Is there any association between myocardial infarction, gastro-oesophageal reflux disease and acid-suppressing drugs?

Aliment Pharmacol Ther 2003; 18: 973 978. doi: 10.1046/j.0269-2813.2003.01798.x Is there any association between myocardial infarction, gastro-oesophageal reflux disease and acid-suppressing drugs? S. JOHANSSON*à, M.-A. WALLANDER à, A. RUIGÓMEZ & L. A. GARCÍA RODRÍGUEZ *The Cardiovascular Institute, Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden; Department of Public Health and Caring Science, Uppsala University, Uppsala, Sweden; àastrazeneca R&D, Mölndal, Sweden; Centro Español de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain Accepted for publication 23 September 2003 SUMMARY Background: A link between gastro-oesophageal reflux disease and coronary heart disease has been suggested. Aim: To estimate the incidence of myocardial infarction in patients with newly diagnosed gastro-oesophageal reflux disease in comparison with that in the general population. Methods: A population-based cohort study was performed in the UK. Patients aged 18 79 years with a first diagnosis of gastro-oesophageal reflux disease (n ¼ 7084) were identified and a group of 10 000 patients free of gastro-oesophageal reflux disease were sampled. A nested case control analysis was performed to assess the risk factors for myocardial infarction. Results: The incidence of myocardial infarction in the general population was 4.0 per 1000 person-years [95% confidence interval (CI), 3.2 4.9] and 5.1 per 1000 person-years (95% CI, 4.1 6.4) in patients with gastro-oesophageal reflux disease. The relative risk of myocardial infarction in patients with gastrooesophageal reflux disease was 1.4 (95% CI, 1.0 1.9). The increased risk of myocardial infarction was limited to the immediate days after the diagnosis of gastrooesophageal reflux disease. Previous chest pain was an important predictor of myocardial infarction in patients free of gastro-oesophageal reflux disease. No association was found between the use of acid-suppressing drugs and the risk of myocardial infarction. Conclusion: Our results suggest that gastro-oesophageal reflux disease is not an independent predictor of myocardial infarction. Rather, the increased risk of myocardial infarction in patients with gastro-oesophageal reflux disease in the immediate days after diagnosis indicates that prodromal ischaemic symptoms were misinterpreted as reflux symptoms. INTRODUCTION Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder that causes substantial morbidity and has a negative impact on the quality of life. 1 Some 20 40% of the adult population in Western countries report symptoms of GERD. 2, 3 Correspondence to: Dr A. Ruigómez, Centro Español de Investigación Farmacoepidemiológica, c/almirante 28, 2, 28004 Madrid, Spain. E-mail: aruigomez@ceife.es Oesophageal pain can closely mimic the characteristic features of cardiac pain, implying that GERD symptoms may be misclassified as coronary heart disease and vice versa. As both GERD and coronary heart disease are prevalent diseases in the population, they frequently co-exist and may further interact in producing chest pain. Furthermore, it has been argued that oesophageal disease may aggravate myocardial ischaemia. 4 Some studies have suggested that oesophageal acid stimulation can produce angina and significantly reduce coronary blood flow. 5, 6 Other studies have suggested that GERD is common in patients with coronary heart Ó 2003 Blackwell Publishing Ltd 973

974 S. JOHANSSON et al. disease and may be increased by drug therapy for this condition. 7 The purpose of this study was to estimate the incidence of a new episode of myocardial infarction in newly diagnosed GERD patients and to compare it with that in an age- and sex-matched general population free of GERD. We also estimated the association between the risk of myocardial infarction and the use of acidsuppressing drugs in the cohort of newly diagnosed GERD patients. POPULATION AND METHODS Study design A retrospective cohort study with nested case control analysis was performed using data from the General Practice Research Database in the UK. Approximately three million residents in the UK are registered with general practitioners geographically distributed throughout the country who participate in the General Practice Research Database. This scheme consists of close to 2000 general practitioners who use computers in their offices for the purpose of recording medical patient information in a standard manner. They have agreed to provide the information anonymously to the Medicines Control Agency which organizes the information for use in research projects. The information recorded includes demographics, medical diagnoses, referrals to consultant and hospital, and a register of written prescriptions. Prescriptions are automatically produced from the computer and recorded on the patient s computerized file. The accuracy and completeness of the data have been documented in previous validation studies of the General Practice Research Database. 8 10 An additional requirement of this data resource is that the indication for any new course of therapy be entered into the computer. Study cohorts The source population included all individuals aged 18 79 years registered in the database and with at least 2 years of enrolment with the general practitioner before 1996. All patients with a first recorded diagnosis of GERD (start date) during the year 1996 were identified. In addition, patients with a diagnosis of GERD or cancer before 1996, as well as pregnant women in 1996, were removed. The computerized profiles of all patients detected by the computer search with a first ever code of GERD (gastro-oesophageal reflux, acid reflux, acid regurgitation, oesophagitis and heartburn) were reviewed manually to further exclude patients with past history, as well as patients with longterm use of acid-suppressing drugs without a specific treatment indication, such as peptic ulcer, gastritis or duodenitis. For a sample of GERD patients (n ¼ 232), a questionnaire was sent to the corresponding general practitioner to request confirmation of the GERD diagnosis based on the clinical history and tests performed. In 98% of the patients, the diagnosis of GERD was confirmed by the general practitioner and in 72% it was defined as the first episode of GERD. Finally, 7084 patients constituted the GERD cohort. A comparison cohort free of GERD was randomly sampled (n ¼ 10 000) from the source population and a random date in 1996 was assigned (start date). The same exclusion criteria as applied to the GERD cohort were used. The comparison cohort was matched by age and sex to the GERD cohort. The two cohorts were followed from the start date until the earliest occurrence of one of the following endpoints: incident myocardial infarction, cancer, 80 years of age, death or September 2000. For all patients identified with a code of myocardial infarction during follow-up, the computerized profiles were reviewed manually. We excluded patients in whom a diagnosis of myocardial infarction was subsequently ruled out. Definite cases (confirmed by a consultant visit or hospitalization) were separated from potential cases. For all potential cases of myocardial infarction, a questionnaire was sent to the general practitioner requesting the confirmation of myocardial infarction and asking for all paper-based information related to the episode of myocardial infarction. A 93% response rate was obtained and 51% of all potential cases were confirmed as a new acute myocardial infarction episode on that date. The non-confirmed patients either had a final diagnosis of angina or long-standing coronary heart disease without a new episode of myocardial infarction. Incidence rates of myocardial infarction were computed for the GERD cohort and the general population cohort free of GERD. The proportion of patients developing myocardial infarction was also estimated in relation to the time of follow-up, and the relative risk of myocardial infarction associated with GERD was calculated using Cox proportional hazard regression. A case control analysis was performed in

MYOCARDIAL INFARCTION, GERD AND ACID-SUPPRESSING DRUGS 975 which all myocardial infarction cases validated in both cohorts were used as cases (n ¼ 168) and the date of diagnosis of myocardial infarction was used as the index date. A group of 1948 patients with a random date generated during the study period was randomly sampled from the pool of the two study cohorts and used as controls. Odds ratios (OR) and 95% confidence intervals (CI) were computed for myocardial infarction associated with GERD and other risk factors. Recorded information on smoking, body mass index, alcohol consumption and a history of heart failure, ischaemic heart disease, hypertension and diabetes was collected. Information on the drug treatment for GERD (H 2 -receptor antagonists, proton pump inhibitors and antacids) was extracted from the computerized records. Current use was assigned when the drug supply lasted until the index date or ended in the previous month. Short-term use was defined as a treatment duration of less than 3 months and long-term use as a treatment duration of more than 3 months. Past use was assigned when the end of the most recent prescription was more than 1 month before the index date, and non-use when there was no drug use recorded in the computerized files. RESULTS During a mean follow-up of 27 months (range, 1 49 months; s.d., 14 months), 76 patients developed a first myocardial infarction in the GERD cohort and 92 in the general population cohort free of GERD. The incidence rate of myocardial infarction in the general population was 4.0 per 1000 person-years (95% CI, 3.2 4.9) and 5.1 per 1000 person-years (95% CI, 4.1 6.4) in GERD patients. The relative risk of myocardial infarction in patients with GERD was 1.4 (95% CI, 1.0 1.9) compared with the general population after adjusting for age and sex. The increased risk was more apparent in patients between 40 and 60 years of age (Figure 1). All the excess risk was concentrated in the very early phase of follow-up after the diagnosis of GERD, as shown in Figure 2. During the first month of follow-up, GERD patients had an elevated relative risk of 11.1 (95% CI, 3.3 37.0). Excluding the first month, the age- and sex-adjusted relative risk of myocardial infarction was 1.1 (95% CI, 0.8 1.5) in GERD patients. Table 1 shows the effect of several risk factors on the occurrence of myocardial infarction. After adjusting for additional risk factors, the estimate of risk associated IR per 1,000person-years 25.00 20.00 15.00 10.00 5.00 0.00 RR in GERD 18-39 GERD Gen. Population 40-49 50-59 60-69 70-79 Age (groups) 1.5 4.6 2.4 1.2 1.0 Figure 1. Incidence rate (IR) and relative risk (RR) of myocardial infarction in the cohort of patients with gastro-oesophageal reflux disease (GERD) compared with the general population by age. Cum. propagation developing MI 0.018 0.016 0.014 0.012 0.010 0.008 0.006 0.004 0.002 0.000 0 2 4 6 GERD Gen.Population 8 10 12 14 16 18 20 22 24 26 28 30 Follow-up (months) 32 34 36 37 40 42 44 46 Figure 2. Cumulative proportion of patients developing myocardial infarction (MI) in the gastro-oesophageal reflux disease (GERD) and general population cohorts during follow-up. with GERD was 1.1 (95% CI, 0.8 1.6). The risk of myocardial infarction increased in those with previous ischaemic heart disease morbidity (OR, 5.4; 95% CI, 3.6 8.0) and diabetes (OR, 2.0; 95% CI, 1.2 3.5). Smoking was associated with a close to two-fold increased risk, and recent chest pain (within 6 months) was an important predictor of myocardial infarction (OR, 4.7; 95% CI, 2.6 8.7). When the two cohorts were studied separately, the risk associated with recent chest pain was noticeably increased in patients free of GERD (OR, 10.3; 95% CI, 4.4 24.4) and, to a much lesser extent, in the GERD cohort (OR, 1.8; 95% CI, 0.7 4.5). Chest pain recorded more than 6 months prior to myocardial infarction was not associated with an excess risk in either of the two cohorts. No association was found between the use of acid-suppressing drugs and

976 S. JOHANSSON et al. MI cases n ¼ 168 (%) Controls n ¼ 1948 (%) OR* (95% CI) Cohort status General population 92 (54.8) 1198 (61.5) 1 Gastro-oesophageal reflux disease 76 (45.2) 750 (38.5) 1.1 (0.8 1.6) Smoking status Non-smoker 79 (47.0) 1051 (54.0) 1 Smoker 52 (31.0) 448 (23.0) 1.8 (1.2 2.7) Ex-smoker 15 (8.9) 116 (6.0) 1.5 (0.8 2.9) Body mass indexà Low medium (< 25) 44 (26.2) 572 (29.4) 1 Medium high (25 29.9) 47 (28.0) 582 (29.9) 0.9 (0.6 1.5) High (30+) 31 (18.5) 256 (13.1) 1.2 (0.7 2.1) Alcohol consumption (units/week) None 70 (41.7) 665 (34.1) 1 Use 1 5 units 20 (11.9) 316 (16.2) 0.7 (0.4 1.2) Use 6 15 units 23 (13.7) 281 (14.4) 0.8 (0.5 1.4) Use > 15 units 16 (9.5) 211 (10.8) 0.7 (0.3 1.4) Previous chest pain None 106 (63.1) 1549 (79.5) 1 Recent (within 6 months) 25 (14.9) 44 (2.3) 4.7 (2.6 8.7) Past (> 6 months before) 37 (22.0) 355 (18.2) 0.8 (0.5 1.2) Previous morbidity status Ischaemic heart disease 76 (45.2) 242 (12.4) 5.4 (3.6 8.0) Heart failure 22 (13.1) 83 (4.3) 1.6 (0.9 2.8) Diabetes 22 (13.1) 104 (5.3) 2.0 (1.2 3.5) Hypertension 58 (34.5) 502 (25.8) 1.3 (0.9 1.8) Hyperlipidaemia 17 (10.1) 192 (9.9) 0.8 (0.5 1.3) Table 1. Distribution of cases and controls and the effect of several factors on the risk of myocardial infarction (MI) * Odds ratio (OR) adjusted for age, sex, calendar year and all the variables included in the table, estimated by multiple regression analysis. In 355 patients (16.8%), the smoking status was unknown. à In 584 patients (27.6%), the body mass index could not be calculated. In 514 patients (24.3%), the alcohol consumption was not recorded. the risk of myocardial infarction in GERD patients (Table 2). DISCUSSION Our results suggest that GERD is not an independent predictor of myocardial infarction. An increased risk was observed in the immediate days after the initial diagnosis of GERD, but no excess risk was observed once this period of time was discounted. As oesophageal and cardiac causes of chest pain may sometimes be clinically indistinguishable, it is reasonable to suggest that prodromal ischaemic symptoms, in some instances, were misdiagnosed as reflux symptoms in the immediate phase after the onset of symptoms. We are not aware of any other studies that have evaluated the impact of GERD on the risk of the development of myocardial infarction. However, the concomitant prevalence of coronary heart disease and oesophageal dysfunction has been reported in 10 70% of subjects in small case series. 11 13 Using simultaneous oesophageal ph monitoring and Holter monitoring in patients with coronary heart disease who had persistent chest pain despite optimal anti-angina therapy, Singh et al. found that 67% had at least one episode of chest pain that was related to an acid reflux event. 13 They also reported that nearly 75% of patients showed improvement in chest pain following treatment with acid-suppressing drugs. The definition of myocardial infarction was not based on specific biochemical markers, but on general practitioner assessment based on their records and patient s discharge letters. This approach may result in a slightly lower number of patients with a diagnosis of myocardial infarction compared with estimates from clinical studies. 14 Nevertheless, the incidence of coronary heart disease observed

MYOCARDIAL INFARCTION, GERD AND ACID-SUPPRESSING DRUGS 977 Table 2. Association between the use of acid-suppressing drugs and myocardial infarction in patients with newly diagnosed gastro-oesophageal reflux disease (GERD) (76 cases and 750 controls) OR (95% CI) H 2 -receptor antagonists Current use 1.1 (0.5 2.3) Short duration 1.6 (0.7 4.1) Long duration 0.8 (0.3 2.3) Proton pump inhibitors Current use 1.0 (0.5 2.1) Short duration 1.1 (0.4 2.9) Long duration 0.9 (0.3 2.4) * Odds ratio (OR) adjusted for age, sex, calendar year, smoking and co-morbidity (diabetes, hypertension, heart failure, ischaemic heart disease), estimated by multiple regression analysis. in the general population cohort in this study is in line with recent results from populations in the UK. 15 A positive association was found with myocardial infarction for all known risk factors, such as smoking and previous heart disease. For some, such as hyperlipidaemia and heart failure, the risk estimates were not more statistically significant once all risk factors studied were adjusted for simultaneously. A doubling in risk of myocardial infarction associated with smoking and diabetes has been reported in men and women in several populations. 16 In our study, the 6-month period after the diagnosis of chest pain was associated with a close to 10-fold increased risk of myocardial infarction in patients free of GERD, but to a much lesser extent in the GERD cohort. In the West of Scotland Coronary Prevention Study, self-reporting of angina by the Rose Questionnaire was associated with a 54% increase in the risk of coronary heart disease-associated death or non-fatal myocardial infarction, and the consumption of nitrates presented a 90% increase in risk. 17 Chest pain, as reported in this study, covered not only stable angina pectoris, but also chest pain developing in the immediate pre-infarction period. Our data indicate that chest pain is a good predictor of subsequent myocardial infarction, especially in the general population free of GERD. In summary, our results suggest that GERD is not an independent predictor of myocardial infarction and the use of acid-suppressing drugs is not associated with a risk of myocardial infarction in the GERD cohort. The increase in risk observed in the immediate days after the first recorded diagnosis of GERD is most likely a reflection of prodromal ischaemic symptoms being initially misinterpreted as reflux symptoms. ACKNOWLEDGEMENTS We thank the staff at the General Practice Research Database and the participating general practitioners for their collaboration. We also thank the Boston Collaborative Drug Surveillance Program for providing access to the database. This study was supported by a research grant from AstraZeneca. REFERENCES 1 Holtmann G. Reflux disease: the disorder of the third millennium. Eur J Gastroenterol Hepatol 2001; 1(Suppl.): 5 11. 2 Spechler SJ. Epidemiology and natural history of gastrooesophageal reflux. Digestion 1992; 51(Suppl.): 24 9. 3 Locke GR, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Prevalence and clinical spectrum of gastroesophageal reflux: a population based study in Olmsted County, Minnesota. Gastroenterology 1997; 112: 1448 56. 4 Smith KS, Papp C. Episodic, postural and linked angina. Br Med J 1962; 2: 1425 30. 5 Chauhan A, Petch MC, Shofield PM. Effect of oesophageal acid instillation on coronary blood flow. Lancet 1993; 341: 1309 10. 6 Chauhan A, Petch MC, Schofield PM. Cardio-oesophageal reflux in humans as a mechanism for linked angina. Eur Heart J 1996; 17: 407 13. 7 Mehta AJ, de Caestecker JS, Camm J, Northfield TC. Gastrooesophageal reflux in patients with coronary heart disease: how common is it and does it matter? Eur J Gastroenterol Hepatol 1996; 8: 973 8. 8 Jick H, Terris BZ, Derby LE, Jick SS. Further validation of information recorded on a general practitioner based computerised data resource in the United Kingdom. Pharmacoepidemiol Drug Safety 1992; 1: 347 9. 9 García Rodríguez LA, Pérez Gutthann S. Use of the UK General Practice Research Database for pharmacoepidemiology. Br J Clin Pharmacol 1998; 45: 419 25. 10 Jick SS, Kaye JA, Vasilakis-Scaramoza C, et al. Validity of the General Practice Research Database. Pharmacotherapy 2003; 23: 686 9. 11 Svensson O, Stenport G, Tibbling L, Wranne B. Oesophageal function and coronary angiogram in patients with disabling chest pain. Acta Med Scand 1978; 204: 173 8. 12 Hewson EG, Dalton CB, Hackshaw BT, Wu WC, Richter JE. The prevalence of abnormal results in patients with cardiovascular disease and unexplained chest pain. Arch Intern Med 1990; 150: 965 9. 13 Singh S, Richter JE, Hewson EG, Sinclair JW, Hackshaw BT. The contribution of gastroesophageal reflux to chest pain in

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