Management of Non-ST Elevation Acute Coronary

Syndromes (NSTE-ACS)

April, 2017

Mark Schmidhofer

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

“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”

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)

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

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

What Happens When Plaque Ruptures?

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

GUSTO IIB Mortality (Early 1990’s)

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

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

Case (continued)

• Troponin 8.2 (ULN 0.9)

• Point of care echocardiogram showed aortic sclerosis, mild LVH, and mild inferior wall hypokinesis

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

Non MI causes of troponin elevation

• Increased myocyte membrane permeability; eg sepsis, SIRS

• Tachycardia • LVH • Afib • Cardioversion • hypotension • Heart failure • Strenuous exercise • Chest trauma

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

2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426

Therapy ala Jake Jentzer

• Reduce ischemia: beta blockers, nitrates, re-vascularize

• Anti Thrombotic: anti platelets, anti thrombin

• Remodeling: ACEI, statins, aldosterone blockade

Pharmacotherapy in Older Adults with ACS DAI, X J Geriatr Card 2016;13:101-108

2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426

2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426

2014 AHA/ACC NSTE ACS Guidelines Amsterdam EA Circ 2014;130:e344-e426

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)

In Hospital Complication vs TIMI Risk

About 5% per point

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

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)

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)

Fraility 307 patients >75 with NSTEMI

Ekerstad, N Circ 2011;124:2397-2404

Ekerstad, N Circ 2011;124:2397-2404

Similar fraility study from Peking Kang L J Geriatric Card 2015;12:662-667

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

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

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

Platelet Activation

Ararchadonic Acid

ASA

Cox 1

Thromboxane A2

Aspirin Ararchadonic Acid

ASA

Cox 1

Thromboxane A2

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

P2Y12 Inhibitors Ararchadonic Acid

ASA

Cox 1

Thromboxane A2

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

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

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

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

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

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%)

GP IIb/IIIa inhibitors Ararchadonic Acid

ASA

Cox 1

Thromboxane A2

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

“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

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

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

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

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

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

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

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

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

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

Other Points

• K+>4.0

• Mg++>2.0

• Probably tight glucose control

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)

TACTICS-TIMI-18

ACS MACE—PCI 4-48 HOURS

VANQWISH NSTEMI

Timing of PCI

• Not clear

• From RITA-3 and TACTICS-TIMI18, probably should do within 48 hours to obtain benefit

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

Tegn N. Lancet 2016;387:1057-65

FRISC II + ICTUS+ RITA (FIR) Routine vs Selective cath for ACS

Damman P Heart 2012;98;207-213

FIR

FIR

FIR

“A dilution of HR efficacy occurred with age”

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

GRACE Registry Global Registry of Acute Coronary Events Devlin G Eur Heart J 2008;29:1275-1282

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

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%

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

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)

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)

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

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

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

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

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

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

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

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

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

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

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

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

GRACE Registry Global Registry of Acute Coronary Events

Devlin G Eur Heart J 2008;29:1275-1282

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%