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

Ludden-Schlatter, Alicia

Stevermer, James J.

University of Missouri: MOspace

694 THE JOURNAL OF FAMILY PRACTICE  |   NOVEMBER 2017  |   VOL 66, NO 11Priority Updates from the Research Literature from the Family Physicians Inquiries NetworkPURLs®Alicia Ludden-Schlatter, MD; James J. Stevermer, MD, MSPHDepartment of Family and Community Medicine, University of Missouri-Columbia D E P U T Y  E D I T O RAnne Mounsey, MDDepartment of Family Medicine, University of North Carolina, Chapel HillThe benefits—and limits— of PPIs with warfarin regimens 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. PRACTICE CHANGERPrescribe a proton pump inhibitor for pa-tients taking dual antiplatelet/antithrombotic therapy to reduce the risk of upper gastroin-testinal bleeding.STRENGTH OF RECOMMENDATIONB: Based on a cohort studyRay WA, Chung CP, Murray KT, et al. Association of proton pump in-hibitors with reduced risk of warfarin-related serious upper gastroin-testinal bleeding. Gastroenterology. 2016;151:1105-1112.1 ILLUSTRATIVE CASEA 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 di-lemma—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.2Physicians have long used PPIs to treat upper GI bleeds. They prevent acid secretion and are the most efficacious drugs for heal-ing peptic ulcers.3,4 However, while previous case-control studies show that PPIs reduce the risk of upper GI bleeds in patients tak-ing 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 ther-apy take a PPI to decrease the risk of upper GI bleeding,2 other guidelines regarding anti-coagulant therapy do not address this clinical question.2,7,8STUDY SUMMARYStudy 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 ex-amined 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 ill-nesses that would predispose a patient to GI bleeding (such as esophageal varices). Pa-tients with risk factors for an upper GI bleed Do you typically prescribe a proton pump inhibitor for your patients  taking warfarin? n  Yesn  NoINSTANT  POLLjfponline.com695JFPONLINE.COM VOL 66, NO 11  |  NOVEMBER 2017  |  THE JOURNAL OF FAMILY PRACTICE(such as abdominal pain, peptic ulcer dis-ease, anemia, etc.) were more likely to be tak-ing 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 co-hort and more than 23,000 person-years in the Medicare cohort). Hospitalizations due to up-per 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 hospitaliza-tion for upper GI bleeding by 24% (adjusted hazard ratio [HR]=0.76; 95% confidence in-terval [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.In patients taking both warfarin and concurrent antiplatelet agents or NSAIDs, PPI co-therapy reduced the risk of hospital-ization for upper GI bleeding by about half (HR=0.55; 95% CI, 0.39-0.77). Hospitaliza-tions 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 bleed-ing risk factors, but were not taking an anti-platelet agent or NSAID, PPI therapy showed no statistically significant effect.WHAT’S NEWPPIs offer benefits, but not to patients taking warfarin aloneThe statistically significant results in this large observational study suggest that PPI co- therapy is beneficial in reducing the risk of upper GI bleeding in patients taking war-farin plus an antiplatelet agent/NSAID, but that PPI co-therapy provides no benefit to pa-tients taking warfarin exclusively. CAVEATSStudy was good, but it wasn’t  a randomized controlled trialThis study is observational, and not a ran-domized control trial (RCT). Therefore, un-known confounding variables may have skewed results. For example, patients could have taken over-the-counter medications that influenced or obscured results, but were not included in the data analysis (misclassifi-cation bias). At best, we can infer a correlation be-tween PPIs and decreased risk of upper GI bleeds. We need RCTs to determine whether PPIs cause a lower risk.❚ Don’t overlook the risk of PPIs. This study assessed the ability of PPIs to prevent bleeds, but did not address the risks of long-term PPI therapy. Adverse effects of PPIs include an increased risk of pneumonia, infection with Clostridium difficile, hip and spine fractures, anemia, and possibly chronic kidney disease and dementia.9-11 In addition, cost-analysis studies of PPI therapy are lim-ited and inconsistent.12 Therefore, it’s best to make decisions regarding PPIs after discuss-ing other risks and benefits.❚ What about DOACs? Another consid-eration is the option to prescribe a direct oral anticoagulant (DOAC), such as dabigatran, rivaroxaban, or apixaban, instead of warfarin. DOACs are at least as effective as warfarin at preventing stroke in patients with atrial fibril-lation and may even be safer.13 Dabigatran 110 mg causes fewer “major bleeding” events than warfarin.13 Rivaroxaban has been shown to result in fewer fatal bleeding events than warfarin due to fatal intracranial bleeds, al-though it is associated with more GI bleed-ding.13 Compared with warfarin, apixaban is Further research is warranted  to determine  if PPI therapy  is beneficial  to patients  taking direct oral anticoagulants. 696 THE JOURNAL OF FAMILY PRACTICE  |   NOVEMBER 2017  |   VOL 66, NO 11PURLs®associated with fewer GI bleeds and lower bleeding rates overall.13 Further research is warranted to determine if PPI therapy is ben-eficial to patients taking DOACs. CHALLENGES TO IMPLEMENTATIONIt’s still a balancing actWhen chronic anticoagulation is necessary, physicians and patients must attempt to pre-vent thrombotic events while minimizing the risk of GI bleeds. PPIs may be beneficial in preventing upper GI bleeds in patients taking dual warfarin and antiplatelet therapy, but the long-term consequences of PPI therapy should not be ignored.                  JFPACKNOWLEDGEMENTThe PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsi-bility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved. 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 Ameri-can 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 antise-cretory 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 suppres-sants reduce risk of gastrointestinal bleeding in patients on an-tithrombotic 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 complica-tions 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 im-plementation strategies to reduce acid suppressive drug prescrip-tions: 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. MEDJOBNETWORK  comPhysician    NP/PA Career CenterThe first mobile job board  for Physicians, NPs, and PAsMobile Job Searches—access MedJobNetwork.com on the go from your smartphone or tabletAdvanced Search Capabilities—search for jobs by specialty, job title, geographic location,  employer, and moreScan this QR code  to access the mobile version  of MedJobNetwork.com

The benefits--and limits-- of PPIs with warfarin regimens

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The benefits--and limits-- of PPIs with warfarin regimens

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