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Author Relationships With Industry and Other Entities (Relevant) 2014 AHA/ACC Guideline for the Management of Patients With Non-St-Elevation Acute Coronary Syndromes Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Ezra A. Amsterdam (Chair) University of California (Davis) Medical Center, Division of Cardiology Professor None None None None None None None Nanette K. Wenger (Vice Chair) Emory University, School of Medicine Professor of Medicine (Cardiology) Abbott Amgen AstraZeneca Gilead Sciences Janssen Pharmaceuticals Medtronic Merck Pfizer None None Abbott Eli Lilly Gilead Sciences Merck Pfizer None None All sections and 8. Ralph G. Brindis University of California, San Francisco Department of Medicine and the Phillip R. Lee Institute for Health Policy Studies Clinical Professor of Medicine None Volcano None None None None None Donald E. Casey, Jr Atlantic Health Vice President of Health and Chief Medical Officer None None None None None None None Theodore G. Ganiats University of California, San Diego School of Medicine Executive Director of Health Services Research Center None None None None None None None David R. Holmes, Jr Mayo Clinic Consultant, Cardiovascular Diseases None None None None None None None Allan S. Jaffe Mayo Clinic, Cardiovascular Division Professor of Medicine Abbott Alere Amgen Beckman- Coulter Critical Diagnostics ET Healthcare Ortho Clinical Diagnostic Radiometer Roche Thermo-Fishert Trinity None None None None None All sections 7.6, and 8. Hani Jneid Baylor College of Medicine The Michael E. DeBakey VA Medical Center Assistant Professor of Medicine None None None None None None None (Continued) Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e415 Rosemary F. Kelly University of Minnesota Professor of Surgery; VA Medical Center Chief, Cardiothoracic Surgery None None None None None None None Michael C. Kontos Virginia Commonwealth University, Pauley Heart Center Medical Director, Coronary Intensive Care Unit, and Associate Professor, Internal Medicine Astellas General Electric Ikaria Prevencio Sanofi-aventis Wellpoint/Anthem Astellas AstraZeneca None None Astellas Eli Lilly Merck Novartis None All sections Glenn N. Levine Baylor College of Medicine Professor of Medicine; Director, Cardiac Care Unit None None None None None None None Philip R. Liebson Rush University Medical Center McMullan-Eybel Chair of Excellence in Clinical Cardiology and Professor of Medicine and Preventive Medicine None None None None None None None Debabrata Mukherjee Texas Tech University Health Sciences Center Chief, Cardiovascular Medicine None None None None None None None Eric D. Peterson Duke University Medical Center Fred Cobb, MD, Distinguished Professor of Medicine; Duke Clinical Research Institute Director Boehringer Ingelheim Genentech Janssen Pharmaceuticals Johnson & Johnson Merck None None Eli Lilly Johnson & Johnson Janssen Pharmaceuticals DCRI has numerous grants and contracts sponsored by industry that are relevant to the content of this CPG. Dr. Peterson participated in discussions but recused himself from writing or voting, in accordance with ACC/AHA policy. See comprehensive RWI table for a complete list of companies pertaining to this organization. None All sections Appendix 1. Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* (Continued) Marc S. Sabatine Brigham and Women s Hospital, Chairman TIMI Study Group, Division of Cardiovascular Medicine; Harvard Medical School Professor of Medicine Amgen AstraZeneca Bristol-Myers Squibb Merck Pfizer Sanofi-aventis None None Abbott Laboratories Amgen AstraZeneca Bristol-Myers Squibb Critical Diagnostics Daiichi-Sankyo Genzyme GlaxoSmithKline Nanosphere Roche Diagnostics Sanofi-aventis Takeda AstraZeneca Daiichi-Sankyo Gilead Johnson & Johnson BRAHMS Proventys Siemens Singulex None All sections except and 8. Richard W. Smalling University of Texas, Health Science Center at Houston Professor and Director of Interventional Cardiovascular Medicine; James D. Woods Distinguished Chair in Cardiovascular Medicine Gilead Maquet None None Cordis E-valve Abbott Vascular Edwards Lifesciences Gilead Maquet Datascope Cordis E-valve None All sections except 7.8, and 8. Susan J. Zieman National Institute on Aging/NIH, Geriatrics Branch, Division of Geriatrics and Clinical Gerontology Medical Officer 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 GWC 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 $10000 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 ACC/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; ore) 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 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 CPG. Significant relationship. No financial benefit. ACC indicates American College of Cardiology, AHA, American Heart Association, BMS, Bristol-Myers Squibb; CPG, clinical practice guideline; DCRI, Duke Clinical Research Institute; NIH, National Institutes of Health; NYU, New York University; RWI, relationships with industry and other entities; TIMI, Thrombolysis In Myocardial Infarction; and VA, Veterans Affairs. Appendix 1. Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals by Section* Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e417 Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Deepak L. Bhatt Official Reviewer AHA VA Boston Healthcare System Professor of Medicine, Harvard Medical School; Chief of Cardiology BMS/Pfizer DCRI (BMS/ Pfizer) DCRI (Eli Lilly) Eli Lilly None None AstraZeneca* Bristol-Myers Squibb* Ethicon* The Medicines Company Medtronic* Sanofi-aventis* Takeda Medscape Cardiology (Advisory Board) WebMD (Steering Committee) None John E. Brush, Jr Official Reviewer ACC Board of Trustees Eastern Virginia Medical School Professor of Medicine, Chief of Cardiology None None None None None None E. Magnus Ohman Official Reviewer ACC/ AHA Task Force on Practice Guidelines Duke Medicine Professor of Medicine AstraZeneca Bristol-Myers Squibb Gilead* Janssen Pharmaceuticals* The Medicines Company Merck Pozen Roche Sanofi-aventis Gilead* Janssen Pharmaceuticals None Daiichi-Sankyo* Eli Lilly* Gilead* None None John F. Robb Official Reviewer ACC Board of Governors Dartmouth-Hitchcock Medical Center Director, Interventional Cardiology and Cardiac Catheterization Laboratories None None None None None Defendant, adverse drug reaction, Sarah A. Spinier Official Reviewer AHA Philadelphia College of Pharmacy, University of the Sciences in Philadelphia Professor of Clinical Pharmacy Bristol-Myers Squibb Daiichi-Sankyo Janssen Pharmaceuticals Merck None None None None Plaintiff, clopidogrel, Gorav Ailawadi Organizational Reviewer STS University of Virginia Health System Thoracic and Cardiovascular Surgery Abbott Atricure None None None None None Srihari S. Naidu Organizational Reviewer SCAI Winthrop University Hospital Director, Cardiac Catheterization Laboratory None None None None None None Robert L. Rich, Jr Organizational Reviewer AAFP Bladen Medical Associates Family Physician None None None None None None Mouaz H. Al-Mallah Content Reviewer ACC Prevention of Cardiovascular Disease Committee King Abdul-Aziz Cardiac Center Associate Professor of Medicine None None None None None None (Continued) John A. Ambrose Content Reviewer University of California San Francisco Fresno Department of Medicine Professor of Medicine; Chief of Cardiology; Program Director, Cardiology Fellowship None None None None None None Giuseppe Ambrosio Content Reviewer-ACC Prevention of Cardiovascular Disease Committee Hospital of University of Perugia School of Medicine Medical Director, Division of Cardiology Bayer* The Medicines Company Merck Schering-Plough Sanofi-aventis Merck Schering-Plough Pfizer None None None None H. Vernon Anderson Content Reviewer University of Texas Professor of Medicine, Cardiology Division None None None None Eli Lilly None Jeffrey L. Anderson Content Reviewer ACC/ AHA Task Force on Practice Guidelines Intermountain Medical Center Associate Chief of Cardiology Sanofi-aventis None None GlaxoSmithKline Harvard (DSMB)-TIMI None None Fred S. Apple Content Reviewer University of Minnesota School of Medicine, Hennepin County Medical Center Professor, Laboratory Medicine and Pathology Abbott Diagnostics Alere Beckman Coulter T2 Biosystems None None Abbott* Alere/Biosite* Biomerieux* Ortho-Clinical Diagnostics-PI Ortho-Clinical Diagnostics* Radiometer* Roche Laboratories* Siemens* Abbott Diagnostics-PI Alere-PI None Emmanouil S. Brilakis Content Reviewer ACC Interventional Section Leadership Council UT Southwestern Medical School Director, Cardiac Catheterization Laboratory, VA North Texas Healthcare System Bridgepoint Medical/Boston Scientific* Janssen Pharmaceuticals Sanofi-aventis None None None Abbott Vascular AstraZeneca Cordis* Daiichi-Sankyo* The Medicines Company Medtronic* None Matthew J. Budoff Content Reviewer ACC Cardiovascular Imaging Section Leadership Council Los Angeles Biomedical Research Institute Program Director, Division of Cardiology and Professor of Medicine None AstraZeneca None General Electric* None P laintiff, cardiac treatment, James A. Burke Content Reviewer ACC Interventional Section Leadership Council Lehigh Valley Health Network Interventional Cardiologist None None None None None None Appendix 2. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness (Continued) Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e419 Robert H. Christenson Content Reviewer AACC University of Maryland School of Medicine Professor of Pathology; Professor of Medical and Research Technology; Director, Rapid Response Laboratory BG Medicine Critical Diagnostics Siemens Medical Diagnostics None None The Medicines Company AACC (President) Roche Diagnostics (University of Maryland School of Medicine)* None Joaquin E. Cigarroa Content Reviewer ACC Interventional Section Leadership Council Oregon Health and Science University Associate Professor of Medicine None None None None Catheterization and Cardiovascular Intervention (Editorial Board) None Marco A. Costa Content Reviewer ACC Cardiovascular Imaging Section Leadership Council University Hospital for Cleveland Cardiologist Abbott Vascular* Boston Scientific Medtronic None None Abbott Vascular* Boston Scientific* Cordis* IDEV Technology The Medicines Company Medtronic* Micell* OrbusNeicht Abbott Cordis Medtronic None Prakash C. Deedwania Content Reviewer ACC Prevention of Cardiovascular Disease Committee University of California San Francisco Chief of Cardiology Amgen Pfizer Pfizer Takeda Pharmaceuticals None None None None James A. de Lemos Content Reviewer UT Southwestern Medical School Associate Professor of Medicine; Director, Coronary Care Unit and Cardiology Fellowship Diadexus Janssen Pharmaceuticals AstraZeneca None Abbott Diagnostics Daiichi-Sankyo None Burl R. Don Content Reviewer University of California Davis Professor of Medicine; Director of Clinical Nephrology None None None None None None Lee A. Fleisher Content Reviewer University of Pennsylvania Department of Anesthesiology Professor of Anesthesiology None None None None None None Mary G. George Content Reviewer HHS Centers for Disease Control and Prevention Senior Medical Officer, Division for Heart Disease and Stroke Prevention None None None None None None Linda D. Gillam Content Reviewer ACC Cardiovascular Imaging Section Leadership Council Morristown Medical Center Professor of Cardiology; Vice Chair, Cardiovascular Medicine None None None None None None (Continued) Appendix 2. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Robert A. Guyton Content Reviewer ACC/ AH A Task Force on Practice Guidelines Emory Clinic Professor and Chief, Division of Cardiothoracic Surgery Medtronic None None None None None Joerg Herrmann Content Reviewer ACC Interventional Section Leadership Council Mayo Medical School- Internal Medicine and Cardiovascular Disease None None None None None None Judith S. Hochman Content Reviewer ACC/ AHA Task Force on Practice Guidelines New York University School of Medicine, Division of Cardiology Clinical Chief of Cardiology GlaxoSmithKline Janssen Pharmaceuticals None None None None None Yuling Hong Content Reviewer HHS Centers for Disease Control and Prevention Associate Director None None None None None None Lloyd W. Klein Content Reviewer ACC Interventional Section Leadership Council Rush Medical College-Professor of Medicine None None None None None None Frederick G. Kushner Content Reviewer Tulane University School of Medicine Clinical Professor of Medicine; Heart Clinic of Louisiana Medical Director None None None None None None Ehtisham Mahmud Content Reviewer ACC Interventional Section Leadership Council University of California, San Diego Professor of Medicine/Cardiology, Chief of Cardiovascular Medicine; Director, Interventional Cardiology and Cardiovascular Catheterization Laboratory Abiomed Cordist Eli Lilly* Gilead Johnson & Johnson Medtronic Eli Lilly* Medtronic None Abbott Vascular* Accumetrics* Merck Schering-Plough Boston Scientific* Gilead* The Medicines Company Sanofi-aventis* None None Carlos Mart nez- S nchez Content Reviewer AIG Cardiology Society of Mexico President None None None AstraZenecat Eli Lilly Sanofi-aventis None None L. Kristen Newby Content Reviewer Duke University Medical Center Associate Professor of Clinical Medicine Johnson & Johnson Daiichi-Sankyo None None Amylin AstraZeneca Bristol-Myers Squibb* Eli Lilly GlaxoSmithKline Merck* None None Patrick T. O Gara Content Reviewer Brigham and Women s Hospital Professor of Medicine, Harvard Medical School; Director, Clinical Cardiology None None None None None None Appendix 2. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness (Continued) Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e421 Narith Ou Content Reviewer Mayo Clinic Pharmacotherapy Coordinator, Pharmacy Services None None None None None None Gurusher S. Panjrath Content Reviewer ACC Heart Failure and Transplant Section Leadership Council George Washington Medical Faculty Associates Assistant Professor of Medicine; Director of Heart Failure and Mechanical Support Program None None None None None None Rajan Patel Content Reviewer ACC Cardiovascular Imaging Section Leadership Council Ochsner Clinic Foundation Interventional Cardiologist None None None None None None Carl J. Pepine Content Reviewer Shands Hospital at University of Florida Professor and Chief, Division of Cardiovascular Medicine Lilly/Cleveland Clinic (DSMB) None None AstraZeneca* Gilead Sciences* Park-Davis* Pfizer* Sanofi-aventis* None None Sunil V. Rao Content Reviewer ACC Interventional Section Leadership Council Duke University Medical Center- Associate Professor of Medicine AstraZeneca Daiichi-Sankyo Eli Lilly Terumo Medical The Medicines Company None None Sanofi-aventis Abbott Vascular None Pasala S. Ravichandran Content Reviewer ACC Surgeons Scientific Council Oregon Health and Science University Associate Professor None None None None None None Michael W. Rich Content Reviewer Washington University School of Medicine Professor of Medicine None None None None None None Frank W. Sellke Content Reviewer- ACC/AHA Task Force on Practice Guidelines Brown Medical School, Rhode Island Hospital Professor; Chief of Cardiothoracic Surgery None None None None None None Alan Wu Content Reviewer AACC San Francisco General Hospital and Trauma Center Chief, Clinical Chemistry Laboratory Abbott Singulex None None None None None This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review and determined to be relevant to this document. It 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 $10000 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. A relationship is considered to be modest if it is less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review. According to the ACC/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. *Significant relationship. No financial benefit. AAAHC indicates Accreditation Association for Ambulatory Health Care; AACC, American Association for Clinical Chemistry; AAFP, American Academy of Family Physicians; AHA, American Heart Association; AIG, Association of International Governors; BMS, Bristol-Myers Squibb; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; HHS, Health and Human Services; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institutes of Health; SCAI, Society for Cardiovascular Angiography and Interventions; STS, Society of Thoracic Surgeons; TIMI, Thrombolysis In Myocardial Infarction; and VA, Veterans Affairs. Appendix 2. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Appendix 3. Abbreviations ACE = angiotensin-converting enzyme ACS = acute coronary syndrome AF = atrial fibrillation AMI = acute myocardial infarction BP = blood pressure CABG = coronary artery bypass graft CAD = coronary artery disease CKD = chronic kidney disease CK-MB = creatine kinase myocardial isoenzyme COX = cyclooxygenase CPG = clinical practice guideline CrCl = creatinine clearance CT = computed tomography DAPT = dual antiplatelet therapy DES = drug-eluting stent ECG = electrocardiogram ED = emergency department GDMT = guideline-directed medical therapy GP = glycoprotein GFR = glomerular filtration rate GWC = guideline writing committee HF = heart failure IABP = intra-aortic balloon pump IV = intravenous LMWH = low-molecular-weight heparin LV = left ventricular LVEF = left ventricular ejection fraction MACE = major adverse cardiac event MI = myocardial infarction = myocardial oxygen consumption NSAID = nonsteroidal anti-inflammatory drug NSTE-ACS = non-ST-elevation acute coronary syndromes NSTEMI = non-ST-elevation myocardial infarction PCI = percutaneous coronary intervention RCT = randomized controlled trial SC = subcutaneous STEMI = ST-elevation myocardial infarction UA = unstable angina UFH = unfractionated heparin VF = ventricular fibrillation VT = ventricular tachycardia Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e423 Appendix 4. Additional Tables Table A. Universal Classification of MI Type 1: Spontaneous MI Spontaneous MI related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in 1 of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe CAD, but on occasion nonobstructive or no CAD. Type 2: MI secondary to ischemic imbalance In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between MVO2 , eg, coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/bradyarrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without LVH. Type 3: MI resulting in death when biomarker values are unavailable Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic electrocardiographic changes or new LBBB, but death occurred before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases where blood was not collected for cardiac biomarker testing. Type 4a: MI related to PCI MI associated with PCI is arbitrarily defined by elevation of cTn values >5 99th percentile URL in patients with normal baseline values (<99th percentile URL) or a rise of cTn values >20% if baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia, (ii) new ischemic electrocardiographic changes or new LBBB, (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow or no flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality is required. Type 4b: MI related to stent thrombosis MI associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with 1 value above the 99th percentile URL. Type 5: MI related to CABG MI associated with CABG is arbitrarily defined by elevation of cardiac biomarker values >10 99th percentile URL in patients with normal baseline cTn values (<99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographically documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. CABG indicates coronary artery bypass graft; CAD, coronary artery disease; cTn, cardiac troponin; LBBB, left bundle-branch block; LVH, left ventricular hypertrophy; MI, myocardial infarction; MVO2 , myocardial oxygen consumption; PCI, percutaneous coronary intervention; and URL, upper reference limit. Modified from Thygesen et al.21 Table B. Pharmacological Therapy in Older Patients With NSTE-ACS Age-Related Pharmacological Change Clinical Effect Dose-Adjustment Recommendations Additional Precautions General principles In renal function (CrCl*): drug clearance, water/ electrolyte balance SCr unreliable measure of renal function in older adults Change in body composition Fat, lean body mass/total water GI absorption Levels renally cleared drug Risk high/low electrolyte levels Levels hydrophilic agents Levels lipophilic agents Longer time to reach steady- state lipophilic agents Calculate CrCl in all pts renal- dose accordingly Start at lowest recommended dose, titrate up slowly Avoid interacting drugs Consider doses in women, malnourished, hypovolemic Caution fall risk with BP agents and diuretics Monitor for ADR, especially delirium Frequent monitoring of renal function/electrolytes Minimize polypharmacy watch for drug-drug interactions ASA Hydrophilic; levels with total body water; age-related plasma concentration for similar dose Bleeding risk with age, dehydration, frailty, diuretics Maintenance=81 mg/d (lowest possible dose) Bleeding with NSAIDs, other AP, AC, AT; risk peptic ulcer with NSAIDs Nitrates Sensitivity Hypotensive response with baroreceptor response Lowest dose possible, especially if hypovolemic Risk OH, syncope, falls ACE inhibitors First-pass metabolism (some) with effect; enalapril effect May have effect May need dose Risk AKI and K+ and effect with NSAIDs; avoid K-sparing diuretics ARBs No significant age-related changes No age-related clinical changes None Risk AKI and K+ and effect with NSAIDs; avoid K-sparing diuretics Alpha blockers Sensitivity; BP with baroreceptor response BP; OH Avoid when possible Risk OH, falls, syncope, especially with loop diuretics Beta blockers Myocardial sensitivity ( postreceptor signaling), conduction system sensitivity Bradycardia/heart block; BP effect vs. younger pts May need dose with age Caution conduction system blocks (Continued) CCBs DHPs (amlodipine; nifedipine) Lipophilic; hepatic and overall clearance; fat storage; sinus node sensitivity; baroreceptor response to BP BP more than non DHP and with age; edema hypotension, bradycardia Initiate low dose, titrate cautiously Inhibits clopidogrel; risk OH, falls, syncope; most potent BP first 3 mo, then less Non-DHP (verapamil; diltiazem) Hepatic and overall clearance; less PR prolongation than DHP and with age; negative inotropy; SA node sensitivity and HR than DHP and with age; AV conduction with age; baroreceptor response to BP BP more with tage; edema; heart block; hypotension; bradycardia and bradyarrhythmias with age Initiate low dose, titrate cautiously Risk OH, falls, syncope; consider rhythm monitoring Diuretics Diuretic/natriuretic response, EC space, drug concentration if GFR; baroreceptor response to volume shifts Sensitivity; hypotension; risk hypokalemia/hypomagnesemia/ hyponatremia; diuretic effect with GFR; risk hypovolemia- thirst May need doses if GFR; may need dose if cotreating with NSAIDs Monitor Na+ , K+ levels; risk OH/falls; With NSAIDs: natriuretic and diuretic effect, K+ Heparins UFH Hydrophilic; concentration, especially if lean body mass or plasma proteins; levels with age Bleeding risk with age; more potent anticoagulation per dose with age; weight-based dosing but with precautions for shift in body composition Weight-based 60 U/kg loading dose + 12 U/kg/h INF. Suggested max loading dose: 400 U and 900 U/h INF or 5000 U loading dose/1000 U/h if pt weight >100 kg Bleeding with ASA; bleeding risk with other AP, AT, and GP IIb/IIIa; vigilantly monitor aPTT LMWH Cleared renally; more predictable dose response than UFH; not dependent on plasma protein levels; levels with lean body mass; effect with age Bleeding risk with age and weight and renally dosed Enoxaparin: Weight-based 1 mg/kg SC q 12 h; CrCl* <30 mL/min avoid or 1 mg/kg SC q 24 h; CrCl Dalteparin: Use caution in older pts with low body weight or renal insufficiency Bleed with ASA Monitor anti-Xa; bleeding with GP IIb/IIIa with age Direct Thrombin Inhibitors Bivalirudin Cleared renally; more predictable dose response; not dependent on plasma protein levels Significantly less bleeding in older pts, even with renal dysfunction vs. UFH + GP IIb/IIIa with similar efficacy CrCl <30 mL/min: 1 mg/kg/h; CrCl: 30 to 60 mL/min less bleeding than UFH Less bleeding than GP IIb/IIIa inhibitor + heparin Fondaparinux Cleared renally Renal/weight adjust; less bleeding but similar efficacy vs. enoxaparin in older pts with NSTE-ACS, even with mild to moderate renal dysfunction Renal adjustment: CrCl over enoxaparin Bleeding vs. enoxaparin; good safety profile vs. UFH/LMWH Inhibitors Clopidogrel Lipophilic; HPR; metabolism; fat distribution; to steady state ( fat distribution/T ) Antiplatelet effect in some older pts Maintenance: 75 mg (no response to higher dose) Effect with proton pump inhibitors; if HPR may respond to prasugrel or ticagrelor Prasugrel l9% Active metabolite >75 y of age Bleeding risk Avoid in pts 75 y of age or if weight 60 kg; 10 mg in very high-risk pts N/A Ticagrelor None known N/A None Reversible GP IIb/IIIa Inhibitors Abciximab N/A Bleeding with age Not recommended N/A Bleeding risk without clinical benefit Table B. Continued Age-Related Pharmacological Change Clinical Effect Dose-Adjustment Recommendations Additional Precautions (Continued) Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e425 GP IIb/IIIa Inhibitors (continued) Eptifibatide Weight/renally dosed Bleeding risk Weight-based: 180 mcg/kg loading dose + 2 mcg/kg/min INF; CrCl 50 mL/min: 1.0 mcg/kg/min INF Less benefit/more bleeding with age Tirofiban Weight/renally dosed Bleeding risk Weight-based: 12 mcg/kg loading dose + 0.14 mcg/kg/min INF; CrCl <30 mL/min: 6 mcg/kg loading dose + 0.05 mcg/kg/min INF In older pts with high bleeding risk, low-dose INF effective with bleeding Warfarin Sensitivity; 20% 40% clearance; protein binding; inhibition vitamin K-dependent clotting factors at same plasma levels with age Bleeding risk at lower INR; higher INR/dose with age risk GI bleeding Loading: 4 mg/d 4 d Maintain mean dose 0.4 mg/w/y of age Multiple drug interactions, frequency of monitoring; ASA potentiates effect New Oral AC N/A N/A Contraindicated if CrCl If pt taking when admitted, stop consider delaying angiogram/ PCI until effect wanes, switch to UFH/dalteparin/bivalirudin/ fondaparinux; AP and DAPT bleeding 2 post-ACS consider BMS and radial access. Avoid GP IIb/IIIa inhibitor if possible; thrombotic risk following discontinuation. Rivaroxaban 35% cleared renally; 65% hepatic (CYP3A4); levels in hepatic and/or renal dysfunction and age Bleeding risk; not reversible CrCl 15 49 mL/min: 15 mg QD; consider avoiding if CrCl 15 30 mL/min if bleeding risk; CrCl >50 mL/min: 20 mg QD Some drug interactions Dabigatran 80% cleared renally; plasma level with age, especially Bleeding risk; not reversible CrCl 15 30 mL/min: 75 mg BID with caution; CrCl 30 49 mL/min: 75 mg BID; CrCl >50 mL/min: 150 mg BID Monitor pt and renal function frequently; longest for effect to wane with CrCl; risk dyspepsia, GI bleeding Apixaban Hepatically cleared (minor CYP3A4); dose adjust if weight 60 kg; highly protein bound Bleeding risk; not reversible CrCl 15 29 mL/min: 2.5 mg BID or with 2 of the following: age 80 y/weight 60 kg/SCr 1.5 mg/ dL: SCr <1.5: 5 mg BID Risk abnormal liver function tests *CrCl should be calculated for all older pts because SCr level does not accurately reflect renal dysfunction: CrCl decreases with age 0.7 mL/min/y. These agents are not approved for NSTE-ACS but are included for management of pts with nonvalvular chronic atrial fibrillation. AC indicates anticoagulants; ACE, angiotensin-converting-enzyme; ACS, acute coronary syndromes; ADR, adverse drug reactions; AKI, acute kidney injury; AP, antiplatelets; aPTT, activated partial thromboplastin time; ARB, angiotensin receptor blocker; ASA, aspirin; AT, antithrombins; AV, atrioventricular; BID, twice daily; BMS, bare-metal stent; BP, blood pressure; CCBs, calcium channel blockers; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; DHP, dihydropyridine; EC, extracellular; GFR, glomerular filtration rate; GI, gastrointestinal; GP, glycoprotein; HPR, high platelet reactivity; HR, heart rate; INF, infusion; INR, international normalized ratio; K+ , potassium; LMWH, low-molecular-weight heparin; max, maximum; Mg, magnesium; N/A, not available; NSAIDs, nonsteroidal anti-inflammatory drugs; NSTE-ACS, non-ST-elevation acute coronary syndromes; OH, orthostatic hypotension; PCI, percutaneous coronary intervention; pts, patients; QD; once daily; SA, sinoatrial; SC, subcutaneous; SCr, serum creatinine; T , half-life; and UFH, unfractionated heparin. Table B. Continued Age-Related Pharmacological Change Clinical Effect Dose-Adjustment Recommendations Additional Precautions Table C. Age-Related Physiological Changes: Clinical Impact in Older Patients With NSTE-ACS Age-Related Change Clinical Alteration Clinical Impact in NSTE-ACS Central arterial stiffness SBP/ DBP; LVH; diastolic function; coronary perfusion pressure; ischemia/infarct threshold for tachycardia/hypertension with and without coronary obstructive disease; PA pressure Risk end-organ damage (cerebrovascular accident, AKI); BP lability; reinfarction/ischemia; orthostatic hypotension; HF; pulmonary edema LV diastolic function LA size; early passive LV filling; late LV filling and LV EDP; PA pressure Risk AF; ( pulmonary edema/ CO), DOE; pulmonary edema with HR/ BP Response to beta-adrenergic stimulation HR/ inotropic responsiveness to stress; resting systolic LV function unchanged with age Hypotension, HF, HR response Conduction system changes Sinus node cells; AV conduction; LBBB; and RBBB Difficult to interpret electrocardiographic MI/ischemia; heart block; SSS; SVT, sensitivity to conduction system drugs Volume regulating hormones Na, K, and water regulation BP lability Altered electrolytes, sensitivity to fluid therapy/diuretics Renal changes GFR (0.8 mL/min/y), Na/K clearance, normal serum creatinine despite moderate to severe CKD, altered drug clearance; urine concentrating ability CrCl or eGFR must be calculated for drug dosing, sensitivity to contrast nephropathy, risk AKI Fat-muscle redistribution Third spacing of fluid, may alter drug storage; Vo2max May alter fluid/drug dosing, decreased CO; DOE; early fatigability Baroreceptor sensitivity BP lability Orthostatic hypotension, fall risk Clotting factor/platelet function/hemostasis Bleeding and clotting risk, sensitivity to anticoagulants/antithrombins Risk cerebrovascular accident/reinfarction/recurrent ischemia, bleeding, thrombosis, PE, DVT; may alter drug dosing/sensitivity; stent thrombosis AF indicates atrial fibrillation; AKI, acute kidney injury; AV, atrioventricular; BP, blood pressure; CKD, chronic kidney disease; CO, cardiac output; CrCl, creatinine clearance; DBP, diastolic blood pressure; DOE, dyspnea on exertion; DVT, deep vein thrombosis; EDP, end-diastolic pressure; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HF, heart failure; HR, heart rate; K, potassium; LA, left atrium; LBBB, left bundle-branch block; LV, left ventricular; LVH, left ventricular hypertrophy; MI, myocardial infarction; NA, sodium; Na/K sodium and potassium clearance; NTSE-ACS, non ST-elevation acute coronary syndrome; PA, pulmonary artery; PE, pulmonary embolism; RBBB, right bundle-branch block, SBP, systolic blood pressure; SSS, sick sinus syndrome; SVT, supraventricular tachycardia; and Vo2max , maximum oxygen consumption. Table D. FREEDOM Trial: Key Outcomes at 2 Years and 5 Years After Randomization Outcome P Value* PCI CABG PCI CABG Number (%) *P values were calculated with the log-rank test on the basis of all available follow-up data (ie, >5 y). The primary composite outcome was rate of death from any cause, MI, or stroke. P=0.006 in the as-treated (non-intention-to-treat) analysis. P=0.16 by the WaLd test of the Cox regression estimate for study-group assignment in 1712 patients after adjustment for average glucose Level after procedure. CABG indicates coronary artery bypass graft; FREEDOM, Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease; MI, myocardial infarction; and PCI, percutaneous coronary intervention. Modified with permission from Farkouh et al.616