Belinda Green, Cardiologist, SDHB, 2016

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1 Acute Coronary syndromes All STEMI ALL Non STEMI Unstable angina Belinda Green, Cardiologist, SDHB, 2016

3 Thrombus in proximal LAD

4 Underlying pathophysiology

14 Be very afraid for your patient

waves Preserved precordial R wave progression Recent history of angina ECG

21 Wellens syndrome Deeply-inverted or biphasic T waves in V2-3 (may extend to V1-6) Isoelectric or minimally-elevated ST segment (< 1mm) No precordial Q waves Preserved precordial R wave progression Recent history of angina ECG pattern present in pain-free state Normal or slightly elevated serum cardiac markers

22 So just how good are we at making the right diagnosis?

The most important clinical predictors of ACS and acute MI seem to be the following: chest pain that radiates (especially bilaterally or to the right side), associated diaphoresis, associated

29 The most important clinical predictors of ACS and acute MI seem to be the following: chest pain that radiates (especially bilaterally or to the right side), associated diaphoresis, associated vomiting, and pain on exertion. Assess every one of your patients with chest pain for these 4 historical features, and if the answer to any of these is "yes," seriously think twice about sending that patient home

31 Thank goodness for

32 Thank goodness for TROPONIN

39 De Winters T waves

Cumulative Incidence (%) PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 0 30 Days Clopidogrel 5.4 4.8 BRILIQUE 0 12 Months ARR=0.

43 Cumulative Incidence (%) PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) Days Clopidogrel BRILIQUE 0 12 Months ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, ) 11.7 Clopidogrel 9.8 BRILIQUE ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, ) No. at risk Months After Randomization BRILIQUE 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,650 5,096 4,047 Both groups included aspirin. *NNT at one year. Wallentin L, et al. N Engl J Med. 2009;361:

44 Cumulative Incidence (%) Cumulative Incidence (%) PLATO: Secondary Efficacy Endpoints 7 Myocardial Infarction Clopidogrel Cardiovascular Death BRILIQUE Clopidogrel BRILIQUE 2 ARR=1.1% RRR=16% 2 ARR=1.1% RRR=21% 1 0 Calculated NNT=91 P=0.005 HR: 0.84 (95% CI, ) Months After Randomisation 1 0 NNT=91 P=0.001 HR: 0.79 (95% CI, ) Months After Randomisation Rate of stroke for BRILIQUE was not different from clopidogrel (1.3% vs 1.1% ), P= Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361: Wallentin L, et al. N Engl J Med. 2009;361: Supplement. BRILIQUE: Summary of Product Characteristics, 2010.

45 What about Statins?

46 Statins and ACS

47 Statins

49 Thank you

Currently, standard of care secondary prevention therapy for patients after ACS is a dual antiplatelet regimen comprising ASA plus clopidogrel, prasugrel (only in patients who have undergone PCI) or

55 Currently, standard of care secondary prevention therapy for patients after ACS is a dual antiplatelet regimen comprising ASA plus clopidogrel, prasugrel (only in patients who have undergone PCI) or ticagrelor. All patients, unless contraindicated, should be discharged from hospital on antiplatelet therapy. Most patients continue taking ASA indefinitely, whereas clopidogrel, prasugrel and ticagrelor are usually given for up to 12 months.

59 AMI and Angiographically normal coronary arteries

61 METHODS AND RESULTS: A total of 897 coronary angiographies were performed as an emergency procedure in our institution. The majority of patients (n = 821) presented with coronary artery disease and the majority was treated by mechanical revascularization (86.3%). In 76 patients (8.5%), no coronary artery stenosis was documented. However, according to the preangiographic risk stratification, coronary artery disease was expected in these patients. Observations documented angiographically included coronary spasms (6.6%) and muscle bridges (5.3%). During a mean follow-up of /- 6.4 months, one patient developed an acute myocardial infarction requiring coronary intervention. All other patients were free of any cardiac event. CONCLUSIONS: In summary, we have to consider that coronary angiography may not always detect the cause of myocardial ischemia in every patient. There is a small group of patients with normal coronary angiograms during acute coronary syndrome. Additional diagnostic procedures like intravascular ultrasound (IVUS) or the assessment of intracoronary physiological parameters may increase the diagnostic value of angiography.

62 Antiplatelet Agents ASPIRIN Clopidogrel Ticagrelor Anticoagulants heparin

63 Imaging OPTICAL COHERENCE TOMOGRAPHY

66 ACS..DIAGNOSIS and treatment Belinda Green Cardiologist SDHB

73 PLATO: Study Design N=18,624 Patients with ACS (UA, NSTEMI, or STEMI*) TICAGRELOR (n=9,333) 180-mg loading dose All patients were hospitalised with symptom onset <24 hours Patients could be taking clopidogrel at time of randomisation 300-mg loading dose Clopidogrel (n=9,291) 90 mg bid + ASA maintenance dose 75 mg qd + ASA maintenance dose Primary efficacy endpoint: Composite of CV death, MI (excluding silent MI), or stroke Primary safety endpoint: Total PLATO major bleeding Randomisation Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Screening <24h Month 1 Month 3 Month 6 Month 9 Month 12 Initial Treatment approaches Medically managed (n=5, %) Invasively managed (n=13, %) Wallentin L, et al. N Engl J Med. 2009;361: James S, et al. Am Heart J. 2009;157: *STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI. A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300 mg allowed at the discretion of the investigator. The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major bleeding event.

75 PLATO Study Summary PLATO (N Engl J Med. 2009;361: ) was a pivotal clinical study, comparing BRILIQUE to clopidogrel A total of 18,624 patients with ACS were randomised early after admission to the hospital within 24 hours of symptom onset and generally prior to angiography The study was designed to reflect clinical practice Allowed prior clopidogrel use Included both intent for invasive management (72%) and intent for medical management (28%) PLATO allowed up to 600-mg clopidogrel loading dose pre-pci PLATO enrolled a broad spectrum of patients with ACS (UA, NSTEMI, or STEMI) Wallentin L, et al. N Engl J Med. 2009;361: James S, et al. Am Heart J. 2009;157: Cannon CP, et al. Lancet. 2010;375:

76 PLATO Efficacy Results Summary In PLATO, BRILIQUE significantly reduced the composite of CV death, MI or stroke vs clopidogrel at 1 year (1.9% ARR, 16% RRR, P<0.001, NNT=54) BRILIQUE significantly reduced CV mortality vs clopidogrel (1.1% ARR, 21% RRR, P=0.001) Risk of CV death and MI were both significantly reduced Risk of stroke was not significantly different The absolute risk reduction with BRILIQUE vs clopidogrel starts early and continues to build over the full 1 year treatment period In PLATO, for every 91 ACS patients treated with BRILIQUE for 1 year, instead of clopidogrel, 1 CV death was prevented (NNT=91) The effect of BRILIQUE over clopidogrel appears consistent across many subgroups Wallentin L, et al. N Engl J Med. 2009;361: BRILIQUE: Summary of Product Characteristics, Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:

77 K-M Estimated Rate (% Per Year) PLATO: Bleeding NS P = BRILIQUE (n=9,235) Clopidogrel (n=9,186) All values presented by PLATO criteria. Both groups included aspirin Major Bleeding 5.8 NS 5.8 Lifethreatening/ Fatal Bleeding 0.3 NS 0.3 Fatal Bleeding Major and Minor Bleeding P = Non-CABG- Major Bleeding 7.4 NS 7.9 CABG- Major Bleeding Wallentin L, et al. N Engl J Med. 2009;361:

78 PLATO: Dyspnoea Dyspnoea in the PLATO trial BRILIQUE Clopidogrel P Value Incidence of dyspnoea adverse events (%) <0.001 Patients who discontinued treatment due to dyspnoea (%) <0.001 BRILIQUE-associated dyspnoea was mostly mild to moderate in severity and did not reduce efficacy Most events were reported as single episode occurring early after starting treatment Not associated with new or worsening heart or lung disease In 2.2% of patients, investigators considered dyspnoea causally related to treatment with BRILIQUE Label precautions and warnings: use with caution in patients with history of asthma and COPD BRILIQUE: Summary of Product Characteristics, Wallentin L, et al. N Engl J Med. 2009;361: Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007.

79 PLATO: Bradycardia-related Events All Patients BRILIQUE (n=9,235) Clopidogrel (n=9,186) P Value Bradycardia-related event, n (%) Pacemaker insertion 82 (0.9) 79 (0.9) 0.87 Syncope 100 (1.1) 76 (0.8) 0.08 Bradycardia 409 (4.4) 372 (4.0) 0.21 Heart Block 67 (0.7) 66 (0.7) 1.00 Ventricular pauses 3 seconds occurred in 5.8% of BRILIQUE-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block) Label precautions and warnings: BRILIQUE should be used with caution in patients at risk of bradycardic events Wallentin L, et al. N Engl J Med. 2009;361: BRILIQUE: Summary of Product Characteristics, 2010.

80 PLATO: Laboratory Parameters All Patients BRILIQUE (n=9,235) Clopidogrel (n=9,186) P Value Mean % increase (± SD) in serum creatinine from baseline At 1 month 10 ± 22 8 ± 21 <0.001 At 12 months 11 ± 22 9 ± 22 < month after end of treatment 10 ± ± Mean % increase (± SD) in serum uric acid from baseline At 1 month 14 ± 46 7 ± 44 <0.001 At 12 months 15 ± 52 7 ± 31 < month after end of treatment 7 ± 43 8 ± Creatinine levels may increase during treatment with BRILIQUE; renal function should be checked after 1 month and thereafter according to medical practice Label precautions and warnings: as a precautionary measure, the use of BRILIQUE in patients with uric acid nephropathy is discouraged Wallentin L, et al. N Engl J Med. 2009;361: BRILIQUE: Summary of Product Characteristics, 2010.

81 Summary 1. Dual antiplatelet therapy is very important 2. Statin therapy is very important 3. ACE inhibitor, beta blockers important 4. Spironolactone in select cases 5. Lifestyle changes and cardiac rehab..very important

Response Variability to P2Y 12 Receptor Inhibitors: Expectations and Reality J Am Coll Cardiol Intv. 2013;6(11):1111-1128. doi:10.1016/j.jcin.2013.06.

94 Response Variability to P2Y 12 Receptor Inhibitors: Expectations and Reality J Am Coll Cardiol Intv. 2013;6(11): doi: /j.jcin Figure Legend: Binding Sites of Platelet Inhibitors at the P2Y12 Receptor Gi = inhibitory G protein; other abbreviations as in Figure 1. Date of download: 5/10/2015 Copyright The American College of Cardiology. All rights reserved.

95 Response Variability to P2Y 12 Receptor Inhibitors: Expectations and Reality J Am Coll Cardiol Intv. 2013;6(11): doi: /j.jcin Figure Legend: Receptors Involved in Platelet Activation and Aggregation and Binding Sites of Platelet Inhibitors ADP = adenosine diphosphate; COX = cyclooxygenase; GP = glycoprotein; TP = thromboxane-prostanoid receptor 1; TXA2 = thromboxane A2. Date of download: 5/10/2015 Copyright The American College of Cardiology. All rights reserved.

96 Response Variability to P2Y 12 Receptor Inhibitors: Expectations and Reality J Am Coll Cardiol Intv. 2013;6(11): doi: /j.jcin Figure Legend: Metabolic Pathways of ADP Receptor Blockers ADP = adenosine diphosphate; CYP = cytochrome P450. Date of download: 5/10/2015 Copyright The American College of Cardiology. All rights reserved.

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What oral antiplatelet therapy would you choose? a) ASA alone b) ASA + Clopidogrel c) ASA + Prasugrel d) ASA + Ticagrelor

What oral antiplatelet therapy would you choose? a) ASA alone b) ASA + Clopidogrel c) ASA + Prasugrel d) ASA + Ticagrelor 76 year old female Prior Hypertension, Hyperlipidemia, Smoking On Hydrochlorothiazide, Atorvastatin New onset chest discomfort; 2 episodes in past 24 hours Heart rate 122/min; BP 170/92 mm Hg, Killip Class