Within-Hospital and 30-Day Outcomes in 107,994 Patients Undergoing Invasive Coronary Angiography With Different Low-Osmolar Iodinated Contrast Media

Within-Hospital and 30-Day Outcomes in 107,994 Patients Undergoing Invasive Coronary Angiography With Different LowOsmolar Iodinated Contrast Media Troy M. LaBounty, MDa, Manan Shah, PharmD, PhDb, Subha V. Raman, MDc, Fay Y. Lin, MDd, Daniel S. Berman, MDa, and James K. Min, MDa,* Comparative clinical outcomes after exposure to alternate low osmolar contrast media (LOCM) during invasive coronary angiography (ICA) and/or percutaneous coronary intervention (PCI) have been incompletely examined. From a retrospective multicenter observational study, we identified 107,994 adults without previous hemodialysis undergoing ICA and/or PCI with iohexol, iopamidol, or ioversol. We created a propensity score for contrast media type using age, gender, coverage status, route of hospitalization, illness severity, physician specialty, co-morbidities, and procedure type. Propensity matching was performed in a 1:1 fashion for iohexol (n ⴝ 10,204) and iopamidol (n ⴝ 10,204) and in a 1:1 fashion for iohexol (n ⴝ 19,482) and ioversol (n ⴝ 19,482). Groups were examined for differences in in-hospital mortality or subsequent hemodialysis, length of stay, and 30-day readmission for contrast-induced nephropathy (CIN). Compared to patients exposed to iohexol, no differences were observed for patients exposed to iopamidol or ioversol for in-hospital hemodialysis (0.5% vs 0.4%, p ⴝ 0.45; 0.3% vs 0.5%, p ⴝ 0.05), in-hospital mortality (0.7% vs 0.6%, p ⴝ 0.60; 0.5% vs 0.6%, p ⴝ 0.42), or composite hemodialysis or mortality (1.1% vs 1.0%, p ⴝ 0.58; 0.8% vs 1.0%, p ⴝ 0.06); for hospital length of stay (2.9 ⴞ 2.7 vs 2.9 ⴞ 2.7 days, p ⴝ 0.05; 2.8 ⴞ 2.6 vs 2.9 ⴞ 3.1 days, p ⴝ 0.35); or for 30-day readmission for CIN (0.1% vs 0.1%, p ⴝ 0.82; 0.1% vs 0.1%, p ⴝ 0.52). In conclusion, for patients undergoing ICA and/or PCI exposed to alternate LOCM, in-hospital death, need for hemodialysis, or readmission for CIN are uncommon, with no apparent clinical advantage among LOCM agents. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109: 1594 –1599) The use of iodinated contrast media in patients undergoing invasive coronary angiography (ICA) and/or percutaneous coronary intervention (PCI) may result in contrastinduced nephropathy (CIN), which is associated with significantly increased morbidity and mortality.1–3 Current societal guidelines recommend the use of other low osmolar contrast media (LOCM) over iohexol in patients with chronic renal insufficiency4 because the latter has been associated with potentially higher rates of acute kidney injury compared to iso-osmolar contrast media in previous meta-analyses.5,6 However, to date no large-scale direct comparisons for different LOCM types have been performed in patients undergoing ICA and/or PCI. To this end, we examined within a retrospective multicenter registry of 107,994 patients undergoing ICA and/or PCI the compara-

a Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California; bXcenda Corporation, Palm Harbor, Florida; cOhio State University, School of Medicine, Columbus, Ohio; dWeill Cornell Medical College, New York Presbyterian Hospital, New York, New York. Manuscript received November 28, 2011; revised manuscript received and accepted January 12, 2012. The study was funded by an unrestricted research grant by GE Healthcare, Milwaukee, Wisconsin. *Corresponding author: Tel: 310-423-4223; fax: 310-423-3763. E-mail address: [email protected] (J.K. Min).

0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2012.01.380

tive clinical outcomes of matched patients exposed to iohexol, iopamidol, and ioversol. Methods We performed a retrospective analysis of hospital data for 107,994 patients in the Premier Perspective Database (Premier, Charlotte, North Carolina). This voluntary feesupported database represents approximately 5.5 million patient discharges per year from ⬎600 geographically disperse hospitals from all regions of the United States. For each patient, the database contains a date-stamped log of all billed items including procedures, medications and laboratory tests. Primary and secondary diagnosis and procedural codes are collected by the International Classification of Diseases, Ninth Revision, Clinical Modification. Identifierlinked enrollment files provided demographic and payer information. All patient records were made anonymous in compliance with the Health Insurance Portability and Accountability Act. All sites were in compliance with institutional review board requirements. Patients were identified for inclusion in this analysis from records of all hospital discharges occurring from January 1, 2007 through December 31, 2008, with ICA with or without PCI deemed as the index procedure. To be eligible for inclusion, patients were (1) ⱖ18 years of age; (2) hospitalized; (3) undergoing diagnostic ICA and/or PCI procedures during hospitalization; and (4) exposed to 1 of 3 www.ajconline.org

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Table 1 Baseline patient characteristics and health care setting before match Variable Demographics Age ⱖ65 years Men Primary payer Medicare Medicaid Commercial Self-pay/indigent Any other payer Point of origin Nonhealth care facility Outside transfer Emergency room Other/unknown All patient-refined diagnosis-related group severity of illness Minor (1) Moderate (2) Major (3) Extreme (4) Attending physician specialty Cardiology Noncardiology Co-morbidities (before study) Diabetes mellitus Chronic renal insufficiency Acute renal insufficiency Heart failure Myocardial infarction Nephritis or nephrosis Hypertension Angina pectoris Anemia Cancer Type of procedure Diagnostic coronary angiography Percutaneous coronary intervention

Iohexol (n ⫽ 20,136)

Iopamidol (n ⫽ 21,539)

Ioversol (n ⫽ 66,31)

43.6% 57.8%

44.6% 58.8%

43.4% 58.9%

0.009 0.03

47.6% 4.8% 36.3% 7.3% 4.0%

50.5% 5.3% 32.9% 8.5% 2.9%

47.6% 6.0% 35.8% 6.9% 3.7%

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

32.9% 11.2% 52.4% 3.5%

24.0% 18.8% 51.6% 5.7%

29.3% 14.6% 47.7% 8.4%

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

42.8% 38.3% 16.3% 2.6%

38.6% 39.0% 18.8% 3.6%

44.1% 37.7% 15.5% 2.7%

⬍0.001 0.003 ⬍0.001 ⬍0.001

65.5% 34.5%

57.5% 42.5%

65.8% 34.2%

⬍0.001 ⬍0.001

30.3% 2.6% 1.3% 14.0% 27.3% 5.7% 61.9% 8.7% 8.4% 1.4%

33.5% 4.7% 2.2% 15.9% 31.5% 9.3% 63.8% 7.2% 10.2% 2.0%

31.2% 2.9% 2.0% 14.4% 30.8% 5.9% 64.2% 10.3% 7.7% 1.6%

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

45.9% 54.1%

48.4% 51.6%

44.1% 55.9%

⬍0.001 ⬍0.001

different contrast media: iohexol, ioversol, or iopamidol. Patients were excluded if they (1) underwent hemodialysis before the index procedure or (2) were exposed to multiple different contrast media during the index hospitalization. Patients could be included if they had undergone ⬎1 procedure with the same contrast media during the hospitalization, if the first procedure using contrast media was the index ICA and/or PCI procedure. Eligible patients were categorized based on the contrast medium used for the procedure during index hospitalization. For each patient, we collected the following information: age, gender, payer status, route of hospitalization, diagnosis-related group illness severity, attending physician specialty, presence of co-morbidities, and type of procedure performed. For payer status, particular focus was paid to patients covered by Medicare and Medicaid. Route of hospitalization was defined as admission to the hospital from a nonhealth care facility, transfer from an outside hospital, or through the emergency room. All patient-refined diagnosisrelated groups enabled determination of illness severity, which was defined as minor, moderate, major, or extreme. Attending

p Value

physician specialty was categorized as cardiologist versus noncardiologist. Co-morbidities included diabetes, chronic renal insufficiency, acute renal insufficiency, congestive heart failure, myocardial infarction, nephritis or nephrosis, hypertension, angina pectoris, anemia, or cancer. Presence of co-morbidities was based on physician diagnoses listed in the medical records. Procedure type consisted of diagnostic ICA and/or PCI. Additional procedures were identified by procedural codes based on temporal use of contrast media. Primary outcome measurements included rates of inhospital mortality, in-hospital hemodialysis, hospital length of stay (LOS), and readmission for CIN within 30 days. Inpatient hemodialysis was defined as any hemodialysis during hospital admission after the index procedure. LOS for the initial hospitalization was defined as days from hospital admission to discharge. LOS in the intensive care unit during the initial hospitalization was also measured. Readmission for CIN was defined as a subsequent hospitalization within 30 days of discharge for which the primary or secondary diagnoses included new renal insufficiency (International Classification of Diseases, Ninth Revision, Clin-

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Table 2 Outcomes and length of stay before match Variable In-hospital events Hemodialysis Mortality Total events Length of stay Intensive care unit stay (days) Total stay (days) Contrast-induced nephropathy 30-day readmission

Iohexol (n ⫽ 20,136)

Iopamidol (n ⫽ 21,539)

Ioversol (n ⫽ 66,319)

0.34% 0.6% 0.9%

0.48% 0.7% 1.1%

0.49% 0.7% 1.1%

2.0 ⫾ 2.2 2.8 ⫾ 2.6 0.1%

2.1 ⫾ 2.3 3.0 ⫾ 3.0 0.1%

2.1 ⫾ 2.2 2.9 ⫾ 3.0 0.1%

p Value 0.02 0.17 0.005 0.06 ⬍0.001 0.77

Values are presented as mean ⫾ SD or percentage. Table 3 Baseline patient characteristics and health care setting: propensity score matched comparison of iohexol to ioversol Variable Demographics Age ⱖ65 years Men Primary payer Medicare Medicaid Commercial Self-pay/indigent Any other payer Point of origin Nonhealth care facility Outside transfer Emergency room Other/unknown All patient-refined diagnosis-related group severity of illness Minor (1) Moderate (2) Major (3) Extreme (4) Attending physician specialty Cardiology Noncardiology Co-morbidities (before procedure) Diabetes mellitus Chronic renal insufficiency Acute renal insufficiency Heart failure Myocardial infarction Nephritis or nephrosis Hypertension Angina pectoris Anemia Cancer Type of procedure Diagnostic coronary angiography Percutaneous coronary intervention

Iohexol (n ⫽ 19,482)

Ioversol (n ⫽ 19,482)

Standardized Difference

p Value

43.7% 58.0%

44.2% 58.2%

1.1% 0.5%

0.22 0.53

47.6% 4.9% 36.3% 7.2% 4.0%

47.4% 4.9% 37.0% 7.1% 3.7%

0.4% 0.0% 1.4% 0.5% 1.8%

0.67 0.98 0.09 0.56 0.06

32.8% 11.5% 52.1% 3.6%

32.9% 11.9% 52.1% 3.1%

0.2% 1.3% 0.1% 3.1%

0.77 0.12 0.95 ⬍0.001

43.0% 38.4% 16.1% 2.6%

42.8% 39.2% 15.6% 2.5%

0.5% 1.6% 1.3% 0.6%

0.55 0.06 0.18 0.53

65.5% 34.5%

66.2% 33.8%

1.4% 1.4%

0.09 0.09

30.2% 2.6% 1.4% 13.9% 27.5% 5.7% 62.2% 8.8% 8.1% 1.4%

29.4% 2.5% 1.3% 13.3% 28.3% 5.4% 61.4% 8.4% 7.9% 1.4%

1.9% 0.8% 1.0% 1.6% 1.9% 1.0% 1.7% 1.5% 0.8% 0.3%

46.2% 53.8%

46.2% 53.8%

⬍0.1% ⬍0.1%

0.03 0.39 0.34 0.07 0.02 0.30 0.047 0.28 0.41 0.76 1.0 — —

Standardized difference was used to assess successful matching, with a difference ⬍10% considered to represent a successful match.

ical Modification 585 or 586), need for new dialysis (International Classification of Diseases, Ninth Revision, Clinical Modification V56A or V45B), or procedure for new dialysis (procedure code v9211, v9212, v9200, v9531, or v9532). Baseline demographics and clinical characteristics were

described with standard summary statistics by means and proportions. Covariates were compared using chi-square tests for categorical variables and t tests and Mann–Whitney tests for continuous variables. Wilcoxon signed-rank test was used to assess differences in LOS, with the McNemar

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Table 4 Baseline patient characteristics and health care setting: propensity score matched comparison of iohexol to iopamidol Variable Demographics Age ⱖ65 years Men Primary payer Medicare Medicaid Commercial Self-pay/indigent Any other payer Point of origin Nonhealth care facility Outside transfer Emergency room Other/unknown All patient-refined diagnosis-related group severity of illness Minor (1) Moderate (2) Major (3) Extreme (4) Attending physician specialty Cardiology Noncardiology Co-morbidities (before procedure) Diabetes mellitus Chronic renal insufficiency Acute renal insufficiency Heart failure Myocardial infarction Nephritis or nephrosis Hypertension Angina pectoris Anemia Cancer Type of procedure Diagnostic coronary angiography Percutaneous coronary intervention

Iohexol (n ⫽ 10,204)

Iopamidol (n ⫽ 10,204)

Standardized Difference

p Value

44.6% 57.9%

44.1% 57.7%

1.1% 0.4%

0.38 0.78

50.3% 5.0% 33.6% 7.0% 4.2%

49.8% 5.1% 34.1% 8.3% 2.7%

1.1% 0.8% 1.1% 5.0% 8.2%

0.41 0.58 0.37 ⬍0.001 ⬍0.001

28.0% 13.3% 54.5% 4.2%

28.3% 13.0% 54.8% 3.9%

0.8% 0.9% 0.6% 1.8%

0.53 0.50 0.62 0.72

39.8% 39.7% 17.5% 3.1%

39.8% 39.2% 18.0% 3.1%

⬍0.1% 1.0% 1.3% 0.1%

0.97 0.43 0.32 0.97

61.7% 38.3%

61.9% 38.1%

0.5% 0.5%

0.67 0.67

32.1% 3.7% 1.9% 15.3% 30.6% 7.4% 62.8% 8.5% 8.9% 1.7%

31.5% 3.4% 1.8% 15.5% 31.8% 7.3% 63.4% 8.4% 9.1% 1.6%

1.2% 1.5% 0.3% 0.6% 2.5% 0.4% 1.1% 0.2% 0.7% 0.6%

49.0% 51.1%

49.0% 51.1%

⬍0.1% ⬍0.1%

0.34 0.27 0.83 0.62 0.04 0.76 0.37 0.89 0.59 0.66 1.0 — —

Standardized difference was used to assess successful matching, with a difference ⬍10% considered to represent a successful match.

test used to assess differences in hemodialysis, mortality, and readmission rates. Propensity scores were created for contrast media type for each patient included in the analysis based on a comprehensive logistic regression model that predicted the probability of being exposed to iohexol at the time of ICA with or without PCI. Propensity score models included age, gender payer type, point of origin, all patient-refined diagnosis-related group severity of illness, attending physician specialty, co-morbidities, and type of procedure. Patients exposed to iohexol were matched to patients receiving ioversol or iopamidol on propensity score using the nearest available pair method, with the balancing property achieved to a minimum of 3 decimal places. We determined the success of the propensity score to decrease bias by evaluating standardized differences in covariates between cohorts after matching, with standardized differences ⬍10% considered acceptable and indicative of a successful match.7 Continuous variables were summarized employing mean ⫾ SD and were compared by paired t test or Wilcoxon signed-

ranks test adjusting for the matched pair. Categorical variables were summarized by frequencies and percentages and compared using the Cochran-Mantel-Haenszel test that adjusted for the matched pair. All statistical analyses tested a 2-sided hypothesis of no difference between treatment cohorts at a significance level of 0.05. Analyses were performed using SAS 9.2 (SAS Institute, Cary, North Carolina). Results Baseline patient characteristics of the 107,994 patients comprising the study population are listed in Table 1, stratified by those exposed to iohexol (n ⫽ 20,136), iopamidol (n ⫽ 21,539) or ioversol (n ⫽ 66,319) at the time of ICA and/or PCI. Significant differences existed between groups for age, gender, payer, point of origin, illness severity, attending physician specialty, co-morbidities, and type of index procedure. Table 2 presents comparisons of in-hospital outcomes, LOSs, and rates of

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Figure 1. Comparison of adverse events in matched patients receiving iohexol (n ⫽ 19,482) versus ioversol (n ⫽ 19,482).

Figure 2. Comparison of adverse events in matched patients receiving iohexol (n ⫽ 10,204) versus iopamidol (n ⫽ 10,204).

30-day readmission for CIN, which differed significantly among groups. Table 3 lists characteristics of matched patients exposed to iohexol (n ⫽ 19,482) versus ioversol (n ⫽ 19,482). Despite matching, small differences were noted for patients admitted to the hospital from an “other/unknown” location who were exposed to iohexol or ioversol, whereas small differences between iohexol- and ioversol-exposed patients also existed in rates of diabetes mellitus and previous myocardial infarction. Table 4 lists characteristics of matched patients exposed to iohexol (n ⫽ 10,204) versus iopamidol (n ⫽ 10,204). Despite matching, slight differences were observed for patients whose payer was listed as “self-pay/ indigent” or “any other payer” and in rates of previous myocardial infarction. After matching, no significant differences were noted in patients exposed to iohexol versus ioversol (Figure 1) for rates of new in-patient hemodialysis (relative risk [RR] 0.72, 95% confidence interval [CI] 0.52 to 1.00, p ⫽ 0.05), inpatient mortality (RR 0.90, 95% CI 0.69 to 1.17, p ⫽ 0.42), or composite of hemodialysis or mortality (RR 0.82, 95% CI 0.67 to 1.01, p ⫽ 0.06). Similarly, no significant differences were noted for total hospital or intensive care unit LOS (Table 5). Overall rates of 30-day readmission for CIN were low, with no differences in patients exposed to iohexol versus ioversol (RR 0.81, 95% CI 0.43 to 1.53, p ⫽ 0.52). In matched patients exposed to iohexol versus iopamidol (Figure 2), no differences were noted for rates of new

in-hospital hemodialysis (RR 1.18, 95% CI 0.77 to 1.81, p ⫽ 0.45), in-hospital mortality (RR 1.09, 95% CI 0.78 to 1.54, p ⫽ 0.60), or the composite of new hemodialysis or mortality (RR 1.08, 95% CI 0.82 to 1.41, p ⫽ 0.58). Similarly, in patients exposed to iohexol versus iopamidol, no differences were observed for total hospital or intensive care unit LOS (Table 5) or for 30-day readmission for CIN (RR 1.11, 95% CI 0.45 to 2.73, p ⫽ 0.82). Discussion The present study represents a large multicenter observational cohort of hospitalized patients undergoing ICA and/or PCI who were exposed to different LOCM. Given the size of the cohort, we were able to successfully create propensity-matched cohorts of patients to directly compare clinical outcomes for patients exposed to iohexol, ioversol, and iopamidol. Encouragingly, in this large dataset, even before matching, rates of in-hospital hemodialysis and mortality and 30-day readmission rates for CIN were low for all patients, irrespective of contrast medium used. After matching, we could not identify any significant differences in adverse events for patients who underwent ICA and/or PCI with different LOCM. Although data on creatinine and creatinine changes were not available, these findings suggest a clinical interchangeability for hard end points among iohexol, iopamidol, and ioversol given their comparable rates of near-term downstream events. Our study results contrast with previous reports, which

Table 5 Length of stay Variable

Iohexol (n ⫽ 19,482)

Ioversol (n ⫽ 19,482)

p Value

Iohexol (n ⫽ 10,204)

Iopamidol (n ⫽ 10,204)

p Value

2.0 ⫾ 2.2 2.8 ⫾ 2.6

2.0 ⫾ 2.1 2.9 ⫾ 3.1

0.73 0.35

2.1 ⫾ 2.3 2.9 ⫾ 2.7

2.0 ⫾ 2.1 2.9 ⫾ 2.7

0.40 0.05

Intensive care unit stay (days) Total stay (days) Values are presented as mean ⫾ SD.

Coronary Artery Disease/Low Osmolar Contrast Media and Outcomes

have suggested that iohexol may be associated with increased rates of CIN compared to an iso-osmolar contrast medium.5,6 As examples, Chalmers and Jackson8 randomized 124 patients undergoing renal or peripheral angiography to iohexol or iodixanol and reported that a ⬎10% increase in creatinine was more frequently observed with iohexol compared to iodixanol (31% vs 15%, p ⬍0.05), whereas Aspelin et al9 noted a higher mean increase in creatinine for iohexol use compared to iodixanol use (0.55 vs 0.13 mg/dl, p ⬍0.01) in 129 diabetic patients with chronic renal insufficiency undergoing peripheral or coronary angiography. Primarily driven by these 2 studies, pooled meta-analyses have suggested that iohexol may be associated with increased rates of CIN compared to isoosmolar contrast media in a pattern not observed with other LOCM such as ioversol and iopamidol,5,6 although direct comparisons between LOCM in large studies are lacking. Because of these data, current guidelines recommend LOCM other than iohexol for use in patients with chronic renal insufficiency.4 Given the reliance of these meta-analyses on smaller studies that primarily examined rates of CIN using multiple surrogate end points, our findings directly extend these previous data by examining a large multicenter cohort that includes ⬎600 hospitals representing a general mix of hospitalized individuals in the United States. By successful propensity scoring techniques, we were able to evaluate 38,964 matched patients exposed to iohexol and ioversol and 20,408 matched patients exposed to iohexol and iopamidol. This allowed us to directly compare patients who were similar in numerous potential confounders including age, gender, payer, severity of illness, and procedure type. In contrast to previous studies that compared LOCM to iso-osmolar contrast media, our study directly compared alternate LOCM for differences in clinical outcomes. Rather than examining CIN rates as a sole end point, as has been done in previous studies, we examined multiple important clinical end points including within-hospital death and need for inpatient hemodialysis, LOS, and 30-day rehospitalization because of CIN. These data enable a broader understanding of the safety profile of LOCM in patients subjected to ICA and/or PCI. The study has limitations. We examined patients without previous hemodialysis and, as such, cannot render conclusions regarding the safety profile of any of these LOCM in patients with previous renal insufficiency requiring hemodialysis. Further, we did not have serum creatinine levels during the hospitalization available to us, and patients with subclinical renal dysfunction that was not so severe as to require hemodialysis cannot be identified by the present

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study design. We attempted to normalize the rates of nonhemodialysis-requiring renal dysfunction by matching techniques through propensity scoring. However, despite successful propensity scoring for numerous potential confounders, it remains possible that our method did not fully account for bias owing to hidden or unmeasured variables.10 Further, we did not have available to us contrast volumes employed for ICA and/or PCI, which may have influenced study results. Moreover, we did not have data on use of prophylaxis for CIN, which may have varied between sites and affected results. 1. Dangas G, Iakovou I, Nikolsky E, Aymong ED, Mintz GS, Kipshidze NN, Lansky AJ, Moussa I, Stone GW, Moses JW, Leon MB, Mehran R. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95:13–19. 2. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell MR, Barsness GW, Mathew V, Garratt KN, Holmes DR Jr. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105:2259 –2264. 3. Gruberg L, Mintz GS, Mehran R, Gangas G, Lansky AJ, Kent KM, Pichard AD, Satler LF, Leon MB. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol 2000;36:1542–1548. 4. Kushner FG, Hand M, Smith SC Jr, King SB III, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE Jr, Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL, Williams DO. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205–2241. 5. Reed M, Meier P, Tamhane UU, Welch KB, Moscucci M, Gurm HS. The relative renal safety of iodixanol compared with low-osmolar contrast media: a meta-analysis of randomized controlled trials. JACC Cardiovasc Interv 2009;2:645– 654. 6. Heinrich MC, Haberle L, Muller V, Bautz W, Uder M. Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials. Radiology 2009;250:68 – 86. 7. Austin PC. A critical appraisal of propensity-score matching in the medical literature between 1996 and 2003. Stat Med 2008;27:2037– 2049. 8. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999;72:701–703. 9. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ; Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and LowOsmolar Non-Ionic Contrast Media Study Investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003;348:491– 499. 10. Rosenbaum PR. Sensitivity to hidden bias. In: Rosenbaum PR, ed. Observational Studies, 2nd Ed. New York: Springer-Verlag, 2002: 110 –124.