Epidemiology • Volume 25, Number 3, May 2014
Letters
ACE Inhibitors and Urinary Tract Infections To the Editor: e recently applied a prescription sequence symmetry analysis to estimate the association between use of angiotensin-converting enzyme inhibitors (ACEi) and urinary tract infections (UTIs) (sequence ratio = 1.56 [95% confidence interval (CI) = 1.11–2.20).1 That study was conducted to further support findings from a post hoc analysis of a randomized clinical trial in which fosinopril, an ACEi, was associated with an increased risk of incident UTIs (hazard ratio = 1.82 [95% CI] = 1.16–2.88).2 Because the prescription sequence symmetry analysis1,3–5 can be regarded as a variation on the case-crossover design,6,7 it would be informative to compare the results of these two designs evaluating the same association in the same database. We reevaluated the association between ACEi initiation and UTIs using a case-crossover design. In the primary analysis, we used a case-crossover design with data from the University Groningen IADB.nl database for the whole data-capturing period (1994 to 2011). The prescription sequence symmetry analyses are described in the eAppendix (http://links.lww.com/EDE/A773). We defined the date of incident use of nitrofurantoin as the index date. Incident use was defined as absence of a prescription of nitrofurantoin in the 12 months before the dispensing date. We excluded persons using other antibiotics indicated for UTIs before their first nitrofurantoin prescription. We defined the risk period as 30 days before the index date, and the control period as 60 to 90 days before the index day. A binary exposure indicator was created for the risk and control period, such that persons were considered exposed to ACEi
W
Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1044-3983/14/2503-0466 DOI: 10.1097/EDE.0000000000000088
466 | www.epidem.com
if they had at least 3 days’ supply within the window. Seven days were added to the number of days’ supply dispensed to allow for modest nonadherence. The following potential time-varying confounders were selected a priori: β-adrenoceptor antagonists (β-blockers), calcium channel blockers, angiotensin receptor blockers, diuretics, lipid-modifying agents, nonsteroidal anti-inflammatory drugs, and glucose-lowering drugs. We identified 116,974 patients who had received a nitrofurantoin prescription between January 1994 and December 2011. Median age was 72 years (interquartile range = 62–80); 81% were women. After excluding all patients not in the database 12 months before their nitrofurantoin prescription, or who had previously received antibiotics that are used to treat UTIs, 3966 cases were exposed to ACEi in the year before their first nitrofurantoin prescription. ACEi use was associated with an increased odds of starting UTI medication (crude odds ratio [OR] = 1.84 [95% CI = 1.51–2.25]), which slightly decreased after adjustment for time-variant prescribing of diuretics (adjusted OR = 1.74 [1.42–2.13]) or after adjustment for use of the other medications listed in the Table (1.74 [1.41–2.15]). When the analysis were restricted to persons within the same age category as the post hoc analysis of the randomized controlled trial (28–75 years of age), the adjusted OR increased to
1.90 (1.44–2.50). When the same study period and similar criteria were used as in the previous prescription sequence symmetry analysis,1 the adjusted OR was 2.09 (95% CI = 1.68–2.61). Using a control window immediately before the risk window did not affect the estimate (2.10 [1.59–2.77]). These findings further support the hypothesis that ACEi therapy increases the risk of first UTIs, even after adjustment for potential time-invariant and time-variant confounders. (The eAppendix, http://links.lww.com/EDE/A773 includes a more complete discussion of differences between the two designs.) Despite their similarities, the application of the case-crossover design and the prescription sequence symmetry design within the same database showed slightly stronger effect estimates with the case-crossover design. Koen B. Pouwels Jens H. J. Bos Eelko Hak Department of Pharmacy Unit of PharmacoEpidemiology and PharmacoEconomics (PE) University of Groningen Groningen, The Netherlands [email protected]
REFERENCES 1. Pouwels KB, Visser ST, Bos HJ, Hak E. Angiotensin-converting enzyme inhibitor treatment and the development of urinary tract infections: a prescription sequence symmetry analysis. Drug Saf. 2013;36:1079–1086.
TABLE. Use of Other Medication by Patients Exposed to Angiotensin-Converting Enzyme Inhibitors in the Year Before Their First Nitrofurantoin Prescription (N = 3,966) Medication Angiotensin-converting enzyme inhibitors β-blockers Calcium channel blockers Angiotensin receptor blockers Diuretics Glucose-lowering medication Lipid-modifying medication NSAIDs
Risk Window No. (%)
Control Window No. (%)
3,492 (88) 1,622 (41) 786 (20) 206 (5) 1,755 (44) 979 (25) 1,381 (35) 429 (11)
3,366 (85) 1,593 (40) 774 (20) 192 (5) 1,692 (43) 943 (24) 1,366 (34) 392 (10)
NSAIDs indicates nonsteroidal anti-inflammatory drugs.
© 2014 Lippincott Williams & Wilkins
Epidemiology • Volume 25, Number 3, May 2014
2. Pouwels KB, Visser ST, Hak E. Effect of pravastatin and fosinopril on recurrent urinary tract infections. J Antimicrob Chemother. 2013;68:708–714. 3. Hallas J. Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology. 1996;7:478–484. 4. Pouwels KB, Kalkman GA, Schagen D, Visser ST, Hak E. Is combined use of SSRIs and NSAIDs associated with an increased risk of starting peptic ulcer treatment? (Letter) Br J Clin Pharmacol. 2013;doi:10.1111/bcp.12300. 5. van Boven JF, de Jong-van den Berg LT, Vegter S. Inhaled corticosteroids and the occurrence of oral candidiasis: a prescription sequence symmetry analysis. Drug Saf. 2013;36: 231–236. 6. Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991;133:144–153. 7. Maclure M, Mittleman MA. Should we use a case-crossover design? Annu Rev Public Health. 2000;21:193–221.
PM10 Oxidative Properties and Asthma and COPD To the Editor: xidative stress is a possible mechanism to explain the toxic effects of particulate matter (PM). Conceptually, PM oxidative burden is an appealing exposure metric because it captures a biological process thought to be responsible for PM-induced airway inflammation. However, few epidemiologic studies have examined this exposure metric, and results have been inconsistent.1 Direct measurement of PM oxidative properties could improve the ability to estimate PM effects and enhance the understanding of its mechanism of action, potentially
O
Supported by grants from the UK Department of Health’s Policy Research Programme, and the Medical Research Council and the Health Protection Agency through the MRC-HPA Centre for Health and the Environment. Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1044-3983/14/2503-0467 DOI: 10.1097/EDE.0000000000000084
© 2014 Lippincott Williams & Wilkins
Letters
leading to targeted public health strategies aimed at removing the most toxic PM components. We previously reported adverse effects of PM10 (mean aerodynamic diameter
Letters
ACE Inhibitors and Urinary Tract Infections To the Editor: e recently applied a prescription sequence symmetry analysis to estimate the association between use of angiotensin-converting enzyme inhibitors (ACEi) and urinary tract infections (UTIs) (sequence ratio = 1.56 [95% confidence interval (CI) = 1.11–2.20).1 That study was conducted to further support findings from a post hoc analysis of a randomized clinical trial in which fosinopril, an ACEi, was associated with an increased risk of incident UTIs (hazard ratio = 1.82 [95% CI] = 1.16–2.88).2 Because the prescription sequence symmetry analysis1,3–5 can be regarded as a variation on the case-crossover design,6,7 it would be informative to compare the results of these two designs evaluating the same association in the same database. We reevaluated the association between ACEi initiation and UTIs using a case-crossover design. In the primary analysis, we used a case-crossover design with data from the University Groningen IADB.nl database for the whole data-capturing period (1994 to 2011). The prescription sequence symmetry analyses are described in the eAppendix (http://links.lww.com/EDE/A773). We defined the date of incident use of nitrofurantoin as the index date. Incident use was defined as absence of a prescription of nitrofurantoin in the 12 months before the dispensing date. We excluded persons using other antibiotics indicated for UTIs before their first nitrofurantoin prescription. We defined the risk period as 30 days before the index date, and the control period as 60 to 90 days before the index day. A binary exposure indicator was created for the risk and control period, such that persons were considered exposed to ACEi
W
Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1044-3983/14/2503-0466 DOI: 10.1097/EDE.0000000000000088
466 | www.epidem.com
if they had at least 3 days’ supply within the window. Seven days were added to the number of days’ supply dispensed to allow for modest nonadherence. The following potential time-varying confounders were selected a priori: β-adrenoceptor antagonists (β-blockers), calcium channel blockers, angiotensin receptor blockers, diuretics, lipid-modifying agents, nonsteroidal anti-inflammatory drugs, and glucose-lowering drugs. We identified 116,974 patients who had received a nitrofurantoin prescription between January 1994 and December 2011. Median age was 72 years (interquartile range = 62–80); 81% were women. After excluding all patients not in the database 12 months before their nitrofurantoin prescription, or who had previously received antibiotics that are used to treat UTIs, 3966 cases were exposed to ACEi in the year before their first nitrofurantoin prescription. ACEi use was associated with an increased odds of starting UTI medication (crude odds ratio [OR] = 1.84 [95% CI = 1.51–2.25]), which slightly decreased after adjustment for time-variant prescribing of diuretics (adjusted OR = 1.74 [1.42–2.13]) or after adjustment for use of the other medications listed in the Table (1.74 [1.41–2.15]). When the analysis were restricted to persons within the same age category as the post hoc analysis of the randomized controlled trial (28–75 years of age), the adjusted OR increased to
1.90 (1.44–2.50). When the same study period and similar criteria were used as in the previous prescription sequence symmetry analysis,1 the adjusted OR was 2.09 (95% CI = 1.68–2.61). Using a control window immediately before the risk window did not affect the estimate (2.10 [1.59–2.77]). These findings further support the hypothesis that ACEi therapy increases the risk of first UTIs, even after adjustment for potential time-invariant and time-variant confounders. (The eAppendix, http://links.lww.com/EDE/A773 includes a more complete discussion of differences between the two designs.) Despite their similarities, the application of the case-crossover design and the prescription sequence symmetry design within the same database showed slightly stronger effect estimates with the case-crossover design. Koen B. Pouwels Jens H. J. Bos Eelko Hak Department of Pharmacy Unit of PharmacoEpidemiology and PharmacoEconomics (PE) University of Groningen Groningen, The Netherlands [email protected]
REFERENCES 1. Pouwels KB, Visser ST, Bos HJ, Hak E. Angiotensin-converting enzyme inhibitor treatment and the development of urinary tract infections: a prescription sequence symmetry analysis. Drug Saf. 2013;36:1079–1086.
TABLE. Use of Other Medication by Patients Exposed to Angiotensin-Converting Enzyme Inhibitors in the Year Before Their First Nitrofurantoin Prescription (N = 3,966) Medication Angiotensin-converting enzyme inhibitors β-blockers Calcium channel blockers Angiotensin receptor blockers Diuretics Glucose-lowering medication Lipid-modifying medication NSAIDs
Risk Window No. (%)
Control Window No. (%)
3,492 (88) 1,622 (41) 786 (20) 206 (5) 1,755 (44) 979 (25) 1,381 (35) 429 (11)
3,366 (85) 1,593 (40) 774 (20) 192 (5) 1,692 (43) 943 (24) 1,366 (34) 392 (10)
NSAIDs indicates nonsteroidal anti-inflammatory drugs.
© 2014 Lippincott Williams & Wilkins
Epidemiology • Volume 25, Number 3, May 2014
2. Pouwels KB, Visser ST, Hak E. Effect of pravastatin and fosinopril on recurrent urinary tract infections. J Antimicrob Chemother. 2013;68:708–714. 3. Hallas J. Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology. 1996;7:478–484. 4. Pouwels KB, Kalkman GA, Schagen D, Visser ST, Hak E. Is combined use of SSRIs and NSAIDs associated with an increased risk of starting peptic ulcer treatment? (Letter) Br J Clin Pharmacol. 2013;doi:10.1111/bcp.12300. 5. van Boven JF, de Jong-van den Berg LT, Vegter S. Inhaled corticosteroids and the occurrence of oral candidiasis: a prescription sequence symmetry analysis. Drug Saf. 2013;36: 231–236. 6. Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991;133:144–153. 7. Maclure M, Mittleman MA. Should we use a case-crossover design? Annu Rev Public Health. 2000;21:193–221.
PM10 Oxidative Properties and Asthma and COPD To the Editor: xidative stress is a possible mechanism to explain the toxic effects of particulate matter (PM). Conceptually, PM oxidative burden is an appealing exposure metric because it captures a biological process thought to be responsible for PM-induced airway inflammation. However, few epidemiologic studies have examined this exposure metric, and results have been inconsistent.1 Direct measurement of PM oxidative properties could improve the ability to estimate PM effects and enhance the understanding of its mechanism of action, potentially
O
Supported by grants from the UK Department of Health’s Policy Research Programme, and the Medical Research Council and the Health Protection Agency through the MRC-HPA Centre for Health and the Environment. Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1044-3983/14/2503-0467 DOI: 10.1097/EDE.0000000000000084
© 2014 Lippincott Williams & Wilkins
Letters
leading to targeted public health strategies aimed at removing the most toxic PM components. We previously reported adverse effects of PM10 (mean aerodynamic diameter
![[Urinary tract infections].](/assets/img/hold.png)
