Twenty-seven bleeding events were captured upon retrospective review; one patient had two events hence a total of 26 patients were reviewed. Nine bleeding events occurred with rivaroxaban while 18 occurred with dabigatran. All except four patients were over the age of 70 years with a median age of 78 years (range 52–91 years). Approximately 69 % (18/26) of patients were male. Three individuals were underweight (less than 60 kilograms) while the median weight was 78.3 (range 50–150) kilograms. The median time taking the DOAC prior to bleeding was 120 days (range 5–810). The indications for DOAC therapy included the following: atrial fibrillation (n = 24), deep vein thrombosis (n = 1), and two patients (7 %) treated for an off-label indication (one for cancer associated pulmonary embolism and the other for prophylaxis for an automated implantable cardioverter-defibrillator. Of the nine rivaroxaban associated bleeds, five occurred at a dosage of 20 mg daily and four at 15 mg daily. Of the 18 dabigatran bleeds, eight occurred at a dosage of 150 mg twice per day and ten at 110 mg twice per day. The median number of concomitant medications was 7 (range 1–16). Five bleeding events occurred while the patient was taking concomitant aspirin therapy, five events with non-steroidal anti-inflammatory drugs (NSAIDs) and three occurred with concomitant P-glycoprotein (P-gp) inhibitors.
Eighty-nine percent of the bleeding events were classified as a major hemorrhage with 50 % requiring RBC transfusion. Of those who were transfused with RBCs, a median of 2.5 units (range 1–9) was required. Half of the dabigatran patients were transfused with RBCs (median 3 units, range 1–3) compared to 44 % treated with rivaroxaban (median 2 units, range 1–4).
Eleven (42 %) bleeding events were intracranial (ICH) and 13 (50 %) were gastrointestinal (GI) in origin. Of note, two of these events were combined ICH and GI hemorrhages. Of the 13 GI hemorrhages, nine were associated with dabigatran use and four with rivaroxaban. There were 11 ICH events, six occurred in dabigatran users and five in rivaroxaban users. There was no statistically significant association between dabigatran versus rivaroxaban use and type of hemorrhage using a two-tailed Fischer’s exact test (p = 0.68). More patients with GI bleeds received RBC transfusion (62 %), as compared to ICH (27 %).
The remaining four bleeds involved the following sites: vaginal, pulmonary, subcutaneous or musculoskeletal with some occurring in combination. One of these events was associated with a motor vehicle collision (Fig. 1).
Data were reviewed for risk factors (found in previous observational studies) associated with DOAC bleeding. In this study, all bleeding events occurred in the context of at least one previously identified associating factor and 63 % occurred with more than one. Specifically, 50 % of subjects were above 80 years of age and 33 % of cases occurred with severe (<30 ml/min) or moderate (30–50 ml/min) impairment in creatinine clearance at time of bleeding. Five subjects had comorbid diabetes mellitus, five were on concomitant aspirin and another 19 % were taking a NSAID (Table 1). Of the 26 patients, 14 were on a reduced dose of dabigatran (110 mg) or rivaroxaban (15 mg). All of those patients were either of older age or had impaired renal function. Fifty percent of those on standard dose DOAC were older or had abnormal kidney function.
Of the 18 dabigatran related bleed events (in 17 patients), five (28 %) received aPCC alone, two (11 %) received aPCC and PCC, 13 (72 %) received at least one hemostatic support of any kind and five (28 %) did not receive any hemostatic therapy. Of the nine rivaroxaban related bleeding events, six (67 %) received at least one hemostatic support (two (22 %) received aPCC, two (22 %) received PCC) and three (33 %) did not receive any hemostatic therapy.
APCC tended to be administered to a larger number of patients with ICH - six (54 %) - compared with isolated GI hemorrhage - one (8 %). However, a similar proportion of individuals received hemostatic therapy of any kind (63 % for ICH and 69 % for GI bleed) (Table 2).
Hemostatic response to aPCC and/or PCC seemed to differ according to the DOAC. Of the nine total patients that received aPCC, three (all dabigatran related) had resolution of bleeding within 12 to 24 h of administration. Of the five total patients that received PCC, one bleed (rivaroxaban related) had resolution of bleeding at 24 h and there was no abnormal intra-operative bleeding in another rivaroxaban related case. CBC, PT and aPTT were the most commonly ordered initial laboratory tests. However, the frequency of repeated testing was highly variable. Concise summarization of laboratory data was not possible. Furthermore, we cannot comment on the pattern of coagulation study normalization due to inconsistencies within the dataset.
There were five TE events in subjects who received transfusion based hemostatic therapy (i.e. aPCC, PCC, FP and/or platelets). All of the events were arterial in nature involving either myocardial infarction or bowel ischemia. A single arterial TE event occurred within 24 h of hemostatic transfusion (aPCC). There were no TE events in patients who did not receive transfusion based hemostatic therapy.
The median length of hospital stay was 11 days (range 1–90). There were six deaths (four dabigatran and two rivaroxaban) (23 % of cases). The cause of death was ICH in five patients and one death occurred secondary to multi-organ failure and myocardial infarction. The proportion of ICH resulting in death was 45 %.
