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Cardiovascular Medications Soon Jun Hong Korea University Anam Hospital • Antiplatelet Therapy –1. Aspirin –2. Clopidogrel, ticlopidine –3. GP IIb/IIIa inhibitor (Abciximab, Eptifibatide, Tirofiban) • Anticoagulants –1. Bivalirudin –2. Dalteparin –3. Enoxaparin –4. Fondaparinux –5. Unfractionated heparin The 3 Most Important Advances in Antiplatelet Therapy for ACS • Aspirin • ADP antagonists • Platelet GP IIb/IIIa receptor antagonists Antiplatelet Agents Different Mechanisms of Action Ticlopidine Clopidogrel Prasugrel ADP Cangrelor (P2Y receptor) Epinephri ne Collage n Thrombin Heparin LMWH Hirudin Arachadonic Acid PGG TxA2 2 Cyclooxygenase PGI2 Aspirin GPIIb/IIIa Receptor GP 2b/3a antagonists Platelet Aggregation Central Role of Platelets in ACS and PCI PCI Plaque Rupture TF Adhesion/ Initial Activation Thrombin Granule Secretion ADP Sustained Activation Membrane PL’s TxA2 (Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006) Central Role of Platelets in ACS and PCI PCI Plaque Rupture Procoagulant State TF PLT-WBC Aggregation/ Microparticles Adhesion/ Initial Activation Thrombin P-selectin CD-40L Granule Secretion ADP Sustained Activation Membrane PL’s TF TxA2 (Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006) Central Role of Platelets in ACS and PCI Hypercoagulability PCI Plaque Rupture Procoagulant State TF Inflammation Cytokine Release TF PLT-WBC Aggregation/ Microparticles Adhesion/ Initial Activation Thrombin Stent Thrombosis P-selectin CD-40L Granule Secretion ADP GPIIb/IIIa Activation Platelet Aggregation Sustained Activation Membrane PL’s TxA2 (Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006) Myocardial Infarction Central Role of Platelets in ACS and PCI Hypercoagulability PCI Plaque Rupture Inflammation Procoagulant State TF Cytokine Release TF PLT-WBC Aggregation/ Microparticles Adhesion/ Initial Activation Thrombin Clopidogrel (modest variable) Granule Secretion ADP X Stent Thrombosis P-selectin CD-40L GPIIb/IIIa Activation X Platelet Aggregation Sustained Activation Membrane PL’s X TxA2 Myocardial Infarction GP IIb/IIIa Inhibitor (potent uniform) Aspirin (modest uniform) (Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006) Long-Term Antiplatelet Therapy – The Clopidogrel Continuum Acute STEMI CLARITY PCI-CLARITY 2005 Occluded infarct – related artery or D/MI by time of angio 2005 Death, MI, or stroke following PCI NSTEMI / ACS PCI Post MI High Risk of Event COMMIT CURE CREDO CAPRIE CHARISMA 2005 2001 2002 1996 2006 D/MI/Stroke Up to 1 yr Vasc D/MI/Stroke Up to 3 yrs Vasc D/MI/Stroke For almost 3 yrs Mortality 28 days D/MI/Stroke Up to 1 yr D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia. Baggish AL, Sabatine MS. Expert Rev Cardiovasc Ther. 2006;4:7-15. Long-Term Antiplatelet Therapy – The Clopidogrel Continuum Acute STEMI CLARITY PCI-CLARITY 2005 2007 Occluded artery 36% D/MI/UR/ RI 20% NSTEMI / ACS PCI Post MI High Risk of Event COMMIT CURE CREDO CAPRIE CHARISMA 2005 2001 2002 1996 2006 Mortality Mortality D/MI/Stroke D/MI/Stroke 46 % 7% 20% 27% Vasc D/MI/Stroke 9% Vasc D/MI/Stroke Benefit in symptomatic patients D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia. Baggish AL, Sabatine MS. Expert Rev Cardiovasc Ther. 2006;4:7-15. CURE Protocol Clopidogrel Aspirin 75-325mg Patients with Acute Coronary Syndrome (UA or MI Without ST elevation) R (6,259 patients) 3 months double-blind treatment 12 months Aspirin 75-325mg Placebo (6,303 patients) R=Randomization The CURE Trial Investigators .N Engl J Med.2001;345:494-502. CURE: Results Primary End-Point CV Death, MI, Stroke Number of events 1000 RRR = 20%; p=0.00005 800 600 723 581 ARR = 2.19 NNT = 46 400 200 0 9.28 % 11.47% Clopidogrel + ASA (n=6259) Aspirin (n=6303) The CURE Trial Investigators .N Engl J Med.2001;345:494-502. Lipid lowering drug therapy • 60s and 70s - nicotinic acid - resins • 70s to 90s - fibrates • the 90s - statins • 21st century - ezetimibe Metabolic Pathways Blocked By Statins Acetyl-CoA + Acetoacetyl-CoA HMG-CoA Statins Block Mevalonate Slower Late Benefit Isopentanyl PP Related to Hepatic LDL Reduction Geranyl PP Early/Rapid and Later Benefit (pleiotropic effect) Important in Vascular Cellular Responses Prenylation Farnesyl PP Geranyl Geranyl PP Squalene Cholesterol Translocates to the Cell Membrane PP = pyrophosphate. Reproduced from Ray and Cannon. Curr Opin Lipidol. 2004;15:637, with permission. Ray and Cannon. Am J Cardiol. 2005;96(suppl):54F. Rho The Pleiotropic Effects of Statins • Increased plaque stability • Decreased inflammation • Improved endothelial function • Reduced oxidative stress • Antithrombotic properties • Effects on bone marrow Atherosclerosis progression varies directly with LDL-cholesterol y = 0.0004 x – 0.0267 0.05 PLAC1-P MLD Decrease (mm/year ) R² = 0.6116 REGRESS-P CCAIT-P LCAS-P p = 0.001 0.04 PLAC1-S 0.03 REVERSAL-PR 0.02 MARS-P MAAS-P CCAIT-S MARS-S 0.01 REGRESS-S LCAS-S 0 MAAS-S P Placebo S Statin PR Pravastatin REVERSAL-AT AT Atorvastatin -0.01 70 80 90 100 110 120 130 140 150 160 170 180 LDL cholesterol (mg/dL) O’Keefe et al. JACC 2004; 43: 2142-6 How Low is Low Enough? LDL-C Levels vs. Events in Landmark Statin Trials 4S-PBO Secondary prevention Primary prevention With CHD event (%) 25 20 LIPID-PBO 4S-Rx 15 CARE-Rx 10 CARE-PBO LIPID-Rx 5 WOS-PBO WOS-Rx AFCAPS-Rx AFCAPS-PBO 0 50 70 90 110 130 150 LDL-C (mg/dL) 170 190 210 Early Statin Therapy in ACS Human Being Has the Highest Serum Cholesterol Levels • ACE inhibitors: Ramipril, Acertil, Captopril • Angiotensin Receptor Blockers: Telmisartan, Valsartan, Candesartan, Losartan, Olmesartan, Eprosartan • Beta blockers: Carvedilol, Bisoprolol, Propranolol • Calcium channel blockers: Amlodipine, Nifedipine, Verapamil, Diltiazem • Diuretics: Furosemide, Dichlozid, Indapamide Renin-Angiotensin Aldosterone System Non-ACE Pathways (e.g., chymase) Vasoconstriction Cell growth Na/H2O retention Sympathetic activation Angiotensinogen renin AT1 Angiotensin I Angiotensin II ACE Cough, Angioedema Benefits? Bradykinin Aldosterone Inactive Fragments AT2 Vasodilation Antiproliferation (kinins) SAVE AIRE Radionuclide EF 40% TRACE Clinical and/or radiographic signs of HF Echocardiographic EF 35% All-Cause Mortality 0.4 Probability of Event 0.35 0.3 Placebo 0.25 ACE-I 0.2 0.15 Placebo: 866/2971 (29.1%) 0.1 ACE-I: 702/2995 (23.4%) 0.05 Years 0 OR: 0.74 (0.66–0.83) 0 1 2 3 4 ACE-I 2995 2250 1617 892 223 Placebo 2971 2184 1521 853 138 Flather MD, et al. Lancet. 2000;355:1575–1581 SAVE Radionuclide EF 40% AIRE TRACE Clinical and/or radiographic signs of HF Echocardiographic EF 35% Death and Major CV Events ACE-I (n = 2995) Placebo (n = 2971) 0.75* (0.67 – 0.83) Events (%) 40 30 0.73* 20 (0.63 – 0.85) 0.80* (0.69 – 0.95) 10 n= 355 0 n= 460 Readmission for HF *odds ratio (95% CI) n= 324 n= 391 Reinfarction n= 1049 n= 1244 Death/MI or Readmission for HF Flather MD, et al. Lancet. 2000;355:1575–1581 Commonly used AT1-antagonists Schieffer et al., J Med Chem 2003 Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible (either clinical/radiologic signs of HF or LV systolic dysfunction) Major Exclusion Criteria: — Serum creatinine > 2.5 mg/dL — BP < 100 mm Hg — Prior intolerance of an ARB or ACE-I — Nonconsent double-blind active-controlled Captopril 50 mg tid (n = 4909) Valsartan 160 mg bid (n = 4909) Captopril 50 mg tid + Valsartan 80 mg bid (n = 4885) median duration: 24.7 months event-driven Primary Endpoint: All-Cause Mortality Secondary Endpoints: CV Death, MI, or HF Other Endpoints: Safety and Tolerability Mortality by Treatment 0.3 Captopril Valsartan Probability of Event 0.25 Valsartan + Captopril 0.2 0.15 0.1 0.05 Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 0 Months 0 Captopril 4909 Valsartan 4909 Valsartan + Cap 4885 6 12 18 24 30 36 4428 4464 4414 4241 4272 4265 4018 4007 3994 2635 2648 2648 1432 1437 1435 364 357 382 Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 Conclusion In patients with MI complicated by heart failure, left ventricular dysfunction or both: • Valsartan is as effective as a proven dose of captopril in reducing the risk of: – Death – CV death or nonfatal MI or heart failure admission • Combining valsartan with a proven dose of captopril produced no further reduction in mortality—and more adverse drug events. Implications: In these patients, valsartan is a clinically effective alternative to an ACE inhibitor. ONTARGET: The ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial Eligibility Criteria • Inclusion: – 55 years or older with one of following – Coronary artery disease – Peripheral artery disease – Cerebrovascular disease – High risk diabetes with evidence of end-organ damage • Exclusion: – Inability to discontinue, hypersensitivity or intolerance to, ACE inhibitors or ARB – Symptomatic CHF; significant primary valvular or outflow tract obstruction; constricitive pericarditis; syncope unknown etiology, CABG or PCI < 3 mths; uncontrolled hypertension – Significant renal artery stenosis; hepatic dysfunction – Other medical conditions or social reasons Non-inferiority Margin ONTARGET Non-Inferiority ONTARGET Comparison Primary Composite (p = 0.0033) CV Death / MI / Stroke (HOPE Composite) (p = 0.0008) Telmisartan better Ramipril better 0.8 0.9 1.0 1.1 1.2 RR (95% CI) Note that the outcomes are presented as point estimates with confidence intervals. The solid line is the 95% CI representing 1.96 SD and the dashed line is the 97.5% CI representing the adjusted CI for each outcome Efficacy Comparison ONTARGET Composite (p = 0.8522) CV Death MI Stroke CHF Hosp Ramipril + Telmisartan better 0.4 0.6 0.8 Ramipril better 1.0 1.2 1.4 1.6 RR (95% CI) Note that the outcomes are presented as point estimates with confidence intervals. The solid line is the 95% CI for each outcome Conclusions: Telmisartan vs. Ramipril 1. Telmisartan is clearly “non-inferior” to ramipril • Primary composite outcome (p=0.0045) • HOPE primary outcome (p=0.001) Most (>90%) of the benefits of ramipril are preserved 2. Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone Beta Blockade Heart rate After load Heart size diastolic perfusion Wall stress O2 vs O2 demand supply Subendocardial ischemia Contractility Less exercise vasoconstriction More spasm? O2 wastage Anti-arrhythmic DEMAND O2 deficit anaerobic metabolism SUPPLY LH Opie, 33 2001 Effect of beta blockade on mortality rate in AMI 34 Benefit of propranolol after myocardial infarction Results of the Beta Blocker Heart Attack Trial which randomized 3837 patients with an AMI to propranolol or placebo. At an average follow-up of 25 months, propranolol significantly reduced total, cardiovascular, and sudden death mortality and reduced the incidence of nonfatal infarction and all coronary events. Benefit occurred in all patient groups, but was more marked in those with heart failure (HF). Data from Chadda, K, Goldstein, S, Byington, R, et al, Circulation 1986; 73:503. Beta blocker reduces mortality in patients with CHF after MI he AIRE trial randomized 2006 patients with congestive heart failure after a myocardial infarction to ramipril or placebo. Cumulative mortality in the 22 percent who were also receiving a beta blocker was significantly lower than in those not receiving a beta blocker (12 versus 22 percent, p = 0.008). Data from Spargias, KS, Hall, AJ, Greenwood, DC, et al, Heart 1999; 81:25 Calcium Channel Blocker Amlodipine Besylate Cl O •H3 C CH3 O O H3C O NH O Amino group side chain NH2 Mechanism of Action Slow Calcium Channel Receptors 2 Amlodipine besylate 1 Muscle Cell 1 2 •일반적으로 칼슘( ) 은 칼슘채널의 수용체에 부착하여 수 축을 일으키는 세포 속으로 유입된다. •NORVASC® 는 칼슘채널 수용체를 억제하여 Ca2+ 의 부착 및 세포 내로의 유입을 억제한다. Median Angina Attack Rate (Episodes per Week) Efficacy in Chronic Stable Angina * P = 0.0225 versus placebo = P = 0.0001 versus placebo 5.0 5 4.0 4 3.0 2.8 Week 4 Week 8 2.5* 3 1.5= 2 1 0 Baseline Week 4 Week 8 NORVASC (n = 180) Adapted from Deanfield et al, 1994 Baseline Placebo (n = 91) Mean Change in Angina Episodes/Day Safety in Patients With Vasospastic Angina 0.0 -0.1 -0.2 -0.3 -0.4 Placebo (n = 28) -0.5 -0.6 -0.7 NORVASC® (n = 24) -0.8 -0.9 -1.0 Adapted from Chahine et al, 1993 P = 0.009 Calcium channel blockers do not change mortality after AMI A meta-analysis of controlled trials of calcium channel blockers in postinfarction patients failed to show any effect on mortality, although the agents that reduce heart rate, particularly verapamil, showed a trend toward an improved survival while nifedipine, which increases heart rate, showed a trend toward an increased mortality. Data from Held, PH, Yusuf, S. In: Cardiovascular Pharmacology and Therapeutics, Singh, BN, Dzau, V, Vanhoutte, PM, Woosley, RL Eds, Churchill Livingstone, New York, 1993, p. 525. PHARMACOLOGICAL ACTIONS OF ANTI-ANGINAL DRUGS Coronary Blood Flow ß-Blockers Heart Rate Arterial Pressure Cardiac Contractility No Effect Ca 2+ Channel Antagonists Long-acting Nitrates No Effect From Stanley, European Heart Journal, 2002. Myocardial Energy Metabolism Under Aerobic Conditions Glycolysis Fatty Acids 60-90% Lactate Pyruvate 10-40% ATP Pyruvate Dehydrogenase O2 Mitochondrion CO2 Contractile Work, Ca2+ uptake, Ion Homeostasis ADP + Pi Glycolysis Pyruvate X Pyruvate Dehydrogenase - Lactate X NADH Acetyl CoA - Fatty Acid Oxidation Trimetazidine, Ranolazine, Etomoxir, Oxfenicine, Perhexiline Lactate Nonesterified Fatty Acids Glucose GLYCOLYSIS Cytosol Triglyceride Lactate Pyruvate Fatty Acyl-CoA Outer Membrane CPT-I Fatty Acyl-Carnitine Inner Membrane NAD+ + CoA-SH PDH Mitochondrial Matrix NADH Acetyl-CoA CO2 CitricAcid Cycle CPT-II CAT Fatty Acyl-CoA Fatty Acid -Oxidation Trimetazidine NAD+ + CoA-SH