A Pair of ACEIs?What is the Role of ACEIs in Unstable Angina

Matthew BronsSukhjinder Sidhu

Interior Health Pharmacy ResidentsCardiology RotationNovember 28, 2013

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

WAID 65 y.o. male (132kg, 185cm) admitted November 11th 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

Allergies NKDASocial Hx 3 pack per day smoker x 40 years

No alcohol/illicit drugsFamily Hx Father – stroke at age 54Vaccinations Not up-to-date

WAPMH MPTAGERD Esomeprazole 40 mg PO daily – Only takes

PRN/infrequentlySmoking Cessation

Varenicline 1 mg PO BID – Never completed full treatment, was not ready to quit

HTN Atenolol 100 mg PO dailyED Sildenafil 50 mg PO PRN Dyslipidemia Atorvastatin 20 mg PO QHS – stopped taking in MarchType II DM Diet Controlled

Review of Systems (WA)VITALS Temp: 36.8oC BP: 121/83 HR: 77 RR: 18 O2Sat: 96% RACNS/NEURO A & O x 3HEENT NormalCVS Distant heart sounds, no extra sounds/rubs/clicks or murmursRESP ClearGI Soft, non-tenderGU NormalMSK/DERM NormalENDO Random glucose 7.2, A1C 6.8%LYTES Na 139 K 4.5 Cl 103 Bicarb 27 SrCr 96

HEME Hgb 158 WBC 10.8 Plts 334 INR 1.2 TROP < 0.04LIPIDS TG 2.08 LDL 1.37 HDL 0.79

Investigations (WA)Diagnostics

Day 0 ECG Ø

Day 2 Angiogram Left Main: Severe DiseaseLAD: Moderate mid-vessel diseaseCircumflex: Proximal occlusionRCA: Moderate proximal diseaseNot a PCI candidate CABG referral

Day 4 TTE Normal LVEF 45 – 50%

Angiogram (WA)

Current Problems & Medications (WA)Medical Problem Current MedicationsUA Atorvastatin 80 mg PO daily

Atenolol 100 mg PO BIDASA 81 mg PO dailyNitroglycerin spray 0.4 mg 1-2 sprays SL Q5min PRNNitroglycerin IV

Hypertension Atenolol 100 mg PO BIDType II Diabetes Diet ControlledSmoking Cessation Nicotine patch 42 mg TDERM dailyGERD Pantoprazole 40 mg PO daily

DRP’s• 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.

BLID 53 y.o. male (133 kg; 183 cm)

Admitted Nov 9th to OMH and transferred to KGH Nov 12th

CC/HPI Sub-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 +/- PCIAllergies Anti-inflammatory (name?) – hives Social Hx 80 pack-year smoking hx

Ø EtOH or illicit drugsØ influenza immunization

BLPMHx: MPTA:OA Acetaminophen 500 mg PO PRN (500 mg Q3days)

Ibuprofen 600-1200 mg PO dailyAsthma/COPD Advair 250/50 1 INH BID PRN

Salbutamol 100-200 mcg INH Q4H PRNGeneral Health Multivitamin 1 tab PO daily

Review of Systems (BL)Vitals T 36.5 HR 56 BP 119/81 RR 18 O2 sat 99% (RA)CNS/Neuro A&O x 3HEENT ØRESP ØCVS ØGI ØGU SrCr 83; eGFR 84ENDO Glu 4.0; TG 3.83; Chol 3.32; LDL 0.85; HDL 0.71MSK/Derm ØCHEM Na 141 K 4.3

Trop <0.04 HEME Hgb 179 WBC 7.9 Neuts 4.6 Plts 234

Investigations (BL)Diagnostics

Day -3 (OMH)

ECG Ø

Day 0 (Admission to KGH)

CXR Ø

Day 1 Echo EF 55-60%Basal inferior hypokinesis

Angiogram Proximal RCA: 90-100% narrowing Mid RCA: 100% narrowingMid LAD: 90% narrowingProximal Mid LCx1: 100% narrowing 3-vessel CAD to be assessed for CABG

Day 2 Carotid Doppler

Mild plaqueØ significant stenosis

Angiogram (BL)

Current Problems & Medications (BL)Indication MedicationUnstable Angina ASA 81 mg PO daily

Atorvastatin 80 mg PO dailyMetoprolol 25 mg PO BIDNitroglycerin spray 0.4-0.8 mg Q5min PRN

Smoking Cessation Nicotine patch 42 mg TDERM dailyAsthma/COPD Advair 250/50 mg 1 INH Q12H

Salbutamol 200 mcg INH QID PRN

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.

DRP Focus

• WA and BL are at risk of experiencing cardiovascular morbidity (e.g. MI, HF) and mortality secondary to not receiving an ACEI and would benefit from optimization of ACS therapy.

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

Unstable AnginaRisk Factors

Non-modifiable ModifiableFamily hx of premature CHD Male genderOlder age

DiabetesHTNDyslipidemiaSmokingObesitySedentary LifestyleNon-adherence to medications

Symptoms

DyspneaChest pain- Sub-sternal pressure- Radiates to arms, jaw,

backHeartburnNausea/vomitingDiaphoresis

Acute Coronary SyndromesUA NSTEMI STEMI

Chest Pain √ √ √Troponin Rise Ø √ √ECG Changes Ø

ST depressionT wave inversion

ST depressionT wave inversion

ST elevationNew LBBBQ waves

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

Therapeutic Approach

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

RAAS Inhibitors

• Improve endothelial function• Inhibit hypertrophy • Increase bradykinin – increases nitric oxide production = vasodilation

• Blood pressure control

Background

• ACC/AHA Guidelines for UA/NSTEMI– An ACEI for all post-ACS patients (Level of

Evidence: B)– 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 for patients with CHF, LV dysfunction (EF < 0.40), HTN, or diabetes (Level of Evidence: A)

ACC/AHA 2007 Guidelines for UA/NSTEMI

Clinical QuestionWA BL

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 MIsØ Increased risk of adverse events

Literature SearchDatabases Cochrane, Embase, Medline, Google ScholarSearh terms Unstable Angina, Cardiovascular Disease, ACE

inhibitor, Diabetes, CABG Limits RCT, meta analysis, systematic reviewResults 2 RCTs

- HOPE- EUROPA

HOPED Randomized, double-blind, multicentre, 2-by-2 factorial; n = 9541P - 55 +

- Hx of CAD, Stroke, PVD; OR/- Diabetes PLUS one of HTN, elevated total cholesterol, smoker,

or microalbuminuria- Excluded: - HF, EF < 0.4, taking ACE inhibitor or Vit E, uncontrolled HTN,

overt nephropathy, MI or stroke within 4 weeks prior- Baseline:- UA ~ 25%; CABG ~ 25%; HTN ~ 47%; DM ~ 38%; Smoker ~

14%I / C - Ramipril 10 mg PO Daily vs. placeboO - Composite of MI, stroke, or death from CV causes

NEJM 2000 342:3;145-53

HOPEOutcome

Ramipril Placebo RR 95% CICV death, MI, stroke

14% 17.8% 0.78 0.70 – 0.86

CV death 6.1% 8.1% 0.74 0.64 – 0.87MI 9.9% 12.3% 0.80 0.70 – 0.90Stroke 3.4% 4.9% 0.68 0.56 – 0.84

NEJM 2000 342:3;145-53

HOPE

Author’s conclusions:• “Our findings show that ramipril, an

angiotensin-converting-enzyme inhibitor, is beneficial in a broad range of patients without evidence of left ventricular systolic dysfunction or heart failure who are at high risk for cardiovascular events.”

NEJM 2000 342:3;145-53

HOPE

Strengths– Large and extensive trial

Limitations– Not all patients were screened for reduced LVEF– Patients may not have been receiving optimal

therapies for their co-morbidities

Generalizability– Patient has DM and HTN – No reduced LVEF

NEJM 2000 342:3;145-53

EUROPAD Randomized, 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 < 110), uncontrolled

HTN (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

EUROPAOutcome

Ramipril Placebo RR 95% CICV death, non-fatal MI, cardiac arrest

8% 9.9% 0.80 0.72 – 0.9

CV death 3.5% 4.1% 0.86 0.72 – 1.03Non-fatal MI 4.8% 6.2% 0.78 0.67 – 0.90Cardiac Arrest 0.1% 0.2% 0.54 0.20 – 1.47

LANCET 2003 362;782-88

EUROPA

Author’s 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

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

Summary of EvidenceOutcomes HOPE EUROPA

- 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 yrsReduce risk of mortality SS SS

Reduce risk of future myocardial infarctions

SS SS

Adverse event ↑ Cough ↑ Cough Hypotension

Clinical QuestionWA BL

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 mortalityPrevent future MIs

Ø Increased risk of adverse events

HOPE and EUROPAApplicable to BL?

HOPE EUROPA

Baseline Previous 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%

Literature SearchDatabases Google Scholar, Medline, EmbaseSearch Terms Angiotensin-Converting Enzyme Inhibitors

Cardiovascular diseases or heart diseases

Limits English language and (guideline or meta analysis or RCT or systematic review)

Results 2 relevant meta-analysis6 relevant RCTs- PEACE- IMAGINE1 relevant observational study

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

PEACED DB, PC, MC RCT, N=8290P Inclusion:

> 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 / C Trandolapril 4mg PO daily vs. placebo x mean duration 4.8 yearsO Composite of death from CV causes, nonfatal MI, or revascularization

NEJM 2004; 351:205-68

PEACETrandolapril Placebo HR 95% CI

CV death, nonfatal MI, revascularization

21.9% 22.5% 0.96 0.88 – 1.06NSS

CV death 3.5% 3.7% 0.95 0.76 – 1.19Non-fatal MI 5.3% 5.3% 1.00 0.83 – 1.20

NEJM 2004; 351:205-68

PEACE

• Author’s 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

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

IMAGINED DB, PC, PG, MC RCT, N=2553P Inclusion:

Post-CABG < 7-10 days; stable after operation; > 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 / C Quinapril 10 or 20 mg PO daily to target of 40 mg PO daily vs. placebo x 2.95 yrs

O Composite of CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF

Circulation. 2008; 117:24-31

IMAGINEQuinapril Placebo HR 95% CI

CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF

13.7% 12.2% 1.15 0.92 – 1.42NSS

CV death 1.4% 1.2% 1.20 0.60 – 2.38Nonfatal MI 1.3% 1.6% 0.76 0.40 – 1.46CV death, nonfatal MI, stroke first 3 months

1.3% 0.8% 1.60 0.73 – 3.52

CV death, nonfatal MI, stroke after 3 months

2.3% 2.7% 0.82 0.50 – 1.35

Circulation. 2008; 117:24-31

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

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

Summary of EvidenceOutcomes PEACE IMAGINE

- 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 (< 7-10 days) with LVEF > 40% and no DM

- Quinapril to target of 40 mg PO daily vs. placebo

- over 2.95 yrs

Reduce risk of mortality NSS NSS

Reduce risk of future myocardial infarctions

NSS NSS

Adverse event ↑ Cough and syncope ↑ Cough and hypotension

Application to WA and BLWA BL

Necessary √ CV risk factors present Ø DM, HTN, prior MI hxEffective √ ?Safe √ √ Adherence ? √

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

Monitoring PlanEfficacy When

S: Ø MI symptoms- Chest pain

Daily

O: BP (<130-140/80), Ø ECG changes

Decreased hospitalizations for CVD

Daily

OngoingToxicity When

S: Headache, dizziness, dry cough, angioedema

Daily

O: SrCr ↑ > 30%, K > 5 mmol/L Daily post-CABG until stable, then 1-2 weeks post dose increase as outpatient, then with routine outpatient blood work thereafter

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

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

Questions?

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