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The Role of ACEIs in Unstable Angina

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Presentation on theme: "The Role of ACEIs in Unstable Angina"— 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 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 Syndromes
UA 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


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