Risk of long-term anticoagulation under sustained severe arterial hypertension: A translational study comparing warfarin and the new oral anticoagulant apixaban

Abstract

New oral anticoagulants for the prevention of stroke and systemic embolism in patients with atrial fibrillation have recently been introduced. In this translational study, we explored the risk of long-term anticoagulation on intracerebral hemorrhage under sustained severe arterial hypertension. We initiated anticoagulation with warfarin or apixaban in spontaneously hypertensive rats prone to develop severe hypertension and subsequent intracerebral bleeding complications. A non-anticoagulated group served as control. During an 11-week-study period, blood pressure, anticoagulation parameters, and clinical status were determined regularly. The incidence of histopathologically proven intracerebral hemorrhage was defined as the primary endpoint. Both warfarin and apixaban anticoagulation was fairly stable during the study period, and all rats developed severe hypertension. Intracerebral hemorrhage was determined in 29% (4/14) of warfarin rats and in 10% (1/10) of apixaban rats. Controls did not show cerebral bleeding complications (chi-square not significant). Mortality rate at study termination was 33% (2/6) in controls, 43% (6/14) in the warfarin group, and 60% (6/10) in the apixaban group. Animals died from extracerebral complications in most cases. Our study describes an experimental intracerebral hemorrhage model in the context of sustained hypertension and long-term anticoagulation. Extracerebral bleeding complications occurred more often in warfarin-treated animals compared with apixaban and control rats.

Blood Pressure Lowering Decreases Intracerebral Hemorrhage Volume and Improves Behavioral Outcomes in Experimental Animals

“…On the clinical side, INTERACT II reported a strong trend towards a benefit of the intervention whereas ATACH II reported neutral or even worse outcomes. 1,2 The ani-mal data in contrast affirms that blood pressure reduction translates into a better functional outcome. In fact, in the ATACH II trial more complications occurred in the intensively treated group such as increased frequency of kidney failure.…”

“…1 The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial II (INTERACT II) study revealed a strong tendency towards improved outcomes in ICH patients subjected to intensive blood pressure lowering, 1 while the Antihypertensive Treatment of Acute Cerebral Hemorrhage Trial II (ATACH II) trial reported worse outcomes. 2 So far, the pathophysiologic consequences of intensive blood pressure lowering in acute ICH are scarcely understood. Here we describe an experimental model with translational reference to the INTERACT II and ATACH II trials.…”

“…From a translational perspective, the rapid drop of blood pressure after nifedipine administration was well comparable to what has been achieved in clinical trials (although different in its absolute size). 1,2 We consider it unlikely that nifedipine has other effects on hematoma volume and functional outcome than what is mediated via blood pressure. Moreover, calcium channel blockers were also used in the pivotal clinical trials.…”

“…Moreover, calcium channel blockers were also used in the pivotal clinical trials. 1,2 In experimental ICH, bleeding begins around 10 minutes after collagenase injection. Thus, our model well covers blood pressure lowering during the phase of hematoma expansion.…”

“…In fact, in the ATACH II trial more complications occurred in the intensively treated group such as increased frequency of kidney failure. 1,2 However, our model was not designed to capture systemic complications of intensive blood pressure lowering.…”