Spironolactone use and the risk of upper gastrointestinal bleeding: a population-based case control study

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1 British Journal of Clinical Pharmacology DOI: /j x Spironolactone use and the risk of upper gastrointestinal bleeding: a population-based case control study Sinem E. Gulmez, 1 Annmarie T. Lassen, 2 Claus Aalykke, 3 Michael Dall, 3 Alin Andries, 4 Birthe S. Andersen, 5 Jane M. Hansen, 3 Morten Andersen 6 & Jesper Hallas 1 1 Research Unit of Clinical Pharmacology, University of Southern Denmark and Departments of 2 Infectious Medicine, 3 Medical Gastroenterology, 4 Endocrinology and 5 Cardiology, 6 Research Unit of General Practice Odense University Hospital, Odense, Denmark WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Recent studies have suggested an increased risk of upper gastrointestinal bleeding (UGB) in spironolactone users. We conducted this population-based case control study to confirm the association between spironolactone use and acute nonvaricose UGB alone or in combination with low-dose aspirin and other antithrombotic drugs. WHAT THIS STUDY ADDS The current use of spironolactone is associated with an increased risk of nonvaricose UGB. The effect is most pronounced for cases aged years. Persons with a high current dose have a higher risk. The risk is not modified by high cumulative doses or by concurrent use of antithrombotic or nonsteroidal anti-inflammatory drugs. Correspondence Dr Sinem Ezgi Gulmez, MD, PhD, University of Southern Denmark, Faculty of Health Sciences, Institute of Public Health, Research Unit of Clinical Pharmacology, Winsløwparken 19, 3, DK-5000 Odense C, Denmark. Tel: Fax: egulmez@health.sdu.dk or gulmezezgi@yahoo.com S.E.G. wrote the first protocol draft, performed the data analyses and wrote the first manuscript draft. J.H. provided input to the protocol, data analysis and manuscript, and validated some cases. M.A., A.T.L., C.A., M.D., A.A., B.S.A. and J.M.H. provided input to the manuscript and validated some cases. All authors have approved the current version. S.E.G. is the guarantor Keywords antithrombotic drugs, case control study, spironolactone, upper gastrointestinal bleeding Received 2 January 2008 Accepted 9 April 2008 Published OnlineEarly 27 May 2008 AIMS Recent studies have suggested an increased risk of upper gastrointestinal bleeding (UGB) in spironolactone users. The aim was to confirm the association, identify the risk factors and quantify the absolute risk. METHODS A population based case control study was conducted in the County of Funen, Denmark. Cases (n = 3652) were all subjects with a first discharge diagnosis of serious UGB during the period 1995 to Age- and gender-matched controls (10 for each case) (n = ) were selected by risk set sampling. Data on all subjects drug exposure and past medical history were retrieved from a prescription database and from the County s patient register. Confounders were controlled by conditional logistic regression. RESULTS The adjusted odds ratio (OR) associating current use of spironolactone with UGB was 2.7 [95% confidence interval (CI) 2.2, 3.2]. The risk increased with higher doses of spironolactone (5.4; 3.4, 8.6) for 100-mg tablets. No trend was found with increasing cumulative dose. The strongest association was found among users aged years (OR 13.1; 6.5, 26.3). Current use of loop diuretics was also associated with an increased risk of UGB (1.9; 1.7, 2.1). CONCLUSION The use of spironolactone is associated with increased risk of UGB. The risk increases with higher doses. 294 / Br J Clin Pharmacol / 66:2 / The Authors Journal compilation 2008 Blackwell Publishing Ltd

2 Spironolactone and risk of upper GI bleeding Introduction Spironolactone is a potassium-sparing diuretic mainly used to treat certain patients with hyperaldosteronism, low potassium levels, and patients with oedema caused by various conditions, including heart or liver disease. It also acts as an aldosterone inhibitor used to treat advanced heart failure when symptoms persist after other drug therapies are optimized [1].When used in this manner, it is not as a diuretic to remove extra fluid from the body, but rather to reduce left ventricular hypertrophy in hypertensive patients and to decrease post-infarction collagen synthesis and improve left ventricular remodelling [2, 3]. It is considered the diuretic of choice in patients with liver cirrhosis. Gastrointestinal (GI) bleeding in users of spironolactone has been reported in a few case reports [4 6]. A recent population-based case control study has reported a 2.7- fold increase in risk of gastroduodenal ulcers or upper gastrointestinal bleeding (UGB) in patients taking spironolactone [7].The strength of association increased with dose and with concomitant use of ulcerogenic drugs.the mechanism is believed to be inhibition of the formation of fibrous tissue by binding to mineralocorticosteroid receptors; the effect is modulated by 11b hydroxysteroid dehydrogenase enzymes [8]. Thus, aldosterone receptor antagonists, such as spironolactone, could impair the healing of gastric or duodenal erosions and result in the formation of gastroduodenal ulcers, with or without bleeding. We conducted this population-based case control study to confirm the association between spironolactone use and acute nonvaricose UGB alone or in combination with low-dose aspirin (ASA) and other antithrombotic drugs. Subjects and methods Setting Data were retrieved from three different sources: the Patient Registry of the County of Funen (FPAS), the Danish Civil Registry and the Odense University Pharmacoepidemiological Database (OPED). The FPAS contains data on all discharges from hospitals in the County of Funen (population ) since 1977 using either International Classification of Diseases, 8th revision (ICD8, ) or 10th revision (ICD10, ) codes [9]. OPED has been described elsewhere [10]. In brief, OPED captures all reimbursed prescriptions from the County of Funen. The substances and quantities are registered according to the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) system and defined daily doses methodology (WHO Collaborating Centre for Drug Statistics Methodology 2006). Data confidentiality is protected by a scrambling of personidentifiers. The Danish Civil Registry was used to identify the source population, to extract controls and to ensure that all subjects were residents of the County of Funen for at least 12 months before their index date. All these data can be linked by using the mutual person identifier, the Central Person Registry code, which is shared with virtually all other health-related registries in Denmark, thereby allowing record-linkage studies. Cases and controls A validated complete dataset of cases of bleeding (n = 3652) along with an age- and sex-matched control group of 10 subjects per case (n = ) was generated as in a previous study by our group [11]. In brief, cases were defined by fulfilment of all of the following criteria: admission with peptic ulcer or gastritis as main diagnosis within one of the County s hospitals during the period 1 August 1995 to 31 July 2006; significant bleeding defined either by melaena, subnormal haemoglobin or the need for transfusions; and a potential bleeding source in the stomach or duodenum identified by endoscopy or surgery. Excluded were gastric varices. Cases were identified by manual review of all discharge summaries with a main diagnosis of peptic ulcer (complicated or not) or gastritis (ICD10 code K25 29) within the study period.cases were assigned an index date equivalent to the first registered date of a UGB diagnosis. Age- and sex-matched controls, 10 for each case, were sampled by use of a risk set sample technique.in brief, controls for a given case were randomly selected among those within the county who matched the case with respect to gender and exact birth year.the controls were assigned an index date identical to the admission date of the corresponding case. For both cases and controls, we required that they had been residents of the county for at least 1 year on the index date. Cases were eligible as control subjects until their first admission with UGB. By this sample technique, the generated odds ratios (ORs) were unbiased estimates of the incidence rate ratios [12]. Exposure definition Subjects were considered as current users if they redeemed a prescription of spironolactone (ATC code C03DA01) within the past 90 days before the index date. Persons whose last prescription was redeemed days before the index date were classified as recent users, and >180 days before the index date as past users. The same exposure criteria were used for all other drugs in the analysis. The choice of a 90-day exposure window for spironolactone was based on analyses of repeat prescriptions, using the waiting-time technique [13]. Unless otherwise stated, analyses were based on current exposure, and the reference was person-time never exposed to spironolactone or whatever other diuretic we analysed for. The antithrombotic drugs (ATC Br J Clin Pharmacol / 66:2 / 295

3 S. E. Gulmez et al. code B01A) included in this study were clopidogrel (ATC code B01AC04), low-dose ASA (ATC code B01AC06), dipyridamole (ATC code B01AC07) and vitamin K antagonists (ATC code B01AA). Data analysis The crude and adjusted ORs with 95% confidence intervals (CI), whenever relevant, were calculated by using conditional logistic regression with adjustment for the mentioned confounders. Age, gender and calendar year were accounted for by the design. Potential confounders included in the analysis were previous diagnosis of gastric ulcer (ICD8-531; ICD10-K25), duodenal ulcer (ICD8-532; ICD10-K26), peptic ulcer (ICD8-533; ICD10-K27), gastritis and duodenitis (ICD8-535; ICD10-K29), current use of lowdose ASA (ATC B01AC06), i.e. a prescription of low-dose ASA within the past 90 days, current use of antithrombotic agents (ATC code B01A), of nitrate vasodilators (ATC code C01DA), ever use of antidiabetics (ATC A10) or a diagnosis of diabetes (ICD8-250, ICD10 E10 14), hypertension (ICD8-40, ICD10-I10), or ever use of antihypertensive agents (ATC C03A, C07, C08, C09), congestive heart failure (ICD8-427; ICD10-I50), ischaemic heart disease or acute myocardial infarction (ICD ; ICD10 I20 25), cerebral ischaemia or stroke (ICD8-431, ; ICD10 I61, I63 and I64 excluding I631 and 641), chronic obstructive pulmonary disease (COPD) (ICD ; ICD10-J44) or ever use of systemic b-agonists or inhaled anticholinergics (ATC R03C and R03BB), any history of alcohol-related disorder (ICD8 303; ICD10-F10) or use of disulfiram (ATC code P03AA04), and psychiatric disorder (ICD ; ICD10- F20, 30 33). Past episodes of peptic ulcer or ulcer bleeding were required to have occurred at least 1 month before the case date, to avoid confusing the manifestations of the current bleeding episode with past episodes. The dose response-like relationship was evaluated both in terms of daily dose taken and cumulative dose before the index date. As most relevant doses were on the market as single tablets (25, 50 and 100 mg), the tablet strength of the last prescription was used as a proxy for prescribed dose. To evaluate the specificity of the spironolactone UGB association, we analysed the association with other diuretics. In this way a 90-day exposure window was assigned to all diuretic prescriptions. Included diuretics were thiazides plain potassium supplement (ATC code C03A), loop diuretics (ATC code C03C) and fixed diuretic combinations thiazide + amiloride (ATC code C03E). In order to express the risk inflicted by the use of spironolactone therapy in absolute terms, the number of patients needed to be treated for one additional patient to be harmed principle (NNTH) was employed. We employed the adjusted ORs and the incidence of UGB in the background population unexposed to spironolactone and who were 60 years old. NNTH was then calculated as NNTH = 1/[ER unexp (OR - 1)], where OR is the odds ratio provided by the case control study and ER unexp is the unexposed event rate [14]. Ninety-five percent CIs for NNTH were calculated as suggested by Altman [15]. The project was approved by the Danish Data Protection Agency. Ethics committee approval was not required. Results We identified 3652 cases (51.2% men) fulfilling our criteria. The characteristics of cases and controls are shown in Table 1. Among the 3652 cases and controls, 204 (5.58%) and 550 (1.5%) were current users of spironolactone, respectively. The adjusted ORs associating use of spironolactone with UGB were 2.7 (95% CI 2.2, 3.2) for current use, 2.9 (1.99, 4.3) for recent use and 1.9 (1.5, 2.3) for past use. The risk increased with higher dose of spironolactone with Table 1 Characteristics of 3652 cases of upper gastrointestinal bleeding and their control subjects Cases (n = 3652) Controls (n = ) Age, mean (SD) and < (19.4) (19.4) (80.6) (80.6) Men 1869 (51.2) (51.2) Current drug use (ATC code) Low-dose aspirin (B01AC06) 621 (17.0) (8.3) Anticoagulants (B01AA) 164 (4.5) 761 (2.1) Antihypertensive agent (C03, C07-C09) 678 (18.6) (12.4) NSAIDs (M01A) 1213 (33.2) (10.6) Systemic corticosteroids 352 (9.6) (4.0) (H02AB) SSRIs (N06AB) 406 (11.1) (5.2) PPIs (A02B) 776 (21.2) (7.5) Spironolactone (C03DA01) 204 (5.6) 550 (1.5) History of Hp eradication 180 (4.9) 519 (1.4) Chronic obstructive lung disease 265 (7.3) (3.3) Peptic ulcer 372 (10.2) (3.6) UGB 91 (2.5) 214 (0.6) Ischaemic heart disease 599 (16.4) (9.4) Hepatic cirrhosis 54 (1.5%) 84 (0.2) Diabetes mellitus 246 (6.7) (3.2) Renal failure 80 (2.2) 157 (0.4) Heart failure 384 (10.5) (5.2) Hypertension 489 (13.4) (6.5) Stroke 315 (8.6) (4.3) Alcohol-related diagnosis or drug use 242 (6.6) 475 (1.3) Unless otherwise indicated, data are shown as numbers (%). SD, standard deviation; ATC, Anatomical Therapeutic Chemical; NSAIDs, nonsteroidal antiinflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; PPIs, proton pump inhibitors; Hp, Helicobacter pylori; UGB, upper gastrointestinal bleeding. 296 / 66:2 / Br J Clin Pharmacol

4 Spironolactone and risk of upper GI bleeding Table 2 Association between exposure to spironolactone or and upper gastrointestinal bleeding Exposure Cases exposed/unexposed Controls exposed/unexposed Crude odds ratio (95 CI) Adjusted odds ratio (95 CI)* Spironolactone, current use 204/ / (3.4, 4.8) 2.7 (2.2, 3.2) Spironolactone, recent use 49/ / (3.1, 6.2) 2.9 (1.9, 4.3) Spironolactone, past use 146/ / (2.4, 3.6) 1.9 (1.5, 2.3) Dose response (current use, tablet strength in mg) Low dose (25) 116/ / (2.8, 4.3) 2.1 (1.7, 2.7) Medium dose (50) 45/ / (2.6, 5.3) 2.8 (1.9, 4.2) High dose (100) 43/ / (5.5, 12.6) 5.4 (3.4, 8.6) Cumulative dose of current users of spironolactone (DDD) Low dose (<500 DDD) 128/ / (3.6, 5.5) 2.7 (2.1, 3.4) Medium dose ( DDD) 41/ / (2.9, 6.1) 3.3 (2.2, 5.0) High dose (>1000 DDD) 35/ / (1.9, 4.2) 2.1 (1.4, 3.3) *Adjusted for age, sex, a previous discharge diagnosis of upper gastrointestinal bleeding, Helicobacter pylori eradication, chronic obstructive pulmonary disease, peptic ulcer, ischaemic heart disease, liver cirrhosis, alcohol-related diagnoses, renal failure, diabetes, heart failure, hypertension, stroke and for current use of low-dose acetylsalicylic acid, oral anticoagulants, clopidogrel, dipyridamole, anti-acid drugs (proton pump inhibitors and histamine-2 receptor antagonists), selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, nitrate vasodilators, and systemic corticosteroids. CI, confidence interval. Table 3 Association between thiazides plain potassium supplement, loop diuretics and fixed diuretic combinations thiazide + amiloride (C03E), and the risk of upper gastrointestinal bleeding Exposure Cases exposed/unexposed Controls exposed/unexposed Crude odds ratio (95 CI) Adjusted odds ratio (95 CI)* Spironolactone, current use 204/ / (3.4, 4.8) 2.7 (2.2, 3.2) Spironolactone, recent use 49/ / (3.1, 6.1) 2.9 (1.9, 4.3) Spironolactone, past use 146/ / (2.4, 3.6) 1.9 (1.5, 2.3) Thiazides plain potassium supplement, current use 389/ / (1.2, 1.6) 1.1 (0.9, 1.2) Thiazides plain potassium supplement, recent use Thiazides plain potassium supplement, past use 145/ / (1.3, 1.90) 1.4 (1.1, 1.7) 742/ / (1.6, 1.9) 1.2 (1.1, 1.4) Loop diuretics, current use 880/ / (2.9, 3.5) 1.9 (1.7, 2.1) Loop diuretics, recent use 178/ / (2.4, 3.4) 1.8 (1.5, 2.3) Loop diuretics, past use 394/ / (1.8, 2.3) 1.3 (1.2, 1.5) Fixed diuretic combinations thiazide + amiloride, current use 133/ / (1.1, 1.6) 1.2 (1.0, 1.5) Fixed diuretic combinations thiazide + amiloride, recent use Fixed diuretic combinations thiazide + amiloride, past use Loop diuretics, current use (all ever users of spironolactone excluded) 53/ / (1.3, 2.5) 1.7 (1.2, 2.3) 342/ / (1.4, 1.8) 1.1 (1.0, 1.3) 635/ / (2.5, 3.1) 1.7 (1.5, 1.9) *Adjusted for age, sex, a previous discharge diagnosis of upper gastrointestinal bleeding, Helicobacter pylori eradication, chronic obstructive pulmonary disease, peptic ulcer, ischaemic heart disease, liver cirrhosis, alcohol-related diagnoses, renal failure, diabetes, heart failure, hypertension, stroke and for current use of low-dose acetylsalicylic acid, oral anticoagulants, clopidogrel, dipyridamole, anti-acid drugs (proton pump inhibitors and histamine-2 receptor antagonists), selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, nitrate vasodilators and systemic corticosteroids. CI, confidence interval. an OR of 5.4 (3.4, 8.6) for 100 mg. The adjusted ORs for cumulative dose response in current users of spironolactone were 2.7 (95% CI 2.1, 3.4), 3.3 (2.2, 5.09) and 2.1 (1.4, 3.3) for low, medium and high cumulative doses, respectively (Table 2). Table 3 shows the association between thiazides plain potassium supplement (C03A), loop diuretics (C03C) and fixed diuretic combinations thiazide + amiloride (C03E), and the risk of UGB. The reference for all analyses was never-use of the particular drug. Current use of loop diuretics was associated with an increased risk of UGB (1.9; 1.7, 2.1). When all ever-users of spironolactone were excluded,we found an OR for the association between loop diuretics and UGB of 1.7 (95% CI 1.5, 1.9) (Table 3). Table 4 lists stratum-specific crude and adjusted ORs for the association between current use of spironolactone Br J Clin Pharmacol / 66:2 / 297

5 S. E. Gulmez et al. Table 4 Stratum-specific odds ratios for the association between current use of spironolactone and upper gastrointestinal bleeding (UGB) Stratum Cases exposed/unexposed Controls exposed/unexposed Crude odds ratio (CI) Adjusted odds ratios (CI)* Men 97/ / (3.5, 5.7) 2.8 (2.1, 3.7) Age (years) 55 & <74 37/670 21/ (10.3, 30.0) 13.1 (6.5, 26.3) / / (2.7, 3.9) 2.2 (1.8, 2.7) Current drug use: ASA users 37/ / (1.5, 6.5) 3.0 (1.2, 7.4) ASA non-users 167/ / (3.8, 5.7) 3.0 (2.4, 3.8) VKA non-users 183/ / (3.3, 4.7) 2.6 (2.1, 3.2) History of: Peptic ulcer 24/348 38/ (1.1, 78.0) 9.2 (0.7, 116.6) Ischaemic heart disease 58/ / (1.47, 3.9) 1.8 (1.03, 3.2) Heart failure (+) 71/ / (0.9, 3.2) 2.5 (1.06, 5.8) Heart failure ( ) 133/ / (3.1, 4.6) 2.8 (2.2, 3.6) Hypertension (+) 55/ / (1.2, 3.07) 1.7 (1.0, 2.8) Hypertension ( ) 149/ / (3.7, 5.6) 3.2 (2.5, 4.05) Stroke 19/296 45/ (0.3, 3.3) 0.5 (0.09, 3.3) Diabetes mellitus 23/223 56/ (0.9, 12.9) 1.6 (0.2, 12.1) COPD 28/237 65/ (1.0, 24.0) 4.1 (0.1, 87.8) No history of alcohol-related diagnosis or drug use 182/ / (3.0, 4.2) 2.4 (1.9, 2.9) * Adjusted for age, sex, a previous discharge diagnosis of UGB, Helicobacter pylori eradication, chronic obstructive pulmonary disease (COPD), peptic ulcer, ischaemic heart disease, liver cirrhosis, alcohol-related diagnoses, renal failure, diabetes, heart failure, hypertension, stroke and for current use of low-dose acetylsalicylic acid, oral anticoagulants, clopidogrel, dipyridamole, anti-acid drugs (proton pump inhibitors and histamine-2 receptor antagonists), selective serotonin reuptake inhibitors, nonsteroidal anti-inflammatory drugs, nitrate vasodilators and systemic corticosteroids. CI, confidence interval. and UGB. No clear subgroup dependency emerged, except for age years (13.1; 6.5, 26.3). No trend was found for index year either (data not shown), and no difference was found among patients with and without a history of heart failure (OR 2.5 vs. 2.8). In particular, no modification occurred with concurrent use of antithrombotic drugs or nonsteroidal anti-inflammatory drugs (NSAIDs). We observed 2778 bleeding cases among persons 60 years old who were unexposed to spironolactone. According to census data, the cumulative person-time that gave rise to these cases was person-years, yielding an unexposed event rate of 2.53 per 1000 person-years. The NNTH was estimated as one excess case per 230 personyears of treatment (95% CI 173, 317). Discussion In this large case control study, we have demonstrated that the current use of spironolactone is associated with an increased risk of nonvaricose UGB. The effect was most pronounced for cases aged years. Persons with a high current dose had a higher risk. An association for cumulative use could not be demonstrated. The risk was not modified by concurrent use of antithrombotic drugs or NSAIDs. To our knowledge, the only epidemiological study reporting an increased risk for GI bleeding in spironolactone users is that by Verhamme et al. [7].They performed a case control study by using a primary care information database in the Netherlands with 523 cases of uncomplicated ulcers and ulcer bleedings and 5230 matched controls, and concluded that the current use of spironolactone was associated with a 2.7-fold (1.2, 6.0) increased risk of a GI event. The strengths of our study are, first, thorough retrieval and ascertainment of a large number of cases, all of which were reviewed manually. Second, we had valid prescription data and a true population-based approach with full coverage of admissions and spironolactone prescriptions, in which a unique personal identifier allowed precise linkage between data sources. Thereby, selection bias is unlikely. Third, we focussed exclusively on bleeding ulcers. Risk factors for bleeding and complicated ulcers may differ substantially, and the timing of an uncomplicated ulcer may be difficult to establish relative to a given exposure. Thus, studies on a mixed set could be difficult to interpret. Moreover, we had the possibility of adjusting for important potential confounders.well-known risk factors for UGB and ulcers are age, previous UGB or ulcers, smoking, alcohol misuse, infection with Helicobacter pylori, and drugs such as NSAIDs, corticosteroids, anticoagulants and selective serotonin reuptake inhibitors [16 18].Our dataset allowed us to adjust for most of these confounding factors except for smoking and alcohol abuse; instead,we adjusted for history of COPD,which could be a crude marker of smoking,and for an alcoholism diagnosis or use of disulfiram. We concede, however, that these are not very sensitive markers, and that there could be some residual confounding. 298 / 66:2 / Br J Clin Pharmacol

6 Spironolactone and risk of upper GI bleeding Confounding by severity could be possible in this study. Patients with more severe heart failure are more likely to be treated with spironolactone than those with less severe disease, but they might also have an inherently higher risk of upper GI events. However, we found no difference in the association between subjects with and without heart failure. We also evaluated if there was an association with other diuretics.interestingly,current use of loop diuretics was also associated with an increased risk of UGB (1.9; 1.7, 2.1). Spironolactone is recommended by most heart failure specialists for selected patients due to a significantly decreased mortality rate in these patients [1]. Although our analyses point towards a genuine biological association between spironolactone and UGB, some of the observations could suggest confounding at play: an apparent association between past use of spironolactone and UGB and an apparent (albeit weaker) association with loop diuretics. There could be a confounded association especially in patients with a history of heart failure and alcohol use. Whatever the nature of the association, patients whom physicians choose to prescribe spironolactone are at high risk of UGB, and the physician should consider preventive measures against this potentially lethal condition. Competing interests J.H. has received fees for teaching from AstraZeneca, MSD and the Danish Association of the Pharmaceutical Industry, and research grants from Novartis, Pfizer and Nycomed. 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