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Management of Non-ST Elevation Acute Coronary
Syndromes (NSTE-ACS)
April, 2017
Mark Schmidhofer
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p≤0.05 usually = NS
• Nothing magic about 0.05; SPC uses0.001 • Statistically “significant” but clinically trivial
– Loscalzo, J Circ 2005; 112:3026-29
• Bayes Theorem – Goodman, SN AnnIntMed 1999;130:995-1004; 1999;130:1005-13
• Composite endpoints – Ferreira-Gonzalez, I BMJ doi:10.1136/bmj.39136.682083.AE
• Multiple testings of the same hypothesis – Loscalzo, J Circ 2005; 112:3026-29
• Subgroup analysis – Wang, R NEJM 2007:357:2189-2194
• Trials stopped early for benefit – Bassler, D JClinEpidemiol 2007;60:869-73
• Meta-analysis of small trials – Farkouh, ME NatureClinPractice 2007; 4:635-6
• Eligibility for most RCTs is a favorable prognostic factor – I say that every day
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“The ASA Statement of p Values: Context, Process, and Purpose” Wasserman RL Am Stat 2016;70(2):129-133
• “Sciences dirty secret: the scientific method of testing hypotheses…stands on flimsy foundation”
• “numerous deep flaws” • “..more flaws than Facebook’s privacy policies” • “Scientfic Method:Statistical Errors (Nuzzo R Nature
2014;506:150-152) now one of the most highly viewed Nature articles
• “statistical community has been deeply concerned about issues of reproducibility and replicability of scientific conclusions”
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Acute Coronary Syndromes
• ST elevation myocardial infarction
• Non-ST elevation acute coronary syndromes (NSTE-ACS)
– Accelerated angina, unstable angina, crescendo angina (negative biomarkers)
– Non ST elevation myocardial infarction (positive biomarkers)
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Definition—Unstable Angina
• New onset angina that markedly limits physical activity
• Rest angina, which is usually more than 20 minutes in duration
• Increasing angina that is more frequent, longer in duration, or occurs with less exertion than previous angina
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Pathogenesis
• Plaques are usually assymp until stenosis 70-80%
• Most ACS and STEMI are due to rupture of a plaque of less than 50% with subsequent thrombus formation
• 80-90% of STEMI have vessel occlusion
• 60-85% of NSTEMI do NOT have vessel occlusion, and have grayish white thrombi (platelet rich) in contrast to reddish (fibrin rich) thrombi of STEMI
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What Happens When Plaque Ruptures?
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ACS is an Inflammatory State
• There is evidence of neutrophil activation when passing through the coronary arteries in ACS but not with stable or vasospastic angina
• Patients with persistant elevation of CRP are at increased risk of recurrent instability
• As many as 50% of patients have no identifiable culprit lesion
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GUSTO IIB Mortality (Early 1990’s)
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Patient
• 83 yo female retired social worker presents to ER with two days of vague malaise, profound fatigue, and significant loss of appetite
• PMH is positive for hypertension, COPD, and known high coronary calcium score discovered as part of a longitudinal women’s health study
• Meds: chlorthalidone, amlodipine, prn albuterol inhaler
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CasPatient (continued)
• Pale, ill appearing woman.
• T37 HR 110 BP 100/60 Wt 105 lbs Ht 59 inches
• Exam unremarkable
• Chest xray clear
• EKG sinus tachycardia LBBB; unchanged from prior
• Lab normal but for H/H 11.5/35 and K+ 3.2
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Case (continued)
• Troponin 8.2 (ULN 0.9)
• Point of care echocardiogram showed aortic sclerosis, mild LVH, and mild inferior wall hypokinesis
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ACS in Older Adults
• Typical symptoms often absent
• Dyspnea, diaphoresis, nausea, vomiting, pre-syncope are common
• Often precipitated by physiologic stressors rather than activity
• EKGs are often non-specific, and frequently there are pre-existing abnormalities
• Biomarkers help
• Echos help
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Non MI causes of troponin elevation
• Increased myocyte membrane permeability; eg sepsis, SIRS
• Tachycardia • LVH • Afib • Cardioversion • hypotension • Heart failure • Strenuous exercise • Chest trauma
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Non MI causes of troponin elevation
• Infiltrative diseases • Chemotherapy • Pericarditis • Myocarditis • Pulmonary embolism • Pulmonary hypertension • Acute stroke • Renal failure • God did it • But, it almost always is bad prognostically
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2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426
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Therapy ala Jake Jentzer
• Reduce ischemia: beta blockers, nitrates, re-vascularize
• Anti Thrombotic: anti platelets, anti thrombin
• Remodeling: ACEI, statins, aldosterone blockade
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Pharmacotherapy in Older Adults with ACS DAI, X J Geriatr Card 2016;13:101-108
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2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426
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2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426
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2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426
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Early Risk Stratification TIMI Score
• Age ≥65 years
• Presence of at least three risk factors for CHD (hypertension, diabetes, dyslipidemia, smoking, or positive family history of early MI)
• Prior coronary stenosis of ≥50 percent
• Presence of ST segment deviation on admission ECG
• At least two anginal episodes in prior 24 hours
• Elevated serum cardiac biomarkers
• Use of aspirin in prior seven days (which is probably a marker for more severe coronary disease)
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In Hospital Complication vs TIMI Risk
About 5% per point
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Early Risk Stratification TIMI Score
• Age ≥65 years • Presence of at least three risk factors for CHD
(hypertension, diabetes, dyslipidemia, smoking, or positive family history of early MI)
• Prior coronary stenosis of ≥50 percent • Presence of ST segment deviation on admission
ECG • At least two anginal episodes in prior 24 hours • Elevated serum cardiac biomarkers • Use of aspirin in prior seven days
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Early Risk Stratification TIMI Score
• Age ≥65 years
• Presence of at least three risk factors for CHD (hypertension, diabetes, dyslipidemia, smoking, or positive family history of early MI)
• Prior coronary stenosis of ≥50 percent
• Presence of ST segment deviation on admission ECG
• At least two anginal episodes in prior 24 hours
• Elevated serum cardiac biomarkers
• Use of aspirin in prior seven days (which is probably a marker for more severe coronary disease)
“All TIMI score points are created equal, but some points are more equal than others”
-------George Orwell (I think)
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Probably higher risk
• Higher KillipClass • VT, VF • Afib (3 to 4 fold higher event rate) • ST depression worse than T wave inversion (30 day
death or MI of 10.5 vs 5.5%) • Anterior infarct worse (3 fold one year event) • Higher troponin • BNP, CRP, maybe esp valuable in women • Claudication • Elevated WBC • Chronic renal insufficiency (creat> 1.5, gfr< 60)
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Fraility 307 patients >75 with NSTEMI
Ekerstad, N Circ 2011;124:2397-2404
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Ekerstad, N Circ 2011;124:2397-2404
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Similar fraility study from Peking Kang L J Geriatric Card 2015;12:662-667
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Early Treatment
• Same as STEMI with exception of thrombolytics
– Mostly white plaque (plts and thrombin poor—thrombolytics not as effective)
– Non occlusive thrombi and impaired microvascular perfusion, probably due to embolization rather than occluded epicardial vessel
– TIMI III showed no benefit and probably harm
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Therapeutic Modalites
• O2 if Pulse Ox less than 90
• SL NTG for CP; IV if persistent—contraindicated with phosphodiesterase inhibitors (Viagra, Cialis)
• Intravenous morphine sulfate at an initial dose of 2 to 4 mg, with increments of 2 to 8 mg repeated at 5 to 15 minute intervals
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Platelets
• Plt adherence to injured vessel mediated by von Willebrand factor (vWF) via its interaction with plt surface receptor glycoprotein
• Plt aggregation requires fibrinogen (Fgn) bridging that occurs at GP IIB/IIIA receptor
• Plt GP IIB/IIIA receptors increase with activation and undergo conformational change that allows it to bind to fibrinogen molecules and enables a bridge to form between two plts
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Platelet Activation
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Ararchadonic Acid
ASA
Cox 1
Thromboxane A2
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Aspirin Ararchadonic Acid
ASA
Cox 1
Thromboxane A2
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Aspirin
• Antiplatelet Trialists Collaboration showed two year 25% reduction (13.5 vs 17%) in MI, stroke, and death in patients with prior MI
• Showed 46% reduction of same endpoints (8 vs 13.3%) in patients with ACS
• Dose still unclear; maybe 162-325 mg; chew it, I guess
• Use it forever
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P2Y12 Inhibitors Ararchadonic Acid
ASA
Cox 1
Thromboxane A2
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Clopidogrel
• CURE randomized 12 000 pts with ACS to ASA vs ASA plus clopidogrel 300 load then 75 daily
• At nine months, CV death, MI and stroke was reduced in combined group to 5.2 vs 6.7%
• Bleeding was increased from 2.7 to 3.7% but was not life threatening or associated with hemorrhagic stroke
• Effective both in medical and PCI managed
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Clopidogrel Side Effects
• Bleeding
• Neutropenia in 2.4%, usually in first three months; need to stop it
• TTP-HUS (thrombotic thrombocytopenia purpura-hemolytic uremic syndrome). Rare but really bad. Stop it and plasma exchange
• Hypersensistivity not common but have to stop it unless they can be desensitized
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How Long To Give It CHARISMA
• 15 000 patients in China
• ASA vs ASA plus clopidogrel in pts with CV disease
• Endpoint of MI+stroke+CV death
• No overall difference (6.8 vs 7.3%)
• In pts with clinical disease there was a reduction with combined therapy from 7.9 to 6.9%
• With only multiple risk factors, trend to worse outcomes
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Prasugrel (Effient)
• More rapid onset; higher inhibition
• TRITON-TIMI 38: ACS pts undergoing PCI; compared with clopidogrel
• Endpoint better for prasugrel: 10% vs 12.2%
• Bleeding worse: 2.4 vs 1.8%
• Increased bleeding; not recommended over 75 yo or if prior stroke or low body weight
• Stop 7 days pre surgery
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Ticagrelor (Brillinta)
• Binds reversibly; faster onset; more potent than clopidogrel;cyclopentyltriazolopyrimidine
• PLATO 18K ACS patients vs clopidogrel
• STEMI, NSTEMI, UA 38, 43, 17%
• Death+MI+stroke better for Ticagrelor 9.8 v 11.7%; bleeding was 11.6 v 11.2
• Worse in USA where higher ASA dose used
• Stop 3-5 days pre surgery
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Timing Unresolved
• Based on CREDO, ASA and plavix arms diverged within a few hours, so most recommend giving it at time of Dx rather than waiting for cath; reasonable to hold if low risk (neg trop, nml ekg), high bleeding risk, or high liklihood of CABG
• 2012 meta analysis of 6 randomized and 9 observational studies did not show pre cath administration improved mortality (1.54 v 1.97), but did show lower death, MI, stroke, urgent revasc (9.8 vs 12.3%)
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GP IIb/IIIa inhibitors Ararchadonic Acid
ASA
Cox 1
Thromboxane A2
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GP IIB/IIIA ABCIXIMAB, eptifibatide, tirofiban
• Meta analysis generally suggest 30 day MACE benefit in
– PCI (7.8 vs 11.6%)
– NSTEMI (11.4 vs 12.8 %)
– STEMI (3.9 vs 7.8%) (though more data for abcix than ept)
– Ept cheaper and bleeds less and lasts less long
• ISAR-REACT4 Compared bivalrudin to heparin+IIb/IIIA inhibitors in NSTEMI; no difference in outcomes; more bleeding in heparin/IIB group
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“Platelet Resistance” HPR-High Platelet Reactivity
• Clopidogrel a pro – drug; maybe 15-50% are slow metabolizers
• Lots of drugs affect metab
• Verify Now: P2Y12 reactive units; greater than 240 is associated with increased events
• PCI studies show increased event rates with HPR; medically managed no difference
• Two studies have failed to show improved outcomes with testing guided therapy
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UFH in ACS (most trials before clopidogrel, IIB/IIIA, and PCI)
• UFH better than no Rx when no ASA and maybe better than ASA alone
• UFH plus ASA much better than placebo (7 day death or MI odds ratio 0.53)
• Risk of reactivation of ischemia within 12 hrs of discontinuation, made less by addition of ASA and may not be an issue if PCI done
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LMWH
• Inactivates Xa, but has a lesser effect on thrombin so doesn’t predictably prolong aPTT
• More predictable dose effect; less thrombocytopenia • Enoxaparin prob as good as or better than UFH but maybe
more bleeding; other LMW the same as UFH but more bleeding
• Prob more PCI related bleeding with LMWH than UFH (SYNERGY, A to Z) so try to get an interventionalist to use it
• Conservatively treated prob do as well or better with LWMH for 48 hrs (ESSENCE and A to Z)
• If pt had UFH pre cath and no intervention, continue LMWH for at least 48 hrs and up to 8 days to avoid rebound
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General Anti-Coagulation Recomendations
• For all ACS, start some AC and anti-platelets
• Many like LMWH in many settings because
– Less HIT
– No monitoring and ease of administration
– Maybe better outcomes if conservative strategy
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CRUSADE Anti Coag OD Alexander KP JAMA 2005;294:3108-3116
• NSTE ACS
• Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines National Quality Improvement Registry
• 20 136 patients, 387 academic and community hospitals between Jan-Sept 2004
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Beta Blockers
• Decrease O2 demand by decreasing HR, BP, contractility
• Prob increase VF thresholds based on animals and trials suggesting 30% red in SCD
• Decreased automaticity and increased threshold for activation
• Bradycardia prolongs diastole and improves coronary diastolic perfusion
• Reduces remodeling and improved LV function • May improve LV diastolic function
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Beta Blockers
• Alas, benefit has been shown in AMI but not so much in ACS
• In pre thrombotic era, in AMI reduced mortality by 10-15%
• In reperfusion era, combined STEMI NSTEMI may have been reduced by 10-23%, including the elderly
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Beta Blockers—How Soon?
• No clear benefit to early Tx
• Cooperative Cardiovascular project looked at 200 000 pts and showed reduction in mortality (11.8 vs 19.6%) in pts taking on DC
• COMMIT/CCS2 randomized 46 000 pts (93% STEMI), half of whom got thrombolytics, to early vs late beta blockers • In early group a reduction in MI was seen that was
completely counterbalanced by an increase in fatal stroke
• Cardiogenic shock more likely in patients >70, HR>110, BP<120, rales on exam
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What about COPD?
• 55 000 non wheezing non beta agonist taking pts were retrospectively looked at; survival was better at one year with beta blockers
• 200,000 pts with the same had 83 vs 72% in favor of beta blockers
• Studies show beta blockers have minimal effect on airway properties in those with mild to moderate reactive airway disease
• One study showed only 15 of 94 pts with hx COPD were treated with beta blockers; but thirty six of the others have never been formally diagnosed with COPD
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Beta Blockers
• Beneficial in patients with low ef and heart failure, but start slowly
• Don’t worry about diabetics; it helps them
• Don’t worry about PVD
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Other Points
• K+>4.0
• Mg++>2.0
• Probably tight glucose control
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PCI
• immediate ("primary") intervention is not as necessary in non-ST elevation ACS because of the 60 to 85 percent rate of at least partial patency
• TIMI 18-TACTICS showed TIMI score ≥3 benefitted from PCI if done within 48 hrs; 2 was a wash; ≤1 maybe worse
• 15% will not have apparent stenosis (lysis, vasospasm, small vessel disease; better short term prognosis)
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TACTICS-TIMI-18
ACS MACE—PCI 4-48 HOURS
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VANQWISH NSTEMI
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Timing of PCI
• Not clear
• From RITA-3 and TACTICS-TIMI18, probably should do within 48 hours to obtain benefit
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AFTER 80 Tegn N. Lancet 2016;387:1057
• NSTEMI
• Stable patients over 80 yo in Norway
• 457 patients randomized to invasive or non-invasive
• Mean age 84
• Each got asa and clopidogrel (a few ticagrelor)
• Invasive group 55% men; 45% women
• Non Invasive group 45% men, 56% women
• GRACE score 138 in both (pretty high risk)
• Prim end point MI + urgent revasc + stroke + death
• Secondary endpoint death from any cause
• No crossovers occurred
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Tegn N. Lancet 2016;387:1057-65
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FRISC II + ICTUS+ RITA (FIR) Routine vs Selective cath for ACS
Damman P Heart 2012;98;207-213
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FIR
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FIR
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FIR
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“A dilution of HR efficacy occurred with age”
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Statins
• Draw fasting lipid profile, but it might be artifactually low
• Statins may have pleotropic effects and benefit well before lipid lowering
• MIRACL and PROVE_IT used atrovastatin 80
• Not a totally settled question
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GRACE Registry Global Registry of Acute Coronary Events Devlin G Eur Heart J 2008;29:1275-1282
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Statins
• Heart Protection Study showed simvistatin 40 showed benefit even if LDL <100
• REVERSAL showed atrovastatin 80 lowered LDL to 79 and arrested plaque progression; pravastatin 40 reduced to 110 and didn’t
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Statins
• CARE used pravastatin 40 in 4100 MI survivors of AMI with chol<240
• At 5 yrs, coronary death and MI was 10.2 vs 13.2% and need for revasc 14.1 vs 18.8%
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Statins
• TNT compared atorvastatin 20 with 80 in stable CAD in 10,001 pts
• High dose had LDL of 77 vs 101
• 22% reduction of combined CV endpoint, 20 % reduction in cardiac deaths BUT no difference in overall mortality because of a 25% increase in non-cardiovascular deaths in high dose
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Statins
• IDEAL compared atorvastatin 10 mg with simvistatin 20 in 8888 pts achieving LDLs of 81 vs 104
• 11% reduction in time to cornary death, MI, or cardiac arrest but HR was 0.78-1.01 (almost)
• Significantly reduced non fatal MI 6 vs 7.2% and revasc 13 vs 16.6
• No difference in all cause mort (HR 0.98), CV mort (HR 1.03) or non CV mort (0.92)
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FOURIER NEJM Mar 13, 2017
DOI:10.1056/NEJM021615664
• PCSK9 inhibitors added to statins for secondary prevention in patients around 62; reduced LDL to 30 from 90
• Primary endpoint CV death, MI, stroke, hosp for UA, or revasc 9.8 vs 11.3% (p<0.001)
• Secondary endpoint CV death, MI, stroke 9.9 vs 7.4% (p<0.001) – Any death 3.2 vs 3.1% (p=0.54)
– CV death 1.8 vs 1.7% (p=0.62)
– Stroke 1.5 vs 1.9 % (p<0.01)
– Revasc 5.5 vs 7.0% (p<0.001)
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Statins in ACS
• MIRACL randomized 3000 pts with ACS to atorvastatin 80 vs placebo between 24 and 96 hrs after admission. LDL went from 124 to 72
• At 16 weeks, non fatal MI, CA and recurrent hosp for ischemia was 14.8 vs 17.4%
• PROVE IT-TIMI 22 in pts with ACS showed atrorvastatin 80 reduced clinical events more than pravastatin 40, though mortality while less, (RR 0.72) had p value<0.07
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Statins
• NCEP recommends drug Rx for secondary prevention in pts with CAD and – Diabetes
– Symptomatic carotid disease
– PVD
– AAA
– Multiple risk factors if confer 10 yr risk of CHD more than 20%
– And maybe renal failure
• Start drug Rx for LDL>100 with target <70
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2013 Statin Guidelines for CAD
• High intensity statin (atorvastatin 40-80, rosuvastatin 5-10) unless high risk for side effect or >75
• If not high, moderate if you can (anything less of atorvastatin , rosuvastatin, or simvastatin 20-40, pravastatin 40, lovastatin 40)
• If >75, assess risks and benefits
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Angiotensin II
• Liver makes angiotensinogen
• Kidney makes renin that turns angiotensinogen into angiotensin I
• ACE (found in lung and vascular endothelium) (and probably other stuff, too) turns angiotensin I into Angiotensin II that does everything but ride a bicycle, affecting brain, kidneys, adrenals, vasculature, heart and kitchen sink. Effects are complicated because of at least two angiotensin receptor types
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Angiotensin II and the heart
• AT II increases inotropy
• May increase chronotropy, but that is inconsistent depending on other affects on vascular resistance, adrenergic stim, etc
• Stimulates hypertrophy directly and independent of hemodynamic affects, adversely affecting remodeling
• Adversely affects electrical remodeling; ACEI can decrease incidence of A fib in AMI and CHF
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Angiotensin II and the heart
• Promotes development of atherosclerosis, esp with hyperlipidemia. Increases level of intercellular adhesion molecule 1 which increases leukocycte adhesion to vascular endothelium
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ACEI/ARB
• Beneficial in STEMI, esp if anterior or with decreased ef
• Less data for UA and NSTEMI • GISSI III: ACS lisinopril ↓ mort 7.2-6.3%
• ACC/AHA Guidelines recommend for DM, CHF, EF<40%, and hypertension; but felt reasonable in lower risk
• Timing unlcear—be careful early to avoid hypotension
• ARB ok if ACEI not tolerated
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ACEI/ARB Contraindications
• Allergy
• BP < 90-100 or < 30 mm Hg below baseline
• Shock
• Bilateral renal artery stenosis
• Prior worsening of renal fx with ACEI
• Impaired renal function not absolute contraindication; retrospective study of 20,000 pts ≥65 with MI and impaired ef, survival benefit even in pts with creat>3
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When and how?
• Guidelines recommend po ACEI within 24 hrs of STEMI; not iv because of risk of hypotension
• Prob less urgent in NSTEMI; start in hosp but maybe not first 24 hrs
• Watch BP and start low • Thought to reduce ventricular remodelling over
days to weeks after myocardial damage but the early benefit is probably due to other, maybe neurohumoralmechanisms
• Enalapril 2.5-5, lisinopril 10 bid, captopril 25 tid
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Mineralocorticoid Receptor Antagonist
• AMI causes release of NE and activation of RAAS with loss of K and Mg
• Aldosterone causes myocardial fibrosis and endothelial dysfunction and increases plasminogenactivator inhibitors
• Mostly based on EPHESUS – 30 day mortality reduced from 4.6 to 3.2% when MI,
ef less than 40 and CHF
• Use spironolactone 25-50 mg/day or eplerenone 25 mg per day
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ESC/ACCF/AHA/WHF Def MI
• Type I garden variety plaque rupture
• Type II Supply/demand mismatch
• Type III Sudden cardiac death
• Type IV Associated with PCI
– Elevation during PCI
– Acute stent thrombosis
• Type V Elevation following cardiac surgery
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Recap
• Risk stratification; if high—PCI
• ASA
• Heparin
• P2Y12 inhibitors
• IIB/IIIA
• Beta blockers—early if stable, if not, late
• Statins early probably can’t hurt
• ACEI/ARB if BP stable
• Spirono/epleronone
• Warfarin
• Probably doesn’t change much with age; just keep your eyes open, ear to the ground, watch doses and prepare for side effects
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GRACE Registry Global Registry of Acute Coronary Events
Devlin G Eur Heart J 2008;29:1275-1282
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Food For Thought
RRR (%) ASA 30 Heparin 20 P2Y12 inhibitors 23 IIB/IIIA 23 PCI 30 Beta blocker 15 Statins 22 ACEI/ARB 12 Spirono/epleronone 30 205%