Ethical Concerns and Outcomes in Early Stopped Clinical Trials

Date: July 29, 2024 Reference: Connolly SJ et al (ANNEXA-I investigators) Andexanet for Factor Xa Inhibitor–Associated Acute Intracerebral Hemorrhage. NEJM May 2024 Guest Skeptic: Dr. Vasisht Srinivasan is an Emergency Medicine physician and neurointensivist at the University of Washington and Harborview Medical Center in Seattle, WA. He is an assistant professor in Emergency Medicine, Neurology, and Neurosurgery at the School of Medicine at the University of Washington. Case: A 65-year-old man is brought into the emergency department (ED) by emergency medical services (EMS) after his family saw him slump over at the dinner table. He was confused, slurring his speech, and had trouble moving his right side. Initial evaluation by medics revealed right arm weakness, a right facial droop, and decreased responsiveness. When he arrives at your ED, the family tells you he was doing fine until dinner. A code stroke is activated, and a CT head shows a left basal ganglia hemorrhage with no vascular lesions on CT angiography. Vital signs show a blood pressure (BP) of 190/110, heart rate (HR) 117 and irregularly irregular, respiratory rate (RR) 18, SpO2 99% on room air. You ask the patient’s family about any other medical conditions, and they report he has high blood pressure and atrial fibrillation. He takes metoprolol and apixaban and last took his medications that morning about eight hours before. As you begin to lower his blood pressure, you start thinking about reversal agents for his anticoagulation. Background: In hemorrhagic stroke, the ABCs for resuscitation remain the same, but can also be categorized as: Airway Management: This is an important aspect for patients with a poor neurologic exam or those who are not protecting their airways. Blood Pressure Control: There is a lot of debate about the aggressiveness of blood pressure lowering. Numerous trials have attempted to determine the optimal blood pressure target to balance the two goals of minimizing hemorrhage expansion and limiting brain ischemia. INTERACT-2 demonstrated that in patients with ICH, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability (SGEM#73). ATACH-2 showed that intensive blood pressure reduction (SBP 110-139 mm Hg) does not provide benefit over standard blood pressure reduction (SBP 140-179 mm Hg) in patients with acute intracerebral hemorrhage (SGEM#172). INTERACT-3 reported the odds of a poor functional outcome were lower in the goal-directed intensive care bundle group compared to usual care (SGEM#413). Coagulopathy Reversal: It makes pathophysiologic sense that patients who take anticoagulants should have the drug rapidly reversed to prevent worsening hemorrhage and poor outcomes. However, the evidence regarding the impact of anticoagulation reversal on patient-oriented outcomes such as decreased mortality or improved neurologic function in patients with acute hemorrhagic stroke is mixed and somewhat limited. Reversal of Warfarin: Freeman et al. (2004) found that recombinant factor VIIa can rapidly reverse warfarin anticoagulation in cases of acute intracranial hemorrhage, but the study did not conclusively demonstrate a reduction in mortality or an improvement in functional outcomes. Direct Oral Anticoagulants (DOACs): Compared to warfarin, DOACs like dabigatran, apixaban, and rivaroxaban have shown lower rates of ICH in randomized controlled trials. However, the management of ICH in the setting of DOAC use remains complex. Hemodialysis can help clear dabigatran, and activated charcoal may be used for recent ingestion. Prothrombin complex concentrate (PCC) may offer some benefit in reversing DOAC-related hemorrhage. The 2022 AHA/ASA guidelines give several recommendations on blood pressure lowering and coagulopathy reversal along with an algorithm. Blood Pressure Lowering: “In patients with spontaneous ICH in whom acute BP lowering is considered, initiating treatment within 2 hours and reaching target within 1 hour can be beneficial to reduce the risk of HE and improve functional outcome” (Class 2a; LoE C-LD) “In patients with spontaneous ICH of mild to moderate severity presenting with SBP between 150 and 220 mmHg, acute lowering of SBP to a target of 140 mmHg with the goal of maintaining in the range of 130 to 150 mmHg is safe and may be reasonable for improving functional outcomes.” (Class 2b; LoE B-RP) “In patients with spontaneous ICH presenting with large or severe ICH or those requiring surgical decompression, the safety and efficacy of intensive BP lowering are not well established.” (Class 2b; LoE C-LD) Reversal: In patients with VKA-associated spontaneous ICH and INR ≥2.0, 4-factor (4-F) prothrombin complex concentrate (PCC) is recommended in preference to fresh-frozen plasma (FFP) to achieve rapid correction of INR and limit HE. (Class I; LoE B-R) In patients with direct factor Xa inhibitor-associated spontaneous ICH, andexanet alfa is reasonable to reverse the anticoagulant effect of factor Xa inhibitors. (Class 2a; LoE B-NR) In patients with direct factor Xa inhibitor-associated spontaneous ICH, a 4-F PCC or activated PCC (aPCC) may be considered to improve hemostasis. (Class 2b; LoE B-NR) In patients with dabigatran- or factor Xa inhibitor-associated spontaneous ICH, when the DOAC agent was taken within the previous few hours, activated charcoal may be reasonable to prevent absorption of the DOAC. (Class 2b; LoE C-LD) In patients with dabigatran-associated spontaneous ICH, when idarucizumab is not available, aPCC or PCCs may be considered to improve hemostasis. (Class 2b; LoE C-LD) In patients with dabigatran-associated spontaneous ICH, when idarucizumab is not available, renal replacement therapy (RRT) may be considered to reduce dabigatran concentration. (Class 2b; LoE C-LD) In patients with unfractionated heparin (UFH)-associated spontaneous ICH, intravenous protamine is reasonable to reverse the anticoagulant effect of heparin. (Class 2a; LoE C-LD) In patients with low-molecular-weight heparin (LMWH)-associated spontaneous ICH, intravenous protamine may be considered to partially reverse the anticoagulant effect of heparin. (Class 2b; LoE C-LD) Today’s episode centers on “C”, and how best to reverse the direct oral anticoagulants (DOACs) (e.g. apixaban, rivaroxaban, edoxaban) that are direct factor Xa inhibitors. The most common agent for anticoagulant reversal was initially fresh frozen plasma (FFP).  Over time, prothrombin complex concentrate (PCC) began to be used, with 3-factor and 4-factor variants, offering high concentrations of clotting factors in a small volume.  4-factor PCC has now largely supplanted FFP to reverse vitamin K antagonists (VKA) (e.g. warfarin).  As newer anticoagulants were developed, specific agents soon followed for directed reversal of those agents. For example, the direct thrombin inhibitor has a targeted reversal agent, idarucizumab.  We have looked at the evidence for idarucizumab on SGEM#139 and our bottom line at that time was idarucizumab is here (USA) and probably works but its patient-oriented efficacy and safety are still pending. When rivaroxaban was first released in 2008 in Europe and Canada, the best reversal agent was still unknown.  With time, PCC became utilized and had effectiveness against DOACs, finding its way into national guidelines [Fonteral et al NCC Guidelines 2016].  In 2018, andexanet alfa came to market as a targeted agent to reverse rivaroxaban and apixaban.  The ANNEXA-4 trial demonstrated reduced anti-factor-Xa activity.[1]  However, this agent was incredibly expensive which significantly limited its use.  We reviewed this on SGEM#251 and our bottom line was that the routine use of andexanet alfa in the management of bleeding patients on factor Xa-inhibitors cannot be recommended at this time. There were reports of increased thrombotic events with andexanet alfa which raised questions about its safety profile.  Finally, by this point, most centers had been using 4-factor PCC for DOAC reversal with good effect [2,3] and did not see the need to add this medication to their formulary, particularly one with a significant cost and without strong data demonstrating effectiveness. Clinical Question: In patients with intracranial hemorrhage, is andexanet alfa superior to usual care? Reference: Connolly SJ et al (ANNEXA-I investigators) Andexanet for Factor Xa Inhibitor–Associated Acute Intracerebral Hemorrhage.  NEJM May 2024 Population: Patients with an ICH who were taking a factor Xa inhibitor, with the last dose taken within 15 hours before randomization. Initially, any ICH was included, but mid-enrollment, a protocol amendment was implemented which restricted enrollment to only patients with acute intracerebral hemorrhage (not subdural or subarachnoid hemorrhage). A second protocol amendment restricted patients based on time; initially, patients were allowed to be enrolled if their scan was done within 12 hours of the onset of bleeding symptoms, and the protocol changed this to 6 hours. Exclusions: Glasgow Coma Scale score < 7, NIH Stroke Scale score > 35, planned surgery within 12 hours post-enrollment, thrombotic event within 2 weeks before enrollment and hematoma volume < 0.5 ml or > 60 ml. Intervention: Andexanet alfa either at a high-dose or low-dose bolus followed by a 2-hour infusion. Comparison: Usual care. This was defined as the intention to use PCC.  The first protocol amendment stratified patients who were to receive usual care based on the time since onset of symptoms to the baseline imaging (< 180 minutes or ≥ 180 minutes) Outcome: Primary Outcome: Hemostatic efficacy (defined as expansion of the hematoma volume by 35% or less at 12 hours after baseline,