Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Secondary Prevention and Risk Reduction for Patients with CHD Lynne T. Braun, PhD, CNP, FAHA, FPCNA, FAAN Professor, Rush University College of Nursing ANP, Rush Heart and Vascular Institute Chicago, IL [email protected] Disclosures • Salary support, NIH • Advisory Board, UpToDate ARS Question #1 Which of the following lifestyle modifications is associated with the greatest effect on blood pressure? 1. 2. 3. 4. Sodium restricted diet Weight reduction Regular physical activity Alcohol restriction 28% 38% 34% 0% ARS Question #2 Which of the following is true about the evidence to support referring patients with ACS, post CABG, and post PCI to cardiac rehabilitation? 1. Evidence is from a single, randomized trial (I, B) 2. Evidence is from expert opinion (I,C) 3. Some conflicting evidence from multiple randomized trials or meta-analyses (IIa, A) 4. Sufficient evidence from multiple randomized trials and meta-analyses (I, A) 1% 2% 14% 84% Epidemiology: Coronary Heart Disease • 15.4 million Americans have CHD – Prevalence is estimated to be ≈ 18% by 2030 • Estimated direct and indirect cost of CHD in 2009 $195.2 billion • CHD is the leading cause of death in the US Go AS, et al. Circulation 2013;127:e6-e245. Smith S et al. Circulation. 2011;124:2458-2473 Secondary Prevention Areas of Intervention • • • • • • • • • • • • Smoking Blood pressure control Lipid management Physical activity Weight management Type 2 diabetes mellitus management Antiplatelet agents / anticoagulants RAAS blockers β-blockers Influenza vaccination Depression Cardiac rehabilitation Classification of Recommendations and Levels of Evidence Smith SC Jr., et al. Circulation 2011;124:2458-2473. Smoking Cessation Algorithm Ask and document pt’s tobacco use status Current User Recent Quitter (<6 months) Advise: Provide a strong, personalized message to quit using tobacco Assess readiness to quit in next 30 days Prevent Relapse • Congratulate successes • Encourage to remain tobacco-free • Discuss benefits experienced by patient • Address weight gain, negative mood, and lack of support Not Ready Ready Assist • Negotiate a plan • STAR** • Discuss pharmacotherapy • Social support • Provide educational materials Arrange follow-up to check plan or adjust meds • Call right before and after quit date • Weekly follow-up x 2 weeks, then monthly x 6 months • Ask about difficulties (withdrawal, depressed mood) • Build upon successes • Seek commitment to stay tobacco-free Increase Motivation • Relevance to patients personal situation • Risks: short and long term, environmental • Rewards: potential benefits of quitting • Roadblocks: identify barriers and potential solutions • Repetition: repeat motivational intervention • Reassess readiness to quit **STAR Set quit date Tell family, friends, and coworkers about it Anticipate challenges: withdrawal, breaks Remove tobacco from the house, car, and social life Treating Tobacco Use and Dependence: 2008 Update, U.S. Department of Health and Human Services, May 2008 Cigarette Smoking Recommendations Goal: Complete Cessation and No Exposure to Environmental Tobacco Smoke •Ask about tobacco use status at every visit. I IIa IIb III •Advise every tobacco user to quit. •Assess the tobacco user’s willingness to quit. •Assist by counseling and developing a plan for quitting. I IIa IIb III •Arrange follow-up, referral to special programs, or pharmacotherapy (including nicotine replacement and bupropion. I IIa IIb III •Urge avoidance of exposure to environmental tobacco smoke at work and home. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Blood Pressure Control Recommendations Goal: <140/90 mm Hg or <130/80 if diabetes or chronic kidney disease Blood pressure 120/80 mm Hg or greater: I IIa IIb III · Initiate or maintain lifestyle modification: weight control, increased physical activity, alcohol moderation, Na + reduction, and increased consumption of fresh fruits vegetables and low fat dairy products I IIa IIb III Blood pressure 140/90 mm Hg or greater (or 130/80 or greater for chronic kidney disease or diabetes) As tolerated, add blood pressure medication, treating initially with beta blockers and/or ACE inhibitors with addition of other drugs as needed to achieve goal blood pressure Smith SC Jr., et al. Circulation 2011;124:2458-2473. 2012 SIHD Guidelines: Blood Pressure Management I IIa IIb III All patients should be counseled about the need for lifestyle modification: weight control; increased physical activity; alcohol moderation; sodium reduction; and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products. I IIa IIb III In patients with SIHD with BP 140/90 mm Hg or higher, antihypertensive drug therapy should be instituted in addition to or after a trial of lifestyle modifications. I IIa IIb III The specific medications used for treatment of high BP should be based on specific patient characteristics and may include ACE inhibitors and/or beta blockers, with addition of other drugs, such as thiazide diuretics or calcium channel blockers, if needed to achieve a goal BP of less than 140/90 mm Hg. (ADA 2013 recommendation 140/80 mm Hg--instead of 130 mm Hg--for individuals with diabetes) Fihn SD et al. J Am Coll Cardiol. 2012;60:e44-e164; 2013 ADA Clinical Practice Recommendations. Diabetes Care 2013;36:S1-110. JNC 7 Lifestyle Modifications for BP Control Modification Recommendation Approximate SBP Reduction Range Maintain normal body weight (BMI=18.5-24.9) 5-20 mmHg/10 kg weight lost Diet rich in fruits, vegetables, low fat dairy and reduced in fat 8-14 mmHg Restrict sodium intake <2.4 grams of sodium per day 2-8 mmHg Physical activity Regular aerobic exercise for at least 30 minutes on most days of the week 4-9 mmHg <2 drinks/day for men and <1 drink/day for women 2-4 mmHg Weight reduction Adopt DASH eating plan Moderate alcohol consumption Chobanian AV, et al. JAMA 2003;289:2560-2572. Lipid Management Recommendations Goal: Treatment with statin therapy LDL-C < 100 mg/dL LDL-C < 70 mg/dL for very high risk patients If TG ≥ 200 mg/dL, non-HDL-C < 130 mg/dL or < 100 mg/dl for very high risk patients Very High Risk Patient = Presence of established cardiovascular disease plus: 1. multiple major risk factors (especially diabetes) 2. severe and poorly controlled risk factors (especially continued smoking) 3. multiple risk factors of the metabolic syndrome (especially high TG ≥ 200 mg/dL plus non-HDL-C ≥130 mg/dL with low HDL-C < 40 mg/dL), and 4. patients with ACS Smith SC Jr., et al. Circulation 2011;124:2458-2473. Lipid Management Recommendations Class I Recommendations I IIa IIb III • Lipid profile established and hospitalized patients should be started on therapy before discharge. • Lifestyle modifications in all patients. • Dietary therapy to include intake of < 7% saturated fats, < 1% trans fatty acids, and < 200 mg/day of cholesterol. • Treatment with statin therapy • Adequate dose of statin to achieve an LDL-C < 100 mg/dL AND at least a 30% lowering of LDL-C. • If TG ≥ 200 mg/dL, treat with statins to achieve a non-HDLC* to < 130 mg/dL. • If TG > 500 mg/dL, start fibrate therapy in addition to statin therapy to prevent acute pancreatitis. I IIa IIb III I IIa IIb III *Non-HDL-C = total cholesterol minus HDL-C Smith SC Jr., et al. Circulation 2011;124:2458-2473. Lipid Management Recommendations Class IIa Recommendations I IIa IIb III • If treatment with a statin does not achieve the goal, addition of a bile acid sequestrant or niacin is reasonable. • If patients do not tolerate statins, therapy with a bile acid sequestrant and/or niacin is reasonable. • If TG ≥ 200 mg/dL, lowering the non-HDL-C to < 100 mg/dL in very high-risk patients is reasonable. • Lowering LDL-C to < 70 mg/dL in very high-risk patients is reasonable. I IIa IIb III Smith SC Jr., et al. Circulation 2011;124:2458-2473. Lipid Management Recommendations Class IIb Recommendations I IIa IIb III • Consider ezetimbe in patients who do not achieve goal or tolerate statins, bile acid sequestrants, and/or niacin. • Consider niacin, fibrate, or fish oil in patients with elevated non-HDL-C while on statin therapy. • Consider omega-3 fatty acids from fish or fish oil capsules (1 g/d) for CVD risk reduction. I IIa IIb III Smith SC Jr., et al. Circulation 2011;124:2458-2473. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Relationship between LDL-C Levels and Event Rates in Secondary Prevention Statin Trials of Patients with Stable CHD 30 Statin Placebo Event (%) 25 4S 4S 20 LIPID CARE HPS LIPID CARE HPS TNT (atorvastatin 10 mg/d) TNT (atorvastatin 80 mg/d) 15 10 5 0 0 70 90 110 130 150 170 190 210 LDL-C (mg/dL) LaRosa JC, et al. N Engl J Med 2005;352:1425-1435. Physical Activity Recommendations Goal: 30 minutes 7 days/week, minimum 5 days/week I IIa IIb III Assess risk with a physical activity history and/or an exercise test, to guide prescription I IIa IIb III I IIa IIb III Encourage 30 to 60 minutes of moderate intensity aerobic activity such as brisk walking, on most, preferably all, days of the week, supplemented by an increase in daily lifestyle activities. Evaluate and counsel patients to report symptoms related to exercise. I IIa IIb III Recommend complementary resistance training at least 2 days per week. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Exercise Evidence: Mortality Risk Observational study of self-reported physical activity in 772 men with established coronary heart disease Light or moderate exercise is associated with lower risk Wannamethee SG, et al. Circulation 2000;102:1358-1363 Weight Management Recommendations Goal: BMI 18.5 to 24.9 kg/m2 Waist Circumference: Men: < 40 inches Women: < 35 inches I IIa IIb III Assess BMI and/or waist circumference on each visit and consistently encourage weight maintenance/ reduction through an appropriate balance of physical activity, caloric intake, and formal behavioral programs when indicated. I IIa IIb III If waist circumference (measured at the iliac crest) >35 inches in women and >40 inches in men, intensify therapeutic lifestyle interventions and focus on weight management.. I IIa IIb III The initial goal of weight loss therapy should be to reduce body weight by approximately 5% to 10% from baseline. With success, further weight loss can be attempted if indicated. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Cardiovascular Risk Increases with Body Mass Index Hazard Ratio Hemorrhagic Stroke Ischemic Stroke Ischemic Heart Disease 4.0 4.0 4.0 2.0 2.0 2.0 1.0 1.0 1.0 0.5 0.5 0.5 16 20 24 28 32 36 16 20 24 28 32 36 16 20 24 28 32 36 Body Mass Index (kg/m2)* Mhurchu N, et al. Int J Epidemiol 2004;33:751-758. Diabetes Mellitus Recommendations Class I Recommendations I IIa IIb III I IIa IIb III Coordinate care for diabetes with patient’s primary care provider or endocrinologist. Lifestyle modification including daily physical activity, weight management, blood pressure control, and lipid management are recommended for all patients with diabetes. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Diabetes Mellitus Recommendations Class IIa Recommendations I IIa IIb III Metformin is an effective first-line pharmacotherapy and can be useful if not contraindicated. I IIa IIb III It is reasonable to individualize the intensity of blood sugar-lowering interventions based on the individual patient’s risk of hypoglycemia during treatment. Smith SC Jr., et al. Circulation 2011;124:2458-2473. 2012 SIHD Guidelines: Diabetes Management I IIa IIb III For selected individual patients, such as those with a short duration of diabetes mellitus and a long life expectancy, a goal HbA1c of 7% or less is reasonable. I IIa IIb III A goal HbA1c between 7% and 9% is reasonable for certain patients according to age, history of hypoglycemia, presence of microvascular or macrovascular complications, or presence of coexisting medical conditions. Fihn SD et al. J Am Coll Cardiol. 2012;60:e44-e164. 2012 SIHD Guidelines: Diabetes Management I IIa IIb III I IIa IIb III Initiation of pharmacotherapy interventions to achieve target HbA1c might be reasonable. Therapy with rosiglitazone should not be initiated in patients with SIHD. Harm Fihn SD et al. J Am Coll Cardiol. 2012;60:e44-e164. Aspirin Recommendations I IIa IIb III I IIa IIb III I IIa IIb III Start and continue indefinitely aspirin 75 to 162 mg/d in all patients unless contraindicated For patients undergoing CABG, aspirin (100 to 325 mg/d) should be started within 6 hours after surgery to reduce saphenous vein graft closure In post-PCI-stented patients, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Antiplatelet Trialists’ Collaboration: Meta-analysis Aspirin Dose # Trials OR* (%) 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 0 Odds Ratio 0.5 Antiplatelet Better 1.0 1.5 2.0 Antiplatelet Worse *Odds reduction. Treatment effect p<0.0001. Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71-86. P2Y12 Receptor Inhibitor Recommendations I IIa IIb III Clopidogrel 75 mg/d for patients allergic or intolerant to aspirin. I IIa IIb III A P2Y12 inhibitor (plus aspirin) for patients post ACS or post PCI with stent placement. I IIa IIb III For patients receiving a stent during PCI for ACS, a P2Y12 inhibitor should be given for at least 12 months: Clopidogrel 75 mg daily or Prasugrel 10 mg daily or Ticagrelor 90 mg twice daily Smith SC Jr., et al. Circulation 2011;124:2458-2473. RAAS Inhibitor Recommendations I IIa IIb III ACE inhibitors should be used in all patients with LVEF < 40%, and in those with hypertension, diabetes, or chronic kidney disease indefinitely, unless contraindicated I IIa IIb III Consider ACE inhibitors for all other patients It is reasonable to use an ARB in patients intolerant to ACE inhibitors I IIa IIb III Use of aldosterone blockage in post-MI patients without renal dysfunction or hyperkalemia is recommended in patients who are already receiving therapeutic doses of an ACE inhibitor and β-blocker, who have a LVEF < 40%, and who have either diabetes or heart failure. Smith SC Jr., et al. Circulation 2011;124:2458-2473. ACE Inhibitor Evidence Secondary Prevention Meta-Analysis of the HOPE, EUROPA, and PEACE Trials* Clinical Trial N HOPE 9,297 1051 HR=0.84 p=0.005 EUROPA 12,218 795 HR=0.89 p=0.10 PEACE 8,290 633 HR=0.89 p=0.13 33,960 >3000 All Trials* Deaths 0.4 0.6 RR of Mortality HR=0.86 p<0.001 0.8 ACE-I Better 1.0 1.2 1.4 1.6 Placebo Better *7 RCTs, 33,960 randomized patients, and 4.4 years of mean follow-up. Other findings include a CVD HR=0.81, MI HR=0.82, and stroke HR=0.77 Danchin N, et al. Arch Intern Med 2006;166:787-796. EMPHASIS-HF Study: Aldosterone Receptor Antagonism for Secondary Prevention in Patients with Mild (Class II) HF Symptoms Death or HF Hospitalization Zannad F, et al. N Engl J Med 2011;364:11-21. β-blocker Recommendations I IIa IIb III Should be used in all patients with LV dysfunction with heart failure or prior MI, unless contraindicated. I IIa IIb III Started and continued for 3 years in all patients with normal LV function who have had MI or ACS I IIa IIb III Reasonable to continue beyond 3 years as chronic therapy in all patients with normal LV function who have had MI or ACS. I IIa IIb III Consider chronic therapy for all other patients with coronary or other vascular disease. Smith SC Jr., et al. Circulation 2011;124:2458-2473. β-blocker Evidence Summary of Secondary Prevention Trials of β-blocker Therapy Phase of Treatment Total # Patients Acute treatment 28,970 0.87 (0.77-0.98) Secondary prevention 24,298 0.77 (0.70-0.84) Overall 53,268 0.81 (0.75-0.87) 0.5 RR (95% CI) 2.0 1.0 RR of death b-blocker Placebo better better Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168. Influenza Vaccination I IIa IIb III Patients with cardiovascular disease should have an annual influenza vaccination. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Influenza Vaccination Evidence Effectiveness of Influenza Vaccination during the Influenza Seasons Community cohort of 140,055 subjects in the 1998–1999 season of which 55.5 % were immunized. Vaccinated Subjects (N=77,738) Unvaccinated Subjects (N=62,317) Adjusted Odds Ratio P value Pneumonia or influenza 495 (0.6) 581 (0.9) 0.68 (0.60–0.78) <0.001 Cardiac disease 888 (1.1) 1026 (1.6) 0.81 (0.73–0.89) <0.001 Ischemic heart disease 457 (0.6) 535 (0.9) 0.80 (0.70–0.91) 0.001 Heart failure 466 (0.6) 538 (0.9) 0.81 (0.70–0.92) 0.002 Cerebrovascular disease 398 (0.5) 427 (0.7) 0.84 (0.72–0.97) 0.018 Death 943 (1.2) 1361 (2.2) 0.52 (0.47–0.57) <0.001 Hospitalization or death 2387 (3.1) 2910 (4.7) 0.65 (0.62–0.70) <0.001 Hospitalization Nichol KL, et al. N Engl J Med 2003;348:1322-1332. Depression Recommendations I IIa IIb III I IIa IIb III For patients with CABG or MI, it is reasonable to screen for depression if patients have access to case management, in collaboration with PCP and mental health specialist. Treatment of depression has not been shown to improve CVD outcomes, but may be reasonable for its other clinical benefits. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Cardiac Rehabilitation Recommendations I IIa IIb III • Patients with ACS, post CABG, or post PCI should be referred to a comprehensive outpatient CR program either prior to hospital discharge or during the first follow-up outpatient visit. • Outpatients with diagnosis of ACS, CABG, PCI, or PAD within the past year should be referred to a comprehensive outpatient CR program. • A home-based CR program can be substituted for a supervised, center-based program for low-risk patients. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Cardiac Rehabilitation Recommendations I IIa IIb III Outpatients with a diagnosis of chronic angina within the past year should be referred to a comprehensive outpatient CR program. I IIa IIb III A comprehensive outpatient CR program can be safe and beneficial for clinically stable outpatients with heart failure. Smith SC Jr., et al. Circulation 2011;124:2458-2473. Evidence for Cardiac Rehabilitation • Meta-analysis of 63 randomized trials (21,295 patients) randomly assigned to exercise-based rehab or usual care • Cardiac rehab reduced total mortality by 15% (95% CI, 0.77 to 0.94) and recurrent MI by 17% (95% CI, .74 to .94) Clark et al., Ann Intern Med 2005;143:659-672. Medication Adherence and CAD Costs and Outcomes • Systematic review shows that medication adherence is associated with: – Reduced CVD events, mortality, readmissions, and costs across a variety of adherence measures and medication classes. • However, few studies considered the “healthy adherer effect” – Patients who adhere to medications are also more likely to adhere to a healthy diet, exercise regularly, and generally lead a healthy lifestyle Bitton A et al, Am J Med 2013;126:357.e7-357.e27. “The nurse is a key link in the successful implementation of medical and life-saving therapies in different patient care settings.” Journal of Cardiovascular Nursing 2011;26:145-167. Nurse Case Management Nurse case management involves: • Overseeing discharge planning and follow-up • Acting as the key point of contact for patients and families • Responding to questions • Assessing the patient’s ability to understand and adhere to complex medical therapies • Oversee the integration of care by multiple providers • Evaluating a patient’s response to therapy and managing untoward effects Berra K, Journal of Cardiovascular Nursing 2011;26:145-167. Trials and Outcomes SCRIP MULTIFIT CHAMP EUROACTION GWTG •Improved adherence to guidelines •Improved CVD risk factors •Improved diet and exercise •Fewer clinical events, less CAD progression •Decreased mortality Fletcher GF, Berra K, Fletcher BJ, Gilstrap L, Wood MJ. Current Problems in Cardiology 2012;37:363-398. Oral Antiplatelet Therapy in ACS Management Robert A. Kloner, MD, PhD Director of Research Heart Institute, Good Samaritan Hospital Professor of Medicine Keck School of Medicine University of Southern California Los Angeles, California Disclosure Statement • Honorarium: AstraZeneca, Gilead Sciences • Grants/Research Support: Gilead Sciences In the TRITON-TIMI 38 trial, when comparing prasugrel with clopidogrel, in terms of efficacy, prasugrel was shown to ______ 1) Decrease the incidence of the composite of CV death, MI, or stroke 2) Decrease the incidence of CV death 3) Both 4) Neither 25% 15% 51% 9% A 73 year old female s/p NSTEMI was treated with aspirin plus ticagrelor and a drug-eluting stent. What discharge aspirin dose should be prescribed with ticagrelor? 1) < 100 mg 2) > 100 but < 300 mg 3) > 300 mg 66% 19% 15% Commonly Used Antiplatelet Agents 1) Thromboxane A2 Inhibitor (Cyclo oxygenase inhibitor) - Acetylsalicylic acid (Aspirin, ASA) 2) Adenosine diphosphate (ADP) receptor antagonists - Clopidogrel (Plavix) - Prasugrel (Effient) - Ticagrelor (Brilinta) - Ticlopidine (Ticlid) 3) Parenteral Glycoprotein (GP) Ilb/IIIa blockers - Abciximab (ReoPro) - Eptifibatide (Integrilin) - Tirofiban (Aggrastat) CURE: Clopidogel in UA/NSTEMI 0.14 All Patients Placebo (n=6303) 0.12 0.10 20% RRR 0.08 Clopidogrel (n=6259) 0.06 0.04 P <.001 N=12,562 0.02 0.00 0 3 6 9 12 Cumulative Hazard Rates Cumulative Hazard Rates 1o Outcome (CV death/MI/stroke) by Management Strategy 0.20 Medical Rx Group 0.15 Placebo 0.10 Clopidogrel 0.05 RR:0.80 (0.69-0.92) 0.00 0 0.20 PCI Group 0.15 Placebo 0.10 Clopidogrel 0.05 RR:0.72 (0.57-0.90) 0.00 0 100 200 200 300 Days of Follow-up 300 Cumulative Hazard Rates Cumulative Hazard Rates Months of Follow-up 100 0.20 CABG Group Placebo 0.15 0.10 Clopidogrel 0.05 RR:0.89 (0.71-1.11) 0.00 0 Days of Follow-up 100 200 300 Days of Follow-up CURE: Clopidogrel vs Placebo (all pts aspirin) Yusuf S, et al. N Engl J Med. 2001;345:494-502. Fox KAA, et al. Circulation. 2004;110:1202-1208. CLARITY-TIMI 28: Clopidogrel with Thrombolysis for STEMI 1O Endpoint: Occluded Artery (or D/MI) 20% Odds Reduction 25 36% Odds Reduction 21.7 15 20 End Point (%) Occluded Artery or Death/MI (%) P<.0001 15.0 10 15 10 Placebo 5 Clopidogrel 5 n=1752 P=.03 n=1739 0 0 Clopidogrel Placebo 0 All patients received aspirin. Sabatine et al. N Engl J Med. 2005;352:1179-1189. 5 10 15 Days 20 25 30 COMMIT: CLOPIDOGREL in 46,000 AMI Pts Mortality Death, Re-MI or Stroke Placebo + ASA: 1846 deaths (8.1%) Clopidogrel +ASA: 1728 deaths (7.5%) Clopidogrel + ASA: 2125 events (9.3%) Dead (%) Death, MI Stroke (%) Placebo + ASA: 2311 events (10.1%) 9% RRR (P=0.002) Days since randomization 7% RRR (P=0.03) Days since randomization Chen et al. Lancet. 2005;366:1607-1621. CURE: Major Bleeding by Aspirin Dose Through Follow-up Aspirin Dose Placebo + Aspirin# Clopidogrel + Aspirin# 1.9%* 2.8%* 3.7%* 3.0%** 3.4%** 4.9%** 75–100 mg 101–199 mg 200–325 mg #, Other standard therapies were used as appropriate. Peters RJ et al. Circulation. 2003;108:1682-87. * P = 0.0001 for comparison of increasing ASA doses in Placebo Group; ** P = 0.0009 for comparison of increasing ASA doses in Clopidogrel group CURRENT-OASIS 7: Clopidogrel Results Patients with UA/NSTEMI or STEMI planned for early invasive strategy (ie, intended for PCI as early as possible within 72 hours) Randomize Clopidogrel Standard-dose Group Clopidogrel 300 mg (+ placebo) day 1 followed by 75 mg (+ placebo) from days 2 to 7; 75 mg from days 8 to 30 Clopidogrel High-dose Group Clopidogrel 600 mg LD day 1 followed by 150 mg from days 2 to 7; 75 mg from days 8 to 30 Standard Double CV death/MI/Stroke Overall (N=25,086) PCI (n=17,263) No PCI (n=7823) 4.4 4.5 4.3 4.2 3.9 4.9 HR (95% CI) P-value 0.94 (0.83-1.06) 0.86 (0.74-0.99) 1.14 (0.92-1.40) 0.30 0.039 0.23 LD = loading dose. CURRENT-OASIS 7 Investigators, et al. N Engl J Med. 2010;363:930-942. Mehta SR, et al. Lancet. 2010;376:1233-1243. The First Clopidogrel Resistance Study (300 mg): A Fingerprint of Clopidogrel Response Variability 2 Hours Resistance = 63% Resistance Patients (%) Patients (%) 24 24 Hours 12 Resistance = 31% 20 Resistance 10 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] Aggregation (%) Aggregation (%) 5 Days Resistance = 31% Resistance = 15% 28 Patients (%) 22 Patients (%) 30 Days Resistance 11 14 ≤ -10 (0,10] (-10,0] (20,30] (10,20] (40,50] (30,40] >60 (50,60] Aggregation (%) Gurbel PA, et al. Circulation. 2003;107:2908-2913. Resistance ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] Aggregation (%) 66 Clopidogrel Metabolism P-Glycoprotein Intestinal Absorption 15% 2C19 1A2 2B6 Inactive metabolite 2 Step Hepatic CYP Conversion 2C19 2C9 3A4 2B6 Variable and inefficient active metabolite generation Note: clopidogrel irreversible binding To P2Y12 receptor Slow, Variable IPA Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-9. IPA, inhibition of platelet aggregation Factors Influencing On-treatment Platelet Reactivity SNP’s CYP2C19, ABCB1? CYP Metabolizer Status Ultra Fast Intermediate Poor DDI PPI, CCB, Warfarin SJW, Smoking Renal Function Age BMI Clinical Outcomes CAD state Variable Response ADP, adenosine diphosphate; CAD, coronary artery disease; to CCB, calcium channel blocker; CYP,cytochrome;BMI, body mass index; DDI, drug-drug interaction; PPI, proton pump inhibitor; SJW, St. John’s Wort; SNP, single nucleotide polymorphism Gurbel PA et al. Eur Heart J. 2012;33:1187-89. Diabetes ADP Unknown Factors TRITON TIMI-38: Cardiovascular risk with CYP2C19 reduced function allele Patients Receiving Clopidogrel Incidence of CV death, MI and stroke (%) 12.1 Carriers 12 10 8.0 Noncarriers 8 6 4 Hazard ratio: 3.09 95% CI: 1.19 – 8.00 P=0.01 2 0 0 30 90 180 270 360 Days since Randomization Mega J et al. N Engl J Med. 2009;360:354-62 450 FDA Boxed Warning on Clopidogrel 3/12/2010 - The Boxed Warning in the drug label includes information to: • Warn about reduced effectiveness in patients who are poor metabolizers of clopidogrel. Poor metabolizers do not effectively convert clopidogrel to its active form in the body. • Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function. • Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for clopidogrel in patients identified as poor metabolizers. Accessed March 29, 2011 at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm Clopidogrel: in ACS Who: UA/NSTEMI (Invasive and Conservative) STEMI (PCI, Fibrinolysis, Med Rx) Who not: Planned CABG, ?2C19 known homozygous Active / very high risk for bleeding Where: Emergency Department When: Early and late – 1 year ?longer How: 300 mg load (or 600 mg load pre-PCI). Platelet and genetic testing unproven. Use with PPI if GI bleed risk factors. Prasugrel Ticagrelor - More rapid onset and greater antiplatelet effect - Lesser/no resistance - No influence of gene polymorphism and major drugdrug interactions Irreversible Reversible binding Prasugrel Is Effective for Clopidogrel Nonresponders 100 Interaction Variability 60 40 20 Interaction Variability IPA at 24 hours (%) 80 Clopidogrel Responder 0 -20 Clopidogrel Non-responder Response to Clopidogrel 300 mg Response to Prasugrel 60 mg * Responder 25% IPA at 4 and 24 hours Brandt JT. Am Heart J. 2007;153:66e9. IPA, inhibition of platelet aggregation PRINCIPLE TIMI 44: Comparison with Higher Dose Clopidogrel IPA (%; 20 mM ADP) N=201 P<0.0001 for each IPA (%; 20 mM ADP) P<0.0001 Prasugrel 60 mg Clopidogrel 600 mg Hours Wiviott SD et al. Circulation. 2007;116:2923-32. Clopidogrel Prasugrel 150 mg 10 mg 14 Days IPA, inhibition of platelet aggregation 74 Prasugrel Labeling Prasugrel was approved for reducing thrombotic cardiovascular events, including stent thrombosis, in the following patients with acute coronary syndrome who will be managed with percutaneous coronary intervention (PCI): those with unstable angina or nonST elevation myocardial infarction (NSTEMI) and those with ST-elevation MI (STEMI), when managed with either primary or delayed PCI. Black Box Warning with Prasugrel Prasugrel can cause significant, sometimes fatal, bleeding Do not use prasugrel in patients with active pathological bleeding or a history of transient ischemic attack or stroke In patients age 75 and older, prasugrel is generally not recommended because of the increased risk of intracranial and fatal bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI). In these situations, the drug's effect appears to be greater, and its use may be considered. Additional risk factors for bleeding include: body weight < 60 kg propensity to bleed concomitant use of medications that increase the risk of bleeding http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022307s003lbl.pdf TRITON-TIMI 38 Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI n=13,600 ASA Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, stroke 2o endpoints: CV death, MI, stroke, rehosp-rec isch CV death, MI, UTVR UTVR = urgent target vessel revascularization; NSTEMI = non-ST segment elevation MI Wiviott SD et al. Am Heart J. 2006;152:627-635. TRITON TIMI-38: Efficacy and Safety 15 End Point (%) CV Death/MI/Stroke Clopidogrel 12.1 9.9 10 Prasugrel 5 TIMI Major Non-CABG Bleeds 0 30 60 90 180 270 Days Wiviott SD et al. N Engl J Med. 2007;357:2001-2015. HR 0.81 (0.73-0.90) P=0.0004 NNT=46 35 events Prasugrel Clopidogrel 0 138 events 360 2.4 1.8 HR 1.32 (1.03-1.68) P=0.03 NNH=167 450 HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm Triton TIMI-38: Major efficacy end points in overall cohort at 15 mo. Pras Clop (N=6813) (N=6795) no. of patients (%) 643 (9.9) 781 (12.1) HR for Prasugrel (95% CI) 0.81 (0.73–0.90) 133 (2.1) 475 (7.3) 150 (2.4) 620 (9.5) 0.89 (0.70-1.12) 0.76 (0.67-0.85) 0.31 <0.001 Nonfatal stroke 61 (1.0) 60 (1.0) 1.02 (0.71-1.45) 0.93 Death from any cause 188 (3.0) 197 (3.2) 0.95 (0.78-1.16) 0.64 CV Death, nonfatal MI, or urgent TVR 652 (10.0) 798 (12.3) 0.81 (0.73-0.89) <0.001 Death from any cause, 692 (10.7) 822 (12.7) 0.83 (0.75-0.92) <0.001 156 (2.5) 233 (3.7) 0.66 (0.54-0.81) <0.001 938 (14.6) 0.84 (0.76-0.92) <0.001 142 (2.4) 0.48 (0.36-0.64) <0.001 End Point CV Death, non-fatal MI or non-fatal stroke (1o end pt) CV Death Nonfatal MI p value <0.001 nonfatal MI, or nonfatal stroke Urgent TVR CV Death, nonfatal MI, nonfatal 797 (12.3) stroke or rehosp for ischemia Stent thrombosis ‡ 68 (1.1) ‡ Definite or Probable Wiviott et al. New Engl J Med 2007 TRITON TIMI-38: Bleeding Events ICH in patients w/ prior stroke/TIA (N = 518) Events (%) Clopidogrel Prasugrel Clop 0 (0%) Pras 6 (2.3%) (P = 0.02) ARD 0.6% HR = 1.32 P = 0.03 NNT =167 ARD 0.5% HR = 1.52 P = 0.01 ARD 0.2% P = 0.23 ARD 0.3% P = 0.002 ARD 0% P = 0.74 ICH = intracranial hemorrhage; ARD = absolute risk difference; TIA = transient ischemic attack. Wiviott SD et al. N Engl J Med. 2007:357:2001-2015. TRILOGY ACS Study Design Medically Managed UA/NSTEMI Patients Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years) Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR on chronic clopidogrel) — 96% of total Medical Management Decision ≤72 hrs (No prior clopidogrel given) — 4% of total Clopidogrel1 300 mg LD + 75 mg MD Median Time to Enrollment = 4.5 Days Prasugrel1 30 mg LD + 5 or 10 mg MD Clopidogrel1 Prasugrel1 75 mg MD 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke 1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1. LD, loading dose; MD, maintenance dose TRILOGY ACS: Primary Efficacy Endpoint to 30 Months (Age < 75 years) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 Roe MT et al. N Engl J Med. 2012;367:1297-1309. Summary: Prasugrel • Prasugrel superior to clopidogrel in ACS undergoing PCI • Prasugrel not superior to clopidogrel in medical management of ACS • Prasugrel is administered initially with a single 60 mg oral loading dose (at time of ACS). Thereafter, treatment is continued with 10 mg orally once daily. – Consider lowering maintenance dose to 5 mg in patients < 60 kg. • Duration of dual oral antiplatelet therapy (DAPT) 1 year or more Ticagrelor: an oral reversible P2Y12 antagonist HO N N N H N HO O F N N S F Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP); not a thienopyridine OH • Direct acting – Not a prodrug; does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y12 receptor – Greater inhibition of platelet aggregation than clopidogrel • Reversibly bound – Degree of inhibition reflects plasma concentration – Faster offset of effect than clopidogrel – Functional recovery of all circulating platelets Clopidogrel vs. Ticagrelor ONSET/OFFSET Study Maintenance and Offset Loading IPA (%; 20 mM ADP, Final) 100 * * * Ticagrelor 180mg * 80 60 * 40 Clopidogrel 600 mg 20 0 0 .5 4 8 12 16 20 24 Hours *P<0.0001; †P<0.005; ‡, P<0.05, ticagrelor vs clopidogrel. Gurbel PA et al. Circulation. 2009;120:2577-85. IPA, inhibition of platelet aggregation PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular Wallentin L et al. NEJM . 2009;361:1045-57. PLATO Primary efficacy endpoint: CV death, MI or stroke Cumulative incidence (%) 18,624 Patients w/in 24 hrs of onset of ACS 13 12 11 10 9 8 7 6 5 4 3 2 1 0 HR 0.84 (95% CI 0.77–0.92) P=0.0003 11.7 Clopidogrel 9.8 Ticagrelor Cardiovascular Death: 4.0% vs. 5.1%, HR 0.79 (0.69-0.91), P=0.001 All-cause Mortality: 4.5% vs. 5.9%, HR 0.78 (0.69-0.89), P<0.001 0 No. at risk Ticagrelor 9,333 Clopidogrel 9,291 60 120 180 240 300 360 5,161 5,096 4,147 4,047 Days after randomisation 8,628 8,521 HR = hazard ratio; CI = confidence interval Wallentin L, et al. NEJM 2009;361:1045-57; Wallentin 2009 ESC Presentation 8,460 8,362 8,219 8,124 6,743 6,743 Treating 54 pts with ticagrelor instead of with clopidogrel for 1 year will prevent one event of CV death, MI or stroke. PLATO: major efficacy endpoints All patients* Primary objective, n (%) CV death + MI + stroke Secondary objectives, n (%) Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Ticagrelor Clopidogrel (n=9,333) (n=9,291) 864 (9.8) HR for (95% CI) p value† 1,014 (11.7) 0.84 (0.77–0.92) <0.001 901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92) <0.001 1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95) <0.001 Myocardial infarction 504 (5.8) 593 (6.9) 0.84 (0.75–0.95) 0.005 CV death 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.001 Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.22 Stent thrombosis (Definite or probable) 118 (2.2) 158 (2.9) 0.75 (0.59 – 0.95) 0.02 Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001 The percentages are K-M estimates of the rate of the endpoint at 12 months. Wallentin L et al. NEJM .2009;361:1045-57 PLATO: Primary Efficacy Outcome US and Non-US and by ASA Dose Mahaffey K et al. Circulation. 2011;124:544-54 PLATO: Major Bleeding, Holter Monitoring and Other Related Events Bleeding Ticagrelor (n=9235) Clopidogrel (n=9186) Total Major — PLATO criteria, % Total Major — TIMI criteria , % 11.6 7.9 11.2 7.7 0.43 0.57 Non-CABG Major — PLATO criteria, % Non-CABG Major — TIMI criteria , % 4.5 2.8 3.8 2.2 0.026 0.025 Ticagrelor (n=1451) Clopidogrel (n=1415) P-value 5.8 2.0 3.6 1.2 0.01 0.10 Ticagrelor (n=9235) Clopidogrel (n=9186) P-value* 13.8 0.9 7.8 0.1 <0.001 <0.001 Holter Monitoring at First Week Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, % All Patients Dyspnea, % Any With discontinuation of study treatment Bradycardia-related Event, % Syncope Bradycardia P-value P-value 1.1 4.4 *P-values were calculated using Fischer’s exact test. Wallentin L, et al. N Engl J Med. 2009;361:1045-1057. 0.8 4.0 0.08 0.21 Ticagrelor – FDA Label “Boxed Warning” WARNING: BLEEDING RISK • Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding (5.1, 6.1). • Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage (4.1, 4.2). • Do not start ticagrelor in patients planned to undergo urgent coronary bypass graft surgery (CABG). When possible, discontinue ticagrelor at least 5 days prior to any surgery (5.1). • Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of ticagrelor (5.1). • If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events (5.5). WARNING: Aspirin Dose and Ticagrelor Effectiveness • Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. After any initial dose, use with aspirin 75-100 mg per day (5.2, 14). http://www.pdr.net/drugpages/productlabeling.aspx?mpcode=04020155 Summary: Ticagrelor • Reduces major cardiovascular events (including cardiovascular mortality and all-cause mortality) in ACS patients managed invasively or medically. • Ticagrelor is administered initially with 180 mg (2 90 mg tablets) as an oral loading dose (at time of ACS). Thereafter, treatment is continued with 90 mg TWICE DAILY • Should be used with low dose aspirin (75-100 mg/day) • Duration of dual oral antiplatelet therapy (DAPT) 1 year or more UA/NSTEMI Guidelines: Key Points on Antiplatelets (Class I and III) • ASA to all (clopidogrel if allergic) • Medium - high risk and an invasive strategy get dual Rx – Before PCI: clopidogrel, ticagrelor, GP IIb/IIIa – At PCI: clopidogrel, ticagrelor, prasugrel, GP IIb/IIIa • Conservative strategy: dual Rx w/ ASA + clopidogrel or ticagrelor • Use loading doses of ADP blockers (clopidogrel, prasugrel and ticagrelor) • Duration of ADP blockers for at least 12 months • Class III (harm or no benefit) – low risk and on ASA/ADP blocker no benefit to GP IIb/IIIa – history stroke/TIA, prasugrel potentially harmful Jneid H et al. J Am Coll Cardiol. 2012;60:645-81. STEMI Guidelines: Key Points on Antiplatelets (Class I and III) • ASA for all and indefinitely • Primary PCI – Loading dose as early as possible or at PCI: clopidogrel, ticagrelor, prasugrel – Clopidogrel, prasugrel, or ticagrelor for 1 year – Class III (harm or no benefit): prasugrel potentially harmful (if h/o stroke/TIA) • Fibrinolysis – Clopidogrel 300 mg loading dose, < 75 years; 75 mg, > 75 years – Clopidogrel at least 14 days and up to 1 year • PCI after fibrinolytic therapy – Clopidogrel 300 mg if no prior loading dose + PCI within 24 hours of fibrinolytic therapy; 600 mg if PCI > 24 hours afterwards – Duration of clopidogrel: BMS, 30 days to 1 year; DES, at least 1 year – Class III (harm or no benefit): prasugrel potentially harmful ( if h/o stroke/TIA) O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-140.