Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm

INTRODUCTION — Unruptured intracranial aneurysms are detected in up to 2 to 3 percent of older adults who undergo high-quality noninvasive intracranial arterial imaging (eg, magnetic resonance angiography, computed tomographic angiography). Subarachnoid hemorrhage from a ruptured intracranial aneurysm is associated with a short-term mortality of 40 percent, with one-half of survivors sustaining permanent neurologic injury. Thus, detection of an asymptomatic unruptured aneurysm creates a management dilemma in patients who have indications for antithrombotic therapy. (See "Unruptured intracranial aneurysms".)

This topic review will discuss issues related to anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm.

THEORETICAL EFFECTS OF ANTITHROMBOTIC MEDICATION USE — Rates of rupture for previously detected unruptured aneurysms vary according to their size (ie, there is a greater risk of rupture in larger aneurysms), specific location (eg, higher rates of rupture with posterior circulation aneurysms) [1], as well as history of prior subarachnoid hemorrhage from a separate aneurysm [2]. This subject is reviewed in depth separately. (See "Unruptured intracranial aneurysms", section on 'Risk factors for aneurysm rupture'.)

It is not known whether antithrombotic therapies influence the rate of rupture of intracranial aneurysms. By reducing thrombus formation in the aneurysmal sac, it is possible that antithrombotic therapy could increase rates of aneurysm rupture. Antithrombotic and antiplatelet therapies also could exacerbate the severity of the hemorrhage in case of rupture, perhaps even converting intramural or minor subarachnoid hemorrhages into major, life-threatening bleeding.

Conversely, aspirin could reduce the risk of rupture by inhibiting inflammatory mediators (such as matrix metalloproteinases and tumor necrosis factor-alpha) that might play a role in the evolution and eventual rupture of intracranial aneurysms [3,4]. Clinical data on these points are sparse, as summarized below.

EFFECT OF ANTIPLATELET THERAPY — Available clinical data are limited and conflicting regarding the influence of aspirin and other antiplatelet agents on rates of aneurysm rupture. Overall, chronic use of antiplatelets appears safe and might even be protective in patients with unruptured, asymptomatic intracranial aneurysms.

●In the Nurses' Health Study, a large prospective longitudinal cohort study, middle-aged females who used >15 aspirin per week had twice the rate of all-cause subarachnoid hemorrhage compared with nonusers [5]. The excess risk was particularly pronounced among older and hypertensive females and was not observed among those taking lower doses of aspirin. In this study, there were an unduly large number of subarachnoid hemorrhages relative to ischemic strokes and intraparenchymal hemorrhages, although the fraction of subarachnoid hemorrhages that were due to ruptured aneurysms was not reported. Despite multivariate statistical adjustments, imbalances in other vascular risk factors between aspirin users versus nonusers in observational trials leave etiologic associations unproven.

●In contrast, aspirin use at least three times weekly was associated with a lower risk of aneurysm rupture in a nested case-control study of the untreated cohort of patients in the International Study of Unruptured Intracranial Aneurysms (ISUIA; adjusted odds ratio [OR] 0.27, 95% CI 0.11-0.67) [3]. Aspirin also prevented intracranial aneurysm rupture in an experimental mouse model [6] and this effect is thought to be mediated by cyclooxygenase-2 inhibition [7].

●A nationwide case-control study in Denmark found that recent initiation of aspirin, clopidogrel, or both was associated with increased risk of subarachnoid hemorrhage [8]. However, this increased risk was restricted to the first three months after starting antiplatelet therapy and the assessment was based on relatively small numbers of patients. Risk of subarachnoid hemorrhage was not affected by longer-term use of antiplatelet agents. Meanwhile, a population-based Dutch case-control study found no association between use of antiplatelet agents and risk of subarachnoid hemorrhage [9].

●Among patients with ischemic stroke, having an intracranial aneurysm did not result in excess risk of adverse outcomes related to antiplatelet therapy [10].

●In a retrospective case series of 362 patients, no cases of subarachnoid hemorrhage occurred despite pretreatment with dual antiplatelet therapy for three months before stent-assisted coiling or flow diversion of unruptured (often large) intracranial aneurysm [11].

Regarding the severity of subarachnoid hemorrhage, data from clinical case series have shown no apparent increase in the initial severity of bleeding and no adverse effect on long-term outcome in patients presenting with aneurysmal subarachnoid hemorrhage who were taking aspirin prior to rupture [12-14]. In an analysis of the National Inpatient Sample including 11,549 patients with aneurysmal subarachnoid hemorrhage who were treated with surgical or endovascular aneurysm repair, aspirin use was not associated with in-hospital mortality but was associated with lower rates of cardiac complications and venous thromboembolic events. Furthermore, among patients treated with endovascular repair, the rate of poor outcomes was lower among aspirin users (32 versus 37 percent; OR 0.63, 95% CI 0.42-0.94) [15].

EFFECT OF ANTICOAGULATION — No data supporting higher rupture rates following the use of anticoagulants are available from randomized clinical trials or large cohort studies. However, these studies do not convincingly exclude higher rates of aneurysmal subarachnoid hemorrhage in anticoagulated patients due to the infrequency of subarachnoid hemorrhage, which is typically combined with other causes of hemorrhagic strokes in reports of clinical trials. A population-based Dutch study noted an increased risk of subarachnoid hemorrhage in patients taking vitamin K antagonists on a case-crossover analysis (adjusted odds ratio [OR] 2.46, 95% CI 1.04-5.82), but the association was not significant on case-control and case-time-control analyses [9]. A Danish nationwide case-control study found an association between short-term (less than one month) of vitamin K antagonists and subarachnoid hemorrhage, but the association was not sustained with longer-term use of these drugs [8]. Among patients with ischemic stroke, presence of an intracranial aneurysm did not contribute to excess risk of adverse outcomes related to anticoagulation [10].

Anticoagulation might worsen the clinical outcome of aneurysmal subarachnoid hemorrhage. Death or dependency following aneurysmal subarachnoid hemorrhage occurred in 93 percent (14 of 15) of anticoagulated patients versus 49 percent of those not receiving anticoagulants in one reported case series [16]. This was due to the worse clinical status at the time of admission of anticoagulated patients as a consequence of more severe initial bleeding. A study using a large registry of hospitalized patients in the United States (the National Inpatient Sample) found that anticoagulated patients had higher crude rates of in-hospital mortality (19 versus 13 percent) and poor outcome (54 versus 38 percent), but both of these findings were not significant on multivariable analysis [15].

EFFECT OF THROMBOLYSIS — Limited data suggest that intravenous thrombolysis with recombinant tissue plasminogen activator (tPA) appears safe in patients with unruptured intracranial aneurysms who have an acute ischemic stroke [17,18]. This argues against an increased risk of rupture from the use of drugs that affect coagulation.

MANAGEMENT — American Heart Association guidelines [19,20] and major reviews [21] concerning management of unruptured intracranial aneurysms do not address the use of antiplatelet agents or anticoagulants. Given the available information as summarized above, it is not clear that antithrombotic therapies increase the risk of aneurysm rupture. However, the following observations have been made:

●Aspirin does not appear to be associated with worse clinical outcomes from aneurysmal subarachnoid hemorrhage, but the existing data are meager (see 'Effect of antiplatelet therapy' above). Consequently, at present, detection of an unruptured intracerebral aneurysm should not be regarded as a contraindication to antiplatelet therapy for patients who have a clear indication for such medication.

●Limited data suggest that anticoagulation with oral vitamin K inhibitors might worsen the severity of initial bleeding if rupture does occur (see 'Effect of anticoagulation' above). The potentially higher rates of death or disability observed after rupture of an intracranial aneurysm in patients taking anticoagulants should be considered in weighing the benefits versus risks of anticoagulation in patients known to harbor an unruptured intracranial aneurysm.

As an example, for an older adult patient with atrial fibrillation and prior stroke or transient ischemic attack who has a 10 mm unruptured aneurysm involving the anterior communicating artery, treatment with warfarin would be expected to produce an absolute reduction in the rate of stroke of approximately 6 percent per year (half of which are likely to be fatal or disabling) [22] but would augment the risk of fatal or disabling subarachnoid hemorrhage by approximately 0.25 percent per year [2,16]. In the absence of other risks, this analysis would lead one to favor anticoagulation in this particular patient.

For those patients with larger aneurysms or those whose absolute benefits from anticoagulation are smaller, the estimated harm from anticoagulation may substantially mitigate its benefits. Thus, the decision must be individualized according to the best estimates of benefits versus risks.

It is unclear how the need for chronic anticoagulation should influence the complex benefit/risk equation regarding repair of unruptured intracranial aneurysms [16,23,24]. Anticoagulation without aneurysm repair is reasonable for patients with a solid indication for anticoagulation who have aneurysms with a low estimated risk of rupture. For patients with aneurysms at higher risk of rupture, and those for whom the absolute benefits from anticoagulation are deemed smaller, the decision regarding the use of anticoagulation must be individualized according to the best estimates of benefits versus risks, accounting for patient values and preferences. Most experts do not consider a requirement for anticoagulation therapy to be an indication for aneurysm repair [25].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)

SUMMARY AND RECOMMENDATIONS

●Prevalence and complications of intracranial aneurysms – Unruptured intracranial aneurysms are detected in 2 to 3 percent of older adults. Subarachnoid hemorrhage from a ruptured intracranial aneurysm is associated with high morbidity and mortality. (See "Unruptured intracranial aneurysms" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Prognosis'.)

●Antiplatelet therapy – Based upon limited evidence, daily use of regular doses of aspirin appears to be safe and there is preliminary evidence that it might even decrease the risk of aneurysm rupture. The risks associated with other antiplatelet agents or with combination of antiplatelet agents are not known. (See 'Effect of antiplatelet therapy' above.)

●Anticoagulation – Anticoagulation may exacerbate the degree of hemorrhage in case of rupture and may worsen the clinical outcome of aneurysmal subarachnoid hemorrhage. (See 'Effect of anticoagulation' above.)

●Individualized management – Management of a patient with an unruptured intracranial aneurysm who requires treatment with an antiplatelet agent or anticoagulation for another indication requires careful evaluation of multiple factors.

•General principles – Two general principles apply to these patients (see 'Management' above):

-Detection of an unruptured intracerebral aneurysm should not be regarded as a contraindication to antiplatelet therapy for patients who have a clear indication for such medication.

-Anticoagulation without treatment of the aneurysm is reasonable for patients with a solid indication for anticoagulation who have aneurysms with a low estimated risk of rupture. For patients with aneurysms at higher risk of rupture, and those for whom the absolute benefits from anticoagulation are deemed smaller, the decision regarding the use of anticoagulation must be individualized according to the best estimates of benefits versus risks, accounting for patient values and preferences.

•Assessment of individual risks – Factors to be considered include the following (see 'Management' above):

-Risk of spontaneous rupture of the aneurysm (eg, size, location)

-Risk of thrombosis/stroke if antiplatelet/anticoagulant treatment is not given

-Risk of exacerbated bleeding from an aneurysmal rupture if anticoagulant treatment is given