The benefits—and limits—of PPIs with warfarin regimens

,; Stevermer, James

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The benefits—and limits—of PPIs with warfarin regimens

J Fam Pract. 2017 November;66(11):694-696

By

Alicia Ludden-Schlatter, MD

James J. Stevermer, MD, MSPH

Patients on warfarin + antiplatelet/NSAID regimens are likely to benefit from the gastroprotective effect of PPIs. For patients taking warfarin alone, it’s a different story.

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PRACTICE CHANGER

Prescribe a proton pump inhibitor for patients taking dual antiplatelet/antithrombotic therapy to reduce the risk of upper gastrointestinal bleeding.

STRENGTH OF RECOMMENDATION

B: Based on a cohort study

Ray WA, Chung CP, Murray KT, et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology. 2016;151:1105-1112.¹

References

1. Ray WA, Chung CP, Murray KT, et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology. 2016;151:1105-1112.

2. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008;52:1502-1517.

3. Salas M, Ward A, Caro J. Are proton pump inhibitors the first choice for acute treatment of gastric ulcers? A meta analysis of randomized clinical rials. BMC Gastroenterol. 2002;2:17.

4. Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep. 2008;10:528-534.

5. Lanas A, García-Rodríguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol. 2007;102:507-515.

6. Lin KJ, Hernández-Díaz S, García Rodríguez LA. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology. 2011;141:71-79.

7. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S.

8. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):257S-298S.

9. Ament PW, Dicola DB, James ME. Reducing adverse effects of proton pump inhibitors. Am Fam Physician. 2012;86:66-70.

10. Gomm W, von HK, Thome F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73:410-416.

11. Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176:238-246.

12. Smeets HM, Hoes AW, de Wit NJ. Effectiveness and costs of implementation strategies to reduce acid suppressive drug prescriptions: a systematic review. BMC Health Serv Res. 2007;7:177.

13. Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? J Thorac Dis. 2015;7:165-171.

ILLUSTRATIVE CASE

A 60-year-old man establishes care with you. He has well-controlled osteoarthritis (as long as he takes his low-dose daily aspirin) and chronic atrial fibrillation, for which he takes warfarin. His international normalized ratio (INR) is consistently within the recommended target range of 2 to 3. He feels well and has never had gastroesophageal reflux disease (GERD) or a gastrointestinal (GI) bleed. Should you recommend a proton pump inhibitor (PPI) to decrease the likelihood of a future upper GI bleed?

Anticoagulation therapy creates a dilemma—the need to balance the benefits of preventing embolization with the risks of serious bleeding. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and other antiplatelet agents further increases the risk of the latter.²

Physicians have long used PPIs to treat upper GI bleeds. They prevent acid secretion and are the most efficacious drugs for healing peptic ulcers.^3,4 However, while previous case-control studies show that PPIs reduce the risk of upper GI bleeds in patients taking antiplatelet agents or NSAIDs, they do not show a statistically significant benefit for patients taking warfarin.^5,6 Further reflecting the confusion and uncertainty surrounding this issue is that while one expert consensus report recommends that patients taking dual warfarin and antiplatelet agent/NSAID therapy take a PPI to decrease the risk of upper GI bleeding,² other guidelines regarding anticoagulant therapy do not address this clinical question.^2,7,8

STUDY SUMMARY

Study lends support to PPI use in a high-risk group

This retrospective cohort study sought to answer the question: “Does PPI co-therapy decrease the rate of serious upper GI bleeds in patients taking warfarin?” Researchers examined rates of hospitalization for upper GI bleeding for Medicare and Medicaid patients taking warfarin with and without PPI co-therapy (tracked via prescription fill dates). They also evaluated concomitant use of NSAIDs and antiplatelet agents.

The authors excluded patients with a recent history of a severe bleed or certain illnesses that would predispose a patient to GI bleeding (such as esophageal varices). Patients with risk factors for an upper GI bleed (such as abdominal pain, peptic ulcer disease, anemia, etc.) were more likely to be taking PPI co-therapy. Researchers analyzed the effect of PPI co-therapy in patients with and without these additional risk factors.

Results. The study followed over 75,000 person-years of active warfarin therapy (more than 52,000 person-years in the Medicaid cohort and more than 23,000 person-years in the Medicare cohort). Hospitalizations due to upper GI bleeding occurred at a rate of 127/10,000 person-years (incidence was similar in both the Medicaid and Medicare groups).

Looking at all patients taking warfarin (regardless of whether or not they were also taking an NSAID or antiplatelet agent), PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by 24% (adjusted hazard ratio [HR]=0.76; 95% confidence interval [CI], 0.63 to 0.91), which translates into 29 fewer hospitalizations per 10,000 person-years. The number needed to treat (NNT) was 345 person-years, meaning 345 patients taking warfarin would have to take a PPI for one year to prevent one hospitalization for an upper GI bleed. As one might expect, PPI co-therapy did not significantly reduce the risk of lower GI, other GI, or non-GI bleeding.

Further research is warranted to determine if PPI therapy is beneficial to patients taking direct oral anticoagulants.

In patients taking both warfarin and concurrent antiplatelet agents or NSAIDs, PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by about half (HR=0.55; 95% CI, 0.39-0.77). Hospitalizations decreased by 128/10,000 person-years (95% CI, -66 to -173), yielding an NNT of 78 person-years. For patients taking warfarin but not antiplatelet agents or NSAIDs, PPI co-therapy did not significantly decrease the risk of hospitalization for upper GI bleeding (HR=0.86; 95% CI, 0.70-1.06).

Additional risk factors for GI bleeds. Researchers also looked at patients who had additional risk factors for GI bleeds (other than the exclusion criteria). For patients taking both warfarin and an antiplatelet agent/NSAID, PPI co-therapy decreased the risk of upper GI bleeding whether or not the patients had other bleeding risk factors. Again, for patients who had additional bleeding risk factors, but were not taking an antiplatelet agent or NSAID, PPI therapy showed no statistically significant effect.