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Abstract
Background and objectives AKI after coronary angiography is associated with poor long-term outcomes. The relationship between contrast-associated AKI and subsequent use of prognosis-modifying cardiovascular medications is unknown.
Design, setting, participants, & measurements A cohort study of 5911 participants 66 years of age or older with acute coronary syndrome who received a coronary angiogram in Alberta, Canada was performed between November 1, 2002, and November 30, 2008. AKI was identified according to Kidney Disease Improving Global Outcomes AKI criteria.
Results In multivariable logistic regression models, compared with participants without AKI, those with stages 1 and 2–3 AKI had lower odds of subsequent use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker within 120 days of hospital discharge (adjusted odds ratio, 0.65; 95% confidence interval, 0.53 to 0.80 and odds ratio, 0.34; 95% confidence interval, 0.23 to 0.48, respectively). Subsequent statin and β-blockers use within 120 days of hospital discharge was significantly lower among those with stages 2–3 AKI (adjusted odds ratio, 0.44; 95% confidence interval, 0.31 to 0.64 and odds ratio, 0.46; 95% confidence interval, 0.31 to 0.66, respectively). These associations were consistently seen in patients with diabetes mellitus, heart failure, low baseline eGFR, and albuminuria; 952 participants died during subsequent follow-up after hospital discharge (mean=3.1 years). The use of each class of cardiovascular medication was associated with lower mortality, including among those who had experienced AKI.
Conclusions Strategies to optimize the use of cardiac medications in people with AKI after coronary angiography might improve care.
Introduction
AKI occurs in 10%–11% of patients after percutaneous coronary angiography and is more frequent among the elderly and patients with diabetes mellitus, heart failure, and preexisting CKD (1,2). Although kidney function returns to baseline in the majority of individuals in this setting, contrast-associated AKI has been associated with adverse short- and long-term outcomes, including cardiovascular morbidity, ESRD, and mortality (3–6).
Several medications, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, and statins, have been shown to lower cardiovascular morbidity and mortality in a wide range of populations with cardiovascular disease (7–12). However, these medications are prescribed 30%–74% less frequently in some high-risk groups, suggesting a risk-treatment paradox that includes the elderly and those with comorbidities (13–17). Although contrast-associated AKI could also influence physician’s decisions to prescribe these medications after a cardiovascular event because of their hemodynamic effects or potential for nephrotoxicity (18–20), little is known about the association between AKI and the use of these medications in patients with cardiovascular disease.
Given this knowledge gap, we examined the relationship between contrast-associated AKI and subsequent cardiovascular medication use in elderly patients after an acute coronary syndrome (ACS). We also examined the association between the use of these medications and subsequent survival among individuals who had experienced AKI. We hypothesized that those with AKI would be less likely to receive these medications after hospitalization with an ACS but that use of these medications would be associated with improved survival.
Materials and Methods
Study Population
We identified the study cohort from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database. The APPROACH database prospectively collects demographics, clinical data, and vital statistics on all patients receiving a coronary angiogram in the province of Alberta in Canada (21). Only nonionic iodinated radio-contrast agents were used in coronary angiography, with the choice of low- or iso-osmolar radio-contrast agents and prophylaxis strategies for AKI made by the treating physicians.
We included all Alberta residents 66 years of age or older hospitalized with an ACS who underwent coronary angiography from November 1, 2002, to November 30, 2008, and survived at least 120 days after hospital discharge. Eligible participants required a minimum of one outpatient serum creatinine measurement within 6 months before coronary angiography and a subsequent measurement within 7 days of the procedure. We excluded patients receiving hemodialysis or peritoneal dialysis or who had a renal transplant before angiography on the basis of the Northern and Southern Alberta Renal Program registries or dialysis billing claims (22).
Measurements of Kidney Function
We obtained all serum creatinine measurements, standardized across provincial laboratories to an Isotope Dilution Mass Spectrometry reference standard, from the Alberta Kidney Disease Network (AKDN) repository (23) and determined preangiography eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation (24). We defined AKI according to the Kidney Disease Improving Global Outcomes definition, with stage 1 AKI defined as a 1.5- to 1.9-fold or >0.3 mg/dl (>26.5 μmol/L) increase in serum creatinine, stage 2 AKI defined as a 2.0- to 2.9-fold increase in serum creatinine, and stage 3 AKI defined as a >3.0-fold or >4 mg/dl (353.6 μmol/L) increase in serum creatinine with an acute increase of >0.3 mg/dl (25). We calculated the change in serum creatinine using the closest measurement before angiography as the baseline and the peak concentration observed between angiography and hospital discharge.
Measurements of Covariates
We determined age, sex, comorbidities, coronary anatomy, left ventricular systolic ejection fraction on the basis of ventriculogram at the time of angiography, and subsequent revascularization procedures performed (none, percutaneous coronary intervention, or coronary artery bypass graft) from the APPROACH database (21). We obtained all quantitative or semiquantitative urinary protein or albumin measurements collected 6 months before angiography from the AKDN laboratory database (23). We classified albuminuria as normal (<30 mg/g albumin-to-creatinine ratio and urine dip negative), increased (30–300 mg/g albumin-to-creatinine ratio and urine dip trace or +1), severely increased (>300 mg/g albumin-to-creatinine ratio and urine dip>+2), or unmeasured using the most recent outpatient urine test within 6 months before hospitalization as classified by Lamb et al. (26)
Measurement of Medication Use
We obtained prescription drug data for all participants ages 66 years or older (they receive universal drug coverage in Alberta). We classified drugs into the following groupings: statins, β-blockers, and ACEIs/ARBs. Antiplatelet agents were not considered, because aspirin is available over the counter in Alberta. For each medication class, we classified participants as users (medication dispensed) or nonusers (medication not dispensed) after hospital discharge. We used a 120-day time frame for ascertainment of drug prescriptions after hospital discharge, because analyses showed that >98% of all medication prescriptions were dispensed within this period.
Statistical Analyses
We compared participant characteristics according to their AKI status using a two-tailed F test for continuous variables and a chi-squared test for categorical variables. We examined the associations between AKI (no AKI, stage 1 AKI, or stage 2–3 AKI) and subsequent use of each class of cardiovascular medication within 120 days after hospital discharge using logistic regression models. We included covariates for age, sex, eGFR, albuminuria, comorbidities, severity of coronary vascular disease, treatment (medical, percutaneous coronary intervention, or coronary artery bypass graft), and prior medication use in logistic regression models. To further explore whether these associations were consistent across clinically important subgroups, we also fit logistic regression models, including an interaction term between AKI and several potential modifying variables (diabetes mellitus, heart failure, eGFR, and albuminuria), and performed subgroup analyses for each medication class within these groups. Next, we determined the associations between cardiovascular medication use and long-term survival by identifying all patients who survived 120 days after hospital discharge and categorizing them according to whether they were prescribed each of the cardiovascular medications within the first 120 days after hospital discharge. These patients were followed from 120 days after hospital discharge to November 30, 2009, to avoid immortal time bias. After observing no significant interactions (P<0.10) between the stage of AKI and use of each cardiovascular medication for the outcome of mortality, we stratified subsequent survival analyses on the basis of the presence or absence of AKI of any stage. Associations between the use of each class of cardiovascular medication and mortality in patients with or without AKI were examined using Kaplan–Meier plots. We also fit Cox proportional hazards models for mortality, stratified according to AKI status and medication use, and adjusted for age, sex, eGFR, albuminuria, comorbidities, severity of coronary vascular disease, left ventricular ejection fraction, treatment, and previous medication use. We included interaction terms between medication use with diabetes mellitus, heart failure, and albuminuria to examine whether associations between the use of each class of medications and survival were consistent across each of these subgroups. We performed all analyses using the SAS and R Statistical software packages (27). Model assumptions were tested and met for all analyses. The study was approved by the Conjoint Health Ethics Research Board at the University of Calgary.
Results
Cohort Formation and Study Participants
During the study period, 10,268 patients over the age of 66 years were hospitalized with an ACS and received a coronary angiogram. We excluded 70 patients with ESRD, 60 patients without a serum creatinine measurement within 6 months before coronary angiogram, 661 patients who died before or within 120 days of discharge, and 3566 patients without an inpatient serum creatinine measurement after the coronary angiogram (Figure 1).
Cohort formation. Scr, serum creatinine.
Among 5911 patients included in the final cohort, the median (interquartile range) length of hospital stay from angiography to discharge was 4 (2–9) days, and the median (interquartile range) number of serum creatinine measurements obtain during this period was 2 (1–5). In total, 906 (15.3%) patients developed AKI, with 748 (82.6%) of those patients classified as stage 1 AKI and 158 (17.4%) of those patients classified as stage 2–3 AKI (25). Patients with AKI were older and had lower baseline eGFR as well as a higher prevalence of comorbidities, higher albuminuria, more high-risk/left main coronary vascular disease, and lower left ventricular ejection fraction than those without AKI (Table 1). Patients with AKI also had a higher prevalence of β-blocker and ACEI/ARB use before angiography than patients without AKI.
Baseline characteristics of study participants
Association between AKI and Subsequent Medication Use
During 120 days of follow-up after hospital discharge, statins were used in 82.6% of patients without AKI, 81.1% of patients with stage 1 AKI, and 65.2% of patients with stage 2–3 AKI, whereas β-blockers were prescribed in 83.0% of patients without AKI, 83.8% of patients with stage 1 AKI, and 71.5% of patients with stage 2–3 AKI (Table 2). Among those patients who used statins in the year before angiography, 9.4% of those without AKI, 8.6% of those with stage 1 AKI, and 30.4% of those with stage 2–3 AKI did not subsequently receive statins after discharge. In those patients who used β-blockers before angiography, 10.6% of those without AKI, 10.3% of those with stage 1 AKI, and 23.3% of those with stage 2–3 AKI did not subsequently receive β-blockers after discharge. In fully adjusted models, the odds of statin and β-blocker use did not significantly differ among patients with stage 1 AKI; however, those with stage 2–3 AKI had 56% and 54% lower odds of using statins (adjusted odds ratio [OR], 0.44; 95% confidence interval [95% CI], 0.31 to 0.64) or β-blockers (adjusted OR, 0.46; 95% CI, 0.31 to 0.66), respectively (Figure 2). ACEIs/ARBs were used in 83.8% of those without AKI, 77.1% of those with AKI stage 1, and 63.9% of those with AKI stage 2–3 (Table 2). In those who used ACEIs/ARBs before angiography, 10.9% of those without AKI, 17.4% of those with stage 1 AKI, and 29.8% of those with stage 2–3 AKI did not receive ACEIs/ARBs after discharge. In adjusted models, patients with stage 1 AKI had 35% lower odds of being treated with an ACEI/ARB than those without AKI (adjusted OR, 0.65; 95% CI, 0.53 to 0.80), whereas patients with stage 2–3 AKI had 66% lower odds of being treated with an ACEI/ARB than those without AKI (adjusted OR, 0.34; 95% CI, 0.23 to 0.48) (Figure 2).
Use of cardiovascular medications according to severity of AKI
Associations between AKI and use of cardiovascular medications in all study participants and specified subgroups. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; 95% CI, 95% confidence interval; OR, odds ratio.
The associations between AKI and the subsequent use of cardiovascular medications were consistent in the presence or absence of diabetes, heart failure, reduced baseline eGFR, albuminuria, and prior medication use from the same class (P interaction >0.10 for all models). Specifically, stage 2–3 AKI remained associated with lower use of statins and β-blockers, whereas stages 1 and 2–3 AKI also remained associated with lower rates of ACEI/ARB use within these subgroups (Figure 2).
Association between Medication Use and Long-Term Mortality
In total, 5911 individuals survived 120 days from hospital discharge, and during the subsequent follow-up (mean=3.1 years), 952 individuals died before the end of the study. The use of each class of cardiovascular medication was associated with lower mortality in those with or without AKI (Figure 3). In the fully adjusted Cox models, the use of statins, β-blockers, and ACEIs/ARBs each remained associated with lower mortality in both individuals with and without AKI (Table 3). Among individuals with AKI, there were no significant interactions (P>0.10) between the use of each class of cardiovascular medication and diabetes, heart failure, or albuminuria, suggesting that the associations between use of these medications and survival remained consistent in those with AKI in the presence or absence of these comorbidities.
Associations between use of cardiovascular medications and survival according to AKI status
Use of cardiovascular medications and mortality according to AKI status
Discussion
In this cohort study, we found that mild and severe contrast-associated AKI were associated with lower use of ACEIs/ARBs, whereas severe episodes of AKI were associated with lower use of statins and β-blockers after hospitalization with ACS. Specifically, the odds of ACEI/ARB use were 35% lower after stage 1 AKI and 66% lower after stage 2–3 AKI compared with in patients without AKI. The odds of statin and β-blocker use were similar in the absence of AKI and after stage 1 AKI but lower after stage 2–3 AKI by 56% and 54%, respectively. These patterns of use were consistent in those with diabetes, heart failure, preexisting CKD, and proteinuria as well as among new users and prior users of these medications. Despite the differences in use of these medications, we found that statin, β-blocker, and ACEI/ARB use was associated with lower long-term mortality, including among those who had experienced AKI.
Although statins, β-blockers, and ACEIs/ARBs have beneficial effects for the management of cardiovascular disease, little is known about their use after an episode of AKI. There are several reasons why ACEIs/ARBs may be used less frequently after an episode of AKI, including concerns that their introduction or continued use could worsen kidney function. The pharmacodynamic effects of ACEI/ARB are well known to include a reduction in GFR caused by glomerular hemodynamic effects, and these medications are often stopped in patients who develop AKI (28). Furthermore, it has been reported in observational studies that the use of ACEIs/ARBs after cardiovascular surgery for ischemic heart disease is associated with a 27% increase in the risk of AKI (29). Although an acute decline in GFR occurs after ACEI/ARB introduction (30), such changes in kidney function do not seem to be associated with an adverse long-term renal prognosis (31), and in fact, several randomized trials have shown long-term benefits of ACEI/ARB relevant to this population, including an attenuation in the long-term rate of kidney function decline in patients with CKD, proteinuria, and diabetes (30,32–34), improved survival in patients with systolic dysfunction (7–10,35), and a reduction in cardiovascular events among high-risk individuals (7,36). This information suggests that any benefit on short-term change in kidney function associated with avoiding use of ACEIs/ARBs after AKI may not outweigh the long-term benefits of these medications, consistent with the findings of our survival analysis.
Although it remains uncertain whether statins lower the risk of contrast-induced AKI or are associated with AKI when used in high doses, they have been consistently shown to lower major adverse cardiovascular events in most populations (37–45). To our knowledge, there are no published reports of AKI associated with β-blocker use. The lower rates of β-blocker use after more severe episodes of AKI could be caused by hemodynamic instability associated with AKI, whereas lower use of statins may result from concerns for toxicity from these medications in the setting of more severe reductions in kidney function.
Our results build on previous work that has identified a risk-treatment paradox in a number of high-risk groups with cardiovascular disease. Recently, Chang et al. (16) reported that the percentage of days covered by pharmacy dispensing of ACEIs/ARBs, β-blockers, and statins was only 50%–60% in the elderly after myocardial infarction. Compared with the general population, patients with nondialysis CKD have also been found to have decreased use of ACEIs/ARBs after myocardial infarction (14). These studies suggest that kidney function may consistently modify the decisions to prescribe cardiovascular medications, even in those at high risk for cardiovascular events and death. Our study extends this knowledge to show that elderly patients who develop AKI after coronary angiography experience lower use of ACEIs/ARBs, independent of baseline kidney function and comorbidities. Likewise, our study shows that elderly patients who develop severe AKI after coronary angiography have lower use of statins and β-blockers, despite apparent benefits, even in those who have experienced AKI.
Our study had several strengths, including a large population-based sample of elderly patients undergoing coronary angiography for ACS in a defined geographic area. This cohort was well characterized with respect to comorbidities and kidney function, including comprehensive drug data from the provincial ministry. Our study also has limitations. Given the observational design of the study, we are unable to prove that AKI plays a causal role in altering the use of these medications or that the prevention of AKI would increase their use. We did not have information on adverse events after angiography, such as low BP or hyperkalemia, to determine whether the lower use of these medications was appropriate or inappropriate. Furthermore, we did not have information on cause of death. Despite these limitations, because AKI is likely to resolve in the majority of patients, we have identified a high-risk group that might benefit from additional follow-up, including medication reconciliation after contrast-associated AKI. Lastly, we were limited to patients 66 years or older for prescription drug information because of the provincial medication coverage plan. There may be greater bias toward avoiding therapies in older individuals, which could limit the generalizability of these findings to younger patients. However, because the majority of those at risk for AKI and myocardial infarction are above 66 years of age, these results may be generalizable to the majority of patients.
Our finding of the decreased use of ACEIs/ARBs, statins, and β-blockers after AKI among patients with indications for these medications identifies a potentially modifiable practice that could be targeted to lower the high risks of adverse cardiovascular events, progressive CKD, and all-cause mortality among this group. Additional research to determine whether interventions to optimize use of these medications may be of value, including studies of community-based medication reconciliation strategies focused on resuming these medication after an episode of AKI, where appropriate. Specifically, additional research seems warranted to determine whether enhancing the follow-up of such patients after hospital discharge could lower differences in the use of these medications and improve long-term cardiovascular and kidney outcomes.
In conclusion, we found that contrast-associated AKI was associated with lower use of ACEIs/ARBs, whereas severe AKI was associated with lower use of statins and β-blockers after ACS. We also found that the use of these medications was associated with lower mortality, including among those who had experienced AKI. Additional research, including trials to optimize the use of these medications and determine effects on long-term morbidity and mortality in individuals with AKI, are warranted. Strategies to reevaluate the introduction of these medications after contrast-associated AKI after hospital discharge should be further studied.
Disclosures
M.L.K. has received honoraria for presentations from the Canadian Cardiovascular Society and Medtronic. M.T.J. has received an honorarium for a presentation from Amgen. The other authors report no conflicts.
Acknowledgments
This study is based, in part, on data provided by Alberta Health and Alberta Health Services.
The study was funded by a seed grant from the University of Calgary. Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) was initially funded with a grant from the W. Garfield Weston Foundation and has also received contributions from Alberta Health and Wellness and the following industry sponsors—Merck Frosst Canada Inc., Eli Lily Canada Inc., Roche Canada, Bristol-Myers Squibb, and Philips Medical Systems Canada—to support the basic infrastructure of this cardiac registry initiative. The ongoing operation of APPROACH has been made possible by support from Alberta Health Services (Calgary Zone and Edmonton Zone), Libin Cardiovascular Institute of Alberta, and Mazankowski Alberta Heart Institute. W.A.G. was supported by a Senior Health Scholar Award from Alberta Innovates–Health Solutions. M.L.K. received partial support from the Libin Trust Fund. B.R.H. was supported by a Population Health Investigator Award from Alberta Innovates–Health Solutions. M.T. was supported by Health Scholar. M.T.J. was supported by a Kidney Research Scientist Core Education and National Training Program New Investigator Award (cofunded by the Canadian Institutes for Health Research, Kidney Foundation of Canada, and Canadian Society of Nephrology).
The study funders had no role in the study design, the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit the article for publication. The interpretation and conclusions are those of the researchers and do not represent the views of the Government of Alberta.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
See related editorial, “AKI and Medical Care after Coronary Angiography: Renalism Revisited,” on pages 1823–1825.
- Received April 5, 2014.
- Accepted July 27, 2014.
- Copyright © 2014 by the American Society of Nephrology
References
