus infusion. No serious adverse or thrombotic events were reported.

Arapazine/Ciraparantag/PER977 (Universal Anticoagulant)

• It is small water soluble molecule that binds to the drug inactivating it. It was originally developed as a reversal agent for heparin and fondaparinux but also seems to have activity against oral anti-Xa agents and dabigatran.

• Current phase II studies have employed a single IV bolus, with laboratory evidence of reversal observed by 30 minutes. No FDA approval yet. 

Conclusion

• Two main reversal agents  Idarucizumab for dabigatran and Andexanet  for Factor Xa Inhibitors is FDA approved and will change how anticoagulants are used and potential bleeding complications are treated. Ongoing development and probable fast track approval of Arapazine a universal anticoagulant may be game changer. 

Updated on 25/10/2024

Reference

• Reed M, Tadi P, Nicolas D. Andexanet Alfa. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519499/
• Milling TJ Jr, Kaatz S. Preclinical and Clinical Data for Factor Xa and "Universal" Reversal Agents. Am J Med. 2016 Nov;129(11S):S80-S88. doi: 10.1016/j.amjmed.2016.06.009. Epub 2016 Aug 27. PMID: 27575436; PMCID: PMC5568764.
• Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2142. doi: 10.1056/NEJMc141180
• Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431-441. doi: 10.1056/NEJMoa1707278. Epub 2017 Jul 11. PMID: 28693366.
• Hu TY, Vaidya VR, Asirvatham SJ. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag. 2016 Feb 17;12:35-44. doi: 10.2147/VHRM.S89130. PMID: 26937198; PMCID: PMC4762436.

Do we need to humidify oxygen in ER ???

What is bubble humidifier ?

• These are simple, low cost device with  water containers in which gas is forced to escape through a tube placed at the bottom. The gas bubbles collect moisture as they move towards the water surface and pass through an outlet connected to an oxygen delivery device.
•  The resultant use of cold bubble humidification generates an absolute humidity of only 10–20 g/m³ at standard room temperature against the physiological requirements of at least 34 g/m³ in trachea and 44 g/m³ below carina.

Evidence

• Zhang et (Medicine.2022) had done a open lable, single centre , RCT (n=213) done to evaluate the effects and safety of humidified versus non humidified low-flow oxygen therapy in children with Pierre-Robin syndrome. Study found  no significant differences in the average arterial PaO₂ and PaCO₂ level on the postoperative day 1, 2, and ICU discharge between humidified group and non humidified group were found (all P > .05). There were no significant differences in the incidence of nasal cavity dryness, nasal mucosal bleeding, bacterial contamination and VAP, the duration of ICU stay between humidified group and non humidified group (all P > .05).

• Santana et al (Scientific Reports. 2021) in a small RCT(n=31)  showed that Cold bubble humidification is not able to reduced nasal inflammation, eNO, oxidative stress, mucociliary clearance, and nasal mucosa moisture. However, subjects report improvement of nasal dryness symptoms (P < 0.05). In the conclusion, cold bubble humidification of low flow oxygen therapy via a nasal cannula did not produce any effect on the nasal mucosa and did not attenuate the oxidative stress caused by oxygen. However, it was able to improve nasal symptoms arising from the use of oxygen therapy.

• Poiroux et al (Annals of Intensive Care. 2018) done a randomised, multicentric, non inferiority trial (n=354) to explore whether delivering dry oxygen instead of bubble-moistened oxygen had an impact on discomfort of ICU patients. study concluded that dry oxygen could not be demonstrated as non-inferior compared to bubble-moistened oxygen after 6–8 h of oxygen administration. At 24 h, dry oxygen was non-inferior compared to bubble-humidified oxygen for flows below 4 L/min.

• Franchini et al (Respiratory Care. 2016) had done a study to investigate the effects of dry- (Nasal Low Flow Oxygen) NLFO and cold bubble humidified-NLFO on nasal mucociliary clearance (MCC), mucus properties, inflammation, and symptoms in subjects with chronic hypoxemia requiring long-term domiciliary oxygen therapy. He concluded that subjects receiving chronic NLFO, cold bubble humidification does not adequately humidify inspired oxygen to prevent deterioration of MCC, mucus hydration, and pulmonary function. The unheated bubble humidification performed no better than no humidification.

BTS 2008 Emergency Oxygen Guidelines - Humidification 

• Humidification is not required for the delivery of low-flow oxygen (mask or nasal cannulae) or for the short-term use of high-flow oxygen. It is not therefore required in prehospital care.
•  It is reasonable to use humidified oxygen for patients who require high-flow oxygen systems for more than 24 hours or who report upper airway discomfort due to dryness.
• Bubble bottles which allow a stream of oxygen to bubble through a container of water should not be used because there is no evidence of a clinically significant benefit but there is a risk of infection.
• Consider use of a large volume oxygen humidifier device for patients requiring high-flow rates or longer term oxygen, especially if sputum retention is a clinical problem.

WHO Guidelines on using humidifiers

The water level in the humidifier should be checked twice daily and topped up as necessary.

• Humidifier equipment must be washed and disinfected regularly to prevent bacterial
• The water in the humidifier should be changed daily, and the humidifier, water jar and catheter should be washed in mild soapy water, rinsed with clean water and dried in air before reuse.
• Once a week (for the same patient) and in between patients, all the components of the humidifier should be soaked in a mild antiseptic solution for 30 minutes, rinsed with clean water and dried in air. Allowing the humidifier to dry completely will discourage bacterial colonization.
• At every change, check for leakages between the flowmeter and humidifier and between he humidifier and oxygen delivery device.
• A spare, clean humidifier filled with clean water should always be available, so that oxygen therapy is not interrupted while the humidifier is being cleaned.

Humidifier and Nosocomial infection

• Fauci et al (J Prev Med Hyg. 2017) done a study to evaluate the safety of the reuse of humidifiers by analysing the rate of microbial contamination in reusable and disposable oxygen humidifiers used during therapy.The study was done at University Hospital of Messina, Italy. They found high rates of microbial contamination were observed in samples from reusable oxygen humidifiers employed in medical (83%), surgical (77%) and emergency (50%) areas. The most relevant pathogens were Pseudomonas aeruginosa, amongst the Gram-negative bacteria, and Staphylococcus aureus, amongst the Gram-positive bacteria. Other pathogens were detected in lower percentage. The disposable oxygen humidifier samples showed no contamination.

• Jadhav et al (J Clin Diagn Res. 2013) done a study  to determine the rate of colonization by bacteria and fungi of the oxygen humidifier chambers of the portable cylinders and central lines at our hospital. The study found 53/70 (75.71%) samples showed fungal growth; out of which, 23/33 (69.70%) were from the ICU, 24/30(80%) were from the wards and 6/7 (85.71%) were from the OPDs. Study also found even after the 70% ethanol disinfection and strict compliance with the hand hygiene, the colonization rates reduced significantly. The fungal colonization rate was reduced and only 15% fungi grew after the disinfection, while only 12% bacterial colonization rate was found.

Conclusion

 Humidification of oxygen for low flow devices or high flow devices for short duration <24 hour is  not recommended. Humidification of oxygen can improve patient comfort, but when used appropriate precautions and guidelines should be followed to prevent infection.

Reference

• O'Driscoll BR, Howard LS, Earis J, Mak V. British Thoracic Society Guideline for oxygen use in adults in healthcare and emergency settings. BMJ Open Respir Res. 2017 May 15;4(1):e000170. doi: 10.1136/bmjresp-2016-000170. PMID: 28883921; PMCID: PMC5531304.
• Dasgupta S, Ghosh S, Chandra A. Cold Bubble Humidification of Oxygen: Old habits die hard. Sultan Qaboos Univ Med J. 2022 Aug;22(3):309-313. doi: 10.18295/squmj.1.2022.002. Epub 2022 Aug 25. PMID: 36072067; PMCID: PMC9423755.
• WHO-UNICEF Technical specifications and guidance for oxygen therapy devices. 

Can snake bite cause ischemic stroke

Snake bite and related complications are common. Bleeding manifestation is one of the dreaded complication mainly IC bleed, but ischemic stroke is rare complication following snake bite.

What is the evidence ?

There are multiple case reports and case series. 

• Sahoo et al (Indian J Crit Care Med. 2018 ) had reported a case of snake bite (hematotoxic) leading to  ischemic stroke.
• Siddalingana et al (Annals of Indian Academy of Neurology.2014) has reported a case of posterior circulation ischemic stroke following russels viper bite.
• Huang et al (Toxins. 2022) in his review article on cerebral complications of snake bite envenoming has reported that ischemic stroke is most frequent CNS complication  following viper envenomation. 
• Jeevagan et al  (Thrombosis Journal.2012) has reported a case of ischemic stroke following humped nose pit viper bite. 

Mechanism

• Viper venom has both anticoagulant and procoagulant effect. the procoagulation and platelet-aggregating properties are due to the presence of cerastobin, factor IVa, cerastocytin, cerastotin, and afaacytin.  These various protein products have thrombin-like enzyme activity; different toxins activate different parts of the coagulation cascade, resulting in the formation of fibrin in the blood stream that leads to small and even large vessel occlusions due to the micro-thrombi which in turn will result in cerebral infarction, or toxin which may cause severe vasospasm.

• Toxic vasculitis may also lead to infract. 

• Hyperviscosity caused by hypovolemia may also lead to vessel occlusion. 

Presumed mechanisms for cerebral complications following snakebite envenoming. SVMPs: Snake-venom metalloproteinases; SVSPs: Snake-venom serine proteases; PLA₂: Phospholipase A2; LAAOs: L-amino-acid oxidase; Snaclecs: Snake C-type lectin-like proteins; N/A: Not applied.

Conclusion

• Ischemic stroke following snake bite is rare complication. multiple mechanism are attributed to developed of ischemic stroke, procoagulation &  platelet aggregation properties of venom is believed to be the main pathway. Russels viper is believed to more associated with ischemic complication.

Reference

• Sahoo AK, Sriramka B. Acute Reversible Ischemic Stroke after Snake Bite. Indian J Crit Care Med. 2018 Aug;22(8):611-612. doi: 10.4103/ijccm.IJCCM_455_17. PMID: 30186014; PMCID: PMC6108302.

• Toxins 2022, 14(7), 436; https://doi.org/10.3390/toxins14070436