The Role of ACEIs in Unstable Angina

Sukhjinder SidhuInterior Health Pharmacy Resident

Cardiology RotationFebruary 21, 2014

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

Our PatientID BL – 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 eventNo chest pain since admission 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

Family Hx Ø

Our Patient

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

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

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

Review of SystemsVitals T 36.5 HR 56 BP 119/81 RR 18 O2 sat 99% (RA)CNS/Neuro A&O x 3HEENT ØRESP ØCVS Trop < 0.04 S1S2 ØS3S4

GI ØGU SrCr 83 eGFR 84 Urea 6.3ENDO Glu 4.0 TG 3.83 Chol 3.32 LDL 0.85 HDL 0.71MSK/Derm ØCHEM Na 141 K 4.3 Cl 103 HCCO3 25HEME Hgb 179 WBC 7.9 Neuts 4.6 Plts 234 INR 1.0

InvestigationsDiagnostics

Day -3 (OMH)

ECG Ø

Day 0 (Admission to KGH)

CXR Ø

Day 1 Echo EF 55-60%

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

RCALCA

Cx

LAD

Current Problems & Medications

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 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.

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 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

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

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 MIsØ Increased risk of adverse events

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- HOPE- EUROPA- PEACE- IMAGINE1 relevant observational study

Trial HOPE (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 2000 342:3;145-33, LANCET 2003 362;782-88, NEJM 2004; 351:205-68

Trial HOPE (n = 9297) EUROPA (n = 12,218) PEACE (n = 8290)

I/C Ramipril 10 mg vs. placebo Perindopril 8 mg vs. placebo Trandolapril 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 (0.70-0.86)

CV death: 6.1% vs. 8.1%RR 0.74 (0.64-0.87)

MI: 9.9% vs. 12.3%RR 0.80 (0.70-0.90)

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 (0.88-1.06)

CV death: 3.5% vs. 3.7%HR 0.95 (0.76-1.19)

Non-fatal MI: 5.3% vs. 5.3%HR 1.03 (0.91-1.16)

Adverse events

HypotensionCough

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 2000 342:3;145-33, LANCET 2003 362;782-88, NEJM 2004; 351:205-68

IMAGINED DB, PC, PG, MC RCT, N=2553

P Inclusion:> 18 y.o; post-CABG < 7-10 days; stable after operation; LVEF > 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 122/70Meds – ASA (91%); statin (65%); BB (79%)

I Quinapril 10 or 20 mg PO daily to target of 40 mg PO daily• median 2.95 yrs

C PlaceboO 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

– 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

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 SS

EUROPA - CAD, no HF, moderate risk factors- Well managed medically- Perindopril 8 mg PO daily vs.

placebo

SS SS

PEACE - CAD, LVEF > 40%, low risk factors- Intensively managed - Trandolapril 4 mg PO daily vs.

placebo

NSS NSS

IMAGINE - Post CABG (< 7-10 days) with LVEF > 40% and low risk factors

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

NSS NSS

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 95-110/60-70

• Adherence– Minimal non-adherence risk

• Patient Factors– Increased pill and cost burden

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

Monitoring PlanEfficacy Toxicity Freq

Vitals BP < 140/90, HR 60-70 BP < 90/50 or symptomaticHR < 60

Daily

HEENT Ø Bleeding nose, gums Daily

CNS Ø Fatigue, headache, dizziness, ↓ exercise tolerance

Daily

CVS Ø chest painØ hospitalizations for CVD

Ø Daily

RESP Ø SOBOE Ø Daily

GI Ø GI upset, hematemesis, melena↓ Hgb

Daily

GU Ø Ø

MSK/DERM Ø Myalgias, weaknessLFTs > 3x ULN, CK > 5x ULN

DailyWhen indicated

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

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

Questions?

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

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