Introduction

Intracranial hemorrhage (ICH) is an inclusive term referring to several different conditions, including hemorrhagic stroke, subdural hematoma, and epidural hematoma, and is characterized by the extravascular accumulation of blood within the skull. Approximately 20% of all strokes are due to ICH. Of these, most consist of intracerebral hemorrhage and subarachnoid hemorrhage.^1,2 Moreover, it is also important to remember two other, less common, pathological entities: subdural and epidural hematoma, which are both frequently associated with head trauma, especially in the elderly.^3-5

These bleeding events are a growing cause of death and disability worldwide due to the increasing number of elderly people, and the increasing use of oral anticoagulants (OACs) and antiplatelet agents.⁶ In particular, ICH is the most serious complication of oral anticoagulant therapy (OAT), with mortality rates in excess of 50%, and three times higher than that of ischemic stroke.⁷

The use of warfarin and other vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) for prevention of ischemic stroke has considerably increased after the publication of several studies proving their efficacy.^8,9 Although more effective than aspirin in preventing ischemic stroke in patients at risk for ischemic stroke, VKAs are, however, associated with a higher risk of ICH.¹⁰ In the 1990's, the use of warfarin in the US quadrupled and, during the same period, an increase was seen in the incidence of hemorrhagic stroke.¹¹ Important evidence suggests that even a perfectly conducted VKA treatment, with international normalized ratio (INR) between 2 and 3 in AF patients, doubles the risk of ICH.¹²

ICH in the Elderly

An important factor that contributes to the increased incidence of ICH is the aging of the world population. Several studies have shown that the annual incidence of these events in populations not treated with any anticoagulant is closely related to patients' age, as shown in Table 1. The incidences of ICH and some of its subtypes have been reported in four important literature reviews, including the comprehensive literature review with combined incidences of intracerebral hemorrhage and subarachnoid hemorrhage, in both high- and low-income countries, by Krishnamurthi et al. in 2013,¹³ the important studies by Friberg et al.¹⁴ and Singer et al.,¹⁵ and the retrospective identification of such events by Shen et al. in a multi-ethnic, stroke-free cohort hospitalized with non-rheumatic AF¹⁶ (Table 1).

Table 1: Annual incidence of intracranial hemorrhage in elderly adults not taking warfarin

Study	Year published	Population characteristics	Age	Population (n)	Intracranial bleeds (%/year)
Krishnamurthi et al10	2013	General population, high income	20-64	409,193	0.051
			65-74	273,711	0.25
			≥75	364,687	0.38
Friberg et al11	2009	AF Swedish patients, never used warfarin	<65	12,748	0.31
			65-74	13,317	0.65
			≥75	64,641	0.67
Singer et al12	2009	AF patients not receiving warfarin	<65	3,263 (<75)	0.10
			65-74		0.12
			75-84	3,090(>75)	0.43
			≥85		0.79
Shen et al13	2007	AF patients not receiving warfarin	<75	22,682	0.09
			≥75	16,343	0.23

A significant percentage of patients treated in these studies were taking aspirin, and this may not have been reported accurately. Although an analysis by Garcia-Rodriguez et al.¹⁷ indicates that the use of aspirin is apparently associated with a null or truly low increased risk of ICH (odds ratio [OR] 1.06, 95% confidence interval [CI] 0.93 to 1.21), this may not necessarily be true in patients treated with aspirin in addition to OAT.

NOACs in the Arena

There are now four non-vitamin K antagonist oral anticoagulants (NOACs) approved for primary and secondary prevention of stroke in patients with non-valvular AF in many countries around the world: dabigatran etexilate, rivaroxaban, apixaban, and edoxaban. Compared with traditional agents such as the VKAs, overall the NOACs offer benefits in terms of reduced risk of ICH (Table 2).

Table 2: Intracranial hemorrhage among patients taking NOACs

Drug and dosage	Trial	Population (n)	Events	Intracranial bleeds ITT (%/year)
Dabigatran 150 mg bid	RE-LY16	6076	36	0.30
Dabigatran 110 mg bid	RE-LY16	6015	27	0.23
Rivaroxaban 20 mg od	ROCKET-AF17	7131	67	0.57
Apixaban 5/2.5 mg bid	ARISTOTLE18	9120	52	0.33
Edoxaban 60/30 mg od	ENGAGE AF19	7035	61	0.39
Edoxaban 30/15 mg od	ENGAGE AF19	7034	41	0.26

The Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes (AVERROES) trial¹⁸ was a randomized double-blind trial designed to compare apixaban 5 mg twice-daily vs. aspirin (81-324 mg/day) for stroke prevention in patients with AF and at least one additional risk factor for stroke, but considered "unsuitable" to treatment with warfarin. In a population with a mean age of 70 years, the study reported a comparable incidence of ICH for aspirin and apixaban. 11 intracranial bleeds were reported with apixaban and 13 with aspirin (0.4% per annum for both, OR for apixaban vs. aspirin: 0.85, 95% CI 0.38-1.90).

We know that the higher the ischemic risk in AF, the greater the bleeding risk. At present, however, advantages with the use of VKAs in patients with AF by far exceed the risk of bleeding in nearly all patients. Therefore, VKAs are truly contraindicated in only a minority of people who derive a risk of bleeding greater than the extent of reduction in ischemic stroke.¹⁹ It is now clear that the NOACs, by significantly reducing the risk of ICH compared with warfarin, shift the balance even more favorably towards the benefit.

As shown in the meta-analysis by Ruff et al²⁰, the NOACs at the higher doses tested are associated with an increased risk of gastrointestinal bleeding (GI), but with a substantial reduction of ICH when compared with warfarin (risk reduction [RR] 0.48, 95% CI 0.39-0.59). The low doses of NOACs had effects comparable to warfarin on GI bleeding, but were associated with a further reduction of ICH (RR 0.31, 95% CI 0.24-0.41).

In an analysis of data from Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48),²¹ the relationship between plasma concentration of edoxaban and ICH was found to be practically flat, suggesting that ICH does not increase (much or at all) with increasing plasma concentrations. This finding contrasts with the exponential correlation between the intensity of anticoagulation with VKAs and the risk of ICH. This would point towards a specific warfarin-dependent hazard for this important clinical endpoint.²² This apparently unique dose-effect relationship is somewhat in contrast with the observed incidences of ICH, which were numerically lower in the group of patients taking a low dose of edoxaban compared with those taking the higher dose. As stated by the authors,²¹ drug concentrations are just one of the factors possibly playing a role in ICH; other individual risk factors, particularly age and renal function, are not reflected by the measurement of plasma concentrations. The effect of patient factors beyond drug concentration on bleeding has also been shown in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.²³

It is still therefore unclear at the moment whether the administration of NOACs (without concomitant antiplatelet treatment) sharply reduces the risk of ICH compared with warfarin, or truly "resets" the risk, with no true effects of these anticoagulants compared with the untreated population. Solving this issue will require additional age-adjusted analyses.

Not only is the occurrence of ICH reduced with NOACs as compared to warfarin, but also the severity of ICH appears to be lesser. ICH in patients taking rivaroxaban, for example, featured relatively smaller hematomas, no expansion of hematomas, and more favorable functional and vital outcomes when compared with warfarin-associated ICH.^24,25

Mechanisms of Reduced ICH with NOACs

Mechanisms in play to explain the lower rate of ICH with NOACs compared with warfarin are still uncertain.²⁶ Tissue factor (TF) is a transmembrane receptor for factor VIIa that is found in high concentrations in the brain.²⁷ Warfarin and the other VKAs block vitamin K–dependent γ-carboxylation of coagulation factors II, VII, IX, and X, thereby suppressing production of factor VIIa.^28,29 Additionally, we know that recombinant factor VIIa (rFVIIa) is a rapidly acting hemostatic agent that works with warfarin-related ICH, and is effective at lowering the INR³⁰ and at reducing hematoma growth.³¹ It has been hypothesized that, by selectively targeting thrombin and not interfering with the formation of TF-VIIa complexes, NOACs preserve hemostatic mechanisms in the brain that protect elderly patients against the risk of spontaneous intracranial bleeding.³²

Another possibility is the interaction of NOACs with the transport mechanism of P-glycoprotein. P-glycoprotein has an important role in restricting the entry of various drugs not only in the intestine, but also in the central nervous system.³³ Since NOACs are actively removed from the nervous system by this protein, it has been speculated that the non-increase of ICH with these drugs is also connected with this important superior safety property.^34,35

Summary

• Intracranial hemorrhage (ICH) is a growing cause of death and disability worldwide, because of the increasing number of elderly people and the increasing use of oral anticoagulants (OACs).
• Even a perfectly conducted VKA treatment, with international normalized ratio (INR) between 2 and 3 in AF patients, doubles the risk of ICH.
• ICH is significantly reduced in patients receiving new oral anticoagulants (NOACs) compared to warfarin; all four pivotal trials reported a risk reduction by roughly a half, which represents a substantial benefit of treatment with NOACs.
• The annual incidence of ICH in populations not treated with any anticoagulant is closely related to patients' age, and – when adjusted by the age of the cohort under study – it seems not too far from the annual incidence reported in patients taking NOACs.
• It has been hypothesized that, by selectively targeting thrombin and not interfering with the formation of TF-VIIa complexes, NOACs preserve hemostatic mechanisms in the brain, while warfarin does not. The lower rate of ICH reported for these drugs compared with warfarin can also be explained by the peculiar interaction of NOACs with the transport mechanism of P-glycoprotein.

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Keywords: Aged, Anticoagulants, Aspirin, Atrial Fibrillation, Brain, Cause of Death, Cerebral Hemorrhage, Confidence Intervals, Craniocerebral Trauma, Antithrombins, Double-Blind Method, Factor V, Factor VIIa, Factor Xa, Hematoma, Hematoma, Subdural, Hemorrhage, Hemostatics, Intention to Treat Analysis, International Normalized Ratio, Intestines, Intracranial Hemorrhages, Myocardial Infarction, Odds Ratio, Odds Ratio, ATP Binding Cassette Transporter, Subfamily B, Member 1, ATP Binding Cassette Transporter, Subfamily B, Pharmaceutical Preparations, Platelet Aggregation Inhibitors, Prevalence, Pyrazoles, Pyridines, Pyridones, Retrospective Studies, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Skull, Stroke, Subarachnoid Hemorrhage, Thiazoles, Thrombin, Thromboplastin, Vitamin K, Warfarin

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