Subgroup analysis of the TACTICS-TIMI-18 (Treat Angina with aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy Thrombolysis In Myocar- dial Infarction 18) study in patients with diabetes, available in abstract form, was consistent with this finding.161 Thus, diabetes, as well as the often concurrent comorbidity of CKD (Section 6.5, Chronic Kidney Disease: Recommendations), is not only a high-risk factor but also benefits from an invasive approach. Accordingly, diabetes has been added to the list of characteristics for which an early invasive strategy is gener- ally preferred (Appendix 6). 6.5. Chronic Kidney Disease: Recommendations (See Table 8, and Online Data Supplement.) 6.5.1. Angiography in Patients With CKD Since the 2007 UA/NSTEMI Guidelines were published,4 several larger randomized trials have been published that reported no difference in contrast-induced nephropathy (CIN) when iodixanol was compared with various other low- osmolar contrast media (LOCM).170 173 These and other randomized trials comparing isosmolar iodixanol with LOCM have been summarized in 2 mutually supportive and complementary meta-analyses involving 16 trials in 2763 patients174 and 25 trials in 3260 patients,175 respectively. When more recent trials were combined with the older studies, the data supporting a reduction in CIN favoring iodixanol were no longer significant (summary RR: 0.79; CI: 0.61 to 1.04; P 0.10,175 respectively). However, subanal- yses showed variations in relative renal safety by specific LOCM: A reduction in CIN was observed when iodixanol was compared to ioxaglate, the only ionic LOCM (RR: 0.58; 95% CI: 0.37 to 0.92; P 0.022174), and to iohexol, a nonionic no difference was noted in comparisons of iodixanol with iopamidol, iopromide, or ioversol,174 and a single trial fa- vored iomeprol.170 A pooled comparison of iodixanol with all nonionic LOCM other than iohexol indicated equivalent Table 8. Recommendations for Chronic Kidney Disease 2012 Focused Update Recommendations 2012 Comments Class I 1. Creatinine clearance should be estimated in UA/NSTEMI patients and the doses of renally cleared medications should be adjusted according to the pharmacokinetic data for specific medications.162,163 (Level of Evidence: B) 2011 recommendation remains current. 2. Patients undergoing cardiac catheterization with receipt of contrast media should receive adequate preparatory hydration.164,165 (Level of Evidence: B) 2011 recommendation remains current. 3. Calculation of the contrast volume to creatinine clearance ratio is useful to predict the maximum volume of contrast media that can be given without significantly increasing the risk of contrast-associated nephropathy.166,167 (Level of Evidence: B) 2011 recommendation remains current. Class IIa 1. An invasive strategy is reasonable in patients with mild (stage 2) and moderate (stage 3) CKD.162,163,168,169 (Level of Evidence: B) (There are insufficient data on benefit/risk of invasive strategy in UA/NSTEMI patients with advanced CKD 2011 recommendation remains current. CKD indicates chronic kidney disease; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Jneid et al 2012 UA/NSTEMI Focused Update 893 were consistent regardless of ancillary preventive therapies (hydration, acetylcysteine), route of administration (IV or intra-arterial), age, sex, dose, or preexisting CKD or diabetes. Of further interest, findings were similar in the 8 studies (n 1793 patients) performed in the setting of coronary angiography.174 A more recent study comparing iodixanol versus iopamidol provides additional supportive evidence.176 However, even these clinical inferences must be tempered by the relative paucity of head-to-head trials comparing CIN rates among the various contrast media and the variability in results (eg, for iohexol versus other low-osmolar compara- tors).177 180 Furthermore, the assumption that a transient rise in serum creatinine after 24 to 48 hours is a reliable predictor of the more serious but somewhat delayed development of renal failure requiring hospitalization or dialysis has been challenged. A nationwide Swedish survey181 of hospitaliza- tions for renal failure after coronary procedures in 57 925 patients found that this risk was paradoxically higher with iodixanol (1.7%) than ioxaglate (0.8%) or iohexol (0.9%; P 0.001). Although the result was observational, hence subject to selection bias, it persisted in analyses of high-risk patient subsets (patients with diabetes, prior history of renal failure), in multivariable analysis, and in hospitals crossing over from ioxaglate to iodixanol. Iodixanol s greater viscosity was speculated but not demonstrated to be a possible mech- anism for the observed effect. Thus, an overall summary of the current database, updated since previous guideline rec- ommendations,4 is that strength and consistency of relation- ships between specific isosmolar or low-osmolar agents and CIN or renal failure are not sufficient to enable a guideline statement on selection among commonly used low-osmolar and isosmolar media. Instead, the writing group recommends focusing on operator conduct issues shown to be important to protect patients, that is, 1) proper patient preparation with hydration, and 2) adjustment of maximal contrast dose to each patient s renal function and other clinical characteristics. With respect to patient preparation, the writing group re- viewed several trials addressing the optimal preparatory regimen of hydration and pharmacotherapy. The basic principle of hydration follows from experimental studies and clinical expe- rience, with isotonic or half-normal saline alone being the historical gold standards.164,165,182 184 More recently, sodium bicarbonate has been tested as the hydrating solution. Some trials have reported superiority of sodium bicarbonate over saline in preventing CIN.185 188 Similarly, some have reported a benefit of N-acetylcysteine administration as adjunctive therapy to hydra- tion,185,189 whereas others have not.190,191 Thus, although the writing group found the evidence compelling for adequate hydration preparatory to angiography with contrast media, it found the evidence insufficient to recommend a specific regimen. With respect to limitation of contrast dose by renal func- tion, mounting evidence points to renal-function specific limits on maximal contrast volumes that can be given without significantly increasing the baseline risk of provoking CIN. In a contemporary study, Laskey et al studied 3179 consecutive patients undergoing PCI and found that a contrast volume to creatinine clearance ratio 3.7 was a significant and inde- pendent predictor of an early and abnormal increase in serum creatinine.166 In an earlier trial, administration of a contrast volume of 5 mL body weight (kg)/serum creatinine (mg/ dL), applied to 16 592 patients undergoing cardiac catheter- ization, was associated with a 6-fold increase in the likelihood of patients developing CIN requiring dialysis.167 Patients with CKD are consistently underrepresented in randomized controlled trials of cardiovascular disease.192 The impact of an invasive strategy has been uncertain in this group. The SWEDEHEART (Swedish Web-System for En- hancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Ther- apies) study included a cohort of 23 262 patients hospitalized for NSTEMI in Sweden between 2003 and 2006 who were age 80 years.169 This contemporary nationwide registry of nearly all consecutive patients examined the distribution of CKD and the use of early revascularization after NSTEMI and evaluated whether early revascularization (by either PCI or CABG) within 14 days of admission for NSTEMI altered outcomes at all stages of kidney function. In SWEDEHEART, all-cause mortality was assessed at 1 year and was available in 99% of patients. Moderate or more advanced CKD (estimated glomerular filtration rate ) was present in 5689 patients (24.4%). After multivariable adjustment, the 1-year mortality in the overall cohort was 36% lower with early P 0.001).169 The magnitude of the difference in 1-year mortality was similar in patients with normal eGFR (early revascularization versus medically treated: 1.9% versus 10%; 95% CI: 0.52 to 0.80; P 0.001), and moderate CKD [eGFR 95% CI: 0.54 to 0.86; P 0.001). The benefit of an invasive therapy was not evident in patients with severe CKD stage 4 ] (22% versus 41%; HR: stage 5 kidney failure [eGFR 15 mL/min per 1.73 m2 or to 3.09; P 0.150). Early revascularization was associated with increased 1-year survival in UA/NSTEMI patients with mild to moderate CKD, but no association was observed in those with severe or end-stage kidney disease.169 The findings from SWEDEHEART are limited by their nonrandomized nature and the potential for selection bias despite the intricate multivariable adjustment.169 On the other hand, SWEDEHEART captured unselected patients with more comor- bidities and is therefore more reflective of real-world patients. Recently, a collaborative meta-analysis of randomized con- trolled trials that compared invasive and conservative treatments in UA/NSTEMI was conducted to estimate the effectiveness of early angiography in patients with CKD.168 The meta-analysis demonstrated that an invasive strategy was associated with a significant reduction in rehospitalization (RR: 0.76; 95% CI: 0.66 to 0.87; P 0.001) at 1 year compared with conservative strategy. The meta-analysis did not show any significant differ- ences with regard to all-cause mortality (RR: 0.76; 95% CI: 0.49 P 0.22), and the composite of death/nonfatal MI (RR: 0.79; Our recommendation is that an early invasive strategy (ie, diagnostic angiography with intent to perform revasculariza- tion) is a reasonable strategy in patients with mild and moderate CKD. Clinicians should exercise judgment in all populations with impaired kidney function when considering whether to implement an invasive strategy. Such implemen- tation should be considered only after careful assessment of the risks, benefits, and alternatives for each individual patient. The observational data with regard to patients with mild to severe CKD also support the recognition that CKD is an underappreciated high-risk characteristic in the UA/NSTEMI population. The increased risk of mortality associated with mild, moderate, and severe CKD remains evident across stud- ies.162,163,168,193 Indeed, the risks of short- and long-term mortal- ity are increased as the gradient of renal dysfunction wors- ens.162,168,193 The optimal role of early revascularization in this heterogeneous population of patients remains an important topic of research and investigation as discussed earlier in this update. 7. Conclusions and Future Directions 7.1. Quality of Care and Outcomes for UA/NSTEMI: Recommendation (See Table 9.) 7.1.1. Quality Care and Outcomes The development of regional systems of UA/NSTEMI care is a matter of utmost importance.196,198,199 This includes encouraging the participation of key stakeholders in collaborative efforts to evaluate care using standardized performance and quality- improvement measures, such as those endorsed by the ACC and the AHA for UN/NSTEMI.199 Standardized quality-of-care data registries designed to track and measure outcomes, complica- tions, and adherence to evidence-based processes of care for UA/NSTEMI are also critical: programs such as the NCDR (National Cardiovascular Data Registry) ACTION Registry- GWTG, the AHA s Get With The Guidelines (GWTG) quality- improvement program, and those performance-measurement systems required by The Joint Commission and the Centers for Medicare and Medicaid Services.194,201 203 More recently, the AHA has promoted its Mission: Lifeline initiative, which was developed to encourage closer cooperation and trust among prehospital emergency services personnel and cardiac care professionals.194 The evaluation of UA/NSTEMI care delivery across traditional care-delivery boundaries with these tools and other resources is imperative to identify systems problems and enable the application of modern quality-improvement methods, such as Six Sigma, to make necessary improve- ments.195,197,200,204 The quality-improvement data coming from registries like the ACTION-GTWG may prove pivotal in ad- dressing opportunities for quality improvement at the local, regional, and national level, including the elimination of health- care disparities and conduct of comparative effectiveness research. President and Staff American College of Cardiology Foundation William A. Zoghbi, MD, FACC, President Thomas E. Arend, Jr, Esq, CAE, Interim Chief Staff Officer William J. Oetgen, MD, MBA, FACC, Senior Vice President, Science and Quality Charlene May, Senior Director, Science and Clinical Policy American College of Cardiology Foundation/American Heart Association Lisa Bradfield, CAE, Director, Science and Clinical Policy Sue Keller, BSN, MPH, Senior Specialist, Evidence-Based Medicine Ezaldeen Ramadhan III, Specialist, Science and Clinical Policy American Heart Association Gordon F. Tomaselli, MD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Judy L. 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KEY WORDS: AHA Scientific Statements antiplatelet therapy focused update glycoprotein IIb/IIIa inhibitors myocardial infarction non ST elevation percutaneous coronary intervention thienopyridines P2Y12 receptor inhibitor unstable angina Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) Committee Member Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Hani Jneid, Chair Baylor College of Medicine The Michael E. DeBakey VA Medical Center Assistant Professor of Medicine None None None None None None None Jeffrey L. Anderson, Vice Chair Intermountain Medical Center Associate Chief of Cardiology AstraZeneca None None None None None 3.2.1 R. Scott Wright, Vice Chair Mayo Clinic Professor of Medicine and Consultant in Cardiology Hoffman LaRoche None None None None None None Cynthia D. Adams Community Health Network/The Indiana Heart Hospital Supervisor None None None None None None None Charles R. Bridges University of Pennsylvania Medical Center Chief, Cardiothoracic Surgery, Pennsylvania Hospital; Associate Professor of Surgery AstraZeneca Bayer Pharmaceuticals None None None None 3.2.1 Donald E. Casey, Jr Atlantic Health Vice President of Quality and Chief Medical Officer None None None None None None None Steven M. Ettinger Pennsylvania State University Penn State Heart and Vascular Institute None None None None None None None Francis M. Fesmire Director, Heart-Stroke Center, Assistant Professor None None None None None None None Theodore G. Ganiats University of California San Diego Professor and Interim Chair None None None None None None None A. Michael Lincoff Cleveland Clinic Foundation Cleveland Clinic Lerner College of Medicine Professor of Medicine AstraZeneca Merck None None AstraZeneca Bristol-Myers Squibb Eli Lilly Novartis Pfizer Roche Schering Plough Takeda None None 3.2.1 Eric D. Peterson Duke Clinical Research Institute Duke University Medical Center Professor of Medicine, Director, Cardiovascular Outcomes None None None Eli Lilly Johnson & Johnson None None 3.2.1 George J. Philippides Boston University School of Medicine Associate Professor of Medicine; Associate Chair for Clinical Affairs and Chief Quality Officer, Cardiovascular Section None None None None None None None Pierre Theroux Montreal Heart Institute Professor of Medicine, University of Montreal AstraZeneca Bristol-Myers Squibb Eli Lilly Sanofi Aventis AstraZeneca Boehringer Ingelheim Bristol-Myers Squibb Sanofi Aventis None None Merck None 3.2.1 Nanette K. Wenger Emory University School of Medicine Professor of Medicine (Cardiology) Abbott AstraZeneca Gilead Sciences (formerly CV Therapeutics) Merck Pfizer None None Abbott Eli Lilly Gilead Sciences (formerly CV Therapeutics) Merck Pfizer None None 3.2.1 (Continued) Jneid et al 2012 UA/NSTEMI Focused Update 901 Appendix 1. Continued Committee Member Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* James Patrick Zidar Rex Heart and Vascular Specialists Clinical Professor of Medicine, University of North Carolina None None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing group during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $10 000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACCF/AHA, a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) The company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) The person or a member of the person s household has a reasonable potential for financial, professional or other personal gain or loss as a result of the issues/content addressed in the document. *Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Section numbers pertain to those in the full-text guideline. Significant relationship. Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) Peer Reviewer Representation Employment Consultant Speaker s Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness John E. Brush Official Reviewer ACCF Board of Trustees Cardiology Consultants Healthcare Incentives Improvement Institute Board Member* United Healthcare Scientific Advisory Board None None None None None David P. Faxon Official Reviewer AHA Brigham and Women s Hospital Professor of Medicine Boston Scientific Sanofi-aventis None RIVA Medical None Circulation: Cardiovascular Interventions Editor None Robert A. Harrington Official Reviewer AHA Duke Clinical Research Institute Professor of Medicine; Duke University Medical Center Director Bristol-Myers Squibb Genentech* Gilead Sciences Merck Mitsubishi-Tanabe Momenta Pharmaceutical Pfizer* Regado Sanofi-aventis WebMD None None AstraZeneca Bristol-Myers Squibb GlaxoSmithKline Merck Portola Sanofi-aventis The Medicines Company None None Judith S. Hochman Official Reviewer ACCF/AHA Task Force on Practice Guidelines New York University School of Medicine Harold Snyder Family Professor of Cardiology; NYU-HHC Clinical and Translational Science Institute Co-Director; Leon Charney Division of Cardiology Clinical Chief; Cardiovascular Clinical Research Center Director Bristol-Myers Squibb Eli Lilly GlaxoSmithKline Sanofi-aventis None None Bayer Healthcare AG DSMB Johnson & Johnson DSMB Merck, TIMI 50 DSMB Schering-Plough, None None Rodney H. Zimmermann Official Reviewer ACCF Board of Governors Regina General Hospital Director of the Cardiac Catheterization Laboratory AstraZeneca Boehringer Ingelheim Hoffmann-La Roche AstraZeneca Boehringer Ingelheim Merck-Frost None Eli Lilly Schering-Plough None None Joseph C. Cleveland Organizational Reviewer STS University of Colorado Anschutz Medical Center Associate Professor of Surgery; Surgical Director, Cardiac Transplantation and MCS Baxter Biosurgery Sorin None None HeartWare Corporation Thoratec Corporation None None Joseph A. DeGregorio Organizational Reviewer SCAI Englewood Hospital Chief, Invasive Cardiology None None None None None None Deborah B. Diercks Organizational Reviewer ACEP UC Davis Medical Center None None None Beckman Coulter* AHRQ, QUADRICS Trial DSMB* Emergencies in Medicine* Society of Academic Emergency Medicine* Society of Chest Pain Centers and Providers* None Benjamin Hatten Organizational Reviewer ACEP Denver Health Medical Center None None None None None None Loren F. Hiratzka Organizational Reviewer STS Cardiac, Vascular and Thoracic Surgeons Medical Director, Cardiac Surgery None None None None None None Nancy M. Albert Content Reviewer ACCF/AHA Task Force on Practice Guidelines Cleveland Clinic, Kaufman Center for Heart Failure, Nursing Research, Innovation and CNS Senior Director Merck* None None None None None (Continued) Jneid et al 2012 UA/NSTEMI Focused Update 903 Appendix 2. 