Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin–angiotensin system inhibitors in the community increases the risk of acute kidney injury
2015; Elsevier BV; Volume: 88; Issue: 2 Linguagem: Inglês
10.1038/ki.2015.101
ISSN1523-1755
AutoresTobias Dreischulte, Daniel R. Morales, Samira Bell, Bruce Guthrie,
Tópico(s)Atrial Fibrillation Management and Outcomes
ResumoNonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin–angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin–angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case–control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin–angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25–2.14)) and dual combinations with either renin–angiotensin system inhibitors (1.60 (1.18–2.17)) or diuretics (1.64 (1.17–2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin–angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin–angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought. Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin–angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin–angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case–control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin–angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25–2.14)) and dual combinations with either renin–angiotensin system inhibitors (1.60 (1.18–2.17)) or diuretics (1.64 (1.17–2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin–angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin–angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought. The incidence of acute kidney injury (AKI) is rising globally and it is increasingly recognized that even relatively small rises of serum creatinine are associated with subsequent chronic and end-stage kidney disease and death.1.Lameire N.H. Bagga A. Cruz D. et al.Acute kidney injury: an increasing global concern.Lancet. 2013; 382: 170-179Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar Nonsteroidal anti-inflammatory drugs (NSAIDs) are estimated to account for up to 7% of all cases of AKI and up to 36% of drug-induced cases.2.Henrich W.L. Agodoa L.E. Barrett B. et al.Analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation.Am J Kidney Dis. 1996; 27: 162-165Abstract Full Text PDF PubMed Scopus (177) Google Scholar,3Lee A. Adverse Drug Reactions. 2nd edn. Pharmaceutical Press, London, UK2006Google Scholar NSAID exposure has been reported to increase the risk of AKI between 1.3- and 4.1-fold and the number needed to harm (NNH) with recent NSAID treatment has been estimated to range from 400 to 12,000 per year, depending on study populations and definitions of AKI used.4.Adam W.R. Non-steroidal anti-inflammatory drugs and the risks of acute renal failure: number needed to harm (Editorial).Nephrology. 2011; 16: 154-155Crossref PubMed Scopus (7) Google Scholar, 5.Evans J.M. McGregor E. McMahon A.D. et al.Non-steroidal anti-inflammatory drugs and hospitalization for acute renal failure.Q J Med. 1995; 88: 551-557Google Scholar, 6.Griffin M.R. Yared A. Ray W.A. Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.Am J Epidemiol. 2000; 151: 488-496Crossref PubMed Scopus (235) Google Scholar, 7.Huerta C. Castellsague J. Varas-Lorenzo C. et al.Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.Am J Kidney Dis. 2005; 45: 531-539Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 8.Lapi F. Azoulay L. Yin H. et al.Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case–control study.BMJ. 2013; 346: e8525Crossref PubMed Scopus (275) Google Scholar, 9.Perez Gutthann S. Garcia Rodriguez L.A. Raiford D.S. et al.Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for acute renal failure.Arch Intern Med. 1996; 156: 2433-2439Crossref PubMed Scopus (155) Google Scholar The adverse renal effects of NSAIDs are primarily mediated by inhibiting the prostaglandin-mediated dilation of the afferent renal arteriole.10.Medicines Healthcare products Regulatory Agency (MHRA) Non-steroidal anti-inflammatory drugs: reminder on renal failure and impairment.Drug Saf Update. 2009; 1: 4Google Scholar Prostaglandins do not usually have a major role in maintaining renal blood flow, but their effect may become crucial in situations of volume depletion, especially when the angiotensin-II-mediated constriction of the efferent renal arteriole is blocked. The renal risks of NSAIDs may therefore be particularly high in users of renin–angiotensin system inhibitors (RASIs) and/or diuretics, and the term 'triple whammy' was first coined in 2000 to highlight the potential nephrotoxic effects of combining all three drug classes.11.Thomas M.C. Diuretics, ACE inhibitors and NSAIDs—the triple whammy.Med J Aust. 2000; 172: 184-185PubMed Google Scholar A single case–control study demonstrated the renal adverse effects of the 'triple whammy' combination but did not find an increased AKI risk for dual combinations of NSAIDs with RASIs or diuretics alone.8.Lapi F. Azoulay L. Yin H. et al.Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case–control study.BMJ. 2013; 346: e8525Crossref PubMed Scopus (275) Google Scholar However, similar to previous studies of NSAID-associated AKI risk,4.Adam W.R. Non-steroidal anti-inflammatory drugs and the risks of acute renal failure: number needed to harm (Editorial).Nephrology. 2011; 16: 154-155Crossref PubMed Scopus (7) Google Scholar, 5.Evans J.M. McGregor E. McMahon A.D. et al.Non-steroidal anti-inflammatory drugs and hospitalization for acute renal failure.Q J Med. 1995; 88: 551-557Google Scholar, 6.Griffin M.R. Yared A. Ray W.A. Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.Am J Epidemiol. 2000; 151: 488-496Crossref PubMed Scopus (235) Google Scholar, 7.Huerta C. Castellsague J. Varas-Lorenzo C. et al.Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.Am J Kidney Dis. 2005; 45: 531-539Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 8.Lapi F. Azoulay L. Yin H. et al.Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case–control study.BMJ. 2013; 346: e8525Crossref PubMed Scopus (275) Google Scholar, 9.Perez Gutthann S. Garcia Rodriguez L.A. Raiford D.S. et al.Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for acute renal failure.Arch Intern Med. 1996; 156: 2433-2439Crossref PubMed Scopus (155) Google Scholar this study relied on hospital discharge coding to identify AKI, which may underestimate true AKI risk, because AKI is commonly under-recorded in hospital discharge data.12.Waikar S.S. Wald R. Chertow G.M. et al.Validity of International Classification of Diseases, Ninth Revision, Clinical Modification Codes for Acute Renal Failure.J Am Soc Nephrol. 2006; 17: 1688-1694Crossref PubMed Scopus (371) Google Scholar NSAIDs are effective analgesics and widely used in the management of acute and chronic pain, especially in the elderly, who also often take RASIs and diuretics for heart failure or cardioprevention. In a recent large cross-sectional study in the United Kingdom, 8.8% of patients aged 65 years and over prescribed RASIs and diuretics received at least one NSAID prescription per year.13.Guthrie B. McCowan C. Davey P. et al.High risk prescribing in primary care patients particularly vulnerable to adverse drug events: cross sectional population database analysis in Scottish general practice.BMJ. 2011; 21: 342Google Scholar Clinicians and patients therefore need robust information on the magnitude of renal risk associated with NSAIDs in this scenario. The aim of this nested case–control study was to examine the risk of community-acquired AKI (measured using laboratory data) associated with exposure to NSAIDs among users of RASIs and/or diuretics and variations in AKI risk by diuretic regimen, baseline renal function, and age. The dynamic study cohort comprised 78,379 patients aged 30 years or older (without prior AKI or otherwise unstable renal function) prescribed RASIs or diuretics at cohort entry (Figure 1). A total of 2804 cases of community-acquired AKI were identified, of which 2226 cases occurred during 327,491 person-years of exposure to RASIs and/or diuretics (incidence rate 68/10,000 patient years), and 1952 cases occurred during RASIs and/or diuretic exposure without concurrent NSAID exposure. Table 1 shows that the background AKI incidence was comparable under monotherapy with RASIs and diuretics, but doubled under treatment with both (99/10,000 patient years). Among diuretic regimens, AKI incidence was highest under loop diuretic/aldosterone antagonist treatment. Background AKI incidence was higher in people with renal impairment than without and increased with age. When only AKI events with emergency hospital admission were considered, incidence rates were considerably lower, but the relative differences among diuretics, renal function, and age strata were similar.Table 1Stratum-specific background incidence rates of community-acquired AKI in a dynamic cohort of RASI or diuretic users (n=78,379) followed up for a total of 444,127 person-yearsNo. of community-acquired AKI events (incidence/10,000 years exposed (95% CI))ExposurePerson-years exposed (% of total)Any AKIAKI with emergency admission within 7 days of AKI onsetAny RASI or diuretic without concurrent NSAID304,121 (68.5)1952 (64 (61, 67))1158 (38 (36, 40))Stratification by dual/triple combination RASI only without concurrent NSAID117,373 (26.4)559 (48 (44, 51))321 (27 (24, 31)) Diuretic only without concurrent NSAID85,205 (19.2)389 (46 (41, 50))258 (30 (27, 34)) RASI plus diuretic without concurrent NSAID101,544 (22.9)1004 (99 (93, 105))579 (57 (52, 62))Stratification by diuretic regimen Thiazide without loop diuretic or aldosterone antagonist without concurrent NSAIDaIncludes cotreatment with amiloride or triamterene.133,811 (30.1)541 (40 (37, 44))279 (21 (18, 23)) Loop diuretic without aldosterone antagonist without concurrent NSAIDbIncludes cotreatment with thiazides and/or amiloride triamterene.46,820 (10.5)605 (129 (119, 139)392 (84 (76, 92)) Loop diuretic plus aldosterone antagonist without concurrent NSAIDbIncludes cotreatment with thiazides and/or amiloride triamterene.6117 (1.4)199 (325 (283, 374))135 (221 (186, 261))Stratification by renal function RASI and/or diuretic with eGFR 30–59 ml/min without concurrent NSAID93,679 (21.1)824 (88 (82, 94))560 (60 (55, 65)) RASI and/or diuretic with eGFR ≥60 ml/min without concurrent NSAID210,442 (47.4)1128 (54 (50, 57))598 (28 (26, 31))Stratification by age RASI and/or diuretic without concurrent NSAID and aged 300) for the triple combination, owing to the higher background AKI incidence under RASI/diuretic combination therapy (Table 1).Table 4Stratum-specific current use of NSAIDs and associated risk of AKI among users of renin–angiotensin system inhibitors and/or diureticsExposureControls (%), n=21,206Cases (%), n=2226RR crudeaNo NSAID exposure served as the reference; cases and controls matched on calendar year of cohort entry, follow-up duration at index date, prevalent user status, renal monitoring pattern, and background treatment with RASIs and/or diuretic, with diuretics stratified as thiazide alone, loop diuretic without aldosterone antagonist, loop diuretic plus aldosterone antagonist, and 'other'.RR adjustedaNo NSAID exposure served as the reference; cases and controls matched on calendar year of cohort entry, follow-up duration at index date, prevalent user status, renal monitoring pattern, and background treatment with RASIs and/or diuretic, with diuretics stratified as thiazide alone, loop diuretic without aldosterone antagonist, loop diuretic plus aldosterone antagonist, and 'other'.,bAdjusted for age at index date, baseline renal function at index date, and those potential confounders listed in Table 2 that were significantly associated with AKI in the multivariate model (at P<0.05 level) or altered the rate ratio for NSAID exposure by≥10%.NNH/yearBackground treatmentNSAIDOverall Any RASI or diureticNo19,461 (91.8)1952 (87.7)1.59**P-value <0.01.1.66**P-value <0.01.237Yes1745 (8.2)274 (12.3)(1.38, 1.82)(1.40, 1.97)Stratification by single/combined use of RASI/diuretic RASI onlyNo5803 (92.6)559 (88.9)1.58**P-value <0.01.1.60**P-value <0.01.347Yes462 (7.4)70 (11.1)(1.21, 2.06)(1.18, 2.17) Diuretic onlyNo3774 (89.5)390 (84.0)1.69**P-value <0.01.1.64**P-value <0.01.340Yes441 (10.5)74 (16.0)(1.28, 2.21)(1.17, 2.29) RASI plus diureticNo9884 (92.1)1004 (88.5)1.54**P-value <0.01.1.64**P-value <0.01.158Yes842 (7.9)130 (11.5)(1.26, 1.87)(1.25, 2.14)Stratification by diuretic regimen Thiazide alonecExcludes patients treated with loop diuretics or aldosterone antagonists.No5866 (91.3)541 (83.4)2.10**P-value <0.01.1.97**P-value <0.01.258Yes559 (8.7)108 (16.6)(1.68, 2.63)(1.49, 2.61) Loop diuretic without aldosterone antagonistdIncludes patients also treated with thiazide diuretics.No5886 (90.8)605 (89.1)1.201.18431Yes597 (9.2)74 (10.9)(0.93, 1.55)(0.83, 1.66) Loop diuretic plus aldosterone antagonistdIncludes patients also treated with thiazide diuretics.No1575 (93.9)199 (93.0)1.243.98*P-value <0.0510Yes102 (6.1)15 (7.0)(0.68, 2.24)(1.20, 13.2)Stratification by renal function Any RASI or diuretic and eGFR ≥60 ml/minNo18 050 (91.9)1 128 (87.0)1.76**P-value <0.01.1.60**P-value <0.01.309Yes1598 (8.1)168 (13.0)(1.43, 2.10)(1.31, 1.95) Any RASI or diuretic and eGFR 30–59 ml/minNo1 411 (90.6)824 (88.6)0.862.51*P-value <0.0575Yes147 (9.4)106 (11.4)(0.53, 1.38)(1.09, 5.78)Stratification by age Any RASI or diuretic and aged <60 yearsNo4074 (89.7)335 (84.8)1.53*P-value <0.051.34684Yes467 (10.3)60 (15.2)(1.05, 2.24)(0.86, 2.07) Any RASI or diuretic and aged 60–74 yearsNo8398 (90.5)782 (85.9)1.52**P-value <0.01.1.41*P-value <0.05413Yes877 (9.5)128 (14.1)(1.21, 1.90)(1.07, 1.87) Any RASI or diuretic and aged 75 years or olderNo6989 (94.6)835 (90.7)2.04**P-value <0.01.2.64**P-value <0.01.68Yes401 (5.4)86 (9.3)(1.54, 2.71)(1.50, 4.64)Abbreviations: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; NNH, number needed to harm; NSAID, nonsteroidal anti-inflammatory drug; RASI, renin–angiotensin system inhibitor; RR, rate ratio.* P-value <0.05** P-value <0.01.a No NSAID exposure served as the reference; cases and controls matched on calendar year of cohort entry, follow-up duration at index date, prevalent user status, renal monitoring pattern, and background treatment with RASIs and/or diuretic, with diuretics stratified as thiazide alone, loop diuretic without aldosterone antagonist, loop diuretic plus aldosterone antagonist, and 'other'.b Adjusted for age at index date, baseline renal function at index date, and those potential confounders listed in Table 2 that were significantly associated with AKI in the multivariate model (at P<0.05 level) or altered the rate ratio for NSAID exposure by≥10%.c Excludes patients treated with loop diuretics or aldosterone antagonists.d Includes patients also treated with thiazide diuretics. Open table in a new tab Abbreviations: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; NNH, number needed to harm; NSAID, nonsteroidal anti-inflammatory drug; RASI, renin–angiotensin system inhibitor; RR, rate ratio. Stratification by diuretic regimen showed elevated adjusted rate ratios for NSAIDs among users of all diuretic regimens (statistically significant for thiazides and loop diuretic/aldosterone antagonist combinations), where the risk was highest for NSAID use among users of loop diuretic/aldosterone antagonist combinations (adjusted rate ratio 3.98; NNH=10). Stratification by renal function showed significantly elevated adjusted rate ratios irrespective of baseline renal function, but a higher risk among those with than those without renal impairment (adjusted rate ratio 2.51 vs. 1.60; NNH=75 vs. 309). Stratification by age showed elevated adjusted rate ratios for NSAID users of all ages (statistically significant for patients aged 60 years or older), but a higher adjusted rate ratio (2.64 vs. 400). In several prespecified sensitivity analyses, we found results generally consistent with the primary analyses, when (1) restricting the cohort to incident users of RASIs or diuretics; (2) excluding people with hospitalization during the 30-day risk window; excluding cases (3) who died within 30 days, (4) with AKI stage 1, (5) without emergency admissions; (6) dropping the continuous exposure assumptions for RASIs and thiazide diuretics; (7) restricting exposures to those overlapping the index date; (8) additionally matching cases and controls by general practice; (9) excluding patients who were started on an RASI or diuretic during the risk window, distinguishing between (10) chronic and (11) acute NSAID exposure; and (12) when adjusting by a propensity score for NSAID exposure. However, there were three partial exceptions. First, acute NSAID exposure was associated with a higher risk of AKI than chronic NSAID exposure among patients treated with diuretics alone (3.40 vs. 1.32). Second, restricting the case definition to AKI stages 2 and 3 yielded a considerably lower adjusted rate ratio for the dual combination of NSAIDs with RASIs (0.89 vs. 1.60). Third, restricting the case definition to those with emergency admissions yielded lower adjusted rate ratios (ranging from 1.27 to 1.40), which is similar to a previous hospital-based study.8.Lapi F. Azoulay L. Yin H. et al.Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case–control study.BMJ. 2013; 346: e8525Crossref PubMed Scopus (275) Google Scholar When we (13) extended the risk window of exposure to 60, 90, 180, and 360 days and the entire follow-up period, the risk estimates increased as the risk window became narrower, which is consistent with increasing exposure misclassification and supports the 30-day risk window. See Supplementary Material online for details. Download .doc (.18 MB) Help with doc files Supplementary Material Within a cohort of RASI and/or diuretic users (aged 30 years or older), the incidence of community-acquired AKI measured using laboratory data was 68/10,000 patient years, which was much higher than in previous studies in the general population relying on hospital discharge coding of AKI (0.25 to 7/10,000 patient years).4.Adam W.R. Non-steroidal anti-inflammatory drugs and the risks of acute renal failure: number needed to harm (Editorial).Nephrology. 2011; 16: 154-155Crossref PubMed Scopus (7) Google Scholar, 5.Evans J.M. McGregor E. McMahon A.D. et al.Non-steroidal anti-inflammatory drugs and hospitalization for acute renal failure.Q J Med. 1995; 88: 551-557Google Scholar, 7.Huerta C. Castellsague J. Varas-Lorenzo C. et al.Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.Am J Kidney Dis. 2005; 45: 531-539Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 8.Lapi F. Azoulay L. Yin H. et al.Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case–control study.BMJ. 2013; 346: e8525Crossref PubMed Scopus (275) Google Scholar, 9.Perez Gutthann S. Garcia Rodriguez L.A. Raiford D.S. et al.Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for acute renal failure.Arch Intern Med. 1996; 156: 2433-2439Crossref PubMed Scopus (155) Google Scholar Of those developing AKI in this study, more than half (58.6%) were hospitalized as an emergency within 7 days, and 13.9% died within 30 days (13 and 49 times more than controls, respectively). Even among those with AKI who were not admitted, 30-day mortality was 4.2%, underlining the clinical significance of identified AKI events. We found that NSAID use was associated with a significantly increased AKI risk overall (adjusted rate ratio 1.66; annual NNH=237), where the annual NNH from NSAID use was much lower than in previous studies relying on hospital discharge coding of AKI (0.25 to 7/10,000 patient years; NNH>4000).4.Adam W.R. Non-steroidal anti-inflammatory drugs and the risks of acute renal failure: number needed to harm (Editorial).Nephrology. 2011; 16: 154-155Crossref PubMed Scopus (7) Google Scholar, 5.Evans J.M. McGregor E. McMahon A.D. et al.Non-steroidal anti-inflammatory drugs and hospitalization for a
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