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ISSUES AND CONTROVERSIES IN PRIMARY PTCA

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  • Patients were candidates for the trial if they were moderate-high risk, had an acute coronary syndrome, and there was a plan to perform PCI. A sample size of 13, 600 was considered necessary to provide at least 90 % power to test the primary hypothesis All patients were to receive ASA. Randomization was stratified by UA/NSTEMI vs STEMI DB study drug therapy consisted either of - standard dosing with clopidogrel with a LD of 300 mg and MD of 75 mg - OR prasugrel with a LD of 60 mg and MD of 10 mg DB study drug was to be given for a median of at least 12 months with a minimum of 6 mos and maximum of 15 months The primary composite EP was CV death, MI, or Stroke through the end of the study Key secondary EPs are listed here and among these was Stent thrombosis Key safety Eps included: TIMI major (non CABG) bleeds, and life-threatening bleeds Two key substudies are evaluating pharmacokinetics and genomics
  • This slide depicts the balance of efficacy and safety observed in the trial. At the top is shown the significant reduction in the primary endpoint as presented a few moments ago. The number needed to treat to prevent one event was 46 At the bottom is the rate of TIMI major non CABG bleeds--a key safety endpoint-- which was 2.4% with prasugrel and 1.8% with clopidogrel—a 0.6% Absolute risk increase. The excess of 35 major bleeds with prasugrel corresponded to an HR of 1.32 and P value of 0.03 . The number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167.
  • The beneficial effect of prasugrel on the primary end point was consistent across key prespecified major subgroups. Notable observations include: A significant benefit in both the UA/NSTEMI and STEMI cohorts There was a consistent reduction in events with prasugrel in men and women, pts with and without diabetes, those treated with either a BMS or DES whether or not a GPI was administered and regardless of the degree of renal function All P values in tests for interaction for the subgroups described were negative. Not depicted on the slide are the data showing a reduction in events with prasugrel regardless of the timing of the LD
  • To evaluate the impact of the LD and MD of prasugrel we performed a landmark analysis of events through 3 days, and from 3 days to the end of the study. As you can see PRASUGREL REDUCED THE PRIMARY ENDPOINT by 18% through 3 days and by 20% from 3 days to the end of the study suggesting that there was a significant benefit of prasugrel compared clopidogrel during both the LD and MD phases of treatment.
  • More details of the bleeding events are shown on this slide. The TIMI major non CABG bleed data are shown in the pair of bar graphs on the left, showing the increase in events with prasugrel Life threatening bleeding--another key safety EP ( defined as requiring a 4 unit txn, fluid or inotropic support, surgical intervention, or an ICH) occurred in 0.9 % of clopidogrel and 1.4% of prasugrel subjects—a 0.5% ARI with prasugrel, associated with a P value of 0.01 Subcategories of life threatening bleeding are shown to the right. Fatal bleeding occurred in 0.1% of pts with clopidogrel and was increased to 0.4% of patients with prasugrel—a 0.3% Absolute risk increase associated with a P value of 0.002. There was no difference in ICH overall in the trial—occurring in 0.3% of pts in both groups. Of note, in the subgroup of 518 patients with a history of prior stroke or TIA, no ICH’s occurred with clopidogrel while 6 occurred with prasugrel—a significant difference at the 0.02 level.
  • † The optimum LD of clopidogrel has not been established. Randomized trials establishing its efficacy and providing data on bleeding risks used a LD of 300 mg orally followed by a daily oral dose of 75 mg. Higher oral LDs such as 600 mg or more than 900 mg of clopidogrel more rapidly inhibit platelet aggregation and achieve a higher absolute level of inhibition of platelet aggregation, but the additive clinical efficacy and safety of higher oral LDs have not been rigorously established. The necessity for giving a LD of clopidogrel prior to PCI is driven by the pharmacokinetics of clopidogrel where several hours are required to achieve desired levels of platelet inhibition.
  • Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. In patients ≥ 75 years of age, prasugrel is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI) where its effect appears to be greater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. Additional risk factors for bleeding include: body weight < 60 kg; propensity to bleed; concomitant use of medications that increase the risk of bleeding ( e.g. , warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDS]).
  • † For post-PCI patients receiving a stent (BMS or DES), a daily maintenance dose should be given for at least 12 months and up to 15 months unless the risk of bleeding outweighs the anticipated net benefit afforded by a thienopyridine. §Patients weighing < 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients < 60 kg. The effectiveness and safety of the 5 mg dose have not been prospectively studied. For post-PCI patients receiving a stent (BMS or DES), a daily maintenance dose should be given for at least 12 months and up to 15 months unless the risk of bleeding outweighs the anticipated net benefit afforded by a thienopyridine. Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. In patients ≥ 75 years of age, prasugrel is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI) where its effect appears to be greater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. When possible, discontinue prasugrel at least 7 days prior to any surgery. Additional risk factors for bleeding include: body weight < 60 kg; propensity to bleed; concomitant use of medications that increase the risk of bleeding (e.g., warfarin, heparin, fibrinolytic therapy, chronic use of non-steroidal anti-inflammatory drugs [NSAIDS]).
  • ‡ Clopidogrel LD post fibrinolytic therapy: for patients given fibrin- and non-fibrin-specific lytic undergoing PCI within 24 hrs, 300 mg; for patients given fibrin-specific lytic undergoing PCI after more than 24 hrs, 300-600 mg; for patients given non-fibrin-specific lytic undergoing PCI between 24-48 hrs, 300 mg; for patients given non-fibrin-specific lytic undergoing PCI after 48 hrs, 300-600 mg.
  • Platelets, procoagulant activity, and coagulation cascade with several key points at which specific drugs may exert their antithombotic activity.
  • Aims of optimal antithrombotic therapy.
  • With provisional abciximab or double-bolus eptifibatide. After coronary arteriography, a second round of randomization was performed, with eligible patients to receive a paclitaxel-eluding stent or a bare metal stent (not shown)- this randomization remains blinded.
  • P values based on log rank test. Event rates represent kaplan meier estimates.
  • P values based on log rank test. Event rates represent Kaplan-Meier estimates. 1-yr difference= 5.8% vs. 9.2%, p=0.001
  • Key Message: HORIZONS AMI builds on a wealth of experience with bivalirudin across a spectrum of patients with acute coronary syndromes (ACS) undergoing PCI and supports the major landmark trials REPLACE-2 1 and ACUITY. 2 References 1. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853-863. 2. Stone GW, McLaruin BT, Cox DA, for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-2216. Stone p2203/Abstract/ Conclusions Stone p2203/Abstract/ Conclusions Lincoff p853/Abstract/ Conclusions Lincoff p853/Abstract/ Conclusions
  • In a post hoc analysis, clinical events were significantly reduced in the fondaparinux group at long-term follow-up at 6 months. At 6 months the incidence of death was 5.8% in the fondaparinux group and 6.5% in the enoxaparin group (P=0.05); the incidence of death/MI was 10.5% in the fondaparinux group and 11.4% in the enoxaparin group (P<0.05); the incidence of stroke was 1.3% in the fondaparinux group and 1.7% in the enoxaparin group (p<0.04). The composite of death, MI and stroke was also significantly lower in the fondaparinux group (11.3% vs 12.5% in the enoxaparin group (p<0.007).
  • As one focuses on the subset of patients undergoing PCI in OASIS 5 (n=6,239), there are significant reductions in major bleeding at net clinical outcome with fondaparinux, but no difference in ischemic events (and trends that slightly favor enoxaparin). It is interesting to note that the close association between bleeding and mortality that was present in the overall patient cohort is NOT present in the PCI subset.
  • This slide shows graphically the cumulative composite ischemic events out to 35 days for the three groups of patients. There were no significant differences between groups.
  • This slide shows graphically the cumulative major bleeding events out to 35 days for the three groups of patients. Major bleeding was significantly lower in the bivalirudin alone group.
  • When both ischemic endpoints and bleeding were factored together into “net clinical outcome”, the bivalirudin alone group did significantly better. This slide depicts cumulative net clinical benefit for the three groups out to 35 days.
  • May be useful in STEMI patients with short ischemic times and large clot burdens
  • Objectives   The aim of this study was to evaluate the use of a new manual thrombus-aspirating device in unselected patients with ST-segment elevation acute myocardial infarction (STEMI) undergoing urgent percutaneous coronary intervention (PCI). Background   Failure to achieve myocardial reperfusion often occurs during PCI in patients with STEMI. The use of thrombus-aspirating devices might improve myocardial reperfusion by reducing distal embolization. Methods   We prospectively randomized before coronary angiography 100 consecutive patients with STEMI to either standard PCI or PCI with manual thrombus-aspiration. Primary end points of the study were post-procedural rates of myocardial blush grade (MBG) ≥2 and ST-segment resolution (STR) ≥70%. Analyses were planned by intention to treat. Results   Ninety-nine patients entered the analyses. The rates of post-procedural MBG ≥2 and STR ≥70% were, respectively, 68.0% and 44.9% in the thrombus-aspiration group compared with 58.0% and 36.7% in the standard PCI group: odds ratio (OR) 2.6 (95% confidence interval [CI] 1.2 to 5.9), p = 0.020, and 2.4 (95% CI 1.1 to 5.3), p = 0.034, respectively. Moreover, the rate of patients achieving both the angiographic and electrocardiographic (ECG) criteria of optimal reperfusion was significantly higher in the thrombus-aspiration group compared with standard PCI: 46.0% versus 24.5%, OR 2.6 (95% CI 1.1 to 6.2), p = 0.025. In multivariate analysis, randomization to thrombus-aspiration was a significant independent predictor of achievement of MBG ≥2 and STR ≥70% (p = 0.013).
  • Conclusions   This prospective randomized study shows that manual thrombus-aspiration in unselected patients with STEMI undergoing primary or rescue PCI is clinically feasible and results in better angiographic and ECG myocardial reperfusion rates compared with those achieved by standard PCI. Study population and randomization The study protocol was approved by the ethics committee of our institution. All patients within 12 h of onset of STEMI referred for primary or rescue PCI to our catheterization laboratory between January 2004 and November 2004 entered the study after obtaining written consent for the procedure. No angiographic exclusion criteria were adopted. After enrollment and before coronary angiography, patients were randomly assigned 1:1 to undergo either standard PCI or PCI with thrombus-aspiration according to a computer-generated random series of numbers. Thrombus-aspirating device The Diver CE (Invatec, Brescia, Italy) is a rapid-exchange, 6-F compatible, thrombus-aspirating catheter. It has a central aspiration lumen and a soft, flexible, 0.026-inch, non-traumatic tip with multiple holes (one large anterior and three smaller lateral ones) communicating with the central lumen. A 30-ml luer-lock syringe is connected to the proximal hub of the central lumen for thrombus-aspiration ( 1 ). Percutaneous coronary intervention and medications In patients randomized to standard PCI (standard PCI group), after crossing of the target lesion with the guidewire, direct stent implantation was attempted if judged possible by the operator, whereas in the remaining cases pre-dilation with an undersized balloon was used before stent implantation. In patients randomized to manual thrombus-aspiration (thrombus-aspiration group), after placement of the guidewire, the Diver CE (Invatec) was slowly advanced in aspiration two to five times (depending on operator choice and on the angiographic result obtained) through the culprit lesion. Thereafter, the procedure was continued at the operator’s discretion. All patients were treated by heparin (initial weight-adjusted intravenous bolus then further boluses administered with the aim of obtaining an activated clotting time of 250 to 300 s in patients treated with abciximab and >300 s in the remaining subjects) and with double antiplatelet therapy with aspirin and clopidogrel (loading dose of 300 mg followed by 75 mg/day) for at least four weeks. Unless contraindicated, abciximab (0.25 mg/kg bolus plus infusion of 0.125 μg/kg/min for 12 h) was intravenously administered in all patients undergoing primary PCI, whereas in those with failed thrombolysis, abciximab use was left to the operator’s discretion. Clinical data collection, electrocardiogram, and laboratory data Clinical data were prospectively collected on dedicated case report forms. Pre-intervention and post-intervention electrocardiograms (ECG) were analyzed as a single group by one trained cardiologist blinded to procedural and clinical data. Single-lead ST-segment resolution (STR) was measured by comparing the most prominent ST-segment deviation before coronary angiography and after the procedure according to Schroder et al. ( 4 ). After the procedure, patients underwent repeated sampling (every 8 h for 2 days, then every day) for creatine kinase-MB mass assessment.
  • Transcript

    • 1. Issues and Controversies inPrimary PTCA DrG.KrishnaKanth Issues and Controversies in Primary PTCA
    • 2.  Various issues involved which can make difference between Primary and conventional PTCA : 1)Primary PTCA vs Thrombolytic therapy 2)Antiplatelet regimen to be given 3)Access Site 4)Anticoagulation 4)Gp IIb-IIIa blocker 5)Thrombosuction 6)Methods to improve Microvascular Perfusion 7)Tackling Multivessel CAD in Primary PTCA 8)LMCA in primary PTCA. 9)DES vs BMS in Primary PTCA. Issues and Controversies in Primary PTCA
    • 3. Issues and Controversies in Primary PTCA
    • 4. Issues and Controversies in Primary PTCA
    • 5. Issues and Controversies in Primary PTCA
    • 6. Issues and Controversies in Primary PTCA
    • 7. Issues and Controversies in Primary PTCA
    • 8. Issues and Controversies in Primary PTCA
    • 9. Issues and Controversies in Primary PTCA
    • 10. www.escardio.org/guidelines
    • 11. Issues and Controversies in Primary PTCA
    • 12. INDICATIONS FOR PRIMARY PCI/CAG Issues and Controversies in Primary PTCA
    • 13. Issues and Controversies in Primary PTCA
    • 14. Issues and Controversies in Primary PTCA
    • 15.  Primary PCI is preferred to fibrinolytic therapy when Time-to-treatment delays are short and The patient presents to a high-volume, well-equipped center staffed with expert interventional cardiologists and skilled support staff. Compared with fibrinolytic therapy in RCTs, primary PCI produces: Higher rates for infarct artery patency, TIMI flow grade 3, and Lower rates for recurrent ischemia, Reinfarction, Emergency repeat revascularization procedures, Intracranial hemorrhage, and Death . Early, successful PCI also greatly decreases the complications of STEMI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Issues and Controversies in Primary PTCA
    • 16. Issues and Controversies in Primary PTCA
    • 17. ESC indications of Primary PCI Issues and Controversies in Primary PTCA
    • 18. Issues and Controversies in Primary PTCA
    • 19. Issues and Controversies in Primary PTCA
    • 20. www.escardio.org/guidelines
    • 21. Antiplatelet therapyIssue of Clopidogrel Resistance & How to overcome it??? Non-responsiveness to clopidogrel may be observed in up to 30% of patients, and it is associated with a worse prognosis after coronary stenting. This issue may be of high clinical relevance particularly in patients receiving drug-eluting stents, due to higher risk of late in-stent thrombosis. Due to the impact of SAT on mortality after primary angioplasty, non-responsiveness to clopidogrel would deserve larger attention. Future randomized trials are certainly needed to identify the optimal strategy to be adopted among these patients, including higher daily dose (150 mg), switch to ticlopidine60 or new ADP antagonist, or adjunctive oral anticoagulation therapy. Issues and Controversies in Primary PTCA
    • 22. Issues and Controversies in Primary PTCA
    • 23.  The PLATO trial (ticagrelor plus aspirin compared with clopidogrel plus aspirin) and TRITON-TIMI 38, which compared prasugrel plus aspirin with clopidogrel plus aspirin in patients (n = 13,608) with ACS and scheduled PCI. The PLATO and TRITON-TIMI 38 trials were similar in many ways, both including populations with ACS, both comparing the intervention plus aspirin to clopidogrel plus aspirin, and both sharing the same primary end point. There were important differences in the use of PCI and medical management, in the size and timing of the loading dose of clopidogrel, and in assessing myocardial infarction. Issues and Controversies in Primary PTCA
    • 24. TRITON-TIMI 38: Wiviott SD et al AHJ 152: 627,2006 Adapted with permission from E.Antman Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600 Double-blind CLOPIDOGREL PRASUGREL 300 mg LD/ 75 mg MD 60 mg LD/ 10 mg MD Median duration of therapy - 12 months1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.)Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic Guidelines Focused Update ACC/AHA 2009 Joint STEMI/PCI 26
    • 25. Balance of TRITON: Results Efficacy and Safety 15 138 events Clopidogrel 12.1 HR 0.81 CV Death / MI / Stroke (0.73-0.90)Endpoint (%) P=0.0004 10 9.9 NNT = 46 Prasugrel 5 35 TIMI Major Prasugrel events NonCABG Bleeds 2.4 HR 1.32 1.8 (1.03-1.68) Clopidogrel P=0.03 0 NNH = 167 0 30 60 90 180 270 360 Joint STEMI/PCI Guidelines Focused Update ACC/AHA 2009 450 Adapted with permission from Wiviott SD et al Days NEJM 357:2007 27
    • 26. CV Death, MI, Stroke TRITON TIMI-38 Major Subgroups Reduction in risk (%) UA/NSTEMI 18 B STEMI 21 Male 21 Female 12 <65 25 Age 65-74 14 >75 6 No DM 14 DM 30 BMS 20 DES 18 GPI 21 No GPI 16 CrCl < 60 14 CrCl > 60 20 OVERALL 19 Pinter = NS 0.5 Prasugrel Better 1 Clopidogrel Better 2 ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused UpdateWiviott SD et al NEJM 357: 2001, 2007 HR 28
    • 27. TRITON TIMI-38 STEMI Cohort N=3534 15 CV Death / MI / Stroke Clopidogrel 12.4% 9.5% Percent (%) 10.0% 10 HR 0.79 Prasugrel (0.65-0.97) 6.5% P=0.02 HR 0.68 NNT = 42 5 (0.54-0.87) P=0.002 TIMI Major Prasugrel 2.4 NonCABG Bleeds 2.1 Clopidogrel 0 0 30 60 90 180 270 360 450Montalescot et al Lancet 2008.Adapted with Days From Randomization ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Updatepermission from Antman EM. 31
    • 28. TRITON TIMI-38 Stent Thrombosis (ARC Definite + Probable) 3 Any Stent at Index PCI N= 12,844 2.4 Clopidogrel (142)Endpoint (%) 2 1.1 (68) 1 Prasugrel HR 0.48 P <0.0001 Significant reductions both with BMS, DES Significant reductions in early and late stent thromboses NNT= 77 0 0 30 60 90 Adapted with permission from Wiviott SD et al 180 270 2009 Joint 360 Guidelines Focused Update ACC/AHA STEMI/PCI 450 Lancet 2008 Days 32
    • 29. Recommendations for the use of Thienopyridines ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 34
    • 30. Loading doses forThienopyridines in Patients with Acute Coronar y Syndromes (STEMI and UA/NSTEMI) ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 35
    • 31. Recommendations for the use of Thienopyridines MODIFIEDRecommendation A loading dose of thienopyridine is recommended for STEMI patients for whom PCI is planned. Regimens should be one of the following:I IIa IIb III Clopidogrel at least 300 mg to 600mg† should be given as early as possible before or at the time of primary or non-primary PCI. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 36
    • 32. Recommendations for the use of Thienopyridines• The optimal loading dose of clopidogrel has not been established• Randomized clinical trials using >300mg of clopidogrel as a loading dose for PCI in STEMI or UA/NSTEMI have not rigorously established superior safety or efficacy• Clopidogrel is a prodrug which must undergo hepatic conversion to its active metabolite for platelet inhibition, a process taking several hours. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 37
    • 33. Recommendations for the use of Thienopyridines MODIFIEDRecommendationI IIa IIb III Prasugrel 60 mg should be given as soon as possible for primary PCI. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 38
    • 34. The duration ofThienopyridine therapy ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 39
    • 35. Thienopyridines The duration of thienopyridine therapy MODIFIEDRecommendation should be as follows: I IIa IIb III a. In patients receiving a stent (BMS or DES) during PCI for ACS, clopidogrel 75 mg daily† or prasugrel 10 mg§ daily should be given for at least 12 months; I IIa IIb III b. If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 40
    • 36. Thienopyridines MODIFIEDRecommendation Continuation of clopidogrel or I IIa IIb III prasugrel beyond 15 months may be considered in patients undergoing drug-eluting stent placement ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 41
    • 37. Thienopyridines NEWRecommendation In STEMI patients with a prior I IIa IIb III history of stroke and transient ischemic attack for whom primary PCI is planned, prasugrel is not recommended as part of a dual antiplatelet therapy regimen ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 42
    • 38. Recommendations for the use of ThienopyridinesMODIFIED For STEMI patients undergoing non-primary PCI, the Rec following regimens are recommended: If the patient has received fibrinolytic therapy…I IIa IIb III a. …and has been given clopidogrel, it should be continued as the thienopyridine of choice. b. …without a thienopyridine, a loading dose of 300- 600‡ mg of clopidogrel should be given as the thienopyridine of choice. If the patient did not receive fibrinolytic therapy…I IIa IIb III c. …either a loading dose of 300-600 mg of clopidogrel should be given or, once the coronary anatomy is known and PCI is planned, a loading dose of 60 mg of prasugrel should be given promptly and no later than 1 hour after the PCI. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 43
    • 39. Thienopyridines MODIFIED Recommendation (prasugrel added)I IIa IIb III In patients taking a thienopyridine in whom coronary artery bypass surgery (CABG) is planned and can be delayed, it is recommended that the drug be discontinued to allow for dissipation of the antiplatelet effect. I IIa IIb III The period of withdrawal should be at least 5 days in patients receiving clopidogrel I IIa IIb III and at least 7 days in patients receiving prasugrel,I IIa IIb III … unless the need for revascularization and/or the net benefit of the thienopyridine outweighs the potential risks of excess bleeding. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 44
    • 40. Access Site Results of the STEMI-RADIAL trial presented at TCT 2012 MIAMI, OCTOBER 26, 2012 – A study found several benefits in using the radial artery in the arm as the entry point for angioplasty or percutaneous coronary intervention (PCI) compared to the femoral artery in the leg. Results of the STEMI-RADIAL trial were presented at the 24th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium. (Sponsored by the Cardiovascular Research Foundation CRF) Issues and Controversies in Primary PTCA
    • 41.  In the STEMI-RADIAL trial, investigators examined the net clinical benefit of using the radial versus femoral approach in patients presenting within 12 hours of symptom onset of acute ST-elevation myocardial infarction (STEMI). All investigators were high-volume (>200 PCI/year) operators with significant experience in the radial approach (>80% cases/year) STEMI-RADIAL was a randomized, national, multicenter, parallel group trial conducted in 707 patients at four high-volume centers. Patients eligible for both access sites without cardiogenic shock were randomized to the radial or femoral access approach. Issues and Controversies in Primary PTCA
    • 42.  The primary endpoint was the cumulative incidence of major bleeding and vascular access site complications (requiring intervention) at 30 days. Secondary endpoints included major adverse cardiovascular events (MACE: death, reinfarction and stroke), technical success, access site failure, procedural and fluoroscopy times, contrast volume, intensive care stay and target lesion revascularization. Issues and Controversies in Primary PTCA
    • 43. STEMI-RADIAL A Prospective Randomized Trial of Radial vs. Femoral Access in Patients with ST-Segment Elevation Myocardial InfarctionI Bernat, D Horak, J Stasek, M Mates, P Ostadal, J Pesek, V Hrabos, J Dusek, J Koza, Z Sembera, M Brtko, O Aschermann, M Smid, P Polansky, AA Mawiri, J Bis, J Vojacek, O Costerousse, OF Bertrand, R RokytaUniversity Hospital and Faculty of Medicine Pilsen, Regional Hospital Liberec, University HospitalHradec Kralove, Na Homolce Hospital Prague, Université Laval Quebec. Czech Republic, Canada (ClinicalTrials.gov. NCT 00136187)
    • 44. STEMI RADIAL - Study design: 707 STEMI patients between October 2009 and February 2012 in 4 PCI centers (24/7)written informconsent in the electronic randomization tocathlab femoral or radial approach (www.fnplzen.cz/radial)immediate CAG + pPCI radial approach femoral approach (n=348) (n=359)Intention to treat Clinical follow- up at 30 days (100%)
    • 45. STEMI RADIAL - results30-day bleeding and access site compl.
    • 46. STEMI RADIAL - results 30-day MACE p = 0.74.2% p = 0.64 3.5% 3.1% p = 0.72 2.3% p = 1.0 1.2% 0.8% 0.3% 0.3% MACE = composite of death, myocardial infarction and stroke
    • 47. DefinitionsMajor Bleeding • Fatal(CURRENT/ • > 2 units of Blood transfusionOASIS 7) • Hypotension requiring inotropes • Leading to hemoglobin drop of ≥ 5 g/dl • Requiring surgical intervention • ICH or Intraocular bleeding leading to significant vision lossMajor Vascular • Large hematomaAccess Site • Pseudoaneurysm requiring closureComplications • AV fistula • Other vascular surgery related to the access site
    • 48. • In patients with STEMI <12 hrs, radial approach was associated with a significant lower incidence of major bleeding and access site complications and a significant better net clinical benefit.• Moreover radial approach reduced significantly ICU stay and contrast volume compared to femoral approach.• The results support the use of radial approach in primary PCI in experienced radial centers as a first choice.
    • 49. Prior Meta-analysis of 23 RCTs of Radial vs. Femoral (N=7030)Major bleeding 0.27 (0.16-0.45)Death 0.74 (0.42-1.30)Death, MI or stroke 0.71 (0.49-1.01)PCI Procedure Failure 1.31 (0.87-1.96) Radial better 1.0 Femoral better Jolly SS, et al. Am Heart J 2009;157:132-40.
    • 50. RIVAL Primary and Secondary Outcomes Radial Femoral (n=3507) (n=3514) HR 95% CI P % %Primary OutcomeDeath, MI, Stroke,Non-CABG Major 3.7 4.0 0.92 0.72-1.17 0.50BleedSecondary OutcomesDeath, MI, Stroke 3.2 3.2 0.98 0.77-1.28 0.90Non-CABG Major 0.7 0.9 0.73 0.43-1.23 0.23Bleeding
    • 51. RIVAL Other Outcomes Radial Femoral (n=3507) (n=3514) HR 95% CI P % %Major VascularAccess Site 1.4 3.7 0.37 0.27-0.52 <0.0001ComplicationsOther Definitions of Major BleedingTIMI Non-CABG 0.5 0.5 1.00 0.53-1.89 1.00Major BleedingACUITY Non-CABG 1.9 4.5 0.43 0.32-0.57 <0.0001Major Bleeding* * Post Hoc analysis
    • 52. RIVAL Other Outcomes Radial Femoral (n=3507) (n=3514) HR 95% CI P % %Death 1.3 1.5 0.86 0.58-1.29 0.47MI 1.7 1.9 0.92 0.65-1.31 0.65Stroke 0.6 0.4 1.43 0.72-2.83 0.30Stent Thrombosis 0.7 1.2 0.63 0.34-1.17 0.14
    • 53. RIVAL Other Outcomes Radial Femoral P (n=3507) (n=3514) Access site Cross-over (%) 7.6 2.0 <0.0001 PCI Procedure duration (min) 35 34 0.62 Fluoroscopy time (min) 9.3 8.0 <0.0001 Persistent pain at access site 2.6 3.1 0.22 >2 weeks (%) Patient prefers assigned access site for next 90 49 <0.0001 procedure (%) • Symptomatic radial occlusion requiring medical attention 0.2% in radial group
    • 54. RIVAL Conclusion  No significant difference between radial and femoral access in primary outcome of death, MI, stroke or non-CABG major bleeding  Rates of primary outcome appeared to be lower with radial compared to femoral access in high volume radial centres and STEMI  Radial had fewer major vascular complications with similar PCI success
    • 55. Anticoagulation The goals of pharmacotherapy during PCI are 2-fold: (1) to mitigate the sequelae of iatrogenic plaque rupture from balloon angioplasty or stenting and (2) to reduce the risk of thrombus formation on intravascular PCI equipment. Central to these thrombotic events is thrombin (factor IIa). Iatrogenic damage to the endothelium during PCI leads to increased expression of tissue factor, activation of the coagulation cascade, and formation of activated factor Xa. This ultimately leads to the generation of thrombin, conversion of fibrinogen to fibrin, and thrombus formation. In addition to its effects on fibrin, thrombin also directly activates platelets, enhances platelet aggregation, and is proinflammatory. Issues and Controversies in Primary PTCA
    • 56. Aims of optimal antithrombotic therapy. De Luca G Eur Heart J Suppl 2008;10:J2-J14Published on behalf of the European Society of Cardiology. All rights reserved. © The Author Issues and Controversies in 2008. For permissions please email: journals.permissions@oxfordjournals.org Primary PTCA
    • 57.  Because of its multiple actions in promoting thrombosis, the focus of most anticoagulant agents is thrombin inhibition. Available agents for use include unfractionated heparin (UFH), low-molecular-weight heparins (LMWH, of which enoxaparin has the largest body of clinical data), the synthetic pentasaccharides (of which fondaparinux has the largest body of clinical data), and the direct thrombin inhibitors (DTIs, of which bivalirudin has the largest body of clinical data) Issues and Controversies in Primary PTCA
    • 58. Issues and Controversies in Primary PTCA
    • 59. Issues and Controversies in Primary PTCA
    • 60. Direct thrombin inhibitors Bivalirudin is a 20-amino acid synthetic polypeptide analog of hirudin. Once bound, bivalirudin is cleaved by thrombin, thereby reducing its antithrombotic activity. Peak bivalirudin concentrations are achieved 15–20 min after intravenous infusion. In patients with normal renal function, the plasma half-life of bivalirudin is 25–36 min. Although it is predominantly eliminated by plasma enzymes (peptidases), approximately 20% of the drug is excreted via the kidneys. Unfortunately, there is no antidote for bivalirudin. Issues and Controversies in Primary PTCA
    • 61. Recommendations for Use of ParenteralAnticoagulants in Patients with STEMI ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 76
    • 62. Use of Parenteral Anticoagulants in STEMI Modified For patients proceeding to primary Recommendation PCI, who have been treated with I IIa IIb III ASA and a thienopyridine, recommended supportive anticoagulant regimens include:a. For prior treatment with UFH, additional boluses of UFH should be administered as needed to maintain therapeutic activated clotting time levels, taking into account whether GP IIb/IIIa receptor antagonists have been administered ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 77
    • 63. Use of Parenteral Anticoagulants in STEMI (cont.) Modified Recommendation For patients proceeding to primary PCI, who have been treated with I IIa IIb III ASA and a thienopyridine, recommended supportive anticoagulant regimens include:b. Bivalirudin is useful as support for primary PCI with orwithout prior treatment with heparin. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 78
    • 64. Use of Parenteral Anticoagulants in STEMI Patients Proceeding to Primary PCI: Modified Class I Recommendations• Bilvalirudin added as an acceptable anticoagulant for primary PCI• Unfractionated heparin (UFH) administration guided by: – Therapeutic activated clotting time (ACT) levels – Prior administration of GP IIb/IIIa receptor antagonists• Enoxaparin and fondaparinux unchanged from 2007 STEMI Focused Update ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 79
    • 65. HORIZONS –AMIA Prospective, Multicenter Randomized Trial ofHeparin Plus GPIIb/IIIa Inhibitors vs. BivalirudiinSTEMI: Final 3-year results from the HORIZONS-AMI Trial Stone GW et al. Lancet 2011: Published online June 13, DOI:10.1016/S0140-6736(11)60764-2
    • 66. Background ● At 1-year in the 2x2 factorial prospective, randomized HORIZONS-AMI trial: – Bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in comparable rates of MI and stent thrombosis, with significantly reduced rates of major bleeding and mortality (all- cause and cardiac) ● 3-year results are assessed in this report – Prespecified endpoints in the pharmacology arm at 3 years included death, reinfarction, ischemia driven target lesion revascularization, stroke, and the composite of these (MACE); non-CABG major bleeding and the composite of all net adverse clinical events (NACE).Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 67. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor Bivalirudin monotherapy (abciximab or eptifibatide) (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… CABG – Primary PCI – Medical Rx 3006 pts eligible for stent randomization R 3:1 Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 3 years; angio FU at 13 monthsStone, GW N Engl J Med 2008;358:2218-30.
    • 68. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa Bivalirudin Randomized N=1802 N=1800 28 • • • Not true MI* • • • 29 1-Year FU Eligible N=1774 N=1771 26 • • • Withdrew • • • 22 46 • • • Lost to FU • • • 53 1-Year FU N=1702 N=1696 17 • • • Withdrew • • • 18 57 • • • Lost to FU • • • 44 3-Year FU N=1628 N=1634 * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 69. 3-Year Major Bleeding(non-CABG)* 12 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 10.5% 10 Major Bleeding (%) 9.4% 8 6.9% 6 6.0% 3-yr HR (95%CI) 4 0.64 (0.51, 0.80) P=0.0001 2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months * Intracranial, intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusionStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 70. Time in Months Time in Months3-Year Car diac Mor tality Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) 6 3-yr HR (95%CI) 0.56 (0.40, 0.80) P=0.001 5.1% 5 Cardiac Mortality (%) 4 3.8% 3 2.9% 2 2.1% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 MonthsStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 71. 3-Year Cardiac Mortality Landmark analysis 5 Heparin + GP IIb/IIIa (n=1802) Bivalirudin (n=1800) 4 30 day HR (95% CI) Cardiac mortality (%) 0.62 (0.40 – 0.96) 3 year HR (95% CI) p=0.03 0.49 0.28 –0.86 3 2.9% p=0.01 2.2% 2 1.8% 1 1.1% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 MonthsStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 72. 3-Year Reinfar ction 10 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 9 8 8.2% Reinfarction (%) 7 6 6.2% 5 4.4% 4 3-yr HR (95%CI) 3 0.76 (0.59, 0.99) 3.6% 2 P=0.04 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 MonthsStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 73. 3-Year Reinfarction Landmark analysis 10 Heparin + GPIIb/IIIa (n=1802) 9 Bivalirudin (n=1800) 8 30-day HR (95% CI) 3-year HR (95% CI) 1.07 (0.66 – 1.73) 0.66 (0.49 – 0.90) Reinfarction (%) 7 p=0.79 p=0.007 6.5% 6 5 4.4% 4 3 2 1.9% 1.8% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 MonthsStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 74. 3-Year All-Cause Mortality or Reinfarction Landmark analysis 5 Heparin + GPIIb/IIIa (n=1802) All-cause mortality or reinfarction (%) Bivalirudin (n=1800) 3-year HR (95% CI) 4 30-day HR (95% CI) 0.72 (0.58 – 0.91) 0.84 (0.61 – 1.16) p=0.005 p=0.30 10.6% 3 7.8% 2 4.5% 3.8% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 MonthsStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 75. 3-year MACE Components * Number UFH + GPI Bivalirudin HR [95%CI] P Value needed (N=1802) (N=1800) to treat Death 7.7% 5.9% 0.75 (0.58,0.97) 0.03 54 - Cardiac 5.1% 2.9% 0.56 (0.40,0.80) 0.001 45 - Non cardiac 2.8% 3.1% 0.62 Reinfarction 8.2% 6.2% 0.76 (0.59,0.92) 0.04 52 - Q-wave 3.8% 3.4% 0.61 - Non Q-wave 4.9% 3.2% 0.009 58 Death or reinfarction 14.5% 11.3% 0.72 (0.58,0.91) 0.005 31 Ischemic TVR 12.1% 14.2% 0.06 Stroke 2.0% 1.7% 0.50*Kaplan-Meier estimates, CEC adjudicated MACE= death, reinfarction, ischemia-driven target vessel revascularization, strokeStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 76. 3-year Bleeding Endpoints Number UFH + GPI Bivalirudin HR (95% CI) P Value needed (N=1802) (N=1800) to treat Major bleeding, non- 10.5% 6.9% 0.64 (0.51-0.80) 0.0001 28 CABG Major bleeding, 12.8% 8.9% <0.0001 25 including CABG Blood transfusion 5.1% 3.5% 0.01 61 TIMI Major or Minor 10.9% 7.0% <0.0001 26 TIMI Major 6.1% 4.1% 0.007 51 TIMI Minor 5.0% 3.2% 0.007 56 GUSTO (any) 12.7% 8.8% 0.0001 26 GUSTO severe/life- 0.9% 1.0% 0.74 threatening GUSTO moderate 6.3% 4.7% 0.03 63 GUSTO mild 6.2% 4.0% 0.003Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 77. 3-Year Stent Thrombosis(ARC Definite/Probable) 6 Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591) 5 5.1% 4.5% Stent Thrombosis (%) 4 3.5% HR (95%CI) 3 3.0% 0.89 (0.65, 1.23) 2 p=0.49 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months ARC= Academic Research ConsortiumStone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 78. Conclusions:Pharmacology Randomization ● In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in: – A significant 36% reduction in major bleeding and a significant 24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke – A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life)Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
    • 79.  The most recent phase 3 trial of bivalirudin is the Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction (HORIZONS AMI) trial. Randomized 3602 patients with STEMI undergoing primary PCI to either UFH+GPI or bivalirudin. Both 30-day major bleeding and 30-day NACE served as the primary end points. There was a significantly lower rate of both the primary bleeding end point (4.9% bivalirudin versus 8.3% UFH+GPI, P<0.001) and the primary NACE end point (9.2% versus 12.1%, P=0.005) among patients assigned to bivalirudin. The 30-day ischemic end points of death, MI, urgent target vessel revascularization, or stroke were nearly identical between the 2 arms (5.4% versus 5.5%, P=0.95). Issues and Controversies in Primary PTCA
    • 80.  Two interesting divergent outcomes also were seen in the HORIZONS AMI trial: a significant increase in 24-hour (ie, acute) stent thrombosis in the bivalirudin arm (1.3% versus 0.3%, P<0.001) but a significant reduction in 30-day mortality in the bivalirudin arm (2.1% versus 3.1%, P=0.047). This reduction in mortality was present at 1 year as well Issues and Controversies in Primary PTCA
    • 81. OASIS-5: Efficacy at Day 9 Non-inferiority Enox Fonda Margin = 1.185 ——%—— Death/MI/RI 5.8 5.9 Death/MI 4.1 4.1 Death 1.9 1.8 MI 2.7 2.7 Refractory 1.9 2.05 Ischemia 0.8 1 1.2 Fonda Better Enox BetterYusuf S, et al. N Engl J Med. 2006;354(14):1464-76 Hazard Ratio
    • 82. OASIS-5: Bleeding Rates at Day 9 Outcome Enox Fonda HR (95% CI) P No. Randomized 10,021 10,057 Total Bleed (%) 7.0 3.2 0.44 (0.39 – 0.51) < 0.0001 Major Bleed (%) 4.0 2.1 0.53 (0.45 – 0.62) < 0.0001 TIMI Major Bleed (%) 1.3 0.7 0.54 (0.41 – 0.73) < 0.0001 Minor Bleed (%) 3.1 1.1 0.35 (0.28 – 0.43) < 0.0001Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
    • 83. OASIS-5 Efficacy End Points at 6 Months End point Enoxaparin Fondaparinux P value Death/MI/ refractory 13.2% 12.3% 0.06 ischemia Death/MI 11.4% 10.5% 0.05 Death 6.5% 5.8% 0.05 MI 6.6% 6.3% NS Stroke 1.7% 1.3% 0.04 Death/MI/stroke* 12.5% 11.3% 0.007Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
    • 84. PCI — Procedural Complications Enoxaparin Fondaparinux Events (30 Days) P value n=3089 n=3118 Any UFH during PCI 53.8% 18.8% Any procedural 8.6% 9.6% 0.18 complication Abrupt closure 1.1% 1.5% 0.20 Catheter thrombus 0.5% 1.3% 0.001 Vascular access 8.1% 3.3% <0.0001 Pseudo-aneurysm 1.6% 1.0% 0.39 Large hematoma 4.4% 1.6% <0.0001Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
    • 85. OASIS - 6 TrialOrganization for the Assessment of Strategies for Ischemic Syndromes 6 (OASIS-6) Trial Presented at The American College of Cardiology Scientific Session 2006 Presented by Dr. Salim Yusuf
    • 86. OASIS - 6 Trial: Background •The goal of the trial was to evaluate treatment with fondaparinux compared with control (unfractionated heparin or placebo) among patients with STEMI. •Patients were separated into Stratum 1 (control group inelligible for UFH treatment, in other words fondaparinux was compared to placebo) and Stratum 2 (active control group was UFH) •Also, there was a PCI substudy that assessed the efficacy of fondaparinux in Stratum 1 and Stratum 2 in the primary PCI setting.www. Clinical trial results.org Presented at ACC 2006
    • 87. OASIS – 6 Trial: Study Design 12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial) Randomized. Blinded. Factorial. 28% female, mean age 62 years, mean follow-up 3-6 months Stratum 1 (No Stratum 2 (UFH) UFH) Fondaparinux Placebo Fondaparinux UFH 2.5mg/day for up to 8 2.5mg/day for up to 8 days or hospital days or hospital discharge discharge   Primary Endpoint: Composite of death or reinfarction at 30 days   Secondary Endpoint: Composite of death or reinfarction at 9 days and at final follow-upwww. Clinical trial results.org Presented at ACC 2006
    • 88. OASIS – 6 Trial: Primary Endpoint Primary Endpoint: Death/Reinfarction 15% (%) 14.8% 13.4% • The primary endpoint was 12% 11.2% lower in the 9.7% fondaparinux 8.9% group compared 9%Frequency 7.4% with the control group (9.7% 6% vs.11.2%, HR 0.86, p=0.008) 3% • The results were p=0.00 p=0.00 p=0.00 similar at 9 days 0% 8 3 8 (HR 0.83, 30 days 9 days 3-6 months p=0.003) and at study end (HR Fondaparinux (n=6036) Control (n=6056) 0.88, p=0.008)www. Clinical trial results.org Presented at ACC 2006
    • 89. OASIS – 6 Trial: Primary Endpoint (cont.) Reduction in Death/MI: Stratum 1 Reduction in Death/MI: Stratum 2 (No UFH indicated) (UFH Indicated) p<0.05 14.0% 14% p=NS 14% 11.2% 12% 12% 10% 10% 8.3% 8.7% 8% 8% p=0.97 6% 6% 4% 4% 2% 2% 0% 0% Fondaparinux Placebo Fondaparinux UFH • The reduction in the primary endpoint at 30 days in the Fondaparinux group was driven by Stratum 1, where death/MI occurred less frequently among Fonda pts than Placebo (11.2 vs. 14%, HR 0.79, p<0.05) • There was no difference in Stratum 2, comparing those patients who received Fondaparinux vs those who received UFH (8.3% vs. 8.7%, HR 0.96, p=NS)www. Clinical trial results.org Presented at ACC 2006
    • 90. OASIS – 6 Trial: Primary Composite Endpoint Components of Primary Composite Endpoint (%) p=0.03 • Among the components of the 10% 8.9% composite at 30 7.8% days, mortality was 8% lower in the fondaparinux group 6% compared to the p=0.06 control group (7.8% 4% 3% vs. 8.9%, HR 0.87, 2.5% p=0.03). 2% • Reinfarction was also lower in the 0% fondaparinux group compared to the Death Reinfarction control group (2.5% Fondaparinux Control vs. 3.0% HR 0.81,www. Clinical trial results.org p=0.06). Presented at ACC 2006
    • 91. OASIS - 6 Trial: PCI Substudy at 30 Days Primary Endpoint of Death or MI in PCI Cohort (%) • There was no difference 8% p=0.19 in the primary endpoint 6.1% for patients who were 6% managed with primary 5.1% PCI (6.1% vs 5.1%, p=0.19). 4% • Guiding catheter thrombosis in the 2% primary PCI cohort occurred more often with fondaparinux compared 0% with control (n=22 vs. n=0, p<0.001) Fondaparinux Controlwww. Clinical trial results.org Presented at ACC 2006
    • 92. OASIS - 6 Trial: PCI Substudy (cont.) Severe Bleeding at 9 days (%) p=NS 2% • There was no difference in severe bleeding at 1.3% 9 days by treatment group 1.0% (1.0% 1% Fondaparinux vs. 1.3% control, p=NS) • Intracranial hemorrhage 0% occurred in 0.2% in each group Fondaparinux Controlwww. Clinical trial results.org Presented at ACC 2006
    • 93. OASIS - 6 Trial: PCI Substudy (cont.) Guiding Catheter Thrombosis p<0.001 25 • There was a higher 22 instance of guiding catheter 20 thrombosis in the PCI cohort treated 15 with fondaparinux compared to 10 control (n=22 vs. n=0, p<0.001) 5 0 0 Fondaparinux Controlwww. Clinical trial results.org Presented at ACC 2006
    • 94. OASIS - 6 Trial: PCI Substudy (cont.) Coronary Complications • Coronary p=0.04 complications occurred in more 280 270 patients treated 240 225 with fondaparinux compared to 200 control (n=270 vs. n=225, p=0.04) 160 • Coronary 120 complications include abrupt 80 closure, no reflow, 40 dissection, new angiographic 0 thrombus, Fondaparinux Control perforation, or catheter thrombuswww. Clinical trial results.org Presented at ACC 2006
    • 95. OASIS – 6 Trial: Conclusions •The benefit of Fondaparinux was confined to patients in Stratum 1 where placebo or no antithrombin was administered •Fondaparinux was not superior to active control UFH •Fondaparinux was associated with a hazard in those patients who underwent PCI including guiding catheter thrombosiswww. Clinical trial results.org Presented at ACC 2006
    • 96. Bivalirudin: A Guidelines-Supported Alternative to UFH/LMWH in ACS► Advantages of the direct thrombin inhibitor bivalirudin No requirement for antithrombin III Effective on clot-bound thrombin Inhibits thrombin-mediated platelet activation No interactions with PF- 4 Plasma half-life 25 minutes No requirement for anticoagulant monitoring► Clinical results with bivalirudin in PCI Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding1► Not previously tested in contemporary ACS patients REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.
    • 97. Glycoprotein IIb–IIIa inhibitors Several randomized trials have been conducted in primary angioplasty, the vast majority of them on abciximab. In the largest trial, the CADILLAC, a total of 2082 patients were randomized to stent or balloon with or without periprocedural administration of abciximab. Abciximab did not improve myocardial perfusion as evaluated by myocardial blush grade and ST-segment resolution. Some benefits in mortality with abciximab were observed in patients undergoing balloon angioplasty only, whereas no benefits were observed in terms of re-infarction. Abciximab did not increase the risk of bleeding complications. Issues and Controversies in Primary PTCA
    • 98.  Periprocedural abciximab administration is associated with a significant reduction in mortality and re-infarction, without an increased risk of major bleeding complications. Data from the BRAVE-3 trial have shown no benefits in infarct size and 30-day mortality when a clopidogrel loading dose of 600 mg was administrated. Keeping in mind the relationship between the risk profile and mortality benefits from abciximab administration, it may be claimed that the absence of benefits would have been expected in a population with the mortality lower than 3%, as observed in the BRAVE-3 trial. Issues and Controversies in Primary PTCA
    • 99.  In the STRATEGY trial, no difference in death and or re- infarction was observed between high-dose tirofiban and abciximab. Further benefits may be expected by adjunctive intracoronary administration of Gp IIb–IIIa inhibitors. A small randomized trial showed that selective intracoronary administration of abciximab distally to the occlusion (through an over-the-wire balloon) was associated with a significant improvement in myocardial perfusion and smaller infarct size Issues and Controversies in Primary PTCA
    • 100.  On-TIME trial, a total of 507 STEMI patients transferred to a PCI centre were randomized to early, pre-hospital initiation of tirofiban (early) or to its initiation in the catheterization laboratory (late). Early tirofiban was associated with a better pre-procedural TIMI 2–3 flow (43 vs. 34%, P ¼ 0.04), and myocardial perfusion (myocardial blush grade 2–3: 30 vs. 22%, P ¼ 0.04). However, no benefits were observed in post-procedural TIMI 3 flow, myocardial perfusion, mortality (4.5 vs. 3.7%, P ¼ 0.66), and re-infarction (2.4 vs. 3.7%, P ¼ 0.43) at 1-year follow-up. Similar results have been observed in the TITAN-TIMI 34, where 316 STEMI patients were randomized to early or late eptifibatide. Issues and Controversies in Primary PTCA
    • 101.  In the large FINESSE trial, up to 2500 STEMI patients were randomized within 6 h from symptom onset to facilitation with half lytic and abciximab, early or periprocedural abciximab administration. When compared with late administration, early abciximab did improve neither pre-procedural TIMI 2–3 flow (26 vs. 25%) nor 90 day mortality (5.5 vs. 4.5%), with a non-significantly higher risk of major bleeding complications (4.1 vs. 2.6%). A recent individual patients’ data meta-analysis (including 1662 patients) of randomized trials comparingearly vs. late administration of Gp IIb–IIIa inhibitors in primary angioplasty114 has demonstrated significant benefits in pre- procedural TIMI flow with all the molecules. Issues and Controversies in Primary PTCA
    • 102.  However, only abciximab was associated with significant benefits in post-procedural TIMI flow, myocardial blush, distal embolization, and survival. For years, there have been concerns about the combination of thrombolysis and mechanical reperfusion in STEMI due to the fact that thrombolytic therapy may induce platelet aggregation and impair the results of adjunctive mechanical revascularization. However, the results of trials on adjunctive thrombolytic therapy have been negative. These data may be explained by the higher rates of early reocclusion and re-infarction, potentially due to the low-rate of abciximab administration. Issues and Controversies in Primary PTCA
    • 103.  Data from the FINESSE trial showed that, despite improvement in pre-procedural TIMI flow, combotherapy did not confer any benefit in terms of survival, but was associated with higher risk of major bleeding complications Issues and Controversies in Primary PTCA
    • 104. PCI of Non Infarct Arteries PCI of a noninfarct artery at the time of primary PCI in stable patients is associated with worse clinical outcomes unless The patient is in cardiogenic shock where PCI of a severe stenosis in a coronary artery supplying a large territory of myocardium might improve hemodynamic stability. Delayed PCI can be performed in noninfarct arteries at a later time if clinically indicated Issues and Controversies in Primary PTCA
    • 105. Cardiogenic Shock: Recommendations Issues and Controversies in Primary PTCA
    • 106.  Mechanical complications: Echocardiography should always be performed in acute heart failure (AHF) to assess LV function and to rule out life-threatening mechanical complications that may require surgery such as acute MR secondary to papillary muscle rupture,VSD, free wall rupture, or cardiac tamponade. The natural history of these conditions is characterized by a rapid downhill course and medical treatment alone results in close to 100% mortality. Incidence of Post MI VSD 0.2%. With persistent haemodynamic deterioration despite the presence of an intra-aortic balloon pump (IABP), surgery should be performed as soon as possible. Issues and Controversies in Primary PTCA
    • 107. Issues and Controversies in Primary PTCA
    • 108. Issues and Controversies in Primary PTCA
    • 109. Issues and Controversies in Primary PTCA
    • 110.  Cardiogenic shock is the leading cause of in-hospital mortality complicating STEMI. Revascularization is the only treatment proven to decrease mortality rates. Although revascularization is almost always accomplished through PCI, selected patients with severe 3-vessel or left main disease can benefit from emergency CABG. Revascularization attempts may be futile and not indicated in cases of severe multiorgan failure. Patient selection for revascularization is more important in the elderly, but several observational reports demonstrate acceptable outcomes in patients with few comorbidities and a reasonable potential for survival Issues and Controversies in Primary PTCA
    • 111.  Patients with cardiogenic shock should receive standard pharmacological therapies, including aspirin, a P2Y12 receptor antagonist, and anticoagulation. Inotropic and vasopressor therapy improves perfusion pressure. Historically, negative inotropes and vasodilators are avoided. GP IIb/IIIa inhibitors have been shown to provide benefit in observational studies but not in 1 small RCT. (Thiele H, Allam B, Chatellier G, et al. Shock in acute myocardial infarction: the Cape Horn for trials? Eur Heart J. 2010;31:1828 –35.) Issues and Controversies in Primary PTCA
    • 112.  Endotracheal intubation and mechanical ventilation with positive end-expiratory pressure is usually necessary in patients with respiratory failure. Placement of a temporary pacemaker is indicated for patients with bradycardia or high-degree atrioventricular heart block. A pulmonary artery catheter can provide information to dose and titrate inotropes and pressors. Further hemodynamic support is available with IABP counterpulsation or percutaneous LV assist devices, although no data support a reduction in mortality rates Issues and Controversies in Primary PTCA
    • 113.  Contrast medium injections should be minimized. Orthogonal angiograms of the left coronary artery and a left anterior oblique angiogram of the right coronary artery are usually sufficient to identify the infarct artery. Although most patients undergoing revascularization will receive a stent as part of the procedure, there are conflicting data on the impact of stenting over balloon angioplasty. Issues and Controversies in Primary PTCA
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    • 115. Multivessel disease In patients with multivessel disease, revascularization of the noninfarct artery may be necessary to maximize myocardial perfusion. Alternatively, in patients with multivessel disease and particularly left main disease, emergency CABG as a primary reperfusion strategy may be preferred. Refractory cardiogenic shock unresponsive to revascularization may necessitate institution of more intensive cardiac support with a ventricular assist device or other hemodynamic support devices to allow for myocardial recovery or subsequent cardiac transplantation in suitable patients. Issues and Controversies in Primary PTCA
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    • 117.  Results: Seventeen of 18 patients (94.4%) experienced pulmonary edema (including 14 patients in cardiogenic shock). Six patients (33.3%) sustained sudden death due to malignant ventricular tachyarrhythmias. Coronary angiography showed that there were variable grade flow of intercoronary collaterals in 12 patients (66.7%), a totally occluded LMCA in 8 patients (44.4%), an incompletely occluded LMCA in 10 patients (55.6%), and a dominant right coronary artery (RCA) in 16 patients (88.9%). Primary angioplasty of the LMCA was performed with a 72.2% procedural success rate. Four patients (22.2%) received coronary artery bypass surgery after angioplasty. Issues and Controversies in Primary PTCA
    • 118.  Six patients (33.3%) died in the hospital. Two patients died after discharge. Ten of 18 patients (55.6%) survived in long-term follow-up (mean SD, 44 14 months). Those patients who survived to be discharged had significantly higher combined coexisting incidence of intercoronary collaterals, dominant RCA, and incompletely occluded LMCA (100% vs 0.0%, p 0.0006) than those patients who died in the hospital. Issues and Controversies in Primary PTCA
    • 119.  Conclusions: Acute obstructive LMCA disease generally presented as pulmonary edema, cardiogenic shock, or sudden death. Only those who had combined coexistence of intercoronary collaterals, a dominant RCA, and an incompletely occluded LMCA could survive to be discharged. Our experience suggests that primary LMCA angioplasty is a feasible and effective procedure, and it may save lives in this clinical setting. Issues and Controversies in Primary PTCA
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    • 124. Recommendations forThrombus Aspiration during PCI for STEMI ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 175
    • 125. Thrombus Aspiration During PCI for STEMI NEWRecommendation I IIa IIb III Aspiration thrombectomy is reasonable for patients undergoing primary PCI ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 176
    • 126. Distal embolization• Despite successful mechanical revascularization, suboptimal reperfusion may occur, resulting in unfavourable outcome.• In the last years, growing interest has been focused on the role of distal embolization as major determinant of poor reperfusion. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
    • 127. From: Manual Thrombus-Aspiration Improves Myocardial Reperfusion: Title and subTitle BreakThe Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus- Aspiration in Primary and Rescue Angioplasty (REMEDIA) TrialJ Am Coll Cardiol. 2005;46(2):371-376. doi:10.1016/j.jacc.2005.04.057 Figure Legend: Study flowchart. *Patients entering the intention-to-treat analysis. ECG = electrocardiogram; MBG = myocardial blush grade; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation acute myocardial infarction; STR = ST-segment resolution. Date of download: Copyright © The American College of Cardiology. Joint STEMI/PCI Guidelines Focused Update ACC/AHA 2009 11/14/2012 All rights reserved.
    • 128. From: Manual Thrombus-Aspiration Improves Myocardial Reperfusion: Title and subTitle BreakThe Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus- Aspiration in Primary and Rescue Angioplasty (REMEDIA) TrialJ Am Coll Cardiol. 2005;46(2):371-376. doi:10.1016/j.jacc.2005.04.057 Figure Legend: Distribution of patients according to the combination of myocardial blush grade (MBG) ≥2 and ST-segment resolution (STR) ≥70% in the thrombus-aspiration group (white bars) and the standard percutaneous coronary intervention group (black bars) (p = 0.025 using chi-square test). Date of download: Copyright © The American College of Cardiology. Joint STEMI/PCI Guidelines Focused Update ACC/AHA 2009 11/14/2012 All rights reserved.
    • 129. From: Manual Thrombus-Aspiration Improves Myocardial Reperfusion: Title and subTitle BreakThe Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus- Aspiration in Primary and Rescue Angioplasty (REMEDIA) TrialJ Am Coll Cardiol. 2005;46(2):371-376. doi:10.1016/j.jacc.2005.04.057 Figure Legend: Odds ratios and 95% confidence intervals for the combination of myocardial blush grade ≥2 and ST-segment resolution ≥70% in the comparison between thrombus-aspiration and standard percutaneous coronary intervention (PCI) according to key baseline clinical and angiographic variables. Cx = circumflex artery; LAD = left anterior descending artery; RCA = right coronary artery; TIMI = Thrombolysis In Myocardial Infarction. Date of download: Copyright © The American College of Cardiology. Joint STEMI/PCI Guidelines Focused Update ACC/AHA 2009 11/14/2012 All rights reserved.
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    • 151. Special Population Issues and Controversies in Primary PTCA
    • 152. Those with Renal Compromise & CKD Issues and Controversies in Primary PTCA
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    • 154. Revascularization for acute graft failure Early graft failure after CABG (,1 month) may occur in 8– 30% of cases. Perioperative angiography showed failure of 8% of saphenous vein grafts (SVGs) and 7% of left ITA grafts. In symptomatic patients, early graft failure can be identified as the cause of ischaemia in 75% of cases, while pericarditis or prolonged spasm is diagnosed in the remainder. PCI in acute post-operative graft failure may be an alternative to re-operation with acceptable results and fewer complications Issues and Controversies in Primary PTCA
    • 155.  The target for PCI is the body of the native vessel or of the ITA graft while freshly occluded SVG or the anastomosis itself should not be targeted due to the risk of embolization or perforation. Surgery should be favoured if the graft or native artery appears unsuitable for PCI, or if several important grafts are occluded. In asymptomatic patients, re-operation or PCI should only be considered if the artery is of good size, severely narrowed and supplies a large territory of myocardium. Issues and Controversies in Primary PTCA
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    • 159. Distal Embolization Issues and Controversies in Primary PTCA
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    • 167.  PercuSurge GuardWire (Medtronic, Santa Rosa, CA, USA) is an occlusion thrombectomy device that consists of a wire containing a central lumen that communicates with a lowpressure distal occlusion balloon incorporated into the tip. The wire serves as both the angioplasty guidewire and provides protection from distal embolization. An inflation device allows controlled expansion and sizing of the occlusion balloon in the treated vessel. An aspiration catheter is used to remove the debris from the treated vessel before the balloon is deflated and antegrade flow in the treated vessel is restored. Issues and Controversies in Primary PTCA
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    • 169.  AngioGuard’s technology incorporates an angioplasty guidewire with a filter that expands to 6 mm and is placed distal to the target lesion to capture and retrieve embolic debris . At the end of the procedure, the filter is collapsed, trapping the particulate matter and facilitating removal from the artery. The AngioGuard filter has multiple, 100 micron, laser-drilled holes that allow perfusion during device deployment. It has been proposed that this is a major advantage of filter devices. In contrast, the balloon occlusion devices result in complete cessation of antegrade flow for as long as it takes to treat the vessel and aspirate the debris (typically 2–3 minutes in the hands of experienced operators) . Issues and Controversies in Primary PTCA
    • 170.  This is a critical clinical consideration in patients with reduced left ventricular function or in patients in whom the treated artery supplies a large amount of myocardium. Conversely, it has been proposed that incomplete vessel occlusion with the filter devices allows passage of debris through the holes of the filter devices. Issues and Controversies in Primary PTCA
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    • 172. Filter Wire EX™ The FilterWire EX (Boston Scientific, Natick, MA, USA) is another filter device currently under clinical investigation. Similar to the AngioGuard, it is a low-profile (< 3.5 French) filter mounted on a 0.014 inch angioplasty wire with pore holes of 80 microns that permit antegrade blood flow while providing distal protection. The filter design is characterized by an off-center position and ‘fish-mouth’ opening, and can be retracted into any standard angioplasty balloon. A radiopaque nitinol framework provides filter support and facilitates fluoroscopic visualization. Issues and Controversies in Primary PTCA
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