Direct thrombin inhibitors and factor Xa inhibitors in patients with cerebrovascular disease

Figures & data

Figure 1. Classification of anticoagulant drugs.

Examples of specific drugs are cited.

Note: this is not meant to be an exhaustive list of all agents.

LMWH: Low-molecular-weight heparin.

Figure 2. Coagulation cascade and the site of action of apixaban, rivaroxaban and dabigatran.

Table 1. Pharmacological comparison of apixaban, rivaroxaban, dabigatran and warfarin.

Studied drug	Mechanism of action	Absorption and onset of action	Bioavailability (%)	Protein binding (%)	Tmax (h)	Half-live (h)	Dosage and administration^†	Excretion (%)	Food interactions^‡	Anti-coagulation monitoring parameters	Management of bleeding complications	Common (≥1%) adverse effects
Apixaban (eliquis)	Direct, reversible factor Xa inhibitor	Rapid	85	Unknown	3	12 (± 2)	5 mg b.i.d.	Renal: 25	No food interactions	Not required PT Antifactor Xa levels	No protocol available	Bleeding
Rivaroxaban (xalerto)	Direct, reversible, factor Xa inhibitor	Rapid	80	95	3	7 (± 2) Elderly 11–13	20 mg daily	Renal: 66 (half active metabolites) Hepatic: 33 (inactive metabolites)	No food interactions	Not required PT Antifactor Xa levels	No protocol available	Nausea Increased liver enzymes Bleeding
Dabigatran (pradaxa)	Direct thrombin inhibitor	Rapid-absorption is initially slow during post-operative period	7	35	2	15 (± 2)	110 mg b.i.d. 150 mg b.i.d.	Renal: 7 Feces: 86	Food may delays absorption to 2 h, No effects of bioavailability	Not required aPTT ECT TT	No protocol available	Dyspepsia Bleeding
Coumadin (warfarin)	Inhibits vitamin K epoxide reductase complex 1	Rapid absorption Anti-coagulation effect: 24–72 h	93	99	4	40 (± 20)	Target to INR of 2.0–3.0	Renal: 92	Balanced diet with consistent vitamin K intake, strict diet required	PT/INR	Vitamin K (Phyton-adione) FFP PCC Recombinant factor VII	Bleeding

^†Dosage for secondary stroke prevention during atrial fibrillation assuming normal renal and hepatic functions.

^‡Grapefruit juice may increase levels/effects of rivaroxaban/apixaban. St John’s wort may decrease levels/effects of rivaroxaban, apixaban and dabigatran.

aPTT: Activated partial thromboplastin time; b.i.d.: Twice daily; ECT: Ecarin clotting time; FFP: Fresh frozen plasma; INR: International normalized ratio; PCC: Prothrombin complex concentrate; PT: Prothrombin time; TT: Thrombin time.

Data taken from [37,38].

Table 2. Summary of key findings of the RE-LY trial.

Studied drug	Stroke or systemic embolism^†, n (% per year)	All strokes, n (% per year)	MI, n (% per year)	Pulmonary embolism, n (% per year)	Vascular mortality, n (% per year)	All-cause mortality, n (% per year)	Major hemorrhage^‡, n (% per year)	Intracranial hemorrhage^§, n (% per year)
D-110 b.i.d. (6015)	182 (1.53)	171 (1.44)	86 (0.72)	14 (0.12)	289 (2.43)	446 (3.75)	322 (3.71)	27 (0.23)
D-150 b.i.d. (6076)	134 (1.1)	122 (1.01)	89 (0.74)	18 (0.15)	274 (2.28)	438 (3.68)	375 (3.11)	36 (0.30)
Warfarin (6022)	199 (1.69)	185 (1.57)	63 (0.53)	11 (0.09)	317 (2.69)	487 (4.13)	397 (3.36)	87 (0.74)

34% RRR of primary outcome with D-150 b.i.d. in comparison to warfarin.

69% RRR of hemorrhagic strokes with D-150 b.i.d. in comparison to warfarin.

60% RRR of all types of intracranial hemorrhage with D-150 b.i.d.

69% RRR of hemorrhagic strokes with D-150 b.i.d.

74% RRR of hemorrhagic strokes with D-110 mg b.i.d.

20% RRR of major hemorrhage with D-110 b.i.d. in comparison to warfarin.

Statistically significant increase rate of MI with D-150 b.i.d.

^†Primary outcome.

^‡Primary safety outcome.

^§Hemorrhagic stroke, subdural and subarachnoid hemorrhage.

b.i.d.: Twice daily: D-110: Dabigatran 110 mg; D-150: Dabigatran 150 mg; MI: Myocardial infarction; RRR: Relative risk reduction.

Data taken from [15].

Table 3. Summary of the ROCKET-AF trial.

Studied drug	Stroke or systemic embolism^†, n (% per year)	All strokes (%)	Myocardial infarction (%)	Non-CNS systemic embolism (%)	Vascular mortality (%)	All-cause mortality (%)	Major bleeding (%)	Intracerebral hemorrhage (%)
Rivaroxaban (7111)	188 (1.7)^‡ 269 (2.1)^§	184 (2.61)	101 (1.43)	5 (0.07)	170 (2.41)	582 (4.5)	395 (5.6)	55 (0.8)
Warfarin (7125)	241 (2.2)^‡ 306 (2.4)^§	1.65 221 (3.12)	126 (1.78)	22 (0.31)	193 (2.73)	632 (4.9)	386 (56)	84 (1.2)

^†Primary outcome.

^‡Per-protocol, as-treated population (6958 patients in the rivaroxaban group; 7004 in the warfarin group).

^§Intention-to-treat population (7081 patients in the rivaroxban group; 7090 in the warfarin group).

Data taken from [20].

Table 4. Summary of the results of the AVERROES trial.

Studied drug	Primary efficacy outcome^†, n (% per year)	Secondary efficacy outcome (% per year)		Composite of stroke, systemic embolism, myocardial infarction, death from vascular causes, and major bleeding (% per year)	First cardiac hospitalization (% per year)
		Major bleeding	Death
Apixaban 2.5 mg b.i.d.	51 patients (1.6)	44 (1.4)	3.5	5.3	12.60
Aspirin 81–324 mg daily	113 patients (3.7)	39 patients (1.2)	4.4	7.2	15.90

There was a 55% relative risk reduction of primary end point with apixaban and less cardiac hospitalizations in the apixaban group. Mortality was nonstatistically significant between groups.

^†Ischemic stroke, hemorrhagic stroke or systemic embolism.

b.i.d.: Twice daily.

Data taken from [21].

Table 5. Summary of the ARISTOTLE trial.

Studied drug	Stroke or systemic embolism^†, n (% per year)	All strokes, n (% per year)	Myocardial infarction, n (% per year)	Non CNS embolism, n (% per year)	Vascular mortality, n (% per year)	All cause mortality, n (% per year)	Major bleeding, n (% per year)	Intracerebral hemorrhage, n (% per year)
Apixaban (9120)	212 (1.27)	199 (1.19)	90 (0.53)	15 (0.09)	1.8	603 (3.53)	327 (2.13)	52 (0.33)
Warfarin (9081)	265 (1.60)	250 (1.51)	102 (0.61)	17 (0.10)	2.2	669 (3.94)	462 (3.09)	122 (0.8)

^†Primary outcome.

Data taken from [23].

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