Abstract
Purpose
The purpose of this study is to investigate if the prescription of proton-pump inhibitors (PPIs) was associated with a sudden risk of acute myocardial infarction (AMI) while controlling for time-invariant confounding by using a case-crossover design. An association might indicate that physicians take prodromal symptoms of myocardial ischaemia for dyspepsia.
Methods
We applied a case-crossover design to investigate all AMI patients admitted to the hospital in the Skåne region, Sweden, between Oct 14, 2005 and Dec 31, 2006 and their PPI prescriptions and dispensations 3 months prior to the AMI onset. We retrieved the information about prescribed medication from the Swedish Drug Register containing individual information on all dispensed drugs prescribed in the outpatient care and dispensed in any of the Swedish pharmacies. Additionally, we stratified the analyses by history of AMI.
Results
We identified 3490 AMI cases aged 40 to 90; 61 % were men. The odds ratio for AMI onset in those with a prescription of PPIs during a hazard period of 3 days compared to control periods was 1.36 (95 % confidence interval (CI) 0.82–2.25) in the whole study cohort and 1.66 (95 % CI 1.00–2.76) in those without history of AMI. The corresponding odds ratio (OR) based on the dispensation date (suggesting use of the drug) was 1.26 (95 % CI 0.92–1.72) and 1.29 (95 % CI 0.92–1.83), respectively.
Conclusions
In our opinion, the previously reported increase in risk of adverse cardiac events in patients using PPIs may reflect the fact that an AMI may be misinterpreted as dyspepsia.
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References
Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS (2009) Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA J Am Med Assoc 301(9):937–944. doi:10.1001/jama.2009.261
Charlot M, Ahlehoff O, Norgaard ML, Jorgensen CH, Sorensen R, Abildstrom SZ, Hansen PR, Madsen JK, Kober L, Torp-Pedersen C, Gislason G (2010) Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med 153(6):378–386. doi:10.7326/0003-4819-153-6-201009210-00005
Charlot M, Grove EL, Hansen PR, Olesen JB, Ahlehoff O, Selmer C, Lindhardsen J, Madsen JK, Kober L, Torp-Pedersen C, Gislason GH (2011) Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study. BMJ (Clin Res Ed) 342:d2690. doi:10.1136/bmj.d2690
O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD (2009) Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 374(9694):989–997. doi:10.1016/s0140-6736(09)61525-7
Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP (2010) Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 363(20):1909–1917. doi:10.1056/NEJMoa1007964
Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, Cooke JP (2013) An unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor ADMA. Circulation. doi:10.1161/circulationaha.113.003602
Schmidt M, Johansen MB, Robertson DJ, Maeng M, Kaltoft A, Jensen LO, Tilsted HH, Botker HE, Sorensen HT, Baron JA (2012) Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation. Aliment Pharmacol Ther 35(1):165–174. doi:10.1111/j.1365-2036.2011.04890.x
Juurlink DN, Dormuth CR, Huang A, Hellings C, Paterson JM, Raymond C, Kozyrskyj A, Moride Y, Macdonald EM, Mamdani MM (2013) Proton pump inhibitors and the risk of adverse cardiac events. PLoS One 8(12):e84890. doi:10.1371/journal.pone.0084890
Blackburn DF, Lamb DA, McLeod MM, Eurich DT (2010) Increased use of acid-suppressing drugs before the occurrence of ischemic events: a potential source of confounding in recent observational studies. Pharmacotherapy 30(10):985–993. doi:10.1592/phco.30.10.985
Edmundowicz S (2002) 20 common problems in gastroenterology. McGraw-Hill Companies, United States
Bruyninckx R, Aertgeerts B, Bruyninckx P, Buntinx F (2008) Signs and symptoms in diagnosing acute myocardial infarction and acute coronary syndrome: a diagnostic meta-analysis. Br J Gen Pract J R Coll Gen Pract 58(547):105–111. doi:10.3399/bjgp08X277014
Piessevaux H, De Winter B, Louis E, Muls V, De Looze D, Pelckmans P, Deltenre M, Urbain D, Tack J (2009) Dyspeptic symptoms in the general population: a factor and cluster analysis of symptom groupings. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 21(4):378–388. doi:10.1111/j.1365-2982.2009.01262.x
Phillips RL Jr, Bartholomew LA, Dovey SM, Fryer GE Jr, Miyoshi TJ, Green LA (2004) Learning from malpractice claims about negligent, adverse events in primary care in the United States. Qual Saf Health Care 13(2):121–126
Bird S (2005) Acute myocardial infarction: medicolegal issues. Aust Fam Physician 34(6):489–490
Kostopoulou O, Delaney BC, Munro CW (2008) Diagnostic difficulty and error in primary care—a systematic review. Fam Pract 25(6):400–413. doi:10.1093/fampra/cmn071
Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 50(7):e1–e157. doi:10.1016/j.jacc.2007.02.013
Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM (2008) 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. Circulation 118(18):1894–1909. doi:10.1161/circulationaha.108.191087
Quinn MJ, Fitzgerald DJ (1999) Ticlopidine and clopidogrel. Circulation 100(15):1667–1672. doi:10.1161/01.cir.100.15.1667
Delaney JA, Suissa S (2009) The case-crossover study design in pharmacoepidemiology. Stat Methods Med Res 18(1):53–65. doi:10.1177/0962280208092346
Maclure M, Mittleman MA (2000) Should we use a case-crossover design? Annu Rev Public Health 21:193–221. doi:10.1146/annurev.publhealth.21.1.193
Etienney I, Beaugerie L, Viboud C, Flahault A (2003) Non-steroidal anti-inflammatory drugs as a risk factor for acute diarrhoea: a case crossover study. Gut 52(2):260–263
Geltman EM, Ehsani AA, Campbell MK, Schechtman K, Roberts R, Sobel BE (1979) The influence of location and extent of myocardial infarction on long-term ventricular dysrhythmia and mortality. Circulation 60(4):805–814
Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM (2009) A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ Can Med Assoc J J Assoc Med Can 180(7):713–718. doi:10.1503/cmaj.082001
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361(11):1045–1057. doi:10.1056/NEJMoa0904327
Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad Olausson P, Bergman U, Persson I, Sundstrom A, Westerholm B, Rosen M (2007) The new Swedish Prescribed Drug Register—opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf 16(7):726–735. doi:10.1002/pds.1294
Merlo J, Lindblad U, Pessah-Rasmussen H, Hedblad B, Rastam J, Isacsson SO, Janzon L, Rastam L (2000) Comparison of different procedures to identify probable cases of myocardial infarction and stroke in two Swedish prospective cohort studies using local and national routine registers. Eur J Epidemiol 16(3):235–243
Hammar N, Alfredsson L, Rosen M, Spetz CL, Kahan T, Ysberg AS (2001) A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden. Int J Epidemiol 30(Suppl 1):S30–S34
Acknowledgments
This work was supported by the Swedish Research Council (VR) (nr. #2013-2484, JM) and the Epidemiology and Register Centre South (AT).
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The authors declare no conflict of interests.
Author contributions
The conception and design of the article were provided by JM, AT and HO; the acquisition of data by JM; the analysis of data by AT, RPV, HO and JM; the interpretation of data by AT, RPV, JM, HO and PT; and the article draft by AT and JM. All authors contributed to the critical revision of the article for important intellectual content and approval of the final version.
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Turkiewicz, A., Vicente, R.P., Ohlsson, H. et al. Revising the link between proton-pump inhibitors and risk of acute myocardial infarction—a case-crossover analysis. Eur J Clin Pharmacol 71, 125–129 (2015). https://doi.org/10.1007/s00228-014-1779-6
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DOI: https://doi.org/10.1007/s00228-014-1779-6