Major upper gastrointestinal bleeding and the use of calcium channel blockers
Authors: Judith P Kelly, Andras Laszlo, David W Kaufman, Anders Sundstrom, Samuel Shapiro
Journal: The Lancet (1999)

An increased risk of upper gastrointestinal bleeding (UGIB) associated with use of calcium-channel blockers (CCB) was recently reported,1Pahor M Guralnik JM Furberg CD Carbonin P Havlik RJ Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old.Lancet. 1996; 347: 1061-1065Summary PubMed Scopus (200) Google Scholar then refuted.2Smalley WE Ray WA Daugherty JR Griffin MR No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease.Am J Epidemiol. 1998; 148: 350-354Crossref PubMed Scopus (26) Google Scholar, 3Suissa S Bourgault C Barkun A Sheehy O Ernst P Antihypertensive drugs and the risk of gastrointestinal bleeding.Am J Med. 1998; 105: 230-235Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar We have explored the relation using data from a case-control study conducted in Massachusetts, Stockholm, Uppsala, and Budapest from 1987 to 1996.4Kaufman DW Kelly JP Sheehan JE et al.Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding.Clin Pharmacol Ther. 1993; 53: 485-494Crossref PubMed Scopus (131) Google Scholar Cases were individuals with a first episode of major UGIB due to gastric or duodenal ulcer or gastritis, presenting with melaena or haematemesis, and confirmed by endoscopy. Individuals with a prior episode of UGIB, a history of gastrointestinal conditions, or other conditions that can cause UGIB (such as oesophageal varices) were excluded. In the US and Sweden, community controls were matched to cases by age, sex, and neighbourhood, using census lists; hospital controls were enrolled in Hungary. The same exclusion factors used for cases were applied to controls. Each subject was interviewed by study nurses who used a standardised questionnaire that included questions on medication use for hypertension or cardiac problems. An index day was defined as a reference point for medication use. For cases, this was the day on which haematemesis or melaena first occurred. For community controls, the index day was the day of interview; for hospital controls, it was the day of the first symptom of the condition for which hospitalisation had occurred. The analysis was confined to drug exposure within the week before the index day. Relative risks (RR) and 95% CI were estimated using conditional multiple-logistic regression. Terms were included for non-steroidal anti-inflammatory agents and other potential risk factors. There were 1441 cases and 3017 controls, of whom 149 and 219, respectively, were current users of CCBs (table). The unadjusted RR and 95% CI was 1·5 (1·2–1·8); the corresponding multivariate estimate was 1·2 (0·9–1·6). The factor that had the strongest effect in reducing the adjusted estimate was aspirin use. 45 cases and 56 controls had taken verapamil, 61 and 97 had taken nifedipine, and 38 and 48 had taken diltiazem. The corresponding multivariate RRs were 1·2 (0·8–1·9), 1·2 (0·9–1·8), and 1·3 (0·8–2·2). The multivariate estimates for all CCBs combined were similar (1·2 and 1·4) for two separate data collection periods in the US. In Hungary and Sweden, the multivariate RRs were 1·2 and 1·1, respectively. The estimate was 1·3 (0·9–1·8) among current aspirin users and 1·1 (0·7–1·5) among non-users of aspirin. The RRs were similar when the data were stratified according to age, indication for use, duration of use, or drug formulation (regular vs slow release).TableRisk of UGIB according to calcium-channel blocker use, overall, by region, and by aspirin useCases exposedControls exposedUnadjusted RR (95% CI)Multivariate RR (95% CI)Total149 (10%)219 (7%)1·5 (1·2–1·8)1·2 (0·9–1·6)RegionUSA I23 (6%)30 (4%)1·6 (0·9–2·7)1·2 (0·6–2·3)USA II63 (14%)88 (10%)1·5 (1·0–2·1)1·4 (0·9–2·1)Hungary32 (14%)53 (12%)1·2 (0·7–1·9)1·2 (0·7–2·1)Sweden31 (7%)48 (5%)1·6 (1·0–2·6)1·1 (0·6–2·0)Aspirin useYes70 (5%)69 (2%)1·2 (0·9–1·6)1·0 (0·7–1·6)No68 (5%)144 (5%)1·3 (0·9–1·8)1·3 (0·9–1·8) Open table in a new tab The present results suggest that use of CCBs does not materially increase the risk of UGIB. The overall adjusted RR estimate was 1·2, and a 70% increase in risk was ruled out with 95% confidence; the upper confidence limit excludes the relative risk estimate of 1·9 that was observed in the study that first reported an association. An elevated unadjusted risk estimate for CCB use was due to confounding by the concurrent use of aspirin, often used for cardioprevention. Based on the present results and the findings of others,2Smalley WE Ray WA Daugherty JR Griffin MR No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease.Am J Epidemiol. 1998; 148: 350-354Crossref PubMed Scopus (26) Google Scholar, 3Suissa S Bourgault C Barkun A Sheehy O Ernst P Antihypertensive drugs and the risk of gastrointestinal bleeding.Am J Med. 1998; 105: 230-235Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar there appears to be little need to consider adverse gastrointestinal effects when weighing the risks and benefits of prescribing CCBs. The authors thank J E Sheehan, R S Koff, and Bengt-Erik Wiholm. Supported by grant RO1 DK36997 from the National Institute of Diabetes and Digestive and Kidney Diseases, and by Sterling Drug (New York, NY), McNeil Consumer Products Company (Fort Washington, PA), Ciba-Geigy Corporation (Summit, NJ), and the National Corporation of Swedish Pharmacies. The Slone Epidemiology Unit also received general support during the course of the study from Marion Merrell Dow (Kansas City, MO) and Hoffman-La Roche (Nutley, NJ). Bayer, Hoechst Marion Roussel, and Knoll provided support for other, unrelated projects.