ACUTE MI AND OTHER ACUTE CORONARY SYNDROMES:
MANAGEMENT-REPERFUSION THERAPY

See also Revascularization Procedures in the section on Treatment of Stable Coronary Artery Disease

I. Categories of Reperfusion Therapy

  1. Coronary Artery Bypass Grafting
  2. Thrombolysis--see also under "Thrombolytics"
  1. Benefits
    1. For acute MI, clearly produces long-term (at least 10y) reductions in mortality despite complications (ISAM, GISSI, GISSI-2, ISIS-2, ASSET, European Cooperative Study Group, AIMS, PAIMS, & International Study Group studies)
    2. Greatest benefit < 6h post sx onset; sig. benefit < 12h post sx onset
    3. Some benefit shown when administered up to 24h post-MI, esp. if AWMI, persistent CP, and no q's (see below)
  2. Comparisons of different thrombolystics
    1. Streptokinase vs. t-PA:
      1. 41,000 pts with ST elevations presenting with < 6h symptoms randomized to streptokinase w/SQ hep, streptokinase w/IV hep, t-PA w/IV hep, or streptokinase, t-PA, and IV hep.  t-PA group had sig. lower 30d mortality (6.3% vs. 7.3%) and 1y mortality (9.1% vs. 10.1%) vs. either stroptokinase group("GUSTO" Trial; Circ. 94:1233, 1996-JW)
      2. A subgroup analysis of pts > 85yo in the above study showed no sig. diff. among the treatments(Circ. 94:1825, 1996-JW)
    2. Reteplase vs. others
      1. Reteplase more effective than single 100mg infusion of t-PA over 3h at restoring coronary patency in 154pts with MI and sx < 6h (Circ. 91:2725, 1995--Med. Letter)
      2. Nonsig. lower mortality at 35d and 6mo in randomized trial with standard dose streptokinase in 6,000 pts with MI and sx < 12h (Lancet 346:329, 1995--Med. Letter)
  3. Adjunctive therapies for thrombolysis
    1. ASA (160mg/d) to be given as well x 2-5d
    2. Clopidogrel
      1. In a randomized study in 3,491 pts with ST-segment elevation acute coronary syndrome with onset of sx < 12h, receiving fibrinolytics (all received ASA), randomized to clopidogrel 300mg then 75mg QD vs. placebo, the incidence of (occluded infarct-related artery on angiography 48-192h after meds administered OR (death or MI) before angiography) was sig. reduced (RR .64) in clopidogrel group; also, the 30d incidence of recurrent MI was sig. reduced (RR 0.69) in the clopidogrel group; no sig. diff. in incidence of bleeding complications (NEJM 352:1179, 2005--AFP).
    3. Platelet Glycoprotein Antagonists
      1. In a study in 888 pts with MI s/ST elevation randomized to the following treatments:
        • Alteplase (100mg accelerated-dose)
        • Abciximab 0.24mg/kg bolus plus 0.125mg/kg/min x 12h
        • Abciximab + low-dose Alteplase (20-65mh)
        • Abciximab + low-dose Streptokinase (500k-1500kU)

        All received ASA, alteplase-only pts got standard-dose heparin; abciximab groups got low-dose heparin; the regimen most successful at producing normal flow through the infarct-related artery at 90min was abciximab + alteplase (50mg bolus then 35mg over 1h); no sig. diff's in rate of major bleeding among group except for higher bleeding in streptokinase arm which was abandoned ("TIMI 14," Circ. 99:2720, 1999--JW, UW Pharm. Letter)

    4. IV Unfractionated Heparin (per ACC/AHA guidelines)
      1. Only "limited evidence" that IV or SQ hep is beneficial with streptokinase, anistreplase, or urokinase
      2. With Alteplase, however, IV heparin increases angiographically assessed patency of infarct-related artery; unknown if it affects clinical outcome. ACC/AHA recommend IV hep at least 48h post-administration of Alteplase
      3. 1036 pts s/p anistreplase for MI randomized to ASA 150mg/d vs. IV hep followed by warfarin. Rates of cardiac death or reinfarction at 30d and 90d no different; anticoag. pts had RR > 2.0 to have CVA or severe bleeding (BMJ 313:1429, 1996-JW)
    5. Low Molecular-Weight Heparin
      1. In a study in 20,506 pts undergoing thrombolysis for ST-segment-elevation MI randomized to enoxaparin vs. IV unfractionated heparin, 30d incidence of (death or recurrent MI) was sig. lower with enoxaparin (9.9% vs. 12.0%) though in subgroup of pts > 75yo there was no sig. diff.  (NEJM 354:1477, 2006--JW)
      2. In a study in 
    6. Adenosine
      1. Thought to have the potential to protect from "reperfusion injury"
      2. 236 pts with acute MI receiving thrombolysis < 6h after onset of sx randomized to IV adenosine vs. placebo; in adenosine group, infarction size was 33% less (67% less for anterior MI) but no sig. diff. in reinfarction, CHF, shock, or death (JACC 34:1711, 1999--AFP)
  1. PTCA
  1. Restenosis rate without stenting = 30-40% in 6 mos; thought to be from smooth musc. proliferation, not thrombosis
  2. Relationship between elapsed time to reperfusion and outcomes
    1. In an observational study of 27,080 pts with acute MI undergoing primary angioplasty, "door-to-balloon" time of < 1h was ass'd with sig. lower mortality c/w > 1.5h (4.2% vs. 8.5%) (JAMA 283:2941, 2000--JW)
    2. Nonetheless, in a study of 365 pts 18-80yo presenting with acute ST-elevation MI 12-48h after symptom onset randomized to PTCA + abciximab vs. conservative (medical) therapy, invasive-strategy pts had sig. smaller LV infarct size and nonsig. lower 30d incidence (RR 0.67) of (death, MI, or CVA) (JAMA 293:2865, 2005--abst)
  3. High-dose IV heparin recommended; I don't know for how long
  4. Administration of Abciximab reduces restenosis rate and mortality with PTCA with or without stenting...
    1. In "high-risk" pts undergoing PTCA only--Improved 3y incidence of combined death, MI, or repeat PTCA c/w placebo (JAMA 278:479, UW Pharm letter)
    2. And in pts undergoing PTCA + stenting (NEJM 341:319, 1999--UW Pharm. Letter)
    3. Benefit from Abciximab given with PTCA may be limited to pts with elevated troponin T on presentation (data from CAPTURE trial, NEJM 340:1623, 1999--JW)
    4. In a randomized trial of 2064 pts undergoing nonurgent PTCA w/stent, eptifibatide started immediately before implantation and continued x 18-24h afterward was ass'd with sig. less risk of composite endpoint of (death or MI) (7.5% vs. 11.5%); 6mo mortality nonsig. less in eptifibatide group (0.8% vs. 1.4%) ("ESPRIT" Trial, JAMA 285:2468, 2001--abst)
    5. Abciximab vs. placebo was ass'd with sig. greater 1y survival rate (95% vs. 88%) in a randomized study of pts with acute MI undergoing infarct-artery stent implantation (Abciximab and Carbostent Evaluation ("ACE") Trial; Circ. 109:1704, 2004--abst)
  5. Intracoronary stenting in addition to PTCA--Better than PTCA alone
    1. 227 pts with acute MI randomized to PTCA vs. stent; at 6mos, cardiac event-free survival rate sig. higher in stent group (95% vs. 80%) (Circ. 97:2502, 1998--JW)
    2. 900 pts with acute MI randomized to PTCA vs. PTCA + stent; over 6mo f/u, incidence of further revascularization procedures sig. less in stent group (7.7 vs. 17%); however, stent group had nonsig. higher 6mo mortality (4.2 vs. 2.7) (NEJM 341:1949, 1999--JW)
    3. 2082 pts with acute MI (nearly all with ST elevation or LBBB) randomized to  PTCA (with stenting only in cases of suboptimal results)vs. PTCA + abciximab vs. PTCA + stent vs. PTCA + stent + abciximab.  At 6mo f/u, composite endpoint of (death, repeat MI, major CVA, or revascularization of target vessel) was 10% in pts who had all 3 tx's, 12% for PTCA + stent, 16% for PTCA + abciximab, and 20% for PTCA alone (diffs between stenting and PTCA groups were sig.) (NEJM 346:957, 2002--JW)
    4. Drug-Eluting Stents in acute MI
      1. In a study of 712 pts with ST-elevation MI undergoing catheterization < 12h after symptom onset, randomized to sirolimus-eluting stent vs. uncoated stent, 1y incidence of primary endpoint of (target-vessel revascularization, reinfarction, or death) was sig. lower with coated stents (7.3% vs. 14.3%) (NEJM 355:1093, 2006--JW)
      2. In a study of 619 pts with ST-elevation MI undergoing catheterization < 6h after symptom onset randomized to paclitaxel-eluting stent vs. uncoated stent, 1y incident of primary endpoint (target-lesion revascularization, hospitalization for reinfarction, or cardiac death) was not sig. diff. in the two groups (NEJM 355:1105, 2006--JW)
      3. In a study in 3,006 pts with ST-segment elevation MI randomized to drug-eluting vs. bare-metal stents, there was no sig. diff. in the 1y incidence of (death, reinfarction, CVA, or stent thrombosis (NEJM 360:1933, 2009-JW)
      4. In a study in 3,006 pts with ST-segment-elevation acute MI requiring coronary reperfusion randomized to paclitaxel-eluting stent vs. bare-metal stent, 12mo incidence of target-lesion revascularization was sig. lower in the paclitaxel-eluting stent group (4.5% vs. 7.5%) with no sig. diff. in 12mo incidence of (death, reinfarction, CVA, or stent thrombosis) (NEJM 360:1946, 2009-JW)
  6. Thrombectomy as an adjunct to PTCA
    1. The idea is that removing the thrombus would reduce the risk of distal embolization
    2. In a study in 480 pts with ST-elevation MI randomized to thrombectomy vs. no thrombectomy before primary percutaneous coronary intervention, the thrombectomy group had sig. higher mean infarct size 14-28d post-procedure and had sig. higher short-term mortality ("AIMI" Trial; J. Am. Coll. Cardiol. 48;244, 2006--JW)
  7. Pre-treatment with thrombolytics before percutaneous formulary intervention
    1. In a study in 1,667 pts with ST-segement-elevation MI with anticipated delays of 1-3h until PCI randomized to tenecteplase vs.  no treatment prior to percutaneous coronary intervention, the 90d incidence of (death, heart failure, or shock) was sig. higher in the tenecteplase group. (Lancet 367:569, 2006--JW)
  1. Ultrasonic thrombolysis, delivered intravascularly into the occluded coronary artery

II. Comparisons among reperfusion therapies

  1. Thrombolysis vs. PTCA in acute MI--PTCA is better
    1. In a meta-analysis of 23 randomized trials involving 7739 pts with acute MI comparing PTCA (& stenting in 12 trials) vs. thrombolytics, PTCA was ass'd with sig. lower short-term (4-6wk) mortality (7% vs. 9%; sig.); long-term (6-18mo) outcomes also sig. better in PTCA recipients (Lancet 361:13, 2003--JW)
  2. Thrombolysis + PTCA/Stenting vs. Thrombolysis alone in acute MI--Combination therapy better
    1. In a study of 500 pts with ST-elevation acute MI but no cardiogenic shock s/p thrombolysis randomized to angiography (with revascularization if needed--82% were revascularized) within 24h of thrombolysis vs. no angiography unless ischemia recurred, 1y incidence of (death, recurrent MI, or revascularization) was sig. lower in angiography group (9% vs. 21%) ("GRACIA-1" Trial; Lancet 364:1045, 2004--JW)
III. Studies of early angiography + revascularization vs. more conservative approaches
  1. In Unstable Angina/Non-Q-Wave MI--Evidence tends to support as a routine intervention early
    1. 920 pts (97% men) with Non-Q Wave MI (evolving MI with sx x < 72h, CK-MB < 1.5x normal; no new Q waves on EKG; no "resting ischemia" or CHF) randomized to "invasive" (immediate cath with PTCA or atherectomy for sig. single-vessel disease and CABG for sig. multivessel disease) vs. "conservative" management (radionucleide ventriculography and, before d/c, nuclear treadmill stress test and angio if that was abnormal or if postinfarction angina occurred; 24% in this conservative group ended up having angio); all received ASA and Diltiazem.  Over average 2y f/u, routine angio group had higher rates of revascularization procedures (44% vs. 33%), also had higher 1y risks of death alone and combined endpoint of death or nonfatal reccurent MI. No sig. diff. in 2y total mortality and combined endpoint. (NEJM 338:1785, 1998--JW; AFP)
    2. 2000 pts with increasing or at-rest angina confirmed with ECG and/or cardiac enzymes randomized to revascularization (within 7d, for all pts with at least 70% occlusion of a major coronary a.) vs. noninvasive ("maximal medical") therapy. At 6mos, pts in invasive tx group had sig. fewer MI's and rehospitalization and nonsig. lower mortality (1.9% vs. 2.9%) (FRagmin and Fast Revascularization during InStability in Coronary Artery Disease ("FRISC II") Study, Lancet 354:708, 1999--AFP)
      1. In a follow-up study of the same cohort at 5y, the incidence of (death or MI) was still sig. lower in invasive group (19.9% vs. 24.5%) (Lancet 368:998, 2006--JW)
    3. 2220 pts with unstable angina or non-ST-segment-elevation MI (all tx'd with ASA, heparin, and glycoprotein IIb/IIIa inhibitors) randomized to cath within 48h or conservative approach (cath only if pos. stress test or recurrent ischemia at rest). 6mo incidence of major outcomes were sig. less in intervention group (death, nonfatal MI, or rehosp. 15.9% vs. 19.4%, death or nonfatal MI 7.3% vs. 9.5%) ("TACTICS-TIMI 18" study; NEJM 344:1879, 2001--JW)
    4. May not be beneficial for pts with normal Troponin I levels--In a secondary analysis of data from the TACTICS-TIMI 18 study, combined endpoint was sig. reduced with early invasive approach among pts with elevated Troponin I (> = 0.1mg/dL) (15.3 vs. 25%, respectively) but not in pts with Troponin I levels < 0.1mg/dL (16% vs. 12.4%, respectively) (JAMA 286:2405, 2001--JW)
    5. In a randomized study in 2,220 pts with non-ST-elevation acute coronary syndrome, an early invasive approach (coronary angio < 48h after onset of sx and revascularization where appropriate) vs. conservative approach (angio only if recurrent ischemia or abnormal exercise tolerance).  Among pts > 65yo, invasive group had sig. lower incidence of (death, MI, or rehospitalization for ACS) at 30d (8.2% vs. 13.2%) and 6mos (17.1% vs. 21.7%); pts > 75yo assigned to invasive management had sig. higher incidence of major bleeding than those assigned to conservative management; no sig. diff. for other age groups (Ann. Int. Med. 141:186, 2004--JW)
    6. In a meta-analysis of seven randomized trials of invasive (routine coronary angiography and revascularization) vs. conservative (cath & revascularization only for recurrent or inducible ischemia) in patients with unstable angina or non-ST-segment elevation MI, over mean 17mo f/u, invasive approach was associated with significantly lower incidence of (death or MI) (12.2% vs. 14.4%); There was no benefit in the subgroup of pts with negative baseline levels of biomarkers of myocardial injury (JAMA 293:2908, 2005--abst)
    7. In a study in 1,200 pts with non-ST-segment acute coronary syndromes and elevated troponin T levels randomized to an "early invasive" strategy (routine angiography) vs. angiography only for (refractory sx, hemodynamic or arrhythmic instability, or substantial ischemia on predischarge stress testing), 1y incidence of (death, MI, or rehospitalization for angina) was not sig. diff. for the two groups (NEJM 353:1095, 2005--JW)
    8. In a study in in 1,810 pts with non-ST-elevation acute coronary syndrome randomized to conservative medical management or coronary angiography + (intervention as indicated within 72h of initial presentation), at 5 years, incidence of (death or nonfatal MI) was sig. less frequent in the angiography group (16.6% vs. 20%); ditto for all-cause mortality.(Lancet 366:914, 2005--JW).
    9. In a meta-analysis of seven randomized trials of early invasive strategies vs. conservative strategies in pts with non-ST-segment-elevation acute coronary syndromes, invasive management was associated with sig. lower incidence of death (4.9% vs. 6.5%) and nonfatal MI (7.6% vs. 9.1%) over 2y  (J. Am. Coll. Cardiol. 48:1319, 2006--JW)
    10. In a study in 3,031 adults with acute coronary syndrome without ST-segment elevation randomized to revascularization within 24h of symptom onset vs. > 36h afterward, there was no sig. diff. in 6mo incidence of (death, MI, or CVA) though early-intervention group had sig. lower prevalence at 6mos of refractory ischemia (1.0% vs. 3.1%) ("TIMACS" trial; NEJM 360:2165, 2009-JW))
  2. In Acute MI--Done in majority of acute MI's when it's available--dual purpose of diagnosis and tx (see below re: PTCA etc.)

IV. Studies of late percutaneous coronary intervention after onset of acute MI

  1. In a study 2,166 stable pts s/p acute MI with total occlusion of infarct-related artery and LVEF < 50% undergoing angiography 3-28d after MI randomized to percutaneous coronary intervention (PCI) vs. no PCI; all received "optimal" medical therapy; at 4y, there was no sig. diff. in incidence of (death, nonfatal MI, or admission for heart failure)  ("Occluded Artery Trial" ("OAT"); NEJM 355:2395, 2006--JW)
  2. In a study in 381 pts undergoing angiography 3-28d after MII with at least one totally occluded infarct-related artery suitable for stenting randomized to PTCA+stent vs. medical treatment alone, after 1y, sig. more PTCA pts had patency of the target artery at 1y (83% vs. 25%) ("TOSCA-2" trial; Circ. 114:2449, 2006--JW)

V. Studies of "rescue" PTCA after unsuccessful treatment with thrombolytics

  1. In a study in 427 pts with acute ST-segment-elevation MI with failure of thrombolytic therapy (< 50% resolution of ST-segment-elevation 90min post-therapy) randomized to PTCA, conservative tx, or repeat thrombolysis, PTCA was associated with a sig. lower 6mo incidence of (death, reinfarction, CVA, or severe HF) (15%) than conservative tx (70%) or repeat thrombolysis (69) (NEJM 353:2758, 2005--JW)