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La terapia medica nel dislipidemico con SCA: dalle statine agli antiaggreganti

La terapia medica nel dislipidemico con SCA: dalle statine agli antiaggreganti. Dott. M. Fineschi U.O.Emodinamica Azienda Ospedaliera Universitaria Senese Siena. Efficacia delle statine. Trials clinici Riduzione LDL-C Riduzione Mortalità. Studi sperimentali Effetti pleiotropici

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La terapia medica nel dislipidemico con SCA: dalle statine agli antiaggreganti

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  1. La terapia medica nel dislipidemico con SCA: dalle statine agli antiaggreganti Dott. M. Fineschi U.O.Emodinamica Azienda Ospedaliera Universitaria Senese Siena

  2. Efficacia delle statine Trials clinici Riduzione LDL-C Riduzione Mortalità Studi sperimentali Effetti pleiotropici Significato clinico ?

  3. Razionale per la terapia ipolipemizzante nella sindrome coronarica acuta • Dati sperimentali dimostrano che le statine: • Migliorano la funzione e la rigenerazione endoteliale • Riducono l’infiammazione • Prevengono gli effetti trombotici • Questi effetti sono teoricamente massimi quanto prima la terapia viene iniziata,in quanto il rischio è piu’ elevato nelle fasi precoci della malattia.

  4. Numero di eventi (%) Endpoint primario Statina Placebo 64 (4,2) 68 (4,4) Morte 101 (6,6) 113 (7,3) IM acuto nonfatale 8 (0,5) 10 (0,6) Arresto cardiaco resuscitato p = 0,02 95 (6,2) 130 (8,4) Peggioramento dell’angina Endpoint secondario p = 0,045 12 (0,8) 24 (1.6) Ictus (fatale e nonfatale) 254 (16,5) 250 (16.1) Rivascolarizzazione (CABG o PTCA) 91 (5,9) 106 (6.8) Peggioramento dell’angina Peggioramento dello scompenso cardiaco 40 (2,6) 43 (2.8) 0,25 0,50 0,75 1,00 1,25 2,00 Statina meglio Placebo meglio Rischio relativo Terapia precoce ed intensiva nella sindrome coronarica acuta(atorva 80 mg entro 24-96 h) Studio MIRACL FU 16 sett. Schwartz GG et al., JAMA 2001;285:1711-1718

  5. Terapia precoce ed intensiva nella sindrome coronarica acuta(entro 10 gg dal ricovero) Studio PROVE IT–TIMI 22 30 Pravastatina 40 mgC-LDL medio 95 mg/dL 16% RR p=0,005 25 20 Atorvastatina 80 mg (entro 10 gg dal ricovero) C-LDL medio 62 mg/dL 15 Morte o eventi CV maggiori (%) 10 5 0 0 3 6 9 12 15 18 21 24 27 30 Numero a rischio Mesi di Follow-up Pravastatina Atorvastatina 2.063 2.099 1.688 1.736 1.536 1.591 1.423 1.485 810 842 138 133 Cannon CP et al. N Engl J Med 2004;350:1495-1504

  6. 1.02 (0.95-1.09) 1.07 (0.94-1.21) 0.84 (0.72-1.02) 0.90 (0.56-1.44) 0.76 (0.70-0.84) 0.53 (0.22-1.26) 0.80 (0.76-0.84) 1.79 (1.08-2.96) 0.81 (0.77-0.87) 0.43 (0.24-0.78) 0.84 (0.76-0.94) 0.89 (0.60-1.33) Qualsiasi evento cardiovascolare 1 mese Infarto miocardico 4 mesi 6 mesi 12 mesi 24 mesi Tutti 1,6 1,2 1,0 0,6 0,2 0,8 0,4 3,0 1,4 Meta-analsisi di 13 studi sulla terapia precoce ed intensiva con statine nelle SCA (n=17.963) 19% morte ed eventi CV Hulten E et al. Arch Intern Med 2006;166:1814-1821


  8. Most patients who present with ACS are hypothesized to be a result of sudden luminal thrombosis in an epicardial coronary artery. Rupture of vulnerable plaque is the main cause af ACS and AMI. • Identification of these vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize them.

  9. Positive remodelling • Plaque burden • Large lipid necrotic core • Thin cap • Inflammation


  11. La regressione di placca Area dell’ateroma 10.16 mm2 IVUS basale Area del lume 6.19 mm2 Area dell’ateroma 5.81 mm2 Follow-up IVUS 24 mesi di rosuvastatina Area del lume 5.96 mm2 Variazione del volume delle lesioniStudio ASTEROID Nissen SE et al. JAMA 2006;295:1556-1565

  12. 1:1 randomization (double-blinded) Hong et al. JACC Interv 2009

  13. p=0.3 p=0.5 Percent change (%) mean change (mm3) p=0.22 p=0.015 Hong et al. JACC Interv 2009

  14. NC 2,3 mm2 (47%) NC 1,1 mm2 (24%) Hong et al. JACC Interv 2009

  15. PLAQUE STABILIZATION / PLAQUE REGRESSION: ”dual goals for statin therapy”

  16. Clinical benefit of statin pretreatment in patients undergoing PCI Numerous studies have demonstrated an association between elevated inflammatory states and adverse events following PCI hsCRP mesurements have been used as a marker of periprocedural inflammation in patients undergoing PCI to help predict plaque instability and subsequent cardiovascular events Attenuation of injury and inflammation associated with PCI is an important issue in cardiovascular medicine Attempts to suppress inflammation have led to favorable outcomes.

  17. ARMYDA-ACS trial: Study design 580 pts excluded for: - 451 statin therapy - 41 emergency angiography - 43 LVEF <30% - 30 contraindications to statins - 15 severe renal failure 20 pts excluded for indication to: - medical therapy (N=8) - bypass surgery (N=12) 30 days Atorvastatin 80 mg 12 hrs pre-angio; further 40 mg 2 hrs before N=96 771 pts with NSTE-ACS sent to early coronary angiography (<48 hours) Jan ’05 - Dec ‘06 PCI atorvastatin N=86 Primary combined end point: 30-day death, MI, TVR Coronary angiography atorvast PCI placebo N=85 Placebo 12 hrs pre-angio; further dose 2 hrs before N=95 Randomization (N=191) 2nd and 3rd blood samples (8 and 24 hrs post-PCI) 1st blood sample (pre-PCI) CK-MB, troponin-I, myoglobin, CRP

  18. The fibrous cap ruptures allowing direct contact between the highly thrombogenic necrotic core and circulating platelets and monocytes. These circulating platelets adhere to and become activated by the exposed subendothelial components. Following activation,these platelets release chemoattractans wich promote further platelet adhesion to the site of endothelial injury. Antiplatelet therapy is used to reduce the risk of further thrombotic complications,including cardiovascular death, myocardial infarction and stroke. For patients who undergo PCI, antiplatelet theraphy also reduce the risk of stent thrombosis.

  19. Clopidogrel together with aspirin has been the backbone of antiplatelet therapy in ACS patients over he past decade Limitations of clopidogrel • Slow onset of action(steady state platelet inhibition: 4 - 5 hour after 300-600 mg load) • Modest inhibition of platelet aggregation(steady state mean platelet inhibition 30 - 40%) • Slow offset of effect(at least 5 – 7 days) • Large interindividual variability in inhibition of platelet aggregation(poor platelet inhibition response in 15 - 40% of pts)

  20. At 30 days the incidence of the primary study outcome(composite of cardiovascular death,MI,or stroke) in the total study population was not significantly reduced by double dose clopidogrel,nor was the incidence of the secondary endpoints.

  21. Among the 17263 pz(69%) who underwent PCI a significant reduction in the risk of the primary endpoint was observed with double-dose clopidogrel. The relative risk of definite stent thrombosis at 30 days was reduced by 46% with double clopidogrel dosing (HR0.54;95%CI,0,39-0,74;P=0.0001)

  22. Even among patiente with ACS it appears that those who undergo PCI may have more of a benefit with higher clopidogrel dosing than patient who do not.This was clearly demonstrated in the CURRENT OASIS 7 Trial The relative risk of definite stent thrombosis at 30 days was reduced by 46% with double vs standard clopidogrel dosing (HR 0.54;95% CI,0.39-0.74:p=0.0001) • The study suggest no benefit but also no excess bleeding with double dose clopidogrel when medical theraphy or bypass surgery is the treatment used(no PCI) • The dose of aspirin does not impact efficacy or safety outcomes of patients with ACS

  23. Platelet reactivity-guided clopidogrel dosing: GRAVITAS (5429 pz) • Among 2214 low-risk drug eluting stent recipients who had high on-clopidogrel platelet reactivity (PRU≥230) as assessed by a single VerifyNow P2Y12 assay 12-24 h after the procedure intensified clopidogrel dosing (additional LD and 150 mg Day MD) did not significantly reduce the 6 month risk of cardiovascular death, MI, or stent thrombosis compared with standard clopidogrel dosing (2.3% vs 2.3%; P=0.98).

  24. Latest from GRAVITAS: Platelet reactivity correlates with adverse events • But they also looked at the post hoc threshold of 208 PRU and they found that patients with platelet reactivity below this 208 PRU cut off did have a lower risk of the primary end point both at 60 days and six months. • He pointed out that less than half the patients on the high dose of clopidogrel in the study got to below 208 PRU in GRAVITAS, which he suggested may explain the negative main results of the study (showing no difference in event rates between patients with high on-treatment platelet reactivity with 150 mg vs 75 mg of clopidogrel). And he therefore suggested that patients showing platelet reactivity above the 208 level may be better treated with a more potent antiplatelet agent such as prasugrelor ticagrelor.

  25. New Antiplatelet Agents

  26. TRITON TIMI38: were randomized after angiography: 99% underwent PCI ACS (STEMI or UA/NSTEMI) & Planned PCI N= 13,608 ASA Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Duration of therapy: 6-15 months 1o endpoint: CV death, MI, Stroke 2o endpoint: Stent Thrombosis Safety endpoints: TIMI major bleeds, Life-threatening bleeds Wiviott SD, Antman EM et al AHJ 2006

  27. Balance of Efficacy and Safety TRITON-TIMI38 13.608 pz 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke 19% 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 32% 2.4 HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days

  28. PRASUGREL is of particular benefit to patients with DM 30%

  29. - Prasugrel significantly reduced the occurrence of events of the primary efficacy endpoint compared with clopidogrel in patients: with DM by 30% (12.2% versus 17.0%, p<0.001); without DM by 14% (9.2% versus 10.6%, p=0.02). - Myocardial infarction (MI) was significantly reduced with prasugrel vs. clopidogrel in both groups of patients: with DM by 40% (8.2% versus 13.2%, p<0.001); without DM by 18% (7.2% versus 8.7%, p=0.006). - DM patients on insulinappeared to show a particularly pronounced benefit with prasugrel over clopidogrel (37% relative risk reduction [RRR] for the primary efficacy endpoint).- TIMI major hemorrhage incidence rates were similar among subjects with DM for prasugrel and clopidogrel (2.6% vs. 2.5%).

  30. PLATO study design: UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI) All receiving ASA; clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 20% 6–12-month exposure Primary endpoint: • CV death + MI + Stroke Key secondary: • CV death + MI + Stroke in patients intended for invasive management • Total mortality + MI + Stroke • CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events • MI alone / CV death alone / Stroke alone / Total mortality Primary safety: •Total major bleeding UA = unstable angina; PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack James S et al. Am Heart J 2009;157:599-605

  31. 16% PLATO genetic substudy showed the benefit of ticagrelor to be indipendent of CYP2C19 genotype

  32. The European guidelines make space for both prasugrel and the new, reversible, P2Y12 inhibitor ticagrelor . Of note, clopidogrel is now recommended only for patients who cannot take ticagrelor or prasugrel (class Ia). NewESCACSguidelines: ticagrelorin,clopidogrelout

  33. Prasugrel anTicagrelor both showed favorable efficacy and safety profiles in their respective trials: subgroup analysis will allow to define the best niche for each drug. Prasugrel appears more effective than ticagrelor in preventing stent thrombosis, but without other clinical benefits, and it may increase bleeding risk. It therefore could be used especially in patients with ACS(STEMI,DIABETES)undergoing PCI with one or more drug-eluting stents, not deemed at high bleeding risk, and started at the time of PCI but not before, in order to minimize bleeding associated with bypass surgery. Patients with prior stent thrombosis, unprotected left main stenting, or complex coronary disease could particularly benefit from prasugrel over several months or even years. Ticagrelor might be started well before PCI and also may prove more beneficial among those with moderately increased bleeding risk, especially before hospitalization, early in the hospital, and before coronary angiography, as its short half-life translates into an acceptable bleeding rate if the patient undergoes bypass surgery during the same hospital admission. Thus, ticagrelor could be the best choice for patients with ACS without severe bleeding risk and managed with an early conservative strategy. Both these agents should be avoided in patients at high risk of bleeding, such as those with previous stroke, advanced age, or severe renal failure, where Clopidogrel, alone or in combination with aspirin, will continue to maintain a major role.

  34. Although this was a pre-specified analysis, randomization of patients enrolled in TRITON was not stratified by diabetic status. - 3146 (23%) subjects in TRITON had a pre-existing history of DM, including 776 receiving insulin. - In agreement with established medical knowledge, CV events occurred significantly more often in all patients with DM than in patients without DM (+45% for the primary efficacy endpoint [= CV death, nonfatal MI or nonfatal stroke]; +95% for stent thrombosis). PRASUGREL is of particular benefit to patients with DM

  35. Genetic polymorphisms and clopidogrel eficacy

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