Influence of Renal Function on the Effects of Early Revascularization in Non-ST-Elevation Myocardial Infarction
Data From the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART)
Background— It is unknown whether patients with non-ST-elevation myocardial infarction derive a similar benefit from an early invasive therapy at different levels of renal function.
Methods and Results— A total of 23 262 consecutive non-ST-elevation myocardial infarction patients ≤80 years old were included in a nationwide coronary care unit register between 2003 and 2006. Glomerular filtration rate (eGFR) was estimated with the Modification of Diet in Renal Disease Study formula. Patients were divided into medically or invasively treated groups if revascularized within 14 days of admission. A propensity score for the likelihood of invasive therapy was calculated. A Cox regression model with adjustment for propensity score and discharge medication was used to assess the association between early revascularization and 1-year mortality across renal function stages. There was a gradient, with significantly fewer patients treated invasively with declining renal function: eGFR ≥90 mL · min−1 · 1.73 m−2, 62%; eGFR 60 to 89 mL · min−1 · 1.73 m−2, 55%; eGFR 30 to 59 mL · min−1 · 1.73 m−2, 36%; eGFR 15 to 29 mL · min−1 · 1.73 m−2, 14%; and eGFR <15 mL · min−1 · 1.73 m−2/dialysis, 15% (P<0.001). After adjustment, the overall 1-year mortality was 36% lower (hazard ratio 0.64, 95% confidence interval 0.56 to 0.73, P<0.001) with an invasive strategy. The magnitude of survival difference was similar in normal-to-moderate renal function groups. The lower mortality observed with invasive therapy declined with lower renal function, with no difference in mortality in patients with kidney failure (eGFR <15 mL · min−1 · 1.73 m−2) or in those receiving dialysis (hazard ratio 1.61, 95% confidence interval 0.84 to 3.09, P=0.15).
Conclusions— Early invasive therapy is associated with greater 1-year survival in patients with non-ST-elevation myocardial infarction and mild-to-moderate renal insufficiency, but the benefit declines with lower renal function, and is less certain in those with renal failure or on dialysis.
Received November 24, 2008; accepted June 15, 2009.
Both the American College of Cardiology/American Heart Association and European Society of Cardiology 2007 guidelines recommend early revascularization for high-risk patients with non-ST-elevation myocardial infarction (NSTEMI).1,2 Patients with renal insufficiency and myocardial infarction (MI) have poor prognosis.3–5 The risk of adverse events increases with mild renal insufficiency6,7 and is extremely high in patients on dialysis, of whom only 41% will be alive 1 year after an MI.8 Therefore, patients with chronic kidney disease and NSTEMI are part of a group in whom “an invasive strategy may be reasonable.”1 The evidence supporting this treatment is based on clinical studies that often used renal insufficiency as an exclusion criterion. The benefit of early revascularization has not been examined in patients with different degrees of renal insufficiency, and it is unknown whether this approach alters the outcome. The aim of the present study, which included a cohort of nearly all consecutive patients with NSTEMI in Sweden between 2003 and 2006, was to describe the distribution of chronic kidney disease and the use of early revascularization, as well as to assess whether an invasive approach is associated with lower mortality at every level of renal function.
Editorial see p 828
Clinical Perspective on p 858
Patients with NSTEMI admitted to a coronary care unit between 2003 and 2006 were recorded in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART), previously known as the Register of Information and Knowledge about Swedish Heart Intensive care Admission (RIKS-HIA). The analyses are based on NSTEMI patients with available creatinine measurements and age ≤80 years (Figure 1). Medically treated patients were compared with patients who were revascularized by either a percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) within the first 14 days of admission. Patients who had coronary angiography but did not have PCI or CABG within 14 days of admission were considered medically treated. All-cause mortality was assessed at 1 year and was available in 99.4% of patients.
Glomerular filtration rate (eGFR) was estimated with the Modification of Diet in Renal Disease Study formula,9 which is calculated with creatinine, age, gender, and race. Everyone was assumed to be of white race. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative definition was used for renal function staging10: eGFR >90 (normal), 60 to 90 (mild), 30 to 59 (moderate), 15 to 29 (severe), and <15 mL · min−1 · 1.73 m−2 (renal failure) or receiving dialysis. Physicians were instructed to enter the most relevant in-hospital creatinine measurement that best reflected the patient’s underlying renal function.
In 2006, SWEDEHEART/RIKS-HIA registered all patients admitted to a coronary care unit at 71 of 74 hospitals admitting patients with acute coronary syndrome in Sweden. Information in SWEDEHEART/RIKS-HIA is collected prospectively for more than 100 variables (see http://www.riks-hia.se for details) and includes baseline characteristics, ECG changes, biochemical markers, in-hospital course, interventions, and discharge medications. NSTEMI was diagnosed with current guidelines.11 An acute MI was diagnosed if troponin T or troponin I levels or 2 successive creatine kinase-MB values were above the 99th percentile for the reference population within 24 hours of the index clinical event or if the creatine kinase-MB value was twice the decision limit. Patients were treated as deemed appropriate by the local physician.
To ensure the correctness of the data entered into the database, a monitor visits ≈20 hospitals each year and compares data entered into the register with the information in the patients’ records in 30 to 40 randomly chosen patients for each hospital. When 586 randomly chosen computer forms containing 36 330 variables were reviewed in 2006, there was 96.5% agreement (http://www.riks-hia.se).
Data on prior stroke, dementia, congestive heart failure, chronic obstructive pulmonary disease, and cancer were obtained from the National Patient Registry, which collects all discharge diagnosis for patients admitted to a hospital in Sweden. The Swedish Renal Registry provided information on dialysis therapy. All-cause mortality data were obtained from the National Death Registry, which includes information about vital status of all Swedish citizens.
All patients were informed about their participation in the registry and the follow-up and had the right to refuse participation. The registry and the merging of registries were approved by the National Board of Health and Welfare, the Swedish Data Inspection Board, and the local ethics committee at Uppsala University.
Continuous baseline characteristics are reported as means with SDs. Categorical variables were analyzed with χ2 test and continuous variables with the Kruskal-Wallis test.
A propensity score12 was created to express the likelihood for revascularization during the first 14 days of admission given the baseline characteristics, medications, and received treatments. A logistic regression model was used to develop the propensity score and included the following 31 clinical characteristics/medications and hospital type: Age (as a second-degree polynomial), gender, diabetes mellitus, hypertension, prior MI, heart failure, PCI, CABG, stroke, chronic obstructive pulmonary disease, dementia, peripheral vascular disease, cancer diagnosis within the last 3 years, medications on admission (aspirin/thienopyridines, warfarin, β-blocker, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, lipid-lowering drug, diuretic, long-acting nitrate, digoxin, and calcium channel blocker), intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin, in-hospital intravenous therapy (β-blocker, nitrate, inotrope, or diuretic), signs of congestive heart failure during hospital stay (Killip class >1 or use of intravenous diuretic or continuous positive airway pressure), year admitted to hospital, university hospital status, and availability of PCI at admitting hospital.
A Cox proportional hazards model was used to assess the adjusted association between revascularization strategy and mortality. In addition to revascularization, propensity score, in-hospital glycoprotein IIb/IIIa receptor inhibitor use, and 10 discharge medications (aspirin/thienopyridines, warfarin, β-blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, digoxin, diuretic, long-acting nitrate, lipid-lowering medication, and antidiabetic medication) were included as covariates in the model. Complete information, including outcome data, in these analyses was available for 21 846 patients. Analyses were stratified for the 5 renal function groups. To reduce the bias caused by the fact that patients who died early were included in the medically treated group, revascularization status was entered as a time-dependent covariate. Patients who were not yet revascularized provided an event-free time for the medically treated group. The interaction between revascularization as a time-dependent covariate and renal function stage was determined in this model, as was the interaction between gender and revascularization as a time-dependent covariate. An additional analysis to evaluate the interaction between renal function class and revascularization in men and women separately was also performed. A separate Cox proportional hazards model was used to assess outcome for 14-day survivors (n=22 399).
To exclude the possible bias caused by missing values (n=1416; 6.1%), a sensitivity analysis was performed. In this analysis, a new propensity score was calculated in which the independent dichotomous variables were coded as “no,” “yes,” or “missing.” The association between treatment strategy and outcome was then adjusted by this new propensity score and medications at discharge. To assess the influence of missing creatinine values on the overall results, a propensity score that included all patients with missing laboratory values was calculated, and outcome was assessed in a Cox regression model. An additional analysis not limited by patient age was performed. All patients who had creatinine measured (n=29 987) were included to assess the influence of revascularization on mortality regardless of age. A new propensity score for early revascularization that included all of these patients was calculated. The propensity score was then included in the Cox proportional hazards model together with revascularization as a time-dependent covariate to assess the effect on mortality across renal function stages. All analyses were performed with SPSS version 15 (SPSS Inc, Chicago, Ill).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline characteristics differed for patients who were treated medically and for those who were revascularized (Table 1). Medically treated patients were older and had more comorbidities, such as prior MI, diabetes mellitus, and heart failure. When baseline characteristics were adjusted for the propensity to be treated with revascularization, no major differences remained between the 2 groups (online-only Data Supplement Table I).
Moderate or more advanced renal insufficiency (eGFR <60 mL · min−1 · 1.73 m−2) was present in 5689 patients (24.4%). Of 278 patients with eGFR <15 mL · min−1 · 1.73 m−2/dialysis, 125 (45.0%) had been on dialysis for a median of 26 months (interquartile range 12 to 48 months) at the time of admission. The majority (105 patients) had hemodialysis. Patients with renal insufficiency differed significantly with more frequent concomitant diseases across the renal function groups (Table 2). Those with lower eGFR were less likely to undergo coronary angiography and to be revascularized within 14 days of admission (P<0.001; Figure 2A). In patients who underwent coronary angiography, declining renal function was associated with more severe coronary artery disease (Figure 2B). Compared with those who were revascularized, patients who only underwent coronary angiography not followed by an intervention had less extensive coronary artery disease. A total of 2321 (20.7%) of the medically treated patients were revascularized between 15 and 365 days after MI.
Overall, 90.3% patients (n=20 996) survived 1 year. Mortality was higher with lower renal function stage (Figure 3). During the first 14 days, there were 619 deaths (5.5%) in the medically treated group and 244 (2.0%) in the group treated with revascularization. In a multivariable Cox regression model with adjustment for propensity score and discharge medication, patients treated with early revascularization had an overall improved survival at 1 year (hazard ratio 0.64, 95% confidence interval 0.56 to 0.73, P<0.001). The magnitude of the difference in mortality was similar in groups with normal-to-moderate renal function (Figure 4). There was a gradient toward less of a mortality difference with early revascularization with decreasing renal function, which was most pronounced in those with kidney failure (eGFR <15 mL · min−1 · 1.73 m−2) or who were receiving dialysis. In these patients, there was a trend toward harm with invasive therapy. There was a significant interaction between revascularization and renal function group (P<0.001). There was no interaction between gender and revascularization (P=0.19). Both for men (P<0.001) and for women (P=0.011), there was a significant interaction between renal function and revascularization.
To assess the effect of early revascularization without the possible bias of treatment group assignment within the first 14 days, 1-year mortality for 14-day survivors was analyzed. A similarly lower mortality in patients who had undergone early revascularization was seen in those with normal-to-moderate renal dysfunction, less of a mortality difference in those with severe renal insufficiency, and no apparent advantage in those with renal failure or receiving dialysis (online-only Data Supplement Figure I). In a sensitivity analysis that also included patients with a missing covariate (n=1416), the point estimate overall (hazard ratio 0.65, 95% confidence interval 0.57 to 0.74, P<0.001) and the stratified analysis were similar to the results obtained with missing covariates (online-only Data Supplement Figure II). When patients with missing serum creatinine values were included (n=25 832) in a Cox regression analysis, the overall point estimate was similar (hazard ratio 0.64, 95% confidence interval 0.57 to 0.72, P<0.001). When all patients with available creatinine values regardless of age (n=29 987) were included, the point estimates across the renal function stages were comparable to the estimates obtained when the results were limited to patients ≤80 years of age (online-only Data Supplement Figure III).
Approximately 25% to 30% of all patients with NSTEMI have at least moderately reduced renal function,4,7 but despite the size of this population, evidence-based data supporting recommended therapies such as early revascularization for this patient group are missing.13 The main finding of the present registry study in a recent, nearly complete, nationwide cohort of NSTEMI patients is that a lower mortality associated with early revascularization is not uniform across the 5 renal function stages. Early revascularization improves 1-year survival in patients with NSTEMI and mild-to-moderate renal insufficiency, but the observed difference in mortality declines with lower renal function, and there is a trend toward harm in those with end-stage renal disease or on dialysis.
Randomized clinical trials have shown that early revascularization after NSTEMI reduces mortality by 22% to 32%.14,15 In high-risk individuals in the VINO study (Value of first-day angiography/angioplasty In evolving NOn-ST segment elevation myocardial infarction),16 mortality was reduced at 6 months, whereas reductions in mortality were shown at 2 years in FRISC (FRagmin during InStability in Coronary artery disease) II15 and at 5 years in RITA (Randomized Intervention Trial of unstable Angina) 3.14 The overall 1-year survival difference with early revascularization in the present registry was 36% lower, which is comparable to the results obtained in randomized trials.14,15 A larger difference in mortality (between 47% and 53%) with early revascularization has been shown in other observational studies.17,18 The smaller difference in mortality with early revascularization seen in the present study compared with those studies, in which 14- and 30-day survivors were analyzed, is explained by the inclusion of all patients from the first day of admission and the use of revascularization as a time-dependent variable during the first 14 days.
The present patient population differs from patients enrolled in clinical trials in several ways. Clinical trials may underestimate the advantage with early revascularization, because between 9% and 40% of patients in the noninvasively treated arm are actually revascularized, which diminishes the observed effect.16,19 Registries evaluating early revascularization better capture less selected patients with more comorbidities, although they are limited by their nonrandomized nature and a tendency to select healthier patients for intervention.20,21 In addition, randomized trials evaluate an invasive compared with a noninvasive approach, whereas the present registry analyzed the effect of revascularization. Patients who underwent a coronary angiography not followed by an intervention within 14 days of admission (≈20%) were analyzed in the medical group. In a randomized trial, these patients would have been distributed evenly between the invasively and noninvasively treated patients. Because these patients had less extensive coronary artery disease and a better prognosis, the overall outcome for the medical group was improved.
Few trials have examined the effect of an early invasive therapy in patients with mild-to-moderate renal insufficiency and NSTEMI. Although the TACTICS-TIMI 18 trial (Treat Angina with aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) 22 excluded patients with a creatinine level >221 μmol/L, it found a similar reduction in recurrent MI/death at 6 months in those with mild-to-moderate renal insufficiency and those with normal renal function.23 In FRISC II,24 which excluded patients with creatinine >150 μmol/L, the absolute reduction in death/MI was larger in those with creatinine clearance <69 mL/min than in those with creatinine clearance >90 mL/min (7.8% versus 0.4%).25 The results from the present registry support the data that patients with mild-to-moderate renal insufficiency appear to have lower mortality when managed with early revascularization. Fewer patients with moderate than with mild renal insufficiency were revascularized (38% versus 55%, respectively). This underuse of revascularization in patients with moderate renal insufficiency may be explained by awareness of the higher risk of complications.26,27
The explanation for the lack of survival difference in more advanced renal insufficiency patients is only speculative. These patients probably have more advanced atherosclerosis that is not easily treated with revascularization.28 Atherosclerosis is caused in part by other mechanisms in patients with severe renal insufficiency. Hyperphosphatemia has been related to atherosclerosis, arterial stiffening, and calcification and may be directly related to mortality.29,30 Patients with renal insufficiency may have comorbidities that increase their risk, both cardiac (such as more advanced heart failure or arrhythmias) and noncardiac, that are unaffected by treatment choices. As renal function worsens, the frequency of noncardiac adverse events, such as stroke and bleeding, increases in patients with acute coronary syndromes,4,7 which may ultimately explain their worse prognosis and lack of difference in mortality with revascularization in particular.
There are some limitations to the present study. This is a registry study, and therapies were not assigned randomly, which could lead to possible selection bias despite adjustments that were made in the statistical models. Patients who were revascularized within the first 14 days may have been healthier than the patients who were treated medically, which may have led to an overestimation of the potential benefit of intervention. To reduce the bias that either therapeutic strategy could have been associated with a survival benefit or increased mortality, we performed an analysis of 14-day survivors. Although patients who were revascularized early may have had a survival advantage because they lived at least until the intervention, the procedure may have been attempted as a last resort. In comparison, patients in the medical group may not have had the chance to benefit from an intervention. No information regarding whether a procedure was urgent, semiurgent, or more elective was collected in the present register; however, there was no major difference in the results obtained if only 14-day survivors were included. The cut point for revascularization within 14 days was arbitrary; however, any cut point would be arbitrary, and the main results were similar for revascularization within 30 days of index hospitalization (data not shown). It is also possible that the apparent benefit attributed to early revascularization may have been achieved by the use of adjunctive therapies, such as more intense antithrombotic medication. Although we adjusted for all known confounders and entered revascularization as a time-dependent variable, residual bias may remain. The estimated propensity score is only an approximation of the true, unknown treatment assignment.
The number of events and the number of patients in the 2 lowest stages of renal function were much smaller than for the other groups. There was a larger uncertainty in the estimates obtained from the models; the power was therefore limited in the present study, and only moderately large differences in mortality between therapies in the 2 lowest renal function groups could have been detected.
In the present registry, creatinine measurement was entered by the treating physician. Although physicians were instructed to report the in-hospital measurement that best represented the baseline creatinine value for each individual, the number of measurements obtained may have varied between hospitals, and some patients may only have had a single measurement of creatinine. In the present study, we used the Modification of Diet in Renal Disease Study formula to estimate GFR, but it is unlikely that our results would have differed significantly if a different estimation of GFR had been used.
We limited the analysis to patients 80 years old or younger, because in clinical practice, older patients are less frequently considered candidates for an invasive strategy. The decision to revascularize in these patients is often based on characteristics such as cognitive function, more advanced comorbidities, and more unstable in-hospital symptoms that are not captured by a register and for which adjustment therefore cannot be made. In the present registry, only 12% of those older than 80 years were revascularized compared with 52% of those 80 years or younger; however, when all patients regardless of age were included in the analyses, the results were comparable.
In conclusion, patients with mild-to-moderate renal function have an associated lower mortality when managed with early revascularization but are less likely to be treated, which may explain part of their worse prognosis. Patients with severe or more advanced renal insufficiency have a remarkably poor prognosis that does not appear to be improved by the use of an invasive therapy. The benefit of early revascularization in those with severe renal insufficiency appears to be lower, and even less certain in those with renal failure or on dialysis.
Sources of Funding
The SWEDEHEART register is supported by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities, and the Swedish Society of Cardiology. This study was supported by grants from the Swedish Heart and Lung Foundation and the National Board of Health and Welfare.
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Renal dysfunction affects approximately 25% to 30% of patients admitted with an acute coronary syndrome. Its presence is associated with an exponential increase in mortality. Data to support current guidelines for early revascularization in patients with renal dysfunction admitted with a non-ST-elevation myocardial infarction are sparse, because clinical trials have often used elevated creatinine as an exclusion criterion. In this current nationwide registry from Sweden that included 23 262 patients between 2003 and 2006 who were 80 years old or younger, we evaluated whether early revascularization (by either percutaneous coronary intervention or coronary artery bypass grafting) within 14 days of admission for a non-ST-elevation myocardial infarction alters prognosis at all degrees of renal dysfunction. We found that patients with mild-to-moderate renal insufficiency had comparable survival benefit at 1 year with early revascularization. Despite this advantage with treatment, there was a lower use of an early invasive therapy in those with moderate renal insufficiency, among whom only 36% were revascularized compared with 62% of those with normal renal function. More frequent use of an invasive approach in those with mild-to-moderate renal dysfunction could potentially alter their worse outcome. In contrast, the advantage with revascularization in those with more advanced renal impairment is lower and less certain, and its use is questionable in those with renal failure or on dialysis, in whom there was a suggestion of harm with therapy. Further research to find the optimal therapy to improve prognosis for this patient group is needed.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA. 108.838169/DC1.