Do Patients on Anticoagulants Also Need Acid Suppressants?

Devada Singh-Franco, PharmD

Disclosures

February 27, 2014

Question

Which patients are appropriate candidates for gastroprotection with acid-suppressive therapies?

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

Several commonly prescribed medications are associated with upper gastrointestinal injury (UGI), including ulceration, bleeding, perforation, and obstruction. UGI of the esophagus, stomach, and duodenum can present as melena, hematochezia, or hematemesis, but may also be asymptomatic.[1,2] Therefore, strategies to prevent gastric injury are important in our effort to reduce morbidity and mortality.[3]

Communication with patients allows clinicians to proactively identify pharmacologic and nonpharmacologic risk factors and provide subsequent recommendations. To lower the risk for UGI, proton pump inhibitors (PPIs) are often administered concomitantly with certain medications.[3,4,5,6,7]

Although PPIs do not entirely remove UGI risk, they may delay onset of UGI, reduce hospitalizations in patients who received PPIs concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) but still developed UGI, and decrease medical-resource costs.[3] Although PPI use may be warranted owing to their protective effects, cost and adverse events associated with this class dictate that their use must be judicious. Continued need for PPI use along with strategies to detect adverse events should be assessed and documented at each encounter.[8]

Other gastroprotective alternatives may be considered. Misoprostol, a synthetic prostaglandin E1 analogue, is used for the prevention of NSAID-induced ulcers. However, such side effects as cramping and diarrhea, along with the need for dosing 4 times daily, limit its use.[9]

Histamine-2-receptor antagonists (H2RAs) can be used in patients who cannot tolerate PPIs or misoprostol, but PPIs are more effective than H2RAs at reducing UGI bleeding.[7,9,10,11] If H2RAs are used, high-dose therapy is recommended (eg, famotidine 40 mg orally twice daily).[9]

Below is a general discussion regarding use of gastroprotection relative to antiplatelet, NSAID, or anticoagulation therapies.

Aspirin

In a patient receiving low-dose aspirin (LDA, ≤ 325 mg/day) for vascular protection, a PPI is recommended if one of the following is present[11]:

  • History of nonbleeding ulcer disease;

  • History of ulcer complication (ie, bleeding or perforation);

  • Dual-antiplatelet therapy; or

  • Concomitant anticoagulant therapy.

If a patient does not meet the criteria above, a PPI is recommended if he or she has more than one of the following:

Enteric-coated or buffered aspirin formulations do not appear to reduce the risk.

In a patient with a history of ulceration (bleeding or nonbleeding), test for Helicobacter pylori infection and treat if positive. If a patient develops gastrointestinal bleeding while receiving LDA without gastroprotection, add a PPI if LDA therapy is to be continued.[11]

Tools are available to help clinicians interested in prescribing LDA. Aspirin for the Prevention of Cardiovascular Disease is an online calculator that can be used to select appropriate patients for LDA therapy. In addition, the Aspirin Cardiovascular/Gastrointestinal Risk Calculator[1] may help clinicians weigh cardiovascular (CV) benefit against GI risk in patients needing antiplatelet therapy. The calculator will estimate baseline CV and GI risks, the number of CV events that LDA could prevent, and the excess number of upper GI events induced by LDA. In addition, it will suggest whether the patient is a candidate for LDA and whether gastroprotection with a PPI should be offered. However, this tool is new and requires further validation.

NSAIDs

Risks for NSAID-related GI injury include[9]:

  1. History of a GI event, especially if complicated;

  2. Age > 65 years;

  3. Concomitant use of anticoagulants; corticosteroids; other NSAIDs, including LDA; or high-dose NSAIDs;

  4. Concomitant chronic debilitating disorders, such as CV disease; and

  5. Presence of H pylori infection.

High-risk patients are those with a history of previously complicated ulcer, especially if recent, or who have more than 2 risk factors.

Moderate-risk patients have 1-2 risk factors:

  1. Age > 65 years;

  2. High-dose NSAID therapy;

  3. Previous history of uncomplicated ulcer; or

  4. Concomitant aspirin, corticosteroid, or anticoagulant therapy.

Low-risk patients are those without any risk factors.

If a patient requires an NSAID but does not require LDA, determine GI risk.[9,12]

  1. If they have low GI risk, recommend an NSAID or celecoxib at the lowest effective dose.

  2. If they have moderate GI risk, recommend an NSAID plus a PPI/misoprostol or celecoxib.

  3. If they have high GI risk, recommend alternative therapy if possible or celecoxib plus a PPI/misoprostol.

If a patient is already receiving LDA but requires an NSAID, determine GI risk.[9]

  1. If they have low or moderate GI risk, recommend treatment with naproxen plus a PPI/misoprostol.

  2. If they have high GI risk, NSAIDs and celecoxib should be avoided and alternative agents used.

Although all NSAIDs and celecoxib (except aspirin) may be associated with increased risk for CV events, naproxen is recommended because it may be associated with less risk.[9] However, a US Food and Drug Administration advisory panel voted against allowing a specific CV safety claim for naproxen on the label. The majority of panel members agreed that there is insufficient evidence that different NSAIDs carry different levels of risks. Members anticipate clarification of this issue with results from the PRECISION trial in 2015.[13,14,15]

Eradication of H pylori infection before initiation of NSAIDs or celecoxib may also reduce risk for subsequent ulceration. Once this risk is removed, assess the presence of other risk factors to determine the need for gastroprotection.[9,16]

Dual-Antiplatelet Therapy

GI risk factors should also be assessed in patients requiring dual-antiplatelet therapy (LDA plus clopidogrel, ticagrelor, or prasugrel).[17] Although there are no guidelines for the newer antiplatelet agents prasugrel or ticagrelor, these have been studied in combination with aspirin and are associated with increased risk for bleeding.[18,19] A PPI should be coprescribed if patients had a previous gastrointestinal bleeding event or have the risk factors of advanced age or concurrent use of NSAIDs, anticoagulants, or steroids; H pylori infection should be treated.[9,10,20] With clopidogrel, any PPI can be used except omeprazole or esomeprazole, because these significantly reduce its antiplatelet activity.[21]

Ticagrelor can be administered with any PPI. However, ticagrelor is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) and should be avoided in those receiving strong cytochrome P450 3A4 (CYP3A4) inhibitors (ie, ketoconazole, clarithromycin, nefazodone, and ritonavir) because these could increase ticagrelor exposure.[22] Ticagrelor can be used in patients with mild hepatic impairment (Child-Pugh class A) but has not been studied in those with moderate hepatic impairment (Child-Pugh class B).[22]

Prasugrel can be administered concomitantly with PPIs, but unlike ticagrelor, it can also be coprescribed with drugs that inhibit or induce CYP enzymes.[23] To further reduce the risk for any bleeding, prasugrel should be avoided in patients with a prior stroke or transient ischemic attack, and in patients who are aged ≥ 75 years or weigh < 60 kg.[23] Although it is advisable to choose another antiplatelet agent in patients with low body weight, the prasugrel package insert recommends patients that weighing < 60 kg receive the 5-mg dose, even though this dose has not been studied.[23] No dosage adjustment is necessary in patients with mild or moderate hepatic impairment,[23,24] but prasugrel should be avoided in patients with severe hepatic impairment because the risk for bleeding is already increased owing to reduced synthesis of coagulation factors.

Anticoagulants

Warfarin. With warfarin, the most important strategy used to reduce the risk for any bleeding is to maintain the therapeutic international normalized ratio (INR).[25] The HAS-BLED bleeding score is used to determine the risk for warfarin-induced major bleeding in patients with atrial fibrillation.[26,27] A score is calculated on the basis of the following clinical characteristics:

  • Hypertension (systolic blood pressure > 160 mm Hg);

  • Abnormal renal function (dialysis, transplantation, or serum creatinine ≥ 2.26 mg/dL) or liver function (chronic hepatic disease, or bilirubin greater than twice the upper limit of normal with aspartate aminotransferase or alanine aminotransferase greater than 3 times the upper limit of normal ) (1 point each);

  • Stroke;

  • Bleeding (major bleeding history, anemia, or predisposition to bleeding);

  • Labile INRs (unable to maintain a stable, therapeutic INR ≥ 60% of the time);

  • Elderly (aged > 65 years); and

  • Drug use (ie, antiplatelet agents or NSAIDs) or alcohol use (≥ 8 drinks/week) (1 point each).

Each characteristic is assigned 1 point, for a maximum of 9 points. A score ≥ 3 suggests increased risk of experiencing bleeding complications.

Previous gastrointestinal bleeding, presence of H pylori infection, and concomitant medications associated with UGI (eg, NSAIDs, corticosteroids) should also be considered. Strategies to reduce bleeding include correcting modifiable characteristics (eg, labile INRs, alcohol use, and hypertension) and adding a PPI for gastroprotection.[7,9,11]

HAS-BLED has not been tested with the newer oral anticoagulants (ie, apixaban, rivaroxaban, and dabigatran); however, the presence of the risk factors described above warrants consideration of PPI coprescription.

Additional Recommendations

Additional recommendations to further reduce risk for bleeding with the novel oral anticoagulants include but are not limited to the following:

Apixaban (factor Xa inhibitor)[28]

  1. Dosing for nonvalvular atrial fibrillation: 5 mg twice daily.

  2. Use the lowest recommended dose (2.5 mg twice daily) in patients:

    • With any 2 of the following characteristics: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL.

    • Who are receiving strong dual inhibitors of CYP3A4 and P-glycoprotein, such as ketoconazole, itraconazole, ritonavir, and clarithromycin.

      • If a patient is already receiving 2.5 mg twice daily, then cotherapy with these dual inhibitors should be avoided.

  3. No dose adjustment for mild, moderate, or severe renal impairment alone, except for those who meet the criteria for the lower dose of 2.5 mg twice daily. No data are available for use in patients with estimated creatinine clearance (CrCl) < 15 mL/min or on dialysis.

  4. No dose adjustment for mild hepatic impairment; however, no recommendation is listed for patients with moderate impairment. Avoid in patients with severe hepatic impairment.

Rivaroxaban (factor Xa inhibitor)[29]

  1. Adjust dose on the basis of CrCl.

    • Nonvalvular atrial fibrillation:

      • CrCl > 50 mL/min: 20 mg daily with evening meal.

      • CrCl 15-50 mL/min: 15 mg daily with evening meal.

      • Avoid if CrCl is < 15 mL/min.

    • Venous thromboembolism (deep vein thrombosis [DVT] or pulmonary embolism [PE]) and reduction of risk for recurrence:

      • Initial treatment of DVT or PE: 15 mg twice daily with food for 21 days.

      • After initial treatment: 20 mg daily with food for the remaining treatment and for long-term reduction in the risk for recurrent thrombosis.

      • Avoid use if CrCl is < 30 mL/min.

    • Prophylaxis of DVT after knee replacement surgery: 10 mg once daily with or without food for 12 days; avoid use if CrCl is < 30 mL/min.

    • Prophylaxis of DVT after hip replacement surgery: 10 mg once daily with or without food for 35 days; avoid use if CrCl is < 30 mL/min.

  2. Avoid concomitant use with dual inhibitors of 3A4 and P-glycoprotein, or in patients with moderate or severe hepatic impairment.

Dabigatran etexilate (direct thrombin inhibitor)[30]

  1. Nonvalvular atrial fibrillation and CrCl > 30 mL/min: 150 mg twice daily.

    • CrCl 15-30 mL/min: 75 mg twice daily (avoid concomitant P- glycoprotein inhibitors).

    • CrCl 30-50 mL/min and receiving concomitant P-glycoprotein inhibitors, such as dronedarone or oral ketoconazole: 75 mg twice daily.

    • No dosage recommendations are available for patients with CrCl < 15 mL/min or on dialysis.

  2. In RE-LY,[31] patients with persistent alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels greater than twice the upper limit of normal were excluded. Use in patients with liver-associated coagulopathy should be avoided.

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