1. Alyssa Morris, R4 September 30, 2010

2.  Mx of UA/NSTEMI in the ED  CRUSADE, COMMIT, ISIS-2, CAPRIE, CURE, PCI- CURE, OASIS-5, OASIS- 7, SYNERGY  NOT covering  GPIIb/IIIa inhibitors  Statins  Decision to go to PCI or medical management  Variants of ACS

4.  See handout

5.  Stable Angina  Angina brought on by exertion and relieved with predictable measures (rest/NTG)  Unstable Angina/ACS  New onset angina w/i 2/12 and at least CCS III  Rest angina lasting >20min w/i 1wk of angina  Change from baseline  NSTEMI/ACS  + markers

6.  Acute Coronary Syndromes is the preferred terminology to refer a spectrum of disease related to myocardial ischemia (stable angina) Unstable Angina NSTEMI STEMI +/- abN ECG, -ve markers +/- abN ECG, +ve markers STE on ECG, +ve markers

7.  60M with RSCP with a +TNT at 6 hrs after pain started, no STE on multiple ECGs  BP= 176/98, P= 90, 02= 94%  How would you treat this person?  Write down all that you would do  What do you think the NNT for each of your therapies is?

8.  ANTI-ISCHEMIC  Inc supply: nitrates, oxygen  Dec demand: BB, morphine, ACE-I  ANTI-PLATELET  ASA, Clopidogrel, GPIIb/IIIa inhibitors  ANTI-THROMBOTIC  Medical: UFH, LMWH, thrombolytics  Invasive: PCI/CABG  ANTI-INFLAMMATORY  Statins

10. LOE: B  Administered to UA/NSTEMI pts with:  Sa02<90%  Respiratory distress  Other high-risk features for hypoxemia LOE: C  Reasonable to administer to all patients in 1 st 6hrs from presentation

11.  Reduces myocardial oxygen demand while enhancing myocardial oxygen delivery  Venous dilation  Arterial dilation  Peripheral and coronary arteries

12. LOE: C  Sublingual NTG for ongoing ischemic discomfort  0.4mg Q5min, max of 3 doses  Assess need for IV NTG  Persistent pain, HF, HTN  Q: How do you titrate your nitro drip?  Not if SBP<90, HR<50, PDE I in last 24-48hr

13.  Venodilation  Modest reductions in HR (inc vagal tone)  Modest reductions in SBP CLASS IIa/ LOE B  Reasonable to administer it IV if uncontrolled ischemic chest pain despite NTG  Provided you use additional therapy to manage the ischemia

14.  Nonrandomized, retrospective, observational study  N= 57,039 (w NSTEMI)  17,003 (29.8%) received morphine  Higher adjusted risk of death (OR 1.48, 95% CI 1.33-1.64

15.  Competitively block the effects of catecholamines on cell membrane R  Reduce myocardial contractility  Reduce sinus node rate  Reduces AV node conduction velocity

16.  Randomized trial  N= 45,852  93% had STE or LBBB  7% had NSTEMI  Randomized to metoprolol or placebo  IV max 15mg then 200mg PO OD  No reduction in composite of death, reinfarction or cardiac arrest  Less VFIB later in study  Increased risk of cardiogenic shock in 1 st day

17.  CLASS I/ LOE B  Oral BB should be started w/i 24hr in patients who do not have 1 of: 1) Signs of HF, 2) low-output state, 3) increased risk for cardiogenic shock, 4) other contraindications to BB  CLASS II/ LOE B  Reasonable to administer IV BB at time of presentation for HTN who do not have 1 of above

18.  Reduce cell transmembrane inward Ca flux  Inhibits myocardial and vascular smooth muscle contraction  Some also slow AV conduction and depress sinus node impulse formation  Verapamil and diltiazem  Coronary dilation  Benefit is from reduced myocardial oxygen demand and improved myocardial flow

19.  CLASS I/ LOE B  Nondihydropyridine CCBs should be given to pts with ongoing or frequently occurring ischemic pain in whom BB are contraindicated  Not if LV dysfunction or other CIs  CLASS IIb/ LOE B  Can use ER nondihydropyridine CCB instead of a BB  Can only use IR dihydropyridine in adequately BB pt

20.  CLASS I/ LOE A  Should be started orally w/i 24h in pts with pulmonary congestion or LVEF <0.4 in absence of hypotension (SBP<100)  CLASS IIa/ LOE B  Can be used in patients w/o pulmonary congestion or LVEF <0.4  CLASS III  IV should not be given in the 1 st 24h b/c of increased risk of hypotension

21.  CLASS I/LOE C  b/c of increased risk of mortality, reinfarction, htn, HF and myocardial rupture associated with their use, NSAIDs (except ASA) should be discontinued and not administered

23.  Irreversibly inhibits COX-1 w/i platelets  Diminishes platelet aggregation  Fully present even with low dose

25.  Meta-analyses of RCTs  195 trials, 143,000 patients  22% reduction in the odds of vascular death, MI, or stroke  ARR 6.1%, NNT 16  75mg to 1500mg of ASA showed similar reductions in the odds of vascular events

26.  RCT  N= 17,187 pts with suspected acute MI  Randomized to 1month of ASA  26 fewer deaths per 1000 during first 35d  ARR for 35d mortality 2.4%  RRR for 35d mortality 23%  NNT=43 (to prevent one death)  Showed benefit if given early

27.  CLASS I/ LOE A  ASA should be administered asap and continued indefinitely  In pts with hx of GIB a PPI should be used  CIs  Intolerance and allergy  Active bleeding  Hemophilia  Severe untreated htn

28.  Platelet effects are irreversible but take several days to achieve  Loading dose shortens this time substantially  Different mechanism than ASA  Potential exists for for additive benefit  Adenosine diphosphate receptor antagonist

29.  Randomised, blinded international study  Efficacy of ASA and Clopidogrel (75mg OD) in reducing risk of a composite of ischemic stroke, MI, vascular death  N= 19,185, Included recent ischemic stroke, MI or symptomatic peripheral artery dz  Plavix annual risk of 5.32% vs ASA 5.83% (P=0.043) (NNT= 194)  No difference in AE

30.  RCT  N= 12,562 with UA/NSTEMI  Placebo or Clopidogrel (300mg loading dose then 75mg daily)  All pts received ASA  Outcome: 1) composite of death from CV cause, MI or stroke 2) refractory ischemia  Results: 1) placebo 11.4% vs Clopidogrel 9.3% 2) placebo 18.8% vs clopidogrel 16.5% (p<0.001) (20% RRR, 2.1% ARR, NNT= 48)

31.  Observational substudy of CURE  N= 2658 pts undergoing PCI  Received the loading dose of Plavix then daily for 10 days, then they got thienopyridine for 4 weeks, then plavix restarted  Outcome: composite of death, MI or urgent revascularization  Results: placebo 6.4% vs clopidogrel 4.5% (p=0.03) (ARR= 3.8%, NNT= 26)

32.  RCT  45852 pts, 7% had UA/NSTEMI  Plavix 75mg OD or placebo  Outcomes: 1) composite of death, reinfarction or stroke; 2) death from any cause  ARR 0.9% and NNT 111  Concluded that adding plavix to ASA safely reduces mortality and major vascular evens and should be done routinely

33.  Approved loading dose in UA/NSTEMI is 300mg  600mg does achieve antiplatelet fxn more quickly  Not enough good evidence to use this much  Considerable inter-individual variation in antiplatelet effect with all loading doses  O mg if you believe pt going to CABG  Increased risk of minor bleeding  Some believe benefit outweighs risk

34.  RCT2x2 factorial design  N= 25,086 w ACS, >70% had UA/NSTEMI  Invasive strategy + loading dose of 600mg Plavix or 300mg Plavix  High or low dose ASA also given randomly  Outcome: cardiovascular death, myocardial infarction or stroke at 30d  4.2% in high Plavix vs 4.4% standard Plavix  Secondary outcome of stent thrombosis in those with PCI (HD 1.6% v SD 2.3%, p= 0.001)

35.  CLASS I  Plavix should be given to pts who are unable to take ASA (LOE A)  Pts with hx GIB should get a PPI if getting Plavix (LOE B)  Plavix should be given to pts in addition to ASA in pts who are receiving an initial invasive stratgey (LOE B)  Plavix should be given to pts in addition to ASA in pts who are receiving conservative therapy (LOE B)

37.  UFH  Accelerates action of antithrombin  inactivates factor IIa (thrombin), factor IXa and Xa  Prevents thrombus propagation but does not lyse existing thrombi  Binds to a number of plasma proteins, blood cells and endothelial cells

39.  LMWH  From depolymerization of chains of heparin  Inactivate Xa>IIa (b/c of molecular weight)  Advantages: ▪ decreased binding to plasma proteins and endothelial cells ▪ Dose-independent clearance ▪ Longer half-life that results in more predictable and sustained anticoagulation w SC administration

41.  Fondaparinux  Synthetic pentasaccharide  Acts proximally in cascade to inhibit multiplier effects of the downstream coagulation rxns  reduce amount of thrombi that is generated  Indirect, selective factor Xa inhibitor  Binds to antithrombin III  Same advantages as LMWH

43. Property UFHLMWHFondaparinux Source animal synthetic T 1/2 ~3h~4h (variable)17-21h Bioavailability (SC) 30%>90%100% Elimination Reticuloendothelial and renal renal Induced HIT* 2-5%1-2%Not observed Inter or intra- patient variability ++++++ Monitoring aPTT Plt count nil Reversal Protamine FFP

44.  Prospective, randomized, open-label  N= 10027 high-risk UA/NSTEMI pts w early invasive strategy  Compare enoxaparin to UFH for composite endpoint of all-cause death or MI in 30d  14% in enox group vs 14.5% in UFH group (p=0.4)  More bleeding in enox group  Post-hoc showed from switching type of anticoagulant at time of PCI

45.  To assess the effects of LMWH compared to UFH for ACS (UA/NSTEMI)  7 studies involving over 10,000 people  No difference in overall mortality  LMWH showed reduced recurrence of MI and the need for revascularization procedures  No difference in recurrent angina, major bleeds, or minor bleeds; there was a decrease in the incidence of HIT  125 patients have to be treated with LMWH to prevent 1 MI, and 50 have to be treated to prevent 1 revascularization procedure Cochrane Database of Systematic Reviews 2003

46.  RCDBT, industry sponsored, non-inferiority  N= 20,078, UA/NSTEMI patients  Enox 1mg SC BID v Fonda 2.5mg SC OD  + UFH at PCI if last dose >6hr ago  Outcomes: 1) death, MI or refractory ischemia at 9d; 2) major bleeding  1) 5.8% w fonda v 5.7% w enox  Satisfies non-inferiority criteria  2) 2.2% w fonda v 4.1% w enox (p<0.001)

47.  CLASS I  Should be added to antiplt therapy at presentation  Invasive Strategy LOE A ▪ UFH or Enoxaparin  Invasive Strategy LOE B ▪ Fondaparinux  Conservative strategy LOE A ▪ UFH or enoxaparin  Conservative strategy LOE B ▪ Fondaparinux  Use fondaparinux if increased risk of bleeding

48.  BB  ASA  NNT 16 in meta-analysis  NNT 43 in ISIS-2  Plavix  NNT 48 in CURE  NNT 194 in CAPRIE  NNT 26 in PCI-CURE  NNT 111 in COMMIT  Anticoagulant