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the story of acute coronary syndrome

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Journal review

  1. 1. Dr.Nagula Praveen MD, (D. M. I yr PG)
  2. 2. The Year in Acute Coronary Syndrome Dr.Robert.P.Giugliano,MD,SM, Dr.Eugene Braunwald,MD. June 2012 – September 2013
  3. 3. Background • Out of 1.1 million patients with diagnoses of ACS discharged from U.S.hospitals in 2010, 74% were classified as having Myocardial Infarction. • Annual rates of Acute MI have been fairly stable over the past decade, despite improvements in the management of coronary heart disease risk factors. • In ACS pts STEMI ranges from 29-47%,this percent is decreasing relative to NSTEMI, in part because of temporal change in risk factor profile. Reduction in classic risk factors such as smoking and HTN,but increase in DM, metabolic syndrome ,CKD,overall aging of the population.
  4. 4. Patients with chest pain at rest without elevation of hs-cTn on 2 measurements made 2 to 4 hours apart most likely have non ischemic chest pain.
  5. 5. Universal definition of MI (2007) Thygesen et al
  6. 6. New Guidelines ACCF/AHA/ESC Key changes: 1. New target of no more than 120 min from first medical contact to initiation of fibrinolysis(for those not undergoing PCI). 2. Early initiation of therapeutic hypothermia in survivors of cardiac arrest, followed by immediate PCI when appropriate. 3. Use of more potent oral antiplatelet drugs (prasugrel or ticagrelor) as alternatives to clopidogrel and provide specific advice on how to minimize bleeding, particularly among patients who require dual antiplatelet therapy (DAPT) in addition to oral anticoagulation.
  7. 7. Pathophysiology Three important reports. 1.Libby – described an updated model in terms of cellular and molecular pathways that underlie the pathogenesis of ACS,with a central role for inflammation,which drives plaque disruption and thrombosis. This has broadened the approach beyond management of a focal intracoronary stenosis in ACS. Mechanisms of acute coronary syndromes and their implications N Eng J Med 2013;368:2004-13
  8. 8. 2. Crea and Liuzzo classified ACS into 3 groups: Obstructive atherosclerosis with systemic inflammation. Obstructive atherosclerosis without systemic inflammation. ACS without obstructive atherosclerosis (Prinzmetal angina,amphetamine induced spasm) Pathogenesis of acute coronary syndromes. J Am Coll Cardiol 2013;61:1-11.
  9. 9. 3. Falk and a group of cardiac pathologists described 3 common coronary artery plaque morphologies resulting in thrombosis (plaque rupture, plaque erosion, disruptive nodular calcifications protruding into the coronary artery lumen, known as “calcified nodules”). Update on ACS,the pathologists’ view. Eur Heart J 2013;34:719-28
  10. 10. • Culprit plaque morphology varies from thrombosis with or without coronary occlusion to sudden narrowing of the lumen from intraplaque haemorrhage. • The coronary artery plaque morphologies primarily responsible for thrombosis are plaque rupture, and plaque erosion. • Plaque rupture being the most common cause of acute myocardial infarction, especially in men. • Autopsy data demonstrate that women <50 years of age more frequently have erosion, whereas in older women, the frequency of rupture increases with each decade.
  11. 11. Plaque morphology Plaque responsible for thrombosis Women <50 yrs >50 yrs Plaque erosion Plaque rupture Men Plaque rupture
  12. 12. • Ruptured plaques are associated with positive (expansive) remodelling and characterized by a large necrotic core and a thin fibrous cap that is disrupted and infiltrated by foamy macrophages. • Plaque erosion lesions are often negatively remodelled with the plaque itself being rich in smooth muscle cells and proteoglycans with minimal to absence of inflammation. • Plaque haemorrhage may expand the plaque rapidly, leading to the development of unstable angina. • Plaque haemorrhage may occur from plaque rupture (fissure) or from neovascularization (angiogenesis).
  13. 13. • Atherosclerosis is now recognized as an inflammatory disease with macrophages and T-lymphocytes playing a dominant role. • Recently at least two subtypes of macrophages have been identified. M1 is a pro-inflammatory macrophage while M2 seems to play a role in dampening inflammation and promoting tissue repair. • A third type of macrophage, termed by us as haemoglobin associated macrophage or M(Hb) which is observed at site of haemorrhage also can be demonstrated in human atherosclerosis.
  14. 14. Vulnerable plaque Contributors to vulnerable plaque : 1. Structural determinants of the plaque (size of the necrotic core,thickness and degree of inflammation within the fibrous cap ) 2. Plaque neovascularization 3. Infiltration with hemoglobin stimulated macrophages(increase the risk of intra plaque hemorrhage). 4. Pattern of calcification (spotty calcification confers higher risk compared with dense local calcification).
  15. 15. Interventions other than revascularization • To reduce infarct size in patients with STEMI. • Unloading the left ventricle with left atrial femoral artery bypass in case of Left anterior coronary artery occlusion, resulted in further reduction of myocardial infarct size.(an intriguing study in Swine) • Cannot be applied routinely in the catheterization laboratory in all patients with STEMI. • Could be lifesaving in patients with large infarctions. Circulation ,2013;128:328-36
  16. 16. Risk Factors miRNAs discovery is an major advance in biology Micro- ribonucleic acids (miRNAs): • Noncoding ribonucleic acid molecules • 21-23 nucleotide long. • Regulate the expression of target genes.  3 circulating miRNAs (126,233 and 197) were found to be risk factors for the development of future MI. Other have been found to be assosciated with reduced myocardial salvage,(133a) more pronounced reperfusion injury, and left ventricular remodelling after first STEMI.(miRNA 150)
  17. 17. miRNAS can be silenced by specific antagonists,known as antagomirs,that might be designed to modify target proteins that predispose plaques to rupture.
  18. 18. Novel Risk Score in patients with STEMI Dynamic TIMI Risk Score
  19. 19. Why this score? • Most risk scores for ACS,are based on findings at the time of the patient’s initial presentation. • They do not take into account events that occur during the hospital stay.  The dynamic TIMI risk score for STEMI includes 6 clinical events occuring after admission 1. Reinfarction 2. Stroke 3. Major bleed 4. Congestive Heart Failure or Shock 5. Arrhythmia (VT,VF or AF) 6. Renal failure Amin et al
  20. 20. Biomarkers • 1. 2. 3. 3 categories of cTn elevation: Ischemic myocardial damage(MI) Nonischemic causes of myocardial damage(myocarditis) Analytical issues that may be either assay based (calibration errors) or sample based.  A prospective analysis of 887 unselected patients with acute chest pain found that a simple algorithm that incorporates ST-segment elevation, the level of hs-cTn at presentation, and the absolute change in hs-cTn during the first hour performed well in separating AMI from non coronary diagnoses. Circulation 2012;126:31-40
  21. 21. • Among 2,544 patients presenting with symptoms consistent with ACS,the combination of normal hs-cTn at presentation and 2 h later, no ischemic changes on ECG,and a TIMI risk score for UA or NSTEMI of 0 or 1 identified approximately 40% of patients in whom the rate of major adverse cardiac events through 30 days was <1% and who therefore were good candidates for early discharge. • Many of these patients may not actually have had ACS. J Am Coll Cardiol 2013;62:1242-9
  22. 22.  In 1,967 patients presenting to ED with chest pain onset within 6 hours demonstrated that a combination of Negative cTn (not hs), Copeptin level < 14 pmol/l and Nondiagnostic echocardiographic findings could rule out MI in the majority of patients. CHOPIN trial ,J Am Coll Cardiol 2013;62:150-60
  23. 23. Minor releases of cTn after PCI…significant? • More patients will have detectable levels of cTn after PCI, are they significant????. • One analysis concluded that elevations in creatine kinase-MB 3 fold to 5-fold above the upper limit of normal after PCI correlated with cTn elevations of 50 fold to 100-fold in both frequency and risk for mortality 1 year after PCI. JAmCollCardiol 2013;62:242-51.
  24. 24. Novel biomarkers Pregnancy assosciated plasma protein-A, • Zinc binding metalloproteinase found in vulnerable plaques that cleaves insulin like growth factor -4 from IGF-1and that causes the destabilization of the fibrous plaque. MERLIN-TIMI 36 trial • 3,782 pts with NSTEMI • Elevated baseline PAPP-A was found to be independently assosciated with increased risk for CV death or MI at 30 days (HR:1.62,p=0.006)and 1 yr (HR:1.35,p=0.012). J Am Coll Cardiol 2012;60:332-8.
  25. 25. Membrane attack complex (MAC) • Ischemia mediated changes to myocardial cell surface molecule expression render the cell membrane a target for the complement system,leading to the formation of a membrane attack complex,which leads to cell lysis. • An analysis of 725 patients with STEMI treated with primary PCI, elevated concentrations of soluble MAC (a stable nonlytic form of MAC that can be used to estimate MAC) after multivariate adjustment were assosciated with all cause mortality(HR:1.81;p=0.029)and major adverse CV events (HR:1.70;p=0.006). AmHeartJ 2012;164:786-92.
  26. 26. Interleukin -17 • Role in host immunity • Pathophysiology of immune mediated diseases • Development of an unstable plaque.  Analysis of 981 pts enrolled in French registry of patients with MI, low levels of IL-17 were independently assosciated with increased risk for death or reinfarction at 2 years(HR:1.40;p=0.03). Eur Heart J 2013;34:570-7
  27. 27. Pentraxin 3 Higher levels of circulating pentraxin-3,a novel inflammatory marker,were associated with thin-cap vulnerable plaques , as determined by optical coherence tomography. Koga et al JAmCollCardiolInterv 2013;6:945-54
  28. 28. Imaging • CMR –helpful in risk stratification of patients with suspected CAD who were followed for 25 months* • CTA based score Morphological characteristics of coronary lesions (stenosis length, plaque volume and attenuation, remodelling index, presence of spotty calcium)was quite accurate in the detection of ACS in a cohort of patients with acute chest pain. • Reduces the mean cost in the ED, shortened lengths of hospital stay.# #Poon et al,JACC,2013;543-52 *JACC2012;60:2316-22
  29. 29. Catheter based imaging techniques Optical coherence tomography, plaque rupture was found to be responsible for the culprit lesion in 44% of 126 pts, while 36% had plaque erosion; plaque erosion: more frequently observed in younger patients with NSTEMI, whose plaques had thicker fibrous caps and less lipid than those with plaque rupture. JACC 2013:62:1748-58
  30. 30. • Near infrared spectroscopy,which allows the detection of lipids in the plaques. Madder et al • Use of this catheter in patients with STEMI revealed that the lipid core in culpirt plaques was larger than observed in non culprit arteries,thereby providing a “biochemical signature of the culprit plaque”. JACCInterven 2013;6:838-46.
  31. 31. Antiplatelet therapy 1. 2. 3. 4. 5. Phase 3 clinical trials results with novel antiplatelet drugs. Bedside monitoring to adjust antiplatelet therapy Duration of DAPT Reduction of stent thrombosis Influence of smoking on antiplatelet inhibition
  32. 32. Novel antiplatelet drugs Cangrelor intravenous, rapidly acting, potent, Reversible P2Y12 inhibitor. CHAMPION PHOENIX trial – double blind,double dummy trial, compared with clopidogrel 11,145 patients(44% -ACS)undergoing either urgent or elective PCI.
  33. 33. • Cangrelor reduced the odds of both the primary CV composite end point of death,MI, ischemia driven revascularization, or stent thrombosis at 48 hr after randomization by 20% (2,810 pts with NSTEMI) 25% (1,991 pts with STEMI) • Stent thrombosis reduced by 38% without increasing bleeding in the overall population,without heterogeneity across the population stratified by the type of ACS at presentation. • The benefit of intense but short duration inhibition of P2Y12 to reduce periprocedural complications,particularly MI and stent thrombosis.
  34. 34. Effect of Prasugrel • Oral thienopyridine prasugrel did not reduce the composite of CV death ,MI or stroke among medically managed patients with NSTEMI compared with clopdiogrel,in the TRILOGY-ACS trial. • Intensive blockade appears most beneficial in high risk patients during PCI TRITON TIMI 38 trial.
  35. 35. ARCTIC trial • 2,440 pts scheduled for coronary stent implantation (30% with prior MI,27% with non STE ACS) were randomized. • Strategy of platelet function monitoring using the Verfiy Now assay followed by intensification of the antiplatelet regimen in patients with high platelet reactivity,compared with a conventional strategy with no monitoring or adjustment of antiplatelet regimen. • Despite increasing the antiplatelet therapy in 1/3 pts in the platelet montioring group,there were no differences in the primary end point,the major secondary endpoint of stent thrombosis or any urgent revascularization or major bleeding.
  36. 36. Why ??? • Suboptimal cut point for high platelet reactivity. • Need for even more potent antiplatelet agents in patients with high reactivity • Some events cannot be influenced by antiplatelet therapy.
  37. 37. Until more successful strategies are developed, current ACS guidelines donot endorse routine testing of platelet function.
  38. 38. Duration of DAPT • DAPT is recommended for 12 months after ACS whether STEMI/NSTEMI/UA and whether patients receive intracoronary stents or not. • Meta analysis 8,231 pts (61% with ACS) undergoing PCI with DES from 4RCTs,extended use of DAPT >12 months significantly increased the risk for TIMI major bleeding by 2.6 fold but did not reduce mortality,MI,or stroke compared with control (3-12 months of DAPT).
  39. 39. TWENTE trial • A very low rate of late stent thrombosis (0.3%) between 12-24 months among patients who received second generation DES (either zotarolimus or everolimus),95% of whom stopped clopidogrel at 12 months. • Interruption of DAPT within the first 90 days after DES placement is not advised. JACC2013;61:2406-16
  40. 40. HIGH RISK GROUPS (patients undergoing intracoronary stent placement into a saphenous vein graft are at increased risk (1.33)for stent thrombosis within the first 3 months, regardless of stent type, if clopidogrel stopped before day 90after stent placement.
  41. 41. What if DAPT not taken for 1-2 days in first yr post PCI/ACS • 1,622 patients in Spanish registry were evaluated(59% ACS) ,29 hospitals. • Brief 7 days mean interruption was noticed • Not statistically assosciated with increase in the risk for stent thrombosis.
  42. 42. DAPT study (NCT00977938) • 26,000 pts,Intracoronary stents (BMSor DES) • Treated with DAPT • After 12 months,patients who were free of major CV events and bleeding were randomized to either placebo (12 month DAPT arm )or an additional 18 month of thienopyridine (30 month DAPT arm ). • First adequately powered evaluation of the clinical efficacy and safety of differing durations of DAPT • Results are anticipated in 2014.
  43. 43. Reduction of stent thrombosis with ticagrelor • TRITON TIMI 38 trial – ACS + stent pts - administration of prasugrel reduced stent thrombosis by 50%. • PLATO trial – 11,289 pts ACS + stent – ticagrelor vs clopidogrel Definite and probable stent thrombosis reduced by 25% • Benefit was consistent across all patient subgroups and types of stents.
  44. 44. Influence of smoking on antiplatelet inhibition PARADOX study,Gurbel et al • Clopidogrel vs Prasugrel • Inhibition of platelet activation on clopidogrel was lower in nonsmokers than in smokers. • Inhibition of platelet activity was greater with prasugrel than clopidogrel in both smokers and nonsmokers • Not affected by smoking status of the patient (Prasugrel)  SMOKER’S PARADOX Clinical benefits of clopidogrel are greater in smokers than in non smokers. JACC2013;60:1333-9
  45. 45. Oral anticoagulants ATLAS ACS 2 TIMI 51 trial • Oral factor Xa rivaroxaban in addition to standard DAPT in pts with ACS. • 7,817 pts with STEMI(>70% PCI) Use of rivaroxaban 4.7 days after the index event was associated with • 19% reduction in primary end point compared to placebo. • Benefit lasted till 30 days. • 2.5 mg bid reduced CV death. • Increased major bleeding,ICH.
  46. 46. ACS + Stent pts • Stent thrombosis reduced by 35% • Mortality reduction of 44% European medical agency approval of rivaroxaban after ACS in 2013. FDA approval ??? “NO” (for use after ACS)
  47. 47. Is there any benefit of high dose aspirin? • Systematic review of literature • 136 studies • 2,89,330 pts  No improvement in clinical outcomes with higher >160 mg /day maintenance doses of aspirin compared with lower doses in patients with ACS receiving coronary stents or being medically managed. • An excess of major bleeding of 23/1,000 with these higher doses of aspirin in medically managed pts. Am Heart J 2012;164:153-62
  48. 48. HORIZONS AMI trial • STEMI pts Rx with primary PCI • Higher doses of aspirin (>200mg/day) increased major bleeding(HR:2.80) • NOT more effective than low dose aspirin in preventing recurrent ischemic CV events.
  49. 49. Does the bleeding have an effect … TRIUMPH study • 3,560 pts received DAPT after MI • Less severe forms of bleeding have an negative impact on the quality of life and may increase the need for re hospitalization.
  50. 50. MI pts with AF • Requires triple therapy • 11,480 pts in Denmark were evaluated 2000-2009 • Excess risk for bleeding with triple therapy begins early (<90 days) and continues to 1 yr. • No improvement in tolerance over time with triple therapy. Substitution of prasugrel for clopidogrel increases TIMI major or minor bleeding 3.2 folds.
  51. 51. Patients who require triple therapy generally should receive low dose aspirin and clopidogrel for the minimum duration recommended (12 months), warfarin with a target INR of 2.0-2.5, and if coronary stenting is indicated ,a BMS.
  52. 52. WOEST trial • Open label • 573 pts –on oral anticoagulants undergoing coronary stenting. • Aspirin was not administered in one arm compared with triple therapy arm (aspirin 80-100 mg/day) • Risk for any bleeding was less in clopidogrel +OAC arm(19.4% vs 44.4%)(p<0.0001) • Secondary end points were also lower with dual therapy (HR :0.60) • Not conclusive (less no .of events)
  53. 53. Invasive management • In North Carolina,a statewide STEMI strategy to transport patients directly to a PCI capable hospital ,the mean time to reperfusion (by either PCI or fibrinolysis) was reduced by a mean of 31 min. • Direct transfer to PCI from ambulance – 20-30 min saved. • Unavoidable delays (1 in 7 pts) Delay in providing consent Difficulty with vascular access Difficulty in crossing the lesion Need for intubation
  54. 54. OPTIMAL REPERFUSION STRATEGY PCI or FIBRINOLYSIS????? • When delays are expected and primary PCI cannot be performed within 120 min of first medical contact, fibrinolytic therapy is recommended. • The optimal method of reperfusion when the delays are shorter(60-120 min) is less clear.
  55. 55. Two complication after primary PCI,are risk factors for subsequent mortality • Recurrent infarction • Major bleeding • Kikkeri et al ,this excess risk persisted beyond 1 year in case of recurrent MI. • In case of bleeding,excess risk returned to normal levels by 1 month. TRITON TIMI 38 trial
  56. 56. Which is superior BMS or DES ???? Bangalore et al. Compared with BMS, Sirolimus eluting stents, Paclitaxel eluting stents,and Everolimus eluting stents were associated with significantly reduced need for vessel revascularization, without increasing the risk for stent thrombosis. Circ Cardiovascul Interven 2013;6:378-90
  57. 57. Palmerini et al. Analysis of 12,453 pts with STEMI Rx with Stents The Everolimus eluting stent (a second generation DES) showed the most favourable safety and efficacy profile.
  58. 58. EXAMINATION trial • 1,498 pts with STEMI Everolimus eluting stents and BMS had similar rates of the primary composite of death , reinfarction, and any revascularization at 1 year. • Rates of repeat target lesion (2.1% vs 5.0%,p=0.003) • Vessel revascularization (3.7% vs6.8% ,p=0.008) were signficantly lower in Everolimus eluting stent group. Lancet,2012;380:1482-90
  59. 59. XAMI trial • 625 pts with STEMI • Everolimus vs Sirolimus • Major CV events were lower in Everolimus (4.0 % vs 7.7%,p=0.048) J Am Coll Cardiol 2012;60:381-7 COMFORTABLE AMI trial Biolimus eluting stents with a biodegradable polymer reduced the primary endpoint of major adverse cardiac events at 1 year compared with BMS (4.3% vs 8.7%,p=0.004) JAMA2012:308:777-87
  60. 60. Adjunctive therapies • Thrombus aspiration reduced both in hospital and longer term(mean 10 months)adjusted mortality rates. • Significant reduction in MACE (risk ratio : 0.76),all cause mortality(risk ratio: 0.71). • Manual thrombus aspiration vs rheolytic thrombectomy,neither technique completely removed the thrombus.  ACCF/AHA/ESC STEMI guidelines state that manual aspiration thrombectomy is reasonable for patients undergoing primary PCI(Class Iia,Level of evidenceB)
  61. 61. Reperfusion injury • Intracoronary microparticles (derived from platelets and endothelial cells) responsible for ongoing thrombosis and microvascular dysfunction leading to microvascular obstruction. • Infusion of Exenatide,a glucagon like peptide-1 analogue , beginning 15 min before primary PCI significantly increased myocardial salvage and reduced infarct size as assessed by MRI compared with placebo (172 pts with STEMI).
  62. 62. Intracoronary adenosine was shown to improve ST segment resolution and angiographic microvascular obstruction in a placebo controlled trial of 240 pts with STEMI Rx by PCI ,thrombus aspiration. REOPEN- AMI study ,J Am Coll Cardiol Intv 2013;6:580-9
  63. 63. • Intracoronary diltiazem and verapamil were more effective than intracoronary NTG in preventing the no reflow phenomenon,as assessed by the corrected TIMI frame count,by degree of ST segment resolution after intervention. • Ischemic post-conditioning,(brief episodes of ischemia induced by multiple low pressure coronary artery balloon inflations shortly after reperfusion) reduced infarct size and myocardial edema(50 pts with STEMI+Stents).
  64. 64. • In NSTEMI pts,undergoing PCI+stent,use of 1-2 doses of P Selectin antagonist – inclacumab reduced myocardial damage as assessed by biomarkers.* EMBRACE STEMI trial # Bendavia,an IV mitochondrial targeting peptide, with placebo in 300 pts with anterior STEMI undergoing PCI, whether reduces infarct size. *SELECT ACS trial,J Am Coll Cardiol 2013;61:2048-55 #EMBRACE STEMI study;Am Heart J 2013;165:509-14
  65. 65. Cardiogenic shock • Meta-analysis of 6 randomized trials • 1,054 pts with cardiogenic shock after MI • IABP did not reduce mortality, HF, reinfarction. • Confirmed in the IABP SHOCK II trial(606 pts). • Downgrade the use of IABP – class IIa to class IIb.
  66. 66. Radial access vs femoral access • 294,469 pts with STEMI Procedure success was similar • Median door to balloon time was only 4 min longer • Bleeding was reduced significantly by 38% with radial compared with femoral approach. • US – 1 in 6 PCIs in 2012,More frequently in West Europe. RIFLE STEACS trial – 1,001 pts with STEMI - radial access – less rate of primary end points (13.6%vs 21.0%),(hospital stay 5 vs 6 days)
  67. 67. RIVAL trial • (1.3% vs 3.2%) STEMI ,but not in NSTEMI pts(1.3% vs 0.8%). • In UK ,radial access was assosciated with a significantly lower mortality,major bleeding and site complications. • $830 lower than femoral access.
  68. 68. Lipids • 33% pts had LDL cholesterol>100mg/dl 6 months after AMI,with fewer than one third achieving levels <70 mg/dl. • Underdosing • Interruption of statin therapy • High intensity therapy is useful
  69. 69. Quality of care • More favourable patient baseline characteristics • A decrease in time from symptom onset to first medical contact (240 to 175 min),use of mobile ICUs) • Increase in the use of reperfusion therapy (49% to 75%),largely primary PCI. • More frequent use of guideline recommended therapies (statins17% to 22%),ACE (19% to 28%).
  70. 70. Computer based physician order entry • Reduces death by 41% and rehospitalizations by 32%.
  71. 71.  Slow gait speed is a measure of fraility,and among STEMI pts,independently assosciated with a 41% increase in the hazard of a CV event for each decline of 0.1m/sec in gait speed. JAmColl Cardiol 2013;61:1964-72
  72. 72. • An orientation appointment within 10 days of discharge,rather than standard approach (mean 35 days). • Improved attendance to 77% (an absolute increase of 18 % over the standard). Circulation 2013:127:349-55
  73. 73. THANK YOU