Anticoagulant-related gastrointestinal bleeding—could this facilitate early detection of benign or malignant gastrointestinal lesions?

Figures & data

Table I. Incidence of GI bleeding (reported as adverse events) with NOACs and warfarin in the phase III studies in patients with AF (ClinicalTrials.gov).

	RE-LY			ROCKET AF		ARISTOTLE
	Dabigatran 110 mg twice daily N = 5982	Dabigatran 150 mg twice daily N = 6059	Warfarin once daily N = 5998	Rivaroxaban 15 mg or 20 mg once daily N = 7111	Warfarin once daily N = 7125	Apixaban 5.0 mg or 2.5 mg, twice daily N = 9052	Warfarin once daily N = 9088
MedDRA preferred terms^a	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Enterocolitis hemorrhagic	NR	NR	NR	0 (0.00%)	1 (0.01%)	NR	NR
Diverticulitis/diverticulum intestinal hemorrhagic	1 (0.02%)	1 (0.02%)	1 (0.02%)	1 (0.01%)	3 (0.04%)	6 (0.07%)	2 (0.02%)
Gastrointestinal hemorrhage	55 (0.92%)	81 (1.34%)	63 (1.05%)	180 (2.53%)	126 (1.77%)	116 (1.28%)	97 (1.07%)
Hemorrhoidal hemorrhage	2 (0.03%)	3 (0.05%)	0 (0.00%)	6 (0.08%)	4 (0.06%)	3 (0.03%)	3 (0.03%)
Intestinal hemorrhage	3 (0.05%)	2 (0.03%)	1 (0.02%)	6 (0.08%)	6 (0.08%)	2 (0.02%)	1 (0.01%)
Intra-abdominal hemorrhage	1 (0.02%)	1 (0.02%)	0 (0.00%)	1 (0.01%)	1 (0.01%)	3 (0.03%)	1 (0.01%)
Lower gastrointestinal hemorrhage	8 (0.13%)	12 (0.20%)	3 (0.05%)	19 (0.27%)	15 (0.21%)	12 (0.13%)	12 (0.13%)
Esophageal hemorrhage	0 (0.00%)	1 (0.02%)	0 (0.00%)	4 (0.06%)	2 (0.03%)	1 (0.01%)	2 (0.02%)
‘Other’ hemorrhage	0 (0.00%)	0 (0.00%)	3 (0.05%)	6 (0.08%)	4 (0.06%)	8 (0.09%)	6 (0.06%)
Pancreatitis hemorrhagic	NR	NR	NR	0 (0.00%)	1 (0.01%)	NR	NR
Peritoneal hemorrhage	0 (0.00%)	2 (0.03%)	1 (0.02%)	2 (0.03%)	0 (0.00%)	2 (0.02%)	2 (0.02%)
Rectal hemorrhage	15 (0.25%)	13 (0.21%)	9 (0.15%)	24 (0.34%)	26 (0.36%)	19 (0.21%)	19 (0.21%)
Retroperitoneal hemorrhage	0 (0.00%)	1 (0.02%)	1 (0.02%)	1 (0.01%)	1 (0.01%)	3 (0.03%)	0 (0.00%)
Rectal ulcer hemorrhage	NR	NR	NR	0 (0.00%)	1 (0.01%)	NR	NR
Total	85 (1.42%)	117 (1.93%)	82 (1.37%)	250 (3.52%)	191 (2.68%)	175 (1.93%)	145 (1.59%)

Incidence for gastrointestinal hemorrhage includes the PTs: duodenal ulcer hemorrhage; duodenitis hemorrhagic; gastric hemorrhage; gastric ulcer hemorrhage; gastritis hemorrhagic; gastrointestinal hemorrhage; hemorrhagic erosive gastritis; upper gastrointestinal hemorrhage; gastrointestinal ulcer hemorrhage; gastroduodenal hemorrhage; peptic ulcer hemorrhage.

Incidence for esophageal hemorrhage includes the PTs: esophageal ulcer hemorrhage; esophageal hemorrhage; esophagitis hemorrhagic; esophageal varices hemorrhage.

Incidence for intestinal hemorrhage includes the PTs: intestinal hemorrhage; large intestinal hemorrhage; small intestinal hemorrhage.

Incidence for ‘other’ hemorrhage includes the PTs: lip hemorrhage; diarrhea hemorrhagic; anal hemorrhage; intestinal polyp hemorrhage; gastric varices hemorrhage; mouth hemorrhage; tooth socket hemorrhage.

ARISTOTLE = Apixaban for the Reduction of Stroke and Other Thromboembolic Events in Subjects With Atrial Fibrillation (NCT00412984) (21); RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy (NCT00262600) (19); ROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (NCT00403767) (20); data accessed on 21 January 2014.

AF = atrial fibrillation; GI = gastrointestinal; MedDRA = Medical Dictionary of Regulatory Activities; NOACs = non-VKA oral anticoagulants; NR = not reported; PT = preferred term.

^aPTs for events from the same anatomical location have been combined together. The complete list of PTs is provided as Supplementary Table I available online at http://informahealthcare.com/doi/abs/10.3109/07853890.2014.952327.

Table II. Incidence of GI cancer (reported as adverse events) with NOACs and warfarin in the phase III studies in patients with AF (ClinicalTrials.gov).

	RE-LY			ROCKET AF		ARISTOTLE
MedDRA-preferred terms^a	Dabigatran 110 mg twice daily N = 5983 n (%)	Dabigatran 150 mg twice daily N = 6059 n (%)	Warfarin N = 5998 n (%)	Rivaroxaban N = 7111 n (%)	Warfarin N = 7125 n (%)	Apixaban N = 9088 n (%)	Warfarin N = 9052 n (%)
Abdominal neoplasm	2 (0.03%)	0 (0.00%)	0 (0.00%)	NR	NR	NR	NR
Anal cancer	0 (0.00%)	1 (0.02%)	0 (0.00%)	NR	NR	1 (0.01%)	0 (0.00%)
Colon cancer	30 (0.50%)	23 (0.38%)	12 (0.20%)	37 (0.52%)	36 (0.51%)	42 (0.46%)	40 (0.44%)
Gastric cancer	2 (0.03%)	3 (0.05%)	3 (0.05%)	9 (0.13%)	7 (1.00%)	13 (0.14%)	6 (0.08%)
Esophageal cancer	7 (0.12%)	5 (0.08%)	3 (0.05%)	6 (0.08%)	5 (0.07%)	2 (0.02%)	2 (0.02%)
Other GI malignancies	3 (0.05%)	2 (0.03%)	2 (0.03%)	3 (0.04)	2 (0.03%)	1 (0.01%)	1 (0.01%)
‘Other’ cancer	3 (0.05%)	3 (0.05%)	2 (0.03%)	4 (0.05%)	2 (0.03%)	4 (0.04%)	3 (0.03%)
Total	47 (0.79%)	37 (0.61%)	22 (0.37%)	59 (0.83%)	52 (0.73%)	63 (0.69%)	52 (0.57%)

Incidence for colon cancer includes the PTs: colon cancer; colon cancer metastatic; colon cancer stage 0; colon cancer stage I, Iii, Iv; colon cancer stage III; colon cancer stage IV; colon neoplasm; colon cancer recurrent; colorectal cancer; colorectal cancer metastatic; rectal cancer; rectal neoplasm; rectosigmoid cancer; rectal cancer stage III; large intestine carcinoma.

Incidence for gastric cancer includes the PTs: gastric cancer; gastric cancer stage I; gastric cancer stage II; gastric cancer stage IV; metastatic gastric cancer; gastro-esophageal cancer; gastric neoplasm.

Incidence for other GI malignancies includes the PTs: gastrointestinal cancer metastatic; gastrointestinal carcinoma; gastrointestinal neoplasm; gastrointestinal stromal tumor; intestinal adenocarcinoma; small intestine carcinoma.

Incidence for esophageal cancer includes the PTs: esophageal adenocarcinoma; esophageal carcinoma; esophageal neoplasm; esophageal squamous cell carcinoma.

Incidence for ‘other’ cancer includes the PTs: lip and/or oral cavity cancer; tongue neoplasm malignant stage unspecified; throat cancer; lip neoplasm malignant stage unspecified; epiglottic carcinoma; intra-abdominal hemangioma; malignant palate neoplasm.

ARISTOTLE = Apixaban for the Reduction of Stroke and Other Thromboembolic Events in Subjects With Atrial Fibrillation (NCT00412984) (21); RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy (NCT00262600) (19); ROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (NCT00403767) (20); data accessed on 21 January 2014.

AF = atrial fibrillation; GI = gastrointestinal; MedDRA = Medical Dictionary of Regulatory Activities; NOACs = non-VKA oral anticoagulants; NR = not reported; PT = preferred term.

^aPTs for events from the same anatomical location have been combined together. The complete list of PTs is provided as Supplementary Table II available online at http://informahealthcare.com/doi/abs/10.3109/07853890.2014.952327.

Table III. Incidence and hazard ratio of major GI bleeding with NOACs and warfarin based on bleeding assessment in phase III studies in patients with AF.

	RE-LY			ROCKET AF		ARISTOTLE
GI major bleed (on-treatment)^a	Dabigatran 110 mg twice daily N = 5983	Dabigatran 150 mg twice daily N = 6059	Warfarin once daily N = 5998	Rivaroxaban 15 mg or 20 mg once daily N = 7111^b	Warfarin once daily N = 7125^b	Apixaban 5.0 mg or 2.5 mg, twice daily N = 9052	Warfarin once daily N = 9088
Incidence, n (%/year)	119 (1.16%)	161 (1.57%)	111 (1.04%)	224 (2.0%)	154 (1.4%)	105 (0.76%)	119 (0.86%)
HR (95% CI) versus warfarin	1.11 (0.86, 1.44)	1.50 (1.18, 1.91)		^c		0.89 (0.70, 1.15)

ARISTOTLE = Apixaban for the Reduction of Stroke and Other Thromboembolic Events in Subjects With Atrial Fibrillation (NCT00412984) (21); RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy (19); ROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (20).

^aMajor bleeding events were assessed on a separate report form outside of the adverse event reporting followed by central adjudication.

^bAnnual rates calculated using exposure time in ROCKET AF (see p. 158, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM272005.pdf).

^cHR and 95% CI not reported, only P value: P < 0.001 (20).

Figure 1. Time to onset from treatment initiation until any GI bleeding and any GI malignancy (days) for dabigatran and warfarin within the first 6 months of treatment—RE-LY database. GI = gastrointestinal; RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy.

Table IV. Hazard ratio of any GI bleeding and any GI cancer within first 6 months of treatment—RE-LY database.

HR (95% CI)	Dabigatran 110 mg versus VKA	Dabigatran 150 mg versus VKA	Dabigatran pooled versus VKA
Any GI bleed	2.00 (1.65, 2.43)	2.35 (1.95, 2.84)	2.18 (1.83, 2.59)
Any GI cancer	2.95 (1.32, 6.60)	2.93 (1.31, 6.55)	2.94 (1.39, 6.23)

GI = gastrointestinal; VKA = vitamin K antagonists.

HR (95% CI) = hazart ratio (95% confidence interinterval).

Table V. Patients with and without any GI bleeding and odds ratio of GI malignancy (RE-LY study).

Number of patients	Dabigatran 110 mg twice daily	Dabigatran 150 mg twice daily	Warfarin
With any GI bleed	558	638	428
With any GI bleed and GI cancer	35	32	22
Odds for GI cancer	6.7%	5.3%	5.4%
Without any GI bleed	5425	5421	5570
Without any GI bleed, but with GI cancer	34	37	21
Odds for GI cancer	0.6%	0.7%	0.4%
Odds ratio (95% CI)	10.61 (6.56, 17.16)	7.68 (4.75, 12.42)	14.32 (7.81, 26.26)

CI = confidence interval; GI = gastrointestinal; RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy.

ARISTOTLE (ClinicalTrials.gov). Apixaban for the prevention of stroke in subjects with atrial fibrillation (ARISTOTLE). Available at: http://clinicaltrials.gov/ct2/show/results/NCT00412984?term=apixaban& recr=Completed&rslt=With&cond=atrial+fibrillation&phase=123& rank=1&sect=X43015 (accessed 21 January 2014).

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