GI Injury: Common With New Antiplatelets and Anticoagulants?

Devada Singh-Franco, PharmD

Disclosures

December 26, 2013

In This Article

Question

How common is upper gastrointestinal injury associated with the newer oral antiplatelet agents and anticoagulants?

Response from Devada Singh-Franco, PharmD
Associate Professor, Nova Southeastern University College of Pharmacy; Clinical Pharmacist, Broward Health Medical Center, Fort Lauderdale, Florida

Between 1998 and 2005, more than 1.4 million hospitalizations were the result of peptic ulcer disease, with an average age-adjusted hospitalization rate of 63.6 per 100,000 population.[1] Age was a factor: The estimated hospitalization rate was highest for those aged 65 years or older (299.8 per 100,000 population).[1] The rate of upper gastrointestinal (UGI) injury, including gastric and duodenal ulcers, was 33.7 per 100,000 and 24.4 per 100,000 population, respectively.[1]

Several nonpharmacologic and pharmacologic risk factors for UGI injury have been identified. Nonpharmacologic risk factors include age 60 years or older (relative risk [RR], 2.0-5.5), history of peptic ulcer disease (RR, 2.3-3.1) or GI bleeding (RR, 2.60-13.5), and presence of Helicobacter pylori infection (RR, 1.8-2.4).[2]

Pharmacologic Risk Factors for GI Injury

Many frequently prescribed medications are associated with increased UGI injury (eg, ulcer formation, bleeding, or perforation); the best-known are traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (LDA).[3] These agents cause GI injury through direct topical damage to the gastric mucosa and reduced production of gastroprotective prostaglandins that increase mucosal blood flow and stimulate synthesis and secretion of mucus and bicarbonate.[4] Concurrent multiple NSAID use, high-dose NSAIDs, and NSAID use of any duration increase the risk for bleeding or perforation.[5]

Celecoxib, a selective cyclooxygenase-2 inhibitor, is less GI-toxic than NSAIDs; however, there may be increased risk when combined with LDA. Concomitant use of LDA or NSAIDs/celecoxib with oral anticoagulants, corticosteroids, bisphosphonates, and selective serotonin reuptake inhibitors are additional risk factors for UGI bleeding.[2,3,4,5,6,7]

The Table lists agents and associated with GI injury. This short review, however, briefly focuses on the newer antiplatelet and anticoagulant therapies.

Table. Risk for GI Injury With Selected Agents

Regimen Risk for GI Injury (95% CI)a
RR vs nonusers[3]  
   LDAb monotherapy 1.79 (1.57-2.03)
   NSAID monotherapy 2.99 (2.50-3.59)
   Coxib monotherapy 2.38 (1.63-3.47)
   LDA + NSAID 4.74 (3.68-6.11)
   LDA + coxib 5.83 (3.26-10.41)
   Clopidogrel monotherapy 1.48 (0.96-2.27)
   Clopidogrel + LDA 3.71 (2.38-5.76)
   Oral anticoagulant monotherapy 1.77 (1.36-2.30)
   LDA + oral anticoagulant 3.62 (2.09-6.29)
   LDA + high-dose steroids 7.87 (3.73-16.63)
RR vs LDA[3]  
   LDA + clopidogrel 2.08 (1.34-3.21)
   LDA + oral anticoagulants 2.00 (1.15-3.45)
   LDA + low- or medium-dose NSAIDs/coxibs 2.63 (1.93-3.60)
   LDA + high-dose NSAIDs/coxibs 2.66 (1.88-3.76)
   LDA + high-dose steroidsc 4.43 (2.10-9.34)
RR of traditional NSAIDs vs nonusers[5]  
   Concurrent multiple NSAID use 8.7 (3.7-20.5)
   Dose Low or medium 2.5 (2.0-3.2)
   Dose High 4.9 (4.0-6.1)
   Duration ≤ 90 days 4.4 (3.5-5.7)
   Duration 91-365 days 3.4 (2.5-4.8)
   Duration < 1 year 3.1 (2.4-4.0)
RR of warfarin vs nonusers[5]  
   Current use 2.0 (1.5-2.6)
   Duration 0-30 days 3.8 (1.9-7.8)
   Duration 31-365 days 2.5 (1.6-3.7)
   Duration > 1 year 1.3 (0.9-2.0)
OR of bisphosphonates[6]  
   NSAIDs + bisphosphonates 2.00 (1.12-3.57)
   Coxibs + bisphosphonates 2.38 (1.26-4.50)
OR of SSRIs[7]  
   SSRI only 2.63 (2.24-3.07)
   NSAID + SSRI 2.93 (2.25-3.82)
Newer oral antiplatelet agents  
   RR of ticagrelor vs clopidogrel (PLATO)[8] 1.23 (0.93-1.64)
   HR of prasugrel vs clopidogrel (TRITON-TIMI 38)[9] 1.32 (0.99-1.77)
Novel oral anticoagulants (RR vs warfarin)  
   Apixaban[10] 0.88 (0.68-1.14)
   Rivaroxaban[10] 1.46 (1.19-1.78)
   Dabigatran GI bleeding (150 mg twice daily)[10] 1.50 (1.20-1.89)
   Dabigatran Nonbleeding upper GI eventd [11] 1.81 (1.66-1.98)

Coxibs = selective cyclooxygenase-2 inhibitors; GI = gastrointestinal; HR = hazard ratio;
LDA = low-dose aspirin
; NSAID = nonsteroidal anti-inflammatory drug; OR = odds ratio;
RR = relative risk; SSRI = selective serotonin reuptake inhibitors

aIncluded studies used different patient populations and estimates were adjusted with varying combinations of risk factors, so direct comparisons should be avoided.
bLDA was defined as 75-300 mg/day.
cHigh-dose steroids were defined as prednisolone ≥ 10 mg/day or the equivalent dosage.
dIncludes gastroesophageal reflux disease (5.5% with dabigatran vs 1.5% with warfarin), upper abdominal pain (4.9% vs 2.1%), dysmotility (6.1% vs 4.9%), and gastroduodenal injury (3.4% vs 2.2%).

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