Pharmacological Management of Spontaneous Intracerebral Hemorrhage in Older Adults

Pharmacological management of intracerebral hemorrhage in adult patients over 65 years of age requires special considerations due to differing clinical presentations, underlying organ dysfunction, and more complex medical histories and medication profiles. A literature review of articles focusing on the age-specific pharmacological management of intracerebral hemorrhage was conducted. Treatment approaches and clinical outcomes specific to older adults were evaluated and therapeutic considerations for this population are summarized. Older adults were commonly included in trials regarding reversal of anticoagulants and antiplatelet agents and these results are generalizable to older adults. Underlying organ dysfunction should frequently be considered throughout the treatment of intracerebral hemorrhage in older adults. Older adults with intracerebral hemorrhage should be managed similarly to younger adult patients; however, consideration of age-related comorbidities and physiological differences is critically important for optimizing patient care.


Introduction
As the population of older adult patients (65 years and older) continues to rise, it is expected that the incidence of intracerebral hemorrhage (ICH) will increase as well [1,2]. There are differences between the presentation and etiology of an ICH in an older adult compared to that of a younger patient, including a higher prevalence of ventricular extension of the hematoma and cerebral amyloid angiopathy in older adults [2,3]. Management of ICH in older adults is challenging from the initial assessment to treatment decisions due to a lack of evidence-based age-specific management strategies, and the fact that older adults may have cognitive disorders that complicate a neurological exam, complex medication regimens, and altered pharmacokinetics [4]. The current ICH guidelines do not specify treatment strategies for older adult patients with ICH; however, consideration of age-related comorbidities and physiological differences is critically important for optimizing patient care.
There are three main considerations for the pharmacological management of ICH -hemostasis, blood pressure management, and venous thromboembolism (VTE) prophylaxis. This article will review these treatment strategies and the supporting evidence in older adults.

Therapeutic Strategies for Hemostasis
Hemostatic abnormalities due to underlying clotting disorders or daily anticoagulant or antiplatelet use contribute to the risk of ICH and to clinical outcomes after ICH [5]. One of the primary goals of ICH treatment is to stop active bleeding and prevent hematoma expansion by rapidly addressing these abnormalities. Patients taking oral anticoagulants have up to a ten times higher risk of developing ICH than the general population [6]. Although the risk of ICH is decreased by about 50% in patients taking direct oral anticoagulants (DOACs) compared to warfarin, patients with ICH who are taking any oral anticoagulant agent have worse clinical outcomes as compared to those who do not, including a 1.62 and 1.21 times higher risk of in-hospital mortality for patients on warfarin and a DOAC, respectively [6,7]. Antiplatelet use also increases the risk of in-hospital mortality [7]. The risk of developing a devastating ICH is higher if a patient is on an antiplatelet or anticoagulant and older adults are more likely to be on these medications than the general population [8].
Hemostasis can be achieved using various treatment strategies, including prothrombin complex concentrates (PCC), vitamin K, blood products including fresh frozen plasma (FFP) and platelets, tranexamic acid, desmopressin, and anticoagulant-specific reversal agents. These therapies have been used to reduce hematoma expansion and improve outcomes in patients with ICH (Table 1). Although only two of the trials reviewed provided subgroup analyses based on age, older adults were well represented in the trials and general management strategies for older patients are similar to those recommended in published ICH guidelines for reversal of antithrombotics (Table 2) [9]. However, ICH treatment differences do exist for drug dosing for the older adult versus the younger adult patients due to the confounding variables.   Table 2 Guideline recommendations for the reversal of antiplatelet and anticoagulants in patients with intracerebral hemorrhage [9]. Treatment considerations for older adults with ICH include more complex medical histories, polypharmacy, decreased renal and hepatic function, and goals of care. When an older adult presents with ICH, home antiplatelet and anticoagulant medications should be highly suspected. A thorough medication history should be performed by interrogating the patient (if possible), family members, and the outpatient and inpatient electronic medical records, as this information may drastically alter the patient's ICH treatment strategy.
Complicated medical histories are generally accompanied by complex medication regimens, especially in older adult patients [20]. Therefore, when reviewing home medication lists, drug interactions with anticoagulant and antiplatelet agents that may increase and prolong the effects of these agents should be suspected and addressed upon admission and at discharge.
Cardiac, renal, and hepatic function must also be considered in older adults with ICH. Organ dysfunction can decrease elimination of anticoagulants and antiplatelet agents and will decrease drug clearance and extend the pharmacodynamic monitoring window for these agents. Doses of discharge medications should be properly adjusted based on organ function and drug interactions to prevent excessive anticoagulant effects and recurrent ICH.
Once ICH is controlled, the timing of anticoagulation or antiplatelet resumption is highly debated [5,21]. For older adults with more complex medical histories, the indication for anticoagulation must be considered. A mechanical heart valve or a recent cardiac stent, for example, would be reasons for restarting home anticoagulation or antiplatelet agents sooner (e.g. 7-10 days) versus later (e.g. 4-6 weeks). Table 1 summarizes the representation of older adults in select hemostasis trials. Except for the special considerations discussed above, ICH management is similar for younger and older adults ( Table 2).

Anticoagulant Reversal
Anticoagulants increase the risk of ICH and poor outcomes in both older and younger adult patients [5,6]. The oral anticoagulants that patients are prescribed in the outpatient setting include vitamin K antagonists and DOACs.
Warfarin is a vitamin K antagonist with a long half-life of about one week. Because it is an older drug, it has the most data regarding reversal of its anticoagulant effect. Vitamin K is always recommended as part of the reversal strategy for warfarin as the replacement of vitamin K is needed to reverse the effects of warfarin over time. A more recent study, the international normalized ratio (INR) normalization in coumadin-associated intracranial hemorrhages trial (INCH), established fourfactor PCC as superior to FFP for the reversal of warfarin-associated ICH [12]. Therefore, for warfarin-associated ICH, both intravenous vitamin K and PCC are recommended (Table 2) [9].
Direct oral anticoagulants consist of dabigatran, a direct thrombin inhibitor, and anti-Xa inhibitors (e.g., apixaban, edoxaban, rivaroxaban, and betrixaban). Idarucizumab, a monoclonal antibody that binds dabigatran was established as a rapid, durable, and safe reversal agent in the study of the reversal effects of idarucizumab on active dabigatran trial (RE-VERSE AD) [15].
As for the anti-Xa agents, the ideal agent for reversal is still controversial. Andexanet alfa is approved for anti-Xa inhibitor reversal with a mechanism of action of binding and sequestering anti-Xa inhibitors. Although shown to be effective in reducing factor Xa activity, andexanet alfa has not been universally accepted due to the limited data on superiority to PCCs, which was the only agent clinically effective and available for use prior to the availability of andexanet alfa, and andexanet alfa's high cost [18].
Drug interactions due to CYP enzyme induction or inhibition need to be considered as all the oral anticoagulants, except dabigatran, are metabolized by CYP3A4 and other CYP enzymes. All the DOACs are p-glycoprotein (P-gp) substrates so drug interactions with this pathway should be considered as well [22]. Dietary intake of vitamin K containing foods and antibiotic reductions in vitamin K producing gut bacteria must also be considered in patients receiving warfarin.
Apixaban, edoxaban, and rivaroxaban are recommended to be reversed with andexanet alfa or PCC when the last dose has been taken with 3-5 half-lives of the drug [9]. All of the new oral anticoagulants require renal dose adjustments, which is likely necessary for those with advanced age [22]. In patients with severe renal dysfunction, the half-lives of these medications can be increased by as much as double (Table 3) [23,24]. Considering the high cost of these newer drugspecific reversal agents, the time of the last dose of an anticoagulant should be determined, if possible, prior to administration. As for blood products such as FFP, renal function and cardiac function should be monitored due to the large fluid volumes associated with these products. Compared to FFP, PCC delivers significantly less fluid volume (approximately 90 mL vs 800 mL) and is associated with less clinical volume overload (4.7% vs 12.7%) [25].

Antiplatelet Reversal
The impact of antiplatelet agents on hematoma expansion and functional outcome is less clear than that of anticoagulant agents [7,9] Older adult patients may be on single or dual antiplatelet therapy for a variety of indications including prior stroke, myocardial infarction, peripheral artery disease, or for primary prevention of these conditions. Unlike with anticoagulants, there are no reversal agents that bind antiplatelet agents. Platelet transfusions aim to replace hindered platelets that are bound by antiplatelet agents, while desmopressin attempts to cause a release of von Willebrand factor to induce platelet adhesion [9]. Platelet infusions have been demonstrated to cause harm in an antiplatelet-associated ICH trial in which a majority of patients received aspirin and older adults were well represented [13]. In vitro studies have demonstrated that platelet transfusions are less effective in reversing the effects of ticagrelor as it and its active metabolite are still available to affect platelet aggregation after the transfusion is completed. This study concluded that platelet infusions may not be effective in reversing ticagrelor until 24 hours after the last dose [26]. More trials are required to confirm this observation. Overall, platelet transfusions have been determined to be ineffective or even to cause harm in patients with antiplatelet-associated ICH and are not recommended, except for patients undergoing surgery. Similarly, a retrospective review of patients with antiplatelet associated ICH receiving desmopressin and a platelet transfusion demonstrated no benefit to either platelet transfusion or desmopressin for this indication [19].
In addition to a lack of specific reversal agents for antiplatelet agents, there are no specific recommendations for older adults presenting with antiplatelet-associated ICH. Physiologically, older adults are likely to have reduced renal and hepatic function and this can impact drug concentrations and effects. Renal and hepatic function have a limited role when estimating the halflife of antiplatelet agents because most agents (except ticagrelor) bind platelets irreversibly and therefore are active for the lifespan of a platelet (8-20 days). Renal function does not impact the duration of action of ticagrelor, but mild hepatic impairment increases drug exposure due to its extensive liver metabolism [9,27].

Other Hemostatic Agents
Hemostatic agents are generally not recommended for spontaneous ICH, but do have use in specific situations [5,9]. Tranexamic acid and aminocaproic acid which inhibit fibrin degradation by inhibiting the conversion of plasminogen to plasmin are suggested to be used for thrombolytic (i.e., alteplase, tenecteplase) associated ICH, but cryoprecipitate is recommended as first line treatment [28]. Recombinant factor VIIa (rFVIIa) is recommended for low-molecular-weight heparin associated ICH if protamine is contraindicated [9].

Blood Pressure Management
Cerebral amyloid angiopathy is one of the more common etiologies of ICH in older adults. However, long-standing, uncontrolled hypertension is also a common cause of ICH, especially in developing countries, with high systolic blood pressures associated with worse outcomes [2,5,29]. The ideal target blood pressure for a patient with ICH is not known and has been the subject of many trials (Table 4). Guidelines have suggested goals for blood pressure control and are summarized in Table 5. However, these goals are still controversial. Based on available evidence, rapidly reducing blood pressure to 140-150 mmHg may likely balance the risk of hemorrhage expansion and cerebral autoregulation issues, although patients with higher presenting blood pressure (i.e. ≥ 180 mmHg) may have a greater risk of renal injury [30][31][32][33][34][35]. Knowledge of the patient's pre-ICH baseline blood pressures readings as well as frequent neurological assessments during hospitalization may help guide antihypertensive therapy and avoid further complications in the acute setting.  Table 5 Guideline recommendations for acute blood pressure management in patients with intracerebral hemorrhage.

Presenting
Blood Pressure 2015 AHA/ASA Guideline [5] 2017 ACC/AHA Guideline [29] SBP 150-220 mmHg SBP < 140 mmHg is safe and can improve functional outcome Immediate lowering of SBP to <140 mmHg is not beneficial and can be harmful SBP >220 mmHg Reasonable to consider aggressive reduction Reasonable to use continuous IV drugs to lower SBP Titratable antihypertensive agents and considerations for older adults are summarized in Table  6 [29]. Drugs eliminated by plasma esterases (i.e., clevidipine, esmolol) will not accumulate in patients with organ dysfunction whereas drug eliminated renally or hepatically may accumulate and cause hypotension. As with all patients, drugs with a faster onset and shorter duration of action may prevent premature escalations in dose causing precipitous drops in blood pressure. For example, clevidipine has a shorter onset and duration of action than nicardipine and therefore may be preferred in older adults. Nitroprusside is an option for blood pressure management, but generally should be avoided due to multiple safety concerns. For patients with a recent history of myocardial infarction, nitroprusside should not be used as it diverts blood from the coronary vessels. Additionally, special attention should be given to nitroprusside if it must be used in patients with renal dysfunction as toxic metabolites may accumulate. In general, older adults should be treated with lower doses and titrated more slowly. As well-defined blood pressure goals have not yet been established for ICH, other approaches to blood pressure management are under review including magnitude of blood pressure lowering and systolic blood pressure variability [40,41]. Blood pressure variability has been independently associated with neurological deterioration and unfavorable outcome (mRS ≥ 3) at 3 months after ICH [42,43]. Age specific results are not yet available for these monitoring parameters. Pretreatment blood pressure should be considered prior to determining an absolute blood pressure goal. Among patients with ICH and a presenting systolic blood pressure of ≥ 220 mmHg, intensive blood pressure lowering resulted in more neurological deterioration and kidney serious adverse events than standard systolic blood pressure lowering [44]. For all patients, the goal should be to prevent large fluctuations in blood pressure and frequent neurological assessments should be utilized to individualize therapy.

Venous Thromboembolism (VTE) Prophylaxis
The rates of symptomatic deep vein thrombosis and pulmonary embolism in patients with ICH are 1-2% and 0.5-2%, respectively, and possibly even higher in older adults with ICH [5,45,46].
Older adult patients are more likely to experience more severe symptoms associated with a VTE, but are also more likely to experience bleeding associated with prophylaxis [45]. Which therapy is preferred and when to start this intervention is not well established in any adult patient with ICH, but is even less well defined for older adults ( Table 7, Table 8).  Table 8 Guideline recommendations for venous thromboembolism prophylaxis in patients with intracerebral hemorrhage.
AHA/ASA Guidelines [5] Neurocritical Care Guidelines [56] Mechanical prophylaxis IPC at hospital admission IPC and/or GPC at hospital admission
Both heparin and low-molecular-weight heparins work by inactivating thrombin and factor Xa through enhancing anti-thrombin activity, although low-molecular-weight heparins are more specific to factor Xa. When choosing VTE prophylaxis, renal function must be considered. The halflife of the anticoagulant effect of heparin is about 1.5 hours and the dose does not change with renal or hepatic function [57]. On the other hand, low-molecular-weight heparins must be doseadjusted or avoided in patients with renal dysfunction. Enoxaparin exposure, for example, is increased by 65% in patients with severe renal impairment [58]. Dosing should be critically evaluated in patients with low body weight as exposure increases in underweight individuals [59]. Other considerations when choosing pharmacological VTE prophylaxis are drug half-life and planned invasive procedures. The half-life of the commonly used agents are 1.5 hours, 4.5 hours, and 4-5 hours for heparin, enoxaparin and dalteparin, respectively. Some institutions will perform invasive procedures while the patient is on prophylactic doses of anticoagulants, while others recommend holding doses for 4-5 half-lives.
VTE prophylaxis tends to be under used in older adults due to a perceived fear of increased risk of bleeding. However, the benefits of VTE prophylaxis frequently outweigh the risks if appropriate precautions are taken [59]. Risk factors for VTE including older age, prolonged immobility, and indwelling central venous catheters or external ventricular drains are common in ICH patients [46,60]. Considering the high risk of VTE after ICH, VTE prophylaxis should be started as soon as the hematoma has stabilized; some institutions start as early as 24 hours after the event. Although there is considerable apprehension about starting VTE prophylaxis after ICH, multiple trials have demonstrated that there is no increased risk of hematoma expansion when VTE prophylaxis is initiated within 48 hours [61][62][63]. Current guidelines recommend initiating mechanical VTE prophylaxis at the time of hospital admission and chemical VTE prophylaxis with unfractionated heparin or low-molecular-weight heparin within 1-4 days of admission in patients with stable hematomas and no evidence of ongoing coagulopathy, but preferentially within 48 hours (Table 8) [5,54]. Appropriately dosed for weight and organ function, VTE prophylaxis is recommended in all older adult patients unless a contraindication exists [64].

Summary
The ideal management of older adults with ICH aligns with guideline recommendations considering the appropriate representation of older adults in clinical trials used as supporting evidence. Older adults continue to be well represented in ICH clinical trials and age-specific outcomes should be reported to ascertain if studied treatments are safe and effective in this population. As in all disease states, patient specific factors may alter the treatment course for older adults. Medications should be appropriately chosen and dosed for renal and hepatic dysfunction, and other comorbidities and potential drug-drug interactions should be considered to optimize personalized treatment strategies.

Author Contributions
MS wrote the first draft of the paper. MS, SA, and GMB revised the manuscript and approve the final version.

Funding
The contents of this manuscript were developed in part under a grant from the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR grant number 90AR5025). NIDILRR is a Center within the Administration for Community Living (ACL), Department of Health and Human Services (HHS). The contents of this manuscript do not necessarily represent the policy of NIDILRR, ACL, HHS, and you should not assume endorsement by the Federal Government.