International Stroke Conference
Danny R. Rose, Jr., MD
New advances in our understanding of intracerebral hemorrhage in recent years have led to new questions, as well as revisiting previously held notions about treatment and prevention. The talks in this session covered coagulopathy reversal, anticoagulant usage in patients with a history of ICH, the relationship between statins and ICH and anti-edema therapy.
Dr. Thorsten Steiner, MD, PhD, began the session by discussing drug-induced coagulopathy reversal in ICH. The primary purpose of such therapies is to prevent hematoma expansion, which occurs in 30% of cases in the first 4 hours after ICH and is associated with increased morbidity and mortality. Anticoagulants increase this rate to upwards of 54% for vitamin K antagonists (VKAs) and 38% with direct-acting oral anticoagulants (DOACs). Timing is an important thing to consider in this scenario, given the half-life of VKAs are around 2 days, while DOACs are all around 14 hours, with peak effect somewhere between 3–4 hours. Specifically, many patients on DOACs may present in a time window when reversal would have little to no effect given the lack of active drug at the time. It is important to consider things that may cause variations in half-life for DOACs, including body size, inhibiting/inducing medications, and renal function (most important for dabigatran).
Laboratory testing plays a significant role in this issue as well. With respect to VKAs, INR is considered the standard with a cutoff value of 1.2 for reversal, but appropriate labs and cutoff values for DOACs remain unclear. Insensitive tests such as PT, aPTT, thrombin time and ecarin clotting time, among others, may not reliably represent the anticoagulant effect of DOACs. Anti-Xa levels adjusted for each individual drug is a more sensitive test, although the level that would require reversal remains unclear. VKA reversal should ideally be done with 4 factor PCC instead of FFP, given the results of the Kcentra study, the INCH trial and other studies that suggest decreased mortality and decreased early hematoma expansion. Dosing of PCC was suggested to be 10u/kg for an INR of 1.2-2 and 50u/kg for INR >2. Dr. Steiner also reviewed the literature for idarucizumab, which has been shown to effectively reverse dabigatran and andexanet alfa, which has been shown to reverse factor Xa inhibitors. Lastly, he discussed the possibility of using PCC to reverse factor Xa inhibitors when such medications are not available. He cited studies suggesting that this therapy improves aPTT time, but no good data exists on whether or not this improves clinical outcomes. In fact, a study by Gerner et. al published in Annals in 2018 (ST Gerner et al. Ann Neurol 83 (1), 186-196.) suggests that there may be no clinical benefit for doing so.
Dr. Ashkan Shoamanesh, MD, reviewed the hotly debated topic of restarting anticoagulation after ICH in patients with atrial fibrillation. AHA guidelines recommended against restarting warfarin in their 2015 guidelines and indicated that data concerning DOACs was insufficient. One reason for this is that a history of previous ICH was an exclusion criterion in all of the initial DOAC trials. Given this uncertainty, the rates of anticoagulant resumption vary widely. One of the more interesting studies he cited was taken from a German registry that showed decreased mortality when anticoagulation was resumed. One striking note from this study was the rate of ischemic stroke in ICH survivors in this cohort was significantly higher than would have been suggested by their CHA₂DS₂-VASc score, which may indicate that this population is at a higher risk of both recurrent hemorrhage and new ischemic stroke that is not adequately reflected in our most used scoring models.
Dr. Shoamanesh cited a study by Biffi et. al (Ann Neurol. 2017 Nov;82(5):755-765) that strongly supported resuming anticoagulation, with a 4-fold increase in favorable outcome in those patients. This was a durable finding, even when separately looking at lobar hemorrhages and patients who met imaging criteria for probable Cerebral Amyloid Angiopathy. He suggested an optimum time of 2–8 weeks for resumption of anticoagulation and aggressive risk mitigation in these patients by discouraging alcohol use, encouraging smoking cessation and exercise, fall prevention and blood pressure control. In the last part of his talk, he discussed the role of left atrial appendage closure, which has shown equivalence to warfarin but has not been compared directly to DOACs. Consistent literature suggesting lower hemorrhage rates in DOACs as compared to warfarin, coupled with the aggressive antiplatelet regimen used in LAA closure, suggests this may not be a superior option to DOACs in this patient population.
Dr. Guido Falcone, MD, discussed the issue of statin therapy in ICH. While statins have several proven benefits related to stroke, including reducing cholesterol, reducing MI/CVA risk and possibly improving functional outcome, data suggesting that they may increase the risk of ICH has made decisions about statin therapy complex in patients with high risk of ICH. He posed two main clinical questions: In patients who have had new ICH and are on a statin, should you stop or continue the medication? In addition, should patients with new ICH who are not on a statin be placed on one?
He cited the well-known and often discussed SPARCL trial, which showed that high dose atorvastatin decreased ischemic stroke risk but slightly raised the risk of ICH, in addition to other studies, which posit that this may be primarily due to reduction of LDL levels. Dr. Falcone also discussed the ERICH study, a Mendelian randomization study that showed, among other things, that high cholesterol might be protective against ICH. Dr. Falcone argued that RCTs are most needed for patients with high risk of ICH and unfavorable untreated lipid profiles with secondary indications for statin therapy to better establish the risk/benefit in this group. He argues against rapid statin discontinuation based on data suggesting harm and not starting a statin in patients at high risk of ICH with favorable untreated lipid profiles.
Dr. Joao A Gomes, MD, gave the final talk of the session regarding anti edema therapy for perihematomal edema (PHE) in ICH. PHE is a radiographic diagnosis that is difficult to differentiate from leukoaraiosis. PHE increases most rapidly in the first 48 hours after ICH, with females having higher PHE, as well as patients with intraventricular hemorrhage. Higher hematoma size is associated with higher PHE, but smaller hematomas have more relative PHE with respect to ICH volume. He notes that APOE allele status, blood pressure, blood glucose, temperature, sodium levels and medications all contribute to PHE. He breaks PHE down into three main stages: Stage 1 (first 24 hours) is the ionic stage and driven mostly by shifts in sodium and other ion concentrations. Stage 2 (days 2–3) is the inflammatory stage, driven mostly by cytokines, and Stage 3 (3d–3 weeks) is driven by iron toxicity. Despite a wealth of studies about PHE, it is unclear what aspects of PHE result in worsened outcomes. The strongest evidence in this regard is the rate of expansion of edema.
Treatment of PHE is specific for each stage. Hypertonic saline is the most commonly used therapy for the ionic stage of PHE, with some studies in patients with ICH of >30cc showing decreased edema with a sodium goal of 145–155 for 12 days. The INTERACT study showed that for every 10 degrees centigrade of ambient temperature increase, PHE increased by approximately 0.12 cc. A study by the Cleveland Clinic looking at forced normothermia for 5 days after ICH showed decrease in PHE. Several medications have been studied to combat the inflammatory phase of edema, including pioglitazone, celecoxib and fingolimod, with the fingolimod trial showing improved clinical exam and outcomes in addition to PHE volume reduction. Iron chelators like desferoxamine have been studied in ICH as well, with some studies suggesting reduced PHE. A major limitation of many of these studies is the primary endpoints being edema reduction instead of clinical outcomes, especially when the link between absolute volume of edema and clinical outcome is so uncertain.
Overall, this session was incredibly informative and densely packed with information regarding advances in our understanding of ICH. As ongoing trials attempt to answer the questions currently being raised in this and other forums, we should have more clarification on several of these topics in the coming years.