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 ID 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 event
No chest pain since admission
Diagnosed with UA and to be medically managed until follow-up SCA +/- PCI
Allergies
Anti-inflammatory (name?) – hives
Social Hx
80 pack-year smoking hx
Ø EtOH or illicit drugs
Ø influenza immunization
Family Hx Ø

4. Our Patient PMHx: MPTA: OA Acetaminophen 500 mg PO PRN (500 mg Q3days)
Ibuprofen mg PO daily
Asthma
Advair 250/50 1 INH BID PRN
Salbutamol mcg INH Q4H PRN
General Health
Multivitamin 1 tab PO daily

5. Review of Systems Vitals T 36.5 HR 56 BP 119/81 RR 18 O2 sat 99% (RA)
CNS/Neuro
A&O x 3
HEENT Ø
RESP
CVS
Trop < S1S2 ØS3S4 GI GU
SrCr eGFR Urea 6.3
ENDO
Glu TG Chol LDL HDL 0.71
MSK/Derm
CHEM
Na K Cl HCCO3 25
HEME
Hgb WBC Neuts Plts INR 1.0
Cholesterol levels were slightly more elevated at OMH with an LDL of 1.48

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

7. LAD RCA LCA Cx RCA – supplies blood to RA, RV & bottom portion of LV
LCA – divides into Cx artery & left anterior descending artery
Cx - supplies blood to LA & side/back of LV
LAD – supplies blood to front & back of LV
Collateral vessels became enlarged when coronary arteries narrowed; allows blood to flow around the blocked artery to another artery nearby or to the same artery past the blockage protecting the heart tissue from injury

8. Current Problems & Medications
Indication
Medication
Unstable Angina
ASA 81 mg PO daily
Atorvastatin 80 mg PO daily
Metoprolol 25 mg PO BID
Nitroglycerin spray mg Q5min PRN
Smoking Cessation
Nicotine patch 42 mg TDERM daily
Asthma
Advair 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
Plaque builds up over decades
NSTEMI/UA
•Slow plaque leakage from rupture
•Platelet activation
•Partial occlusion
heartcurrents.com

11. Unstable Angina Risk Factors Symptoms Non-modifiable Modifiable
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 SyndromesUA
NSTEMI
STEMI
Chest Pain √
Troponin Rise Ø
ECG Changes
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
Goal door to balloon time = 90 min
Goal door to needle time = 30 min

14. Therapeutic Approach ASA 81 mg PO daily P2Y12 inhibitors
High dose statin
Beta-blockers
RAAS inhibitors
Nitroglycerin PRN
ASA is an antiplatelet and will prevent further clots from forming
P2Y12 inhibitors, such as clopidogrel, prasugrel, ticagrelor are also antiplatelets that prevent clots from forming and are especially used in patients who are medically managed or receive stents to prevent re-stenosis and in-stent thrombosis; not frequently used in patients post CABG (CURE, CAPRIE, CLARITY)
Statins help stabilize the plaque already present in the arteries and help prevent further plaque build up (PROVE-IT, MIRACL)
Beta-blockers help the heart pump more efficiently and heal after a heart attack (MERIT-HF, CIBISII, ISIS-1)
Nitroglycerin spray is used to relieve angina and has no mortality benefits, unlike the other therapies.

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
Various proposed mechanisms that are beneficial in patients with CAD beyond BP 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)
Benefit of ACEI in those with LV dysfxn has been shown in the TRACE (trandolapril), AIRE (ramipril), SMILE (lisinopril), SAVE (captopril) trials
ACC/AHA 2007 Guidelines for UA/NSTEMI

17. Clinical Question P I C O
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 Databases Google Scholar, Medline, Embase
Search 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-analysis
6 relevant RCTs
HOPE
EUROPA
PEACE
IMAGINE
1 relevant observational study
TRACE

19. 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 :3;145-33, LANCET ;782-88, NEJM 2004; 351:205-68

20. Trial HOPE (n = 9297) EUROPA (n = 12,218) PEACE (n = 8290) I/C Outcome
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 ( )
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
- Not all had LVEF tested
- 81% of perindopril cohort taking study med at 3 years
- EF available for most of cohort
- Sponsored by US NHLBI
- Patients received more intensive management vs. HOPE, EUROPA
- Lowest risk cohort vs. HOPE, EUROPA
PEACE demonstrates that, as the absolute risk of a patient decreases, if LV fxn is preserved and intensive contemporary management given, with good control of all risk factors, the absolute benefits of an ACEI decrease and their routine use in these patients may not be warranted
HOPE – 12.3% taking open-label ACEI in placebo cohort at 5 yrs
PEACE - 8.3% of placebo pts taking an open-label ACEI at 3 yrs
NEJM :3;145-33, LANCET ;782-88, NEJM 2004; 351:205-68

21. IMAGINE D 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 122/70
Meds – 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
Placebo O
Composite of CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF
Circulation. 2008; 117:24-31

22. IMAGINE Quinapril Placebo HR 95% CI 13.7% 12.2% 1.15 0.92 – 1.42 NSS
CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHF
13.7%
12.2%
1.15
0.92 – 1.42
NSS
CV death
1.4%
1.2%
1.20
0.60 – 2.38
Nonfatal MI
1.3%
1.6%
0.76
0.40 – 1.46
CV death, nonfatal MI, stroke first 3 months
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
Increase in primary end point with quinapril largely the result of increased risk of recurrent angina and UA
Primary composite during first 3 months and found a SS increase in rates in the quinapril arm vs. placebo (4.8% vs. 3.2%; p = 0.036)
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
ACC/AHA Guidelines:
Class I
1. ACEI/ARBs given before CABG should be reinstituted post-op once the patient is stable, unless CI (B)
2. ACEI/ARBs should be initiated post-op and continued indefinitely in CABG pts who were not receiving them pre-op, who are stable, and who have an LVEF < 40%, HTN, DM, or CKD, unless CI (A)
Class IIa
1. It is reasonable to initiate ACEI/ARBs post-op and to continue them indefinitely in all CABG pts who were not receiving them pre-op and are considered to be at low risk (i.e. normal LVEF, CV risk factors well controlled), unless CI (B)
Class IIb
1. The safety of pre-op administration of ACEI/ARB in pts on chronic therapy is uncertain (B)
2. The safety of initiating ACEI/ARBs before hospital discharge is not well established (B)
Circulation. 2008; 117:24-31

24. IMAGINE Strengths Limitations Generalizability 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
Only 4.5% of quinapril group wasn’t taking med at discharge & 2.6% in placebo group
ACC/AHA Guidelines:
Class I
1. ACEI/ARBs given before CABG should be reinstituted post-op once the patient is stable, unless CI (B)
2. ACEI/ARBs should be initiated post-op and continued indefinitely in CABG pts who were not receiving them pre-op, who are stable, and who have an LVEF < 40%, HTN, DM, or CKD, unless CI (A)
Class IIa
1. It is reasonable to initiate ACEI/ARBs post-op and to continue them indefinitely in all CABG pts who were not receiving them pre-op and are considered to be at low risk (i.e. normal LVEF, CV risk factors well controlled), unless CI (B)
Class IIb
1. The safety of pre-op administration of ACEI/ARB in pts on chronic therapy is uncertain (B)
2. The safety of initiating ACEI/ARBs before hospital discharge is not well established (B)
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
PEACE
CAD, LVEF > 40%, low risk factors
Intensively managed
Trandolapril 4 mg PO daily vs. placebo
NSS
IMAGINE
Post CABG (< 7-10 days) with LVEF > 40% and low risk factors
Quinapril to target of 40 mg PO daily vs. placebo
These and other data may be harmonized by postulating that ACE inhibitors provide general benefit in stable CAD but that the absolute benefit is proportional to disease-related risk, with those at lowest risk benefiting least
The PEACE and IMAGINE studies emphasize the importance of addressing modifiable risk factors and incorporating an assessment of individual risks and benefits in making decisions about ACEI therapy in low risk patients with CHD and preserved left ventricular function.

26. Application Necessary Effective Safety Adherence Patient Factors
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 Efficacy Toxicity Freq Vitals BP < 140/90, HR 60-70
BP < 90/50 or symptomatic
HR < 60
Daily
HEENT Ø
Bleeding nose, gums
CNS
Fatigue, headache, dizziness,
↓ exercise tolerance
CVS
Ø chest pain
Ø hospitalizations for CVD
RESP
Ø SOBOE GI
GI upset, hematemesis, melena
↓ Hgb GU
MSK/DERM
Myalgias, weakness
LFTs > 3x ULN, CK > 5x ULN
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?

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