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A Pair of ACEIs? What is the Role of ACEIs in Unstable Angina Matthew Brons Sukhjinder Sidhu Interior Health Pharmacy Residents Cardiology Rotation November 28, 2013

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Learning Objectives By the end of this 45-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 State the benefits of ACEI in patients with decreased LVEF, high risk CAD and ACS Be able to determine the need for ACEI in an UA patient

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WA ID65 y.o. male (132kg, 185cm) admitted November 11 th CC/HPI Severe chest pain (tightness) SOBOE and chest pain on exertion -8 month hx of intermittent episodes of discomfort Diagnosed with UA and to be medically managed until follow-up SCA +/- PCI AllergiesNKDA Social Hx 3 pack per day smoker x 40 years No alcohol/illicit drugs Family HxFather stroke at age 54 VaccinationsNot up-to-date

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WA PMHMPTA GERD Esomeprazole 40 mg PO daily Only takes PRN/infrequently Smoking Cessation Varenicline 1 mg PO BID Never completed full treatment, was not ready to quit HTNAtenolol 100 mg PO daily EDSildenafil 50 mg PO PRN DyslipidemiaAtorvastatin 20 mg PO QHS stopped taking in March Type II DMDiet Controlled

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Review of Systems (WA) VITALSTemp: 36.8 o C BP: 121/83 HR: 77 RR: 18 O2Sat: 96% RA CNS/NEUROA & O x 3 HEENTNormal CVSDistant heart sounds, no extra sounds/rubs/clicks or murmurs RESPClear GISoft, non-tender GUNormal MSK/DERMNormal ENDORandom glucose 7.2, A1C 6.8% LYTESNa 139 K 4.5 Cl 103 Bicarb 27 SrCr 96 HEMEHgb 158 WBC 10.8 Plts 334 INR 1.2 TROP < 0.04 LIPIDSTG 2.08 LDL 1.37 HDL 0.79

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Investigations (WA) Diagnostics Day 0ECG Day 2AngiogramLeft Main: Severe Disease LAD: Moderate mid-vessel disease Circumflex: Proximal occlusion RCA: Moderate proximal disease Not a PCI candidate CABG referral Day 4TTENormal LV EF 45 50%

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Angiogram (WA)

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Current Problems & Medications (WA) Medical ProblemCurrent Medications UA Atorvastatin 80 mg PO daily Atenolol 100 mg PO BID ASA 81 mg PO daily Nitroglycerin spray 0.4 mg 1-2 sprays SL Q5min PRN Nitroglycerin IV HypertensionAtenolol 100 mg PO BID Type II DiabetesDiet Controlled Smoking CessationNicotine patch 42 mg TDERM daily GERDPantoprazole 40 mg PO daily

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DRPs WA is at increased risk of developing morbidity complications (e.g. MI, HF) and mortality secondary to not receiving an ACE inhibitor and would benefit from the initialization of therapy WA is at risk of developing severe hypotension secondary to a drug-drug interaction with nitroglycerin and sildenafil and would benefit from counselling. WA is at risk of developing influenza and pneumonia secondary to not receiving vaccinations and would benefit from administration of vaccinations. WA is at risk of experiencing adverse effects secondary to receiving a high dose of atenolol and would benefit from increased monitoring of his BP and HR. WA is at increased risk of developing CV and respiratory complications (e.g. MI, COPD) and death secondary to smoking and would benefit from additional counselling. WA is at risk of developing macrovascular and microvascular complications secondary to not receiving drug therapy for type II diabetes and may benefit from initialization of therapy. WA is at risk of developing CV complications (e.g. MI, HF, stroke) secondary to a history of non-adherence to medications and would benefit from counselling.

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BL ID53 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 Diagnosed with UA and to be medically managed until follow-up SCA +/- PCI AllergiesAnti-inflammatory (name?) hives Social Hx80 pack-year smoking hx EtOH or illicit drugs influenza immunization

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BL PMHx:MPTA: OAAcetaminophen 500 mg PO PRN (500 mg Q3days) Ibuprofen 600-1200 mg PO daily Asthma/COPDAdvair 250/50 1 INH BID PRN Salbutamol 100-200 mcg INH Q4H PRN General HealthMultivitamin 1 tab PO daily

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Review of Systems (BL) VitalsT 36.5 HR 56 BP 119/81 RR 18 O2 sat 99% (RA) CNS/NeuroA&O x 3 HEENT RESP CVS GI GUSrCr 83; eGFR 84 ENDOGlu 4.0; TG 3.83; Chol 3.32; LDL 0.85; HDL 0.71 MSK/Derm CHEMNa 141 K 4.3 Trop

EUROPA DRandomized, double-blind, multicentre, n = 12 218 P -18 + -Hx of CAD documented by previous MI, PCI or CABG, or angiographic evidence of 70% + narrowing of one or more major coronary arteries; Men with positive ECG, echo, or nuclear stress test and chest pain -Excluded: -HF, planned revascularisation, hypotension (SBP 180, DBP > 100), recent use of ACE or ARB, renal insufficiency, high serum potassium -Baseline: -CABG ~ 30%; HTN ~ 27%; DM ~ 12%; Angiogram ~ 60% I / C-Perindopril 8 mg PO Daily vs. placebo O-Composite of CV death, non-fatal MI, cardiac arrest with successful resuscitation LANCET 2003 362;782-88

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EUROPA Outcome RamiprilPlaceboRR95% CI CV death, non-fatal MI, cardiac arrest 8%9.9%0.800.72 0.9 CV death3.5%4.1%0.860.72 1.03 Non-fatal MI4.8%6.2%0.780.67 0.90 Cardiac Arrest0.1%0.2%0.540.20 1.47 LANCET 2003 362;782-88

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EUROPA Authors conclusions: We show a substantial benefit with perindopril in a broad population of patients with stable coronary artery disease and no evidence of heart failure or notable hypertension. LANCET 2003 362;782-88

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EUROPA Strengths Large and extensive trial Limitations Patients may not have been receiving optimal therapies for their co-morbidities Generalizability Patient has DM and HTN No impaired LVEF CABG patients

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Summary of Evidence OutcomesHOPEEUROPA -Hx of CAD, stroke, PVD or DM + HTN, cholesterol, smoker, or microalbuminuria -Ramipril 5 mg PO daily vs. placebo -over 4.6 yrs -Hx CAD: MI, PCI, CABG; or 70% narrowing of coronary artery -Perindopril 8 mg PO daily vs. placebo -over 4.2 yrs Reduce risk of mortalitySS Reduce risk of future myocardial infarctions SS Adverse event Cough Hypotension

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Clinical Question WABL P UA with hx of type II DM, HTN & CAD awaiting CABG UA awaiting CABG I ACEI + ACS therapy (ASA, atorvastatin, beta-blocker) C Placebo + ACS therapy (ASA, atorvastatin, beta-blocker) O Decrease mortality Prevent future MIs Increased risk of adverse events

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HOPE and EUROPA Applicable to BL? HOPEEUROPA BaselinePrevious MI 52% Revascularization 40% DM 39% HTN 47% Chol > 5.2 mmol/L 66% BB 40% Lipid-lowering agents 29% Previous MI 65% Revascularization 54% DM 12% HTN 27% Chol > 6.5mmol/L 63% BB 62% Lipid-lowering agents 58%

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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 -PEACE -IMAGINE 1 relevant observational study

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Milonas et al. N~38000, prospective observational trial ACEI treatment at discharge = 24% 1- year mortality driven by those with hx or current signs of HF In patients without HF, no significant benefit of ACEI Except in those with at least moderate renal dysfunction AM J Cardiol 2010; 105:1229-1234

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PEACE DDB, PC, MC RCT, N=8290 PInclusion: > 50 y.o.; CAD (MI, CABG, PCI > 3 mo before enrollment; > 50% block of > 1 coronary vessel); LVEF > 40% > 80% compliance with meds in run-in phase Baseline: Mean age 64; 82% men; 55% prev. MI; 61% CAD; 72% revascularization; 17% DM; 45% HTN; 12% DM + HTN; SBP 134 +/- 17; EF 58 +/- 10%; 60% BB; 90% antiplatelet; 70% lipid lowering I / CTrandolapril 4mg PO daily vs. placebo x mean duration 4.8 years OComposite of death from CV causes, nonfatal MI, or revascularization NEJM 2004; 351:205-68

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PEACE TrandolaprilPlaceboHR95% CI CV death, nonfatal MI, revascularization 21.9%22.5%0.960.88 1.06 NSS CV death 3.5%3.7%0.950.76 1.19 Non-fatal MI 5.3% 1.000.83 1.20 NEJM 2004; 351:205-68

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PEACE Authors conclusions: PEACE Trial does not demonstrate the benefits of ACE inhibition shown by HOPE and EUROPA because the patients enrolled in the PEACE Trial were at lower risk for CV events In a population of patients with CAD and preserved EF who receive intensive current therapy, usually including coronary revascularization and lipid-lowering agents, and in whom the rate of CV events are therefore already quite low, there appears to be no evidence of CV benefit from the addition of ACEI therapy NEJM 2004; 351:205-68

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PEACE Strengths ITT High compliance (82% - 1yr; 79% -2yr; 75% - 3yr) Majority of patients receiving appropriate cardiac medications Limitations Patients in the placebo arm who had DM with HTN or had proteinuria were given an ACEI as open-label Generalizability Population included was low-risk Majority of patients had received revascularization NEJM 2004; 351:205-68

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IMAGINE DDB, PC, PG, MC RCT, N=2553 PInclusion: Post-CABG 18 y.o.; LVEF > 40% Baseline: Mean age 61; 87% men; 10% DM; 47% HTN; LVEF 60%; SBP 122 +/- 14; 91% ASA; 65% statin; 79% BB; 23% ACEI I / CQuinapril 10 or 20 mg PO daily to target of 40 mg PO daily vs. placebo x 2.95 yrs OComposite of CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF Circulation. 2008; 117:24-31

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IMAGINE QuinaprilPlaceboHR95% CI CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF 13.7%12.2%1.150.92 1.42 NSS CV death1.4%1.2%1.200.60 2.38 Nonfatal MI1.3%1.6%0.760.40 1.46 CV death, nonfatal MI, stroke first 3 months 1.3%0.8%1.600.73 3.52 CV death, nonfatal MI, stroke after 3 months 2.3%2.7%0.820.50 1.35 Circulation. 2008; 117:24-31

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IMAGINE Authors 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

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IMAGINE Strengths High compliance Large number of patients receiving appropriate cardiac medications Limitations Would results be similar if ACEI started prior to surgery? Stroke and CHF added to primary outcome due to low event rate Generalizability Patient had CABG surgery Nov 21, 2013 Normal LVEF Excluded DM patients Circulation. 2008; 117:24-31

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Summary of Evidence OutcomesPEACEIMAGINE -CAD, LVEF > 40%, low CV risk factors -on ASA, statin and BB, -trandolapril 4 mg PO daily vs. placebo -over 4.8 yrs -Post CABG ( 40% and no DM -Quinapril to target of 40 mg PO daily vs. placebo -over 2.95 yrs Reduce risk of mortalityNSS Reduce risk of future myocardial infarctions NSS Adverse event Cough and syncope Cough and hypotension

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Application to WA and BL WABL Necessary CV risk factors present DM, HTN, prior MI hx Effective? Safe Adherence?

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Therapeutic Plan WA Initiate ramipril 5 mg PO daily, titrating up to target dose of 10 mg PO daily as appropriate Administer influenza vaccine 0.5 mL IM x 1 Administer pneumococcal vaccine 0.5 mL IM x1 Provided adherence strategies for all ACS medications Re-enforced need to continue with smoking cessation BL Do not initiate an ACEI 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

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Monitoring Plan EfficacyWhen S: MI symptoms -Chest pain Daily O:BP ( 30%, K > 5 mmol/LDaily post-CABG until stable, then 1-2 weeks post dose increase as outpatient, then with routine outpatient blood work thereafter

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Follow Up WA Ramipril 5 mg PO daily initiated Influenza and pneumococcal vaccine to be given as outpatient Metformin 500 mg PO BID initiated WA appeared receptive to smoking cessation and importance of adherence to medications Successful CABG BL ACEI not initiated Influenza vaccine administered BL receptive to smoking cessation BL receptive to avoiding use of NSAID and using acetaminophen for pain control Successful CABG

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Conclusion No studies have evaluated ACEI solely in UA patients ACEI decreased CV death and non-fatal MI in UA if other risk factors are present HTN, DM, chol, or LVEF ACEI have not shown similar results in low CV risk patients

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Questions? IMAGE: http://comicsthatsaysomething.quora.com/A-Day-at-the-Park?ref=fb