Our goal was to compile the most recent and accurate data on the side effects of proton pump inhibitors (PPI). We also compared the efficacy of PPI to the efficacy of different surgical options for acid reflux control.
Background
Proton pump inhibitors are the primary therapy for chronic control of gastroesophageal reflux disease (GERD), but newer studies demonstrate deleterious side effects. Collating this information and contrasting it with surgical therapy for GERD provides evidence for possible practice changes in treatment.
Methods
A literature search utilizing PubMed was performed evaluating for PPI and anti-reflux surgery (ARS), focusing on articles that reflected information regarding the usage and efficacy of symptom control of both PPI and ARS. Search terms included “ARS, fundoplication, MSA, acute interstitial nephritis, acute kidney injury, chronic kidney disease, meta-analysis, PPI, H2 blocker, cardiovascular risk, and gut dysbiosis.” We evaluated 271 articles by title, abstract, and data for relevance and included 70.
Results
Long-term control of GERD with PPI may have a greater than expected side effect profile than initially thought. Surgical options may provide greater symptom control than PPI without the side effects of long-term medical therapy.
Conclusions
Anti-reflux control can be safely achieved with either PPI or surgical options; however, the long-term side effects noted in the review such as increased risk of cardiovascular events, renal disease, and gut dysbiosis may suggest surgical anti-reflux control as a better long-term option.
LundellLMiettinenPMyrvoldHE, et al.Comparison of outcomes twelve years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis. Clin Gastroenterol Hepatol. 2009;7(12):1292-1298. doi:10.1016/j.cgh.2009.05.021
2.
PengYCLinCLYehHZChangCSWuYLKaoCH, et al.Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: A population-based, case-control study. Medicine (Baltimore). 2016;95(15):e3363. doi:10.1097/MD.0000000000003363
3.
LeeJMarkRGCeliLADanzigerJ. Proton pump inhibitors are not associated with acute kidney injury in critical illness. J Clin Pharmacol. 2016;56(12):1500-1506. doi:10.1002/jcph.805
4.
NochaiwongSRuengornCAwiphanR, et al.The association between proton pump inhibitor use and the risk of adverse kidney outcomes: A systematic review and meta-analysis. Nephrol Dial Transplant. 2018;33(2):331-342. doi:10.1093/ndt/gfw470
5.
LazarusBChenYWilsonFP, , et al.Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238-246. doi:10.1001/jamainternmed.2015.7193
6.
AroraPGuptaAGolzyM, et al.Proton pump inhibitors are associated with increased risk of development of chronic kidney disease. BMC Nephrol. 2016;17(1):112. doi:10.1186/s12882-016-0325-4
7.
JacobsCAdameECAttaluriAValestinJRaoSSC. Dysmotility and proton pump inhibitor use are independent risk factors for small intestinal bacterial and/or fungal overgrowth. Aliment Pharmacol Ther. 2013;37(11):1103-1111. doi:10.1111/apt.12304
8.
XieYBoweBLiTXianHBalasubramanianSAl-AlyZ. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J Am Soc Nephrol. 2016;27(10):3153-3163. doi:10.1681/ASN.2015121377
9.
XieYBoweBLiTXianHYanYAl-AlyZ. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. 2017;91(6):1482-1494. doi:10.1016/j.kint.2016.12.021
10.
ShihC-JChenY-TOuS-MLiS-YChenT-JWangS-J. Proton pump inhibitor use represents an independent risk factor for myocardial infarction. Int J Cardiol. 2014;177(1):292-297. doi:10.1016/j.ijcard.2014.09.036
11.
ShahNHLePenduPBauer-MehrenA, et al.Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS One. 2015;10(6):e0124653. doi:10.1371/journal.pone.0124653
12.
CorsonelloALattanzioF. Cardiovascular and non-cardiovascular concerns with proton pump inhibitors: Are they safe?Trends Cardiovasc Med. 2019;29(6):353-360. doi:10.1016/j.tcm.2018.10.008
13.
ManolisAAManolisTAMelitaHKatsikiNManolisAS. Proton pump inhibitors and cardiovascular adverse effects: Real or surreal worries?Eur J Intern Med. 2020;72:15-26. doi:10.1016/j.ejim.2019.11.017
14.
BrunoGZaccariPRoccoG, et al.Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified. World J Gastroenterol. 2019;25(22):2706-2719. doi:10.3748/wjg.v25.i22.2706
HelgadóttirHLundSHGizurarsonSMetzDCBjörnssonES. Predictors of gastrin elevation following proton pump inhibitor therapy. J Clin Gastroenterol. 2020;54(3):227-234. doi:10.1097/MCG.0000000000001200
17.
BuresJCyranyJKohoutovaD, et al.Small intestinal bacterial overgrowth syndrome. World JGastroenterol. 2010;16(24):2978-2990. doi:10.3748/wjg.v16.i24.2978
18.
TsaiC-FChenM-HWangY-P, et al.Proton pump inhibitors increase risk for hepatic encephalopathy in patients with cirrhosis in a population study. Gastroenterology. 2017;152(1):134-141. doi:10.1053/j.gastro.2016.09.007
19.
LewisDSLeeT-HKonanurM, et al.Proton pump inhibitor use is associated with an increased frequency of new or worsening hepatic encephalopathy after transjugular intrahepatic portosystemic shunt creation. J Vasc Interv Radiol. 2019;30(2):163-169. doi:10.1016/j.jvir.2018.10.015.
20.
DominitzJADireCABillingsleyKGTodd–StenbergJA. Complications and antireflux medication use after antireflux surgery. Clin Gastroenterol Hepatol. 2006;4(3):299-305. doi:10.1016/j.cgh.2005.12.019
21.
LundellLMiettinenPMyrvoldHE, et al.Continued (5-year) followup of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll Surg. 2001;192(2):172-179. doi:10.1016/s1072-7515(00)00797-3.
22.
Klinkenberg-KnolECNelisFDentJ, et al.Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology. 2000;118(4):661-669. doi:10.1016/s0016-5085(00)70135-1
23.
FinksJFWeiYBirkmeyerJD. The rise and fall of antireflux surgery in the United States. Surg Endosc. 2006;20(11):1698-1701. doi:10.1007/s00464-006-0042-3
24.
Maret-OudaJWahlinKEl-SeragHBLagergrenJ. Association between laparoscopic antireflux surgery and recurrence of gastroesophageal reflux. J Am Med Assoc. 2017;318(10):939-946. doi:10.1001/jama.2017.10981
25.
Maret-OudaJYanesMKoningsPBrusselaersNLagergrenJ. Mortality from laparoscopic antireflux surgery in a nationwide cohort of the working-age population. Br J Surg. 2016;103(7):863-870. doi:10.1002/bjs.10141
26.
NikolicMSchwameisKSemmlerG, et al.Persistent dysphagia is a rare problem after laparoscopic Nissen fundoplication. Surg Endosc. 2019;33(4):1196-1205. doi:10.1007/s00464-018-6396-5
27.
SchietromaMColozziSRomanoL, et al.Short- and long-term results after laparoscopic floppy Nissen fundoplication in elderly versus non-elderly patients. J Minim Access Surg. 2019;16(3):256-263. doi:10.4103/jmas.JMAS_269_18
28.
HatlebakkJGZerbibFVarannesSBD, et al.Gastroesophageal acid reflux control 5 years after antireflux surgery, compared with long-term esomeprazole therapy. Clin Gastroenterol Hepatol. 2016;14(5):678-685. doi:10.1016/j.cgh.2015.07.025
29.
SinghSGargSKSinghPPIyerPGEl-SeragHB. Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: A systematic review and meta-analysis. Gut. 2014;63(8):1229-1237. doi:10.1136/gutjnl-2013-305997
30.
HuQSunT-THongJFangJ-YXiongHMeltzerSJ. Proton pump inhibitors do not reduce the risk of esophageal adenocarcinoma in patients with Barrett's Esophagus: A systematic review and meta-analysis. PLoS One. 2017;12(1):e0169691. doi:10.1371/journal.pone.0169691
31.
SchietromaMPiccioneFClementiM, et al.Short- and long-term, 11-22 years, results after laparoscopic Nissen fundoplication in obese versus nonobese patients. J Obes. 2017;2017:7589408. doi:10.1155/2017/7589408
32.
ParkJ-MKimBJKimJGChiK-C. Factors predicting outcomes of laparoscopic Nissen fundoplication for gastroesophageal reflux disease: Experience at a single institution in Korea. Ann Surg Treat Res. 2017;92(4):184-190. doi:10.4174/astr.2017.92.4.184
33.
CampoSEMDChaudhryUIKanjiASuzoAJPerryKA. Laparoscopic Nissen fundoplication controls reflux symptoms and improves disease-specific quality of life in patients with class I and II obesity. Surgery. 2017;162(5):1048-1054. doi:10.1016/j.surg.2017.07.006
34.
SanfordZJayaramanSWeltzASZahiriHRParkA. The role of body mass index in determining clinical and quality of life outcomes after laparoscopic anti-reflux surgery. Surg Endosc. 2020;34(2):646-657. doi:10.1007/s00464-019-06811-0
35.
AbdelrahmanTLatifAChanDS, et al.Outcomes after laparoscopic anti-reflux surgery related to obesity: A systematic review and meta-analysis. Int J Surg. 2018;51:76-82. doi:10.1016/j.ijsu.2018.01.013
36.
AbbasMKZaidiARZRobertCAThihaSMalikBH. The safety of long-term daily usage of a proton pump inhibitor: A literature review. Cureus. 2019;11(9):e5563. doi:10.7759/cureus.5563
37.
ZhangCHuZ-WYanC, et al.Nissen fundoplicationvsproton pump inhibitors for laryngopharyngeal reflux based on pH-monitoring and symptom-scale. World J Gastroenterol. 2017;23(19):3546-3555. doi:10.3748/wjg.v23.i19.3546
38.
TianZ-CWangBShanC-XZhangWJiangD-ZQiuM. A meta-analysis of randomized controlled trials to compare long-term outcomes of Nissen and Toupet fundoplication for gastroesophageal reflux disease. PLoS One. 2015;10(6):e0127627. doi:10.1371/journal.pone.0127627
39.
AbbasAEDeschampsCCassiviSD, et al.Barrett's esophagus: The role of laparoscopic fundoplication. Ann Thorac Surg. 2004;77(2):393-396. doi:10.1016/S0003-4975(03)01352-3
40.
DuXHuZYanCZhangCWangZWuJ. A meta-analysis of long follow-up outcomes of laparoscopic Nissen (total) versus Toupet (270°) fundoplication for gastro-esophageal reflux disease based on randomized controlled trials in adults. BMC Gastroenterol. 2016;16(1):88. doi:10.1186/s12876-016-0502-8
41.
BellRLiphamJLouieB, et al.Laparoscopic magnetic sphincter augmentation versus double-dose proton pump inhibitors for management of moderate-to-severe regurgitation in GERD: A randomized controlled trial. Gastrointest Endosc. 2019;89(1):14-22. doi:10.1016/j.gie.2018.07.007
42.
GanzRAEdmundowiczSATaiganidesPA, et al.Long-term outcomes of patients receiving a magnetic sphincter augmentation device for gastroesophageal reflux. Clin Gastroenterol Hepa. 2016;14(5):671-677. doi:10.1016/j.cgh.2015.05.028
43.
LiphamJCDeMeesterTRGanzRA, et al.The LINX reflux management system: Confirmed safety and efficacy now at 4 years. Surg Endosc. 2012;26(10):2944-2949. doi:10.1007/s00464-012-2289-1
44.
LouieBEFarivarASShultzDBrennanCVallièresEAyeRW. Short-term outcomes using magnetic sphincter augmentation versus Nissen fundoplication for medically resistant gastroesophageal reflux disease. Ann Thorac Surg. 2014;98(2):498-505. doi:10.1016/j.athoracsur.2014.04.074.
45.
RieglerMSchoppmanSFBonavinaLAshtonDHorbachTKemenM. Magnetic sphincter augmentation and fundoplication for GERD in clinical practice: One-year results of a multicenter, prospective observational study. Surg Endosc. 2015;29(5):1123-1129. doi:10.1007/s00464-014-3772-7
46.
ReynoldsJLZehetnerJNiehA, et al.Charges, outcomes, and complications: a comparison of magnetic sphincter augmentation versus laparoscopic Nissen fundoplication for the treatment of GERD. Surg Endosc. 2016;30(8):3225-3230. doi:10.1007/s00464-015-4635-6
47.
ReynoldsJLZehetnerJWuPShahSBildzukewiczNLiphamJC. Laparoscopic magnetic sphincter augmentation vs laparoscopic Nissen fundoplication: A matched-pair analysis of 100 patients. J Am Coll Surg. 2015;221(1):123-128. doi:10.1016/j.jamcollsurg.2015.02.025
48.
WarrenHFReynoldsJLLiphamJC, et al.Multi-institutional outcomes using magnetic sphincter augmentation versus Nissen fundoplication for chronic gastroesophageal reflux disease. Surg Endosc. 2016;30(8):3289-3296. doi:10.1007/s00464-015-4659-y
49.
AstiEBonittaGLoveceALazzariVBonavinaL. Longitudinal comparison of quality of life in patients undergoing laparoscopic Toupet fundoplication versus magnetic sphincter augmentation: Observational cohort study with propensity score analysis. Medicine (Baltimore). 2016;95(30):e4366. doi:10.1097/MD.0000000000004366
50.
GawronAJFrenchDDPandolfinoJEHowdenCW. Economic evaluations of gastroesophageal reflux disease medical management: A systematic review. Pharmacoeconomics. 2014;32(8):745-758. doi:10.1007/s40273-014-0164-8
51.
GrantABoachieCCottonS, et al.Clinical and economic evaluation of laparoscopic surgery compared with medical management for gastro-oesophageal reflux disease: 5-year follow-up of multicentre randomised trial (the REFLUX trial). Health Technol Assess. 2013;17(22):1-167. doi:10.3310/hta17220
52.
GoereeRHopkinsRMarshallJK, et al.Cost-utility of laparoscopic Nissen fundoplication versus proton pump inhibitors for chronic and controlled gastroesophageal reflux disease: A 3-year prospective randomized controlled trial and economic evaluation. Value Health. 2011;14:263-273. doi:10.1016/j.jval.2010.09.004
53.
FreedbergDEKimLSYangY-X. The risks and benefits of long-term use of proton pump inhibitors: Expert review and best practice advice from the American gastroenterological association. Gastroenterology. 2017;152(4):706-715. doi:10.1053/j.gastro.2017.01.031
