Antiplatelet-Related ICH
Antiplatelet medication has been shown to be a risk factor for spontaneous ICH as well as increased ICH volume and increased mortality, but the exact increase has not been consistently demonstrated for any specific drug among many reports. The risk for ICH appears to be dose dependent with aspirin, the most studied agent, but exists with other agents as well. Naidech et al. demonstrated that increased platelet inhibition (as measured with VerifyNow ASA and P2Y12 tests [Accumetrics, Inc.] for aspirin and clopidogrel, respectively), correlated with increased ICH volume growth at 12 hours, volume of intraventricular hemorrhage, increased chance of death at 14 days, and poor outcome at 3 months. Additionally, Naidech et al. demonstrated that the chance of undergoing a craniotomy for ICH, when controlling for size of hemorrhage and location, was increased with pre-event aspirin use and platelet inhibition as determined by VerifyNow ASA. In a retrospective comparison of patients presenting with ICH on aspirin or Plavix (clopidogrel), Campbell et al. noted larger ICH size and decreased chance of discharge to home in the clopidogrel group. They also noted increased mortality, but this failed to reach statistical significance.
Given the likely association between antiplatelet use, ICH volume, intraventricular hemorrhage, and death, 1 possible strategy for reducing hematoma growth and mortality is to reverse the effect of antiplatelet medications by administering a platelet transfusion. A platelet transfusion of 10–12.5 units of platelets has been shown to restore normal platelet function in patients on aspirin and clopidogrel. Desmopressin has been known to increase platelet reactivity in patients treated with aspirin by releasing a greater number of von Willibrand multimers. The role of intravenous desmopressin in decreasing bleeding during cardiac surgery is controversial, whereas rVIIa has shown promise preclinically as a possible agent.
Some authors have described variations of platelet reversal regimens as standard at their centers. Naidech et al. evaluated this hypothesis by treating 45 patients with spontaneous ICH and an assay consistent with platelet inhibition, with a platelet transfusion within 12 hours of admission. Transfusion resulted in a decrease of platelet inhibition out of therapeutic range for most patients, although the dose of platelets was not standardized. Within their cohort, they identified 32 patients with a high degree of platelet inhibition, and within this subset, those who received a transfusion within 12 hours had less hematoma growth and a better outcome than those who received a transfusion after 12 hours.
The limited positive outcome of antiplatelet reversal is counterbalanced by many studies showing no benefit. Ducruet et al. compared the clinical course and outcomes in 35 patients presenting with ICH on antiplatelet therapy reversed with platelet transfusion, to 31 patients without platelet transfusion, and found no difference in hematoma growth or outcome. Nishijima et al. performed a retrospective meta-analysis of ICH secondary to trauma in patients receiving antiplatelet medication before injury. These authors identified 635 studied patients in 5 retrospective reviews in which 3 studies revealed no benefit, 1 revealed higher mortality in the transfusion cohort, and 1 demonstrated decreased mortality with transfusion (although there were 92 patients in the transfusion arm and 19 in the no-transfusion arm). Another literature review by Campbell et al. also found no clear evidence of benefit with platelet transfusion, but suggested the following protocol as a starting point for further investigation: 1) for a patient with ICH on aspirin alone, transfuse 1 pack of platelets; 2) for a patient with a small ICH on clopidogrel or a combination of therapies, administer 2 units of platelets; 3) for patients with large ICH on clopidogrel or multiple agents, administer desmopressin 3 mcg/kg intravenously and 1 pack of platelets every 12 hours for 48 hours. There is a randomized trial currently underway to evaluate antiplatelet agent reversal in ICH (Platelet Transfusion in Cerebral Hemorrhage [PATCH] trial).
One limitation of testing strategies that use platelet assays is the variability in the types of assays available. As described in Table 2, platelet activity and levels of inhibition can be measured by many different types of platelet function assays. There are multiple laboratory and point-of-care testing systems available and results are reported in units of time, change in light transmission, platelet count, surface area covered, and flow cytometry. On many of these systems, high platelet inhibition has been associated with bleeding events and low platelet inhibition with in-stent thrombosis after coronary artery stenting. Moreover, aspirin and clopidogrel resistance has been associated with poor outcome in patients with stroke. Nonetheless, multiple comparison studies have been unable to establish a correlation between the results of the various testing systems. Furthermore, point-of-care testing tends to have greater inaccuracy than hematology lab testing. There is currently no established standard to define inappropriate platelet activity.
The impact of these limitations is illustrated in multiple studies that have attempted to use platelet assay–guided therapy protocols to tailor patient medical regimens with poor results. Collet et al. randomized patients undergoing coronary artery stenting into 2 groups, 1 receiving antiplatelet medication without monitoring and 1 with monitoring utilizing the VerifyNow P2Y12 assay with medication adjustments made as necessary. At 1 year there was no difference between the 2 groups in any of the outcome measures, including death, myocardial infarction, stroke, urgent revascularization, or major bleeding event. Along similar lines, Depta et al. retrospectively reviewed patients with ischemic stroke who were subsequently placed on antiplatelet therapy, comparing patients given antiplatelet medication without testing to those followed by platelet aggregometry with appropriate dose adjustments. The authors describe a higher rate of death, ischemic events, and bleeding in the patients followed by aggregometry who subsequently received dose increases.
Stopping antiplatelet medication is not without risk. Withdrawal of antiplatelet agents before elective surgery has been shown to be a risk factor for heart attack and death. Cessation of antiplatelet therapy for those with cardiac stents is associated with a high rate of stent thrombosis and infarction, especially for drug-eluting stents. Patients with intracranial stents are at increased risk of stroke and transient ischemic attack with early withdrawal of an antiplatelet agent or resistance.
When considering antiplatelet-related ICH, determining the exact role that antiplatelet agents play in ICH formation, growth, and outcome as well as the role for antiplatelet reversal in patients with ICH requires significantly more clinical data. Currently, there is no well-supported algorithm for treating these patients. The decision to stop all antiplatelet medication needs to be carefully considered, weighing the size and morbidity of the ICH against the reason the agents were initiated. The value of platelet function assays in patients presenting with ICH is uncertain at this time. Reversing antiplatelet medication with transfusion, desmopressin, or other factors is not currently supported by strong clinical data and should be considered investigational at this juncture.