Presentation on theme: "The Role of ACEIs in Unstable Angina"— Presentation transcript:
1 The Role of ACEIs in Unstable Angina Sukhjinder SidhuInterior Health Pharmacy ResidentCardiology RotationFebruary 21, 2014
2 Learning ObjectivesBy 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 STEMIState the evidence for ACEI in UABe 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 12thCC/HPISub-sternal chest discomfort (burning) x 2 episodesSOBOE x months prior to eventNo chest pain since admissionDiagnosed with UA and to be medically managed until follow-up SCA +/- PCIAllergiesAnti-inflammatory (name?) – hivesSocial Hx80 pack-year smoking hxØ EtOH or illicit drugsØ influenza immunizationFamily HxØ
4 Our Patient PMHx: MPTA: OA Acetaminophen 500 mg PO PRN (500 mg Q3days) Ibuprofen mg PO dailyAsthmaAdvair 250/50 1 INH BID PRNSalbutamol mcg INH Q4H PRNGeneral HealthMultivitamin 1 tab PO daily
5 Review of Systems Vitals T 36.5 HR 56 BP 119/81 RR 18 O2 sat 99% (RA) CNS/NeuroA&O x 3HEENTØRESPCVSTrop < S1S2 ØS3S4GIGUSrCr eGFR Urea 6.3ENDOGlu TG Chol LDL HDL 0.71MSK/DermCHEMNa K Cl HCCO3 25HEMEHgb WBC Neuts Plts INR 1.0Cholesterol 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) CXRDay 1EchoEF 55-60%AngiogramProximal RCA: % narrowingMid RCA: 100% narrowingMid LAD: 90% narrowingProximal Mid LCx1: 100% narrowing 3-vessel CAD to be assessed for CABGDay 2Carotid DopplerMild plaqueØ 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 arteryCx - supplies blood to LA & side/back of LVLAD – supplies blood to front & back of LVCollateral 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 IndicationMedicationUnstable AnginaASA 81 mg PO dailyAtorvastatin 80 mg PO dailyMetoprolol 25 mg PO BIDNitroglycerin spray mg Q5min PRNSmoking CessationNicotine patch 42 mg TDERM dailyAsthmaAdvair 250/50 mg 1 INH Q12HSalbutamol 200 mcg INH QID PRN
9 DRP’sBL 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 AnginaAngina is caused by poor blood flow through the coronary vessels of the myocardiumAcute reduction in myocardial oxygen supplyCAD due to atherosclerosis is the most common cause of UAPlaque builds up over decadesNSTEMI/UA•Slow plaque leakage from rupture•Platelet activation•Partial occlusionheartcurrents.com
11 Unstable Angina Risk Factors Symptoms Non-modifiable Modifiable Family hx of premature CHDMale genderOlder ageDiabetesHTNDyslipidemiaSmokingObesitySedentary LifestyleNon-adherence to medicationsSymptomsDyspneaChest painSub-sternal pressureRadiates to arms, jaw, backHeartburnNausea/vomitingDiaphoresis
13 Goals of Therapy Prevent mortality Minimize myocardial damage and total ischemic timeEstablish and maintain patency of the infarct-related arteryAlleviate signs and symptomsPrevent re-occlusion, re-infarction, re-hospitalizationMinimize adverse eventsPromote smoking cessationGoal door to balloon time = 90 minGoal door to needle time = 30 min
14 Therapeutic Approach ASA 81 mg PO daily P2Y12 inhibitors High dose statinBeta-blockersRAAS inhibitorsNitroglycerin PRNASA is an antiplatelet and will prevent further clots from formingP2Y12 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 hypertrophyIncrease bradykininIncreases nitric oxide production = vasodilationAnti-atherosclerotic effectsAntagonize the rupture of plaquesEnhance fibrinolysisBlood pressure controlVarious 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 CADACEI 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) trialsACC/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 LVEFIACEI + ACS therapy (ASA, atorvastatin, beta-blocker)CPlacebo + ACS therapy (ASA, atorvastatin, beta-blocker)ODecrease mortalityPrevent future MIsØ Increased risk of adverse events
18 Literature Search Databases Google Scholar, Medline, Embase Search TermsAngiotensin-Converting Enzyme InhibitorsCardiovascular diseases or heart diseasesLimitsEnglish language and (guideline or meta analysis or RCT or systematic review)Results2 relevant meta-analysis6 relevant RCTsHOPEEUROPAPEACEIMAGINE1 relevant observational studyTRACE
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)PVDStrokeDM + > 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 testExcluded 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 traits66 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 medsAntiplatelet (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. placeboPerindopril 8 mg vs. placeboTrandolapril 4 mg vs. placeboOutcomeComposite of death from CV causes, MI, or stroke- Median duration: 4.5 yearsComposite of CV death, non-fatal MI or cardiac arrest with successful resuscitation- Mean duration: 4.2 yearsComposite of death from CV causes, non-fatal MI, or coronary revascularizatoin- Median duration: 4.8 yearsResultsPrimary: 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 eventsHypotensionCoughCritique- 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, EUROPAPEACE 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 warrantedHOPE – 12.3% taking open-label ACEI in placebo cohort at 5 yrsPEACE - 8.3% of placebo pts taking an open-label ACEI at 3 yrsNEJM :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 MIBaseline:Mean age 61; men (87%); DM (10%); HTN (47%); LVEF 60%; BP 122/70Meds – ASA (91%); statin (65%); BB (79%)IQuinapril 10 or 20 mg PO daily to target of 40 mg PO dailymedian 2.95 yrsCPlaceboOComposite of CV death, resuscitated cardiac arrest, nonfatal MI, coronary revascularization, UA requiring hospitalization, angina, stroke and CHFCirculation. 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 CHF13.7%12.2%1.150.92 – 1.42NSSCV death1.4%1.2%1.200.60 – 2.38Nonfatal MI1.3%1.6%0.760.40 – 1.46CV death, nonfatal MI, stroke first 3 months0.8%1.600.73 – 3.52CV death, nonfatal MI, stroke after 3 months2.3%2.7%0.820.50 – 1.35Increase in primary end point with quinapril largely the result of increased risk of recurrent angina and UAPrimary 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 eventsACC/AHA Guidelines:Class I1. 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 IIa1. 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 IIb1. 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 medicationsLimitations11% of placebo cohort was taking open-label ACEI at 3 yearsIndustry sponsoredGeneralizabilityPatient had CABG surgeryNormal LVEFExcluded majority of DM patientsOnly 4.5% of quinapril group wasn’t taking med at discharge & 2.6% in placebo groupACC/AHA Guidelines:Class I1. 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 IIa1. 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 IIb1. 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 factorsRamipril 5 mg PO daily vs. placeboSSEUROPACAD, no HF, moderate risk factorsWell managed medicallyPerindopril 8 mg PO daily vs. placeboPEACECAD, LVEF > 40%, low risk factorsIntensively managedTrandolapril 4 mg PO daily vs. placeboNSSIMAGINEPost CABG (< 7-10 days) with LVEF > 40% and low risk factorsQuinapril to target of 40 mg PO daily vs. placeboThese 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 leastThe 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 ↓ LVEFEffectiveIn CABG patients with no clear indication for ACEI, they have conflicting evidence in reducing CV death, non-fatal MI, and revascularizationSafetyRisk of hypotension and coughBP was consistently /60-70AdherenceMinimal non-adherence riskPatient FactorsIncreased pill and cost burden
27 Therapeutic Plan Do not initiate an ACEI at present Administer influenza vaccine 0.5 mL IM x 1Hydrocortisone cream 1% apply to affected areas BID PRNProvided counseling regarding A/E of NSAID useProvided counseling on the use of acetaminophen over NSAIDs for OA painProvided counseling and reinforcement regarding smoking cessation
28 Monitoring Plan Efficacy Toxicity Freq Vitals BP < 140/90, HR 60-70 BP < 90/50 or symptomaticHR < 60DailyHEENTØBleeding nose, gumsCNSFatigue, headache, dizziness,↓ exercise toleranceCVSØ chest painØ hospitalizations for CVDRESPØ SOBOEGIGI upset, hematemesis, melena↓ HgbGUMSK/DERMMyalgias, weaknessLFTs > 3x ULN, CK > 5x ULNWhen indicated
29 Follow Up ACEI not initiated at this time Influenza vaccine administeredBL receptive to smoking cessationBL receptive to avoiding use of NSAIDs and using acetaminophen for pain controlSuccessful 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 presentHTN, DM, ↑ chol, or ↓ LVEFACEI have not shown similarly consistent results in lower CV risk patients
32 NSAIDs & CV RiskCOX-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 remodelingCOX-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 prostacyclinNSAIDs 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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