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The Role of ACEIs in Unstable Angina Sukhjinder Sidhu Interior Health Pharmacy Resident Cardiology Rotation February 21, 2014.

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Presentation on theme: "The Role of ACEIs in Unstable Angina Sukhjinder Sidhu Interior Health Pharmacy Resident Cardiology Rotation February 21, 2014."— Presentation transcript:

1 The Role of ACEIs in Unstable Angina Sukhjinder Sidhu Interior Health Pharmacy Resident Cardiology Rotation February 21, 2014

2 Learning Objectives By the end of this 20-min session the audience should be able to: – Describe the pathophysiology and clinical presentation of unstable angina (UA) – Compare and contrast the diagnostic criteria of UA, NSTEMI and STEMI – State the evidence for ACEI in UA – Be able to determine the need for ACEI in an UA patient

3 Our Patient IDBL – 53 y.o. male (133 kg; 183 cm) Admitted Nov 9 th to OMH and transferred to KGH Nov 12 th CC/HPISub-sternal chest discomfort (burning) x 2 episodes SOBOE x months prior to event No chest pain since admission Diagnosed with UA and to be medically managed until follow-up SCA +/- PCI AllergiesAnti-inflammatory (name?) – hives Social Hx80 pack-year smoking hx Ø EtOH or illicit drugs Ø influenza immunization Family HxØ

4 Our Patient PMHx:MPTA: OAAcetaminophen 500 mg PO PRN (500 mg Q3days) Ibuprofen mg PO daily AsthmaAdvair 250/50 1 INH BID PRN Salbutamol mcg INH Q4H PRN General HealthMultivitamin 1 tab PO daily

5 Review of Systems VitalsT 36.5 HR 56 BP 119/81 RR 18 O2 sat 99% (RA) CNS/NeuroA&O x 3 HEENTØ RESPØ CVSTrop < 0.04 S 1 S 2 ØS 3 S 4 GIØ GUSrCr 83 eGFR 84 Urea 6.3 ENDOGlu 4.0 TG 3.83 Chol 3.32 LDL 0.85 HDL 0.71 MSK/DermØ CHEMNa 141 K 4.3 Cl 103 HCCO 3 25 HEMEHgb 179 WBC 7.9 Neuts 4.6 Plts 234 INR 1.0

6 Investigations Diagnostics Day -3 (OMH) ECGØ Day 0 (Admission to KGH) CXRØ Day 1EchoEF 55-60% AngiogramProximal RCA: % narrowing Mid RCA: 100% narrowing Mid LAD: 90% narrowing Proximal Mid LCx1: 100% narrowing  3-vessel CAD to be assessed for CABG Day 2Carotid Doppler Mild plaque Ø significant stenosis

7 RCA LCA Cx LAD

8 Current Problems & Medications IndicationMedication Unstable AnginaASA 81 mg PO daily Atorvastatin 80 mg PO daily Metoprolol 25 mg PO BID Nitroglycerin spray mg Q5min PRN Smoking CessationNicotine patch 42 mg TDERM daily AsthmaAdvair 250/50 mg 1 INH Q12H Salbutamol 200 mcg INH QID PRN

9 DRP’s BL is at risk of recurrent MI and death secondary to not receiving an ACEI and would benefit from optimization of ACS therapy. BL is at risk of experiencing recurrent MI and death secondary to smoking and would benefit from smoking cessation. BL is at risk of experiencing recurrent MI, worsening heart function and death secondary to ibuprofen use and would benefit from discontinuing ibuprofen and counseling on its adverse effects. BL is at risk of experiencing influenza (fever, night sweats, myalgias, fatigue, nausea, vomiting, diarrhea) secondary to not receiving an influenza vaccine and would benefit from receiving the influenza vaccine. BL is experiencing a mild rash secondary to the adhesives on the ECG strips and nicotine patch and would benefit from receiving a topical corticosteroid formulation.

10 Unstable Angina Angina is caused by poor blood flow through the coronary vessels of the myocardium – Acute reduction in myocardial oxygen supply CAD due to atherosclerosis is the most common cause of UA heartcurrents.com

11 Unstable Angina Risk Factors Non-modifiableModifiable Family hx of premature CHD Male gender Older age Diabetes HTN Dyslipidemia Smoking Obesity Sedentary Lifestyle Non-adherence to medications Symptoms Dyspnea Chest pain -Sub-sternal pressure -Radiates to arms, jaw, back Heartburn Nausea/vomiting Diaphoresis

12 Acute Coronary Syndromes UANSTEMISTEMI Chest Pain√√√ Troponin RiseØ√√ ECG ChangesØ ST depression T wave inversion ST depression T wave inversion ST elevation New LBBB Q waves

13 Goals of Therapy Prevent mortality Minimize myocardial damage and total ischemic time Establish and maintain patency of the infarct-related artery Alleviate signs and symptoms Prevent re-occlusion, re-infarction, re-hospitalization Minimize adverse events Promote smoking cessation

14 Therapeutic Approach ASA 81 mg PO daily P2Y12 inhibitors High dose statin Beta-blockers RAAS inhibitors Nitroglycerin PRN

15 RAAS Inhibitors Improve vascular endothelial function Inhibit hypertrophy Increase bradykinin – Increases nitric oxide production = vasodilation Anti-atherosclerotic effects – Antagonize the rupture of plaques – Enhance fibrinolysis Blood pressure control

16 Background ACC/AHA Guidelines for UA/NSTEMI – ACEI should be given and continued indefinitely for patients recovering from UA/NSTEMI with HF, LV dysfunction, HTN, or DM, unless contraindicated (Class I A) – ACEIs have been shown to reduce mortality rates in patients with AMI and in patients with recent MI or with LV systolic dysfunction, in diabetic patients with LV dysfunction, and in a broad spectrum of patients with high-risk chronic CAD – ACEI are reasonable for patients recovering from UA/NSTEMI in the absence of LV dysfunction, HTN, or DM, unless contraindicated (Class IIa B) ACC/AHA 2007 Guidelines for UA/NSTEMI

17 Clinical Question P UA patient awaiting CABG with no hx of type II DM or HTN and preserved LVEF I ACEI + ACS therapy (ASA, atorvastatin, beta-blocker) C Placebo + ACS therapy (ASA, atorvastatin, beta-blocker) O Decrease mortality Prevent future MIs Ø Increased risk of adverse events

18 Literature Search DatabasesGoogle Scholar, Medline, Embase Search TermsAngiotensin-Converting Enzyme Inhibitors Cardiovascular diseases or heart diseases LimitsEnglish language and (guideline or meta analysis or RCT or systematic review) Results2 relevant meta-analysis 6 relevant RCTs -HOPE -EUROPA -PEACE -IMAGINE 1 relevant observational study

19 TrialHOPE (n = 9297) EUROPA (n = 12, 218) PEACE (n = 8290) Population> 55 y.o. with one of: Documented CAD (> 1 mo post-MI, PTCA, or CABG, > 50% stenosis on > 2 arteries) PVD Stroke DM + > 1 risk factor (HTN, ↑ chol, ↓ HDL, smoking, microalbuminuria) Excluded LVEF < 40% > 18 y.o. with one of: Documented CAD (> 3 mo post-MI, > 6 mo post- PTCA or CABG, > 70% stenosis) Men with hx of chest pain and positive ECG/stress test Excluded clinical evidence of HF > 50 y.o. with: Documented CAD (> 3 mo post-MI, PTCA or CABG, > 50% stenosis) LVEF > 40% (< 18 mo before randomization) Baseline traits 66 y.o. CAD (80%) MI (52%) – CABG (26%) HTN (47%) DM (38%) PVD (43%) 60 y.o. – MI (65%) PTCA/CABG (59%) CABG (29%) HTN (27%) DM (12%) PVD (7%) 64 y.o. CAD (61%) MI (55%) PTCA/CABG (72%) CABG (39%) HTN (46%) DM (17%) – Baseline meds Antiplatelet (75%) Beta-blocker (39%) Lipid-lowering (28%) Antiplatelet (92%) Beta-blocker (62%) Lipid-lowering (57%) Antiplatelet (90%) Beta-blocker (60%) Lipid-lowering (70%) NEJM :3;145-33, LANCET ;782-88, NEJM 2004; 351:205-68

20 TrialHOPE (n = 9297) EUROPA (n = 12,218) PEACE (n = 8290) I/C Ramipril 10 mg vs. placeboPerindopril 8 mg vs. placeboTrandolapril 4 mg vs. placebo Outcome Composite of death from CV causes, MI, or stroke - Median duration: 4.5 years Composite of CV death, non- fatal MI or cardiac arrest with successful resuscitation - Mean duration: 4.2 years Composite of death from CV causes, non-fatal MI, or coronary revascularizatoin - Median duration: 4.8 years Results Primary: 14% vs. 17.8% RR 0.78 ( ) CV death: 6.1% vs. 8.1% RR 0.74 ( ) MI: 9.9% vs. 12.3% RR 0.80 ( ) Primary: 8.0% vs. 9.9% RRR 20% (9 to 29) CV death: 3.5% vs. 4.1% RRR 14% (-3 to 28) Non-fatal MI: 4.8% vs. 6.2% RRR 22% (10 to 33) Primary: 21.9% vs. 22.5% HR 0.96 ( ) CV death: 3.5% vs. 3.7% HR 0.95 ( ) Non-fatal MI: 5.3% vs. 5.3% HR 1.03 ( ) Adverse events Hypotension Cough Critique - Multi-center - Not all had LVEF tested (8.1% had low EF) - Patient’s not fully optimized on cardiac meds - 79% of ramipril cohort taking study med at F/U - Industry sponsored - Multi-center - Not all had LVEF tested - 81% of perindopril cohort taking study med at 3 years - Industry sponsored - Multi-center - EF available for most of cohort - Sponsored by US NHLBI - Patients received more intensive management vs. HOPE, EUROPA - Lowest risk cohort vs. HOPE, EUROPA NEJM :3;145-33, LANCET ;782-88, NEJM 2004; 351:205-68

21 IMAGINE DDB, PC, PG, MC RCT, N=2553 PInclusion: > 18 y.o; post-CABG 40% Exclusion: Insulin-dependent DM or type 2 DM with microalbuminuria; significant valve stenosis/cardiomyopathy; K > 5.6; Cr > 200 umol/L; BP > 160/90; significant perioperative MI Baseline: Mean age 61; men (87%); DM (10%); HTN (47%); LVEF 60%; BP 122/70 Meds – ASA (91%); statin (65%); BB (79%) IQuinapril 10 or 20 mg PO daily to target of 40 mg PO daily median 2.95 yrs CPlacebo OComposite of CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF Circulation. 2008; 117:24-31

22 IMAGINE QuinaprilPlaceboHR95% CI CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF 13.7%12.2% – 1.42 NSS CV death1.4%1.2% – 2.38 Nonfatal MI1.3%1.6% – 1.46 CV death, nonfatal MI, stroke first 3 months 1.3%0.8% – 3.52 CV death, nonfatal MI, stroke after 3 months 2.3%2.7% – 1.35 Circulation. 2008; 117:24-31

23 IMAGINE Author’s conclusions: – At least in low risk-patients treated with contemporary therapy, early initiation of an ACEI after CABG has no benefit, and this strategy may even be associated with an increase in adverse events Circulation. 2008; 117:24-31

24 IMAGINE Strengths – High compliance – Large number of patients receiving appropriate cardiac medications Limitations – 11% of placebo cohort was taking open-label ACEI at 3 years – Industry sponsored Generalizability – Patient had CABG surgery – Normal LVEF – Excluded majority of DM patients Circulation. 2008; 117:24-31

25 Summary of Evidence ↓ risk of mortality↓ risk of future MI HOPE-CAD, LVEF > 40%, high risk factors -Ramipril 5 mg PO daily vs. placebo SS EUROPA-CAD, no HF, moderate risk factors -Well managed medically -Perindopril 8 mg PO daily vs. placebo SS PEACE-CAD, LVEF > 40%, low risk factors -Intensively managed -Trandolapril 4 mg PO daily vs. placebo NSS IMAGINE-Post CABG ( 40% and low risk factors -Quinapril to target of 40 mg PO daily vs. placebo NSS

26 Application Necessary – No prior risk factors, such as DM, HTN or ↓ LVEF Effective – In CABG patients with no clear indication for ACEI, they have conflicting evidence in reducing CV death, non-fatal MI, and revascularization Safety – Risk of hypotension and cough – BP was consistently /60-70 Adherence – Minimal non-adherence risk Patient Factors – Increased pill and cost burden

27 Therapeutic Plan Do not initiate an ACEI at present Administer influenza vaccine 0.5 mL IM x 1 Hydrocortisone cream 1% apply to affected areas BID PRN Provided counseling regarding A/E of NSAID use Provided counseling on the use of acetaminophen over NSAIDs for OA pain Provided counseling and reinforcement regarding smoking cessation

28 Monitoring Plan EfficacyToxicityFreq VitalsBP < 140/90, HR 60-70BP < 90/50 or symptomatic HR < 60 Daily HEENTØBleeding nose, gumsDaily CNSØFatigue, headache, dizziness, ↓ exercise tolerance Daily CVSØ chest pain Ø hospitalizations for CVD ØDaily RESPØ SOBOEØDaily GIØGI upset, hematemesis, melena ↓ Hgb Daily GUØØ MSK/DERMØMyalgias, weakness LFTs > 3x ULN, CK > 5x ULN Daily When indicated

29 Follow Up ACEI not initiated at this time Influenza vaccine administered BL receptive to smoking cessation BL receptive to avoiding use of NSAIDs and using acetaminophen for pain control Successful CABG

30 Conclusion No studies have evaluated ACEI solely in UA patients ACEI decreased CV death and non-fatal MI in CAD patients if other risk factors are present – HTN, DM, ↑ chol, or ↓ LVEF ACEI have not shown similarly consistent results in lower CV risk patients

31 Questions? IMAGE:

32 NSAIDs & CV Risk COX-1 is active in platelets - Thromboxane A2 is a vasoconstrictor and potent stimulator of platelet aggregation - TXA2 increases renal salt & fluid retention, increases BP, enhances MI & vascular remodeling COX-2 is active in cells that line blood vessels - Prostacyclin is a potent vasodilator and inhibitor of platelet function = vasculoprotective - PGI2 facilitates renal salt & fluid excretion, lowers BP - inhibition decreases prostacyclin - Endothelial cells are a source of prostacyclin NSAIDs tip the TXA2/PGI2 balance increasing CV risk - Nonselective NSAIDs with high COX2 inhibition seem to have higher cardiovascular risk - Also increase risk of fluid retention and edema


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