Gastrointestinal Bleeding with Dabigatran, a Comparative Study with Warfarin: A Multicenter Experience

Muhammed Sherid; Humberto Sifuentes; Samian Sulaiman; Salih Samo; Husein Husein; Ruth Tupper; Charles Spurr; Subbaramiah Sridhar

doi:10.4166/kjg.2015.65.4.205

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Sherid, Sifuentes, Sulaiman, Samo, Husein, Tupper, Spurr, and Sridhar: Gastrointestinal Bleeding with Dabigatran, a Comparative Study with Warfarin: A Multicenter Experience

Original Article

Korean J Gastroenterol 2015;65(4):205-214.

Published online: 4 October 2015

DOI: https://doi.org/10.4166/kjg.2015.65.4.205

Gastrointestinal Bleeding with Dabigatran, a Comparative Study with Warfarin: A Multicenter Experience

Muhammed Sherid, Humberto Sifuentes, Samian Sulaiman¹, Salih Samo², Husein Husein³, Ruth Tupper¹, Charles Spurr, Subbaramiah Sridhar

Section of Gastroenterology and Hepatology, Georgia Regents University, Augusta, GA, USA

¹Division of Gastroenterology, Department of Internal Medicine, Saint Francis Hospital, Evanston, IL, USA

²Department of Medicine, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

³Division of Gastroenterology, Department of Internal Medicine, Trinitas Regional Medical Center, Seton Hall University, School of Health and Medicine Sciences, Elizabeth, NJ, USA

Correspondence to: Muhammed Sherid, Section of Gastroenterology and Hepatology, Georgia Regents University, 1120 15th Street-BBR2538, Augusta, Georgia 30912, USA. Tel: +1-224-420-0229, Fax: +1-706-721-0331, E-mail: muhammedsherid@gmail.com

Received 9 June 201426 January 2015 Accepted 13 February 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

The risk of gastrointestinal (GI) bleeding with dabigatran when compared to warfarin has been controversial in the literature. The aim of our study was to assess this risk with the use of dabigatran.

Methods

We examined the medical records of patients who were started on dabigatran or warfarin from October 2010 to October 2012. The study was conducted in two hospitals.

Results

A total of 417 patients were included (208 dabigatran vs. 209 warfarin). GI bleeding occurred in 10 patients (4.8%) in the dabigatran group compared to 21 patients (10.1%) in the warfarin group (p=0.0375). Multivariate analysis showed that patients who were on dabigatran for ≤100 days had a higher incidence of GI bleeding than those who were on it for >100 days (p=0.0007). The odds of GI bleeding in patients who were on dabigatran for ≤100 days was 8.2 times higher compared to those who were on the drug for >100 days. The incidence of GI bleeding in patients >65 years old was higher than in those <65 years old (p=0.0453, OR=3). History of previous GI bleeding was another risk factor for GI bleeding in the dabigatran group (p=0.036, OR=6.3). The lower GI tract was the most common site for GI bleeding in the dabigatran group (80.0% vs. 38.1%, p=0.014).

Conclusions

The risk of GI bleeding was lower with dabigatran. The risk factors for GI bleeding with dabigtran were the first 100 days, age >65 years, and a history of previous GI bleeding.

Keywords: Gastrointestinal hemorrhage, Dabigatran, Warfarin, Platelet aggregation inhibitors, Antithrombins

References

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Fig. 1.

Cumulative gastrointestinal bleeding free survival in total subjects, including both warfarin and dabigatran groups.

Fig. 2.

The rate of gastrointestinal bleeding for both drugs over time.

Fig. 3.

The survival rate without gastrointestinal bleeding for both drugs over time.

Table 1.

Patients' Characteristics in Both Groups

Characteristic	Dabigatran group (n=208)	Warfarin group (n=209)	p-value
Mean age (yr)	72.72	71.83	0.474
Age >85 yr	35 (16.8)	29 (13.9)	0.403
Sex (female)	104 (50.0)	113 (54.1)	0.406
Race (Caucasian)	190 (91.4)	198 (94.7)	0.130
Indication for drug: atrial fibrillation	206 (99.0)	149 (71.3)	0.001 ^a
Dose (mg)
150	166 (79.8)	NA	NA
75	42 (20.2)	NA	NA
Mean duration being on drug (day)	289.66	355.86	0.004 ^a
Duration ≤100 days	47 (22.6)	46 (22.0)	0.886
Drug was discontinued	39 (18.8)	51 (24.4)	0.161
Concomitant use with
Aspirin	100 (48.1)	101 (48.3)	0.960
Thienopyridines	26 (12.5)	33 (15.8)	0.929
Dual antiplatelet agents	16 (7.7)	19 (9.1)	0.607
NSAIDs	14 (6.7)	14 (6.7)	0.990
GFR ≤30 mL/min/1.73 m²	10 (4.8)	8 (3.8)	0.622
Previous GI bleeding	11 (5.3)	19 (9.1)	0.053

Values are presented as n (%).

GFR, glomerular filtration rate; GI, gastrointestinal; NA, not applicable.

^a Statistically significant.

Table 2.

Characteristics of Patients with Gastrointestinal (GI) Bleeding in Both Groups

Characteristic	Dabigatran group	Warfarin group	p-value
GI bleeding event	10 (4.8)	21 (10.1)	0.038 ^a
Mean age (yr)	79.20	75.86	0.441
Age >85 yr	3 (30.0)	4 (19.1)	0.495
Sex (female)	8 (80.0)	13 (61.9)	0.428
Race (Caucasian)	8 (80.0)	21 (100)	0.097
Indication for drug: atrial fibrillation	10 (100)	17 (81.0)	0.277
Dose (mg)
150	7 (70.0)	NA	NA
75	3 (30.0)	NA	NA
Mean duration being on drug (day)	108.50	188.86	0.189
Duration ≤100 days	8 (80.0)	9 (42.8)	0.052
Concomitant use with
Aspirin	4 (40.0)	11 (52.4)	0.704
Thienopyridines	1 (10.0)	7 (33.3)	0.165
Dual antiplatelet agents	1 (10)	6 (28.6)	0.248
NSAIDs	0	0	NA
GFR≤30 mL/min/1.73 m²	2 (20.0)	2 (9.5)	0.416
Previous GI Bleeding	2 (20.0)	2 (9.5)	0.416
Upper GI tract	1 (10.0)	9 (42.8)	0.067
Lower GI tract	8 (80.0)	8 (38.1)	0.014 ^a
Occult obscure GI bleeding	1 (10.0)	4 (19.0)	1.00
Death related to GI bleeding	0	0	NA

Values are presented as n (%).

GFR, glomerular filtration rate; NA, not applicable.

^a Statistically significant.

Table 3.

Multivariate Analysis for the Dabigatran Group

Variable	Adjusted OR (95% CI)	p-value
Age >65 years	2.989 (1.785-24.782)	0.0453 ^a
Sex (female)	2.732 (0.514-14.509)	0.238
Race (Caucasian)	0.612 (1.33-2.816)	0.528
Duration <100 days	8.176 (1.993-38.547)	0.0007 ^a
Concomitant with
Aspirin	1.739 (1.64-4.781)	0.657
Thienopyridines	1.051 (0.752-7.438)	0.279
Dual antiplatelet	0.856 (0.675-9.409)	0.492
NSAIDs	1.297 (1.824-5.721)	0.573
GFR≤30 mL/min/1.73 m²	4.534 (0.682-30.138)	0.118
Previous GI bleeding	6.284 (0.612-28.591)	0.036 ^a

GFR, glomerular filtration rate; GI, gastrointestinal.

^a Statistically significant.

Table 4.

Source of Gastrointestinal (GI) Bleeding in Both Groups

Source of GI bleeding	Dabigatran group (n)	Warfarin group (n)
Upper GI tract	Severe hemorrhagic gastritis with pneumatosis of gastric wall and portal vein air on CT scan (1)	PUD (3)
		AVM in stomach/duodenum (3)
		Bleeding from sphinctertomy site that performed recently (1)
		Scopes were not performed ^a (2)
Lower GI tract	Colorectal cancer (2)	Colorectal cancer (2)
	Ischemic colitis (2)	Internal hemorrhoids (1)
	Internal hemorrhoids/diverticulosis (1)	Diverticulosis (1)
	Scopes were not performed because patients’ refusal ^b (3)	Large cecal polyp (1)
		Sigmoid ulcer (1)
		Anal fissure (1)
		Scopes were not performed because patients’ refusal ^b (1)
Occult obscure GI bleeding	EGD/colonoscopy/push enteroscopy were negative (1)	EGD/colonoscopy/push enteroscopy were negative (4)

PUD, peptic ulcer disease; AVM, arteriovenous malformation; EGD, esophegogastroduodenoscopy.

^a Patients had hematemesis or coffee ground emesis which indicated upper GI bleeding in their clinical scenarios, but scopes were not performed;

^b patients had bright red blood per rectum which indicated lower GI bleeding in their clinical scenarios, but scopes were not performed because of patients’ refusal.

Table 5.

Secondary Aims of Our Study

Event	Dabigatran group (n=208)	Warfarin group (n=209)	p-value
Major bleeding other than GI bleeding	3 (1.4)	9 (4.3)	0.080
ICH	0 (0)	1 (0.5)	1.00
Stroke or TIA	4 (1.9)	6 (2.9)	0.751
DVT or PE	0 (0)	3 (1.4)	0.083
ACS	4 (1.9)	17 (8.1)	0.006 ^a
Death	7 (3.4)	15 (7.2)	0.082

Values are presented as n (%).

GI, gastrointestinal; ICH, intracranial hemorrhage; TIA, transient ischemic attack; DVT, deep vein thrombosis; PE, pulmonary embolism; ACS, acute coronary syndrome.

^a Statistically significant.

Table 6.

Comparison of the Results of Our Studies with Other Studies

Study	Indication	Duration^a (mo)	Group (patient)	Mean age (yr)	Sex (male, %)	Race (Caucasian, %)	Drug discontinued ^c (%)	GI bleeding	Major bleeding ^d (%)	ICH (%)	Stroke or TIA (%)	DVT/PE (%)	ACS (%)	Death
RE-LY	AF	24	Dabigatran ^b (6,076)	71.5	63.20	NA	21.20	1.51%/yr	3.11/yr	0.30/yr	1.01/yr	0.15/yr	0.74/yr	3.64/yr
			Warfarin (6,022)	71.6	63.30	NA	16.60	1.02%/yr (p−0.001)	3.36/yr (p=0.31)	0.74/yr (p<0.001)	)1.57/yr (p<0.001)	0.09/yr (p=0.21)	0.53/yr (p=0.048)	4.13/yr (p=0.051)
RE-COVER	DVT/PE	6	Dabigatran ^b (1,274)	55	58	95.20	16	4.20%	1.60	0	NA	2.40	0.40	1.60
			Warfarin (1,265)	54.4	58.90	94.40	14.50	2.80%	1.90	0.23	NA	2.1 (p<0.001)	0.2 (p=0.73)	1.70
Danish registry	AF	17	Dabigatran ^b (2,239)	67.4	61.50	NA	NA	1.50%	2.20	0.10	3.50	0.20	0.90	3
			Warfarin (8,936)	69.7	59.80	NA	NA	1.5% (p=0.26)	2.9/yr (p=0.15)	0.70	3 (p=0.05)	0.50	1.9 (p=0.06)	4.7 (p=0.03)
Mini-Sentinel initiative FDA		15	Dabigatran (12,195)	NA	NA	NA	NA	1.6 per 100,00 days at risk	NA 00	0.90	NA	NA	NA	NA
			Warfarin (119,940)	NA	NA	NA	NA	3.1 per 100,00 days at risk	00 NA	1.90	NA	NA	NA	NA
Our study		24	Dabigtran (208)	72.72	50	91.40	18.80	4.80%	6.30	0	1.90	0	1.90	3.40
			Warfarin (209)	71.83	45.90	94.70	24.40	10.1% (p=0.0375)	14.40	0.50	2.9 (p=0.751)	1.4 (p=0.083)	8.1 (p=0.006)	7.2 (p=0.082)

GI, gastrointestinal; ICH, intracranial hemorrhage; TIA, transient ischemic attack; DVT, deep vein thrombosis; PE, pulmonary embolism; ACS, acute coronary syndrome; AF, atrial fibrillation; NA, not available.

^a Duration of the study;

^b dabigatran 150 mg twice a day;

^c drug was discontinued permanently; ^d including GI bleeding.

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