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  • 4 There are a number of therapeutic approaches to acute coronary syndrome (ACS) treatment based on the various pathophysiological steps in the process. 1.  -Blockers and nitrates are symptomatic therapies and exert their action downstream from the thrombus by balancing myocardial oxygen supply and demand. 2. Heparin is used to prevent further clot formation by inhibiting fibrin formation. 3. Antiplatelet agents, such as aspirin, clopidogrel and GP IIb/IIIa inhibitors, reduce platelet adhesion and aggregation, which play a key role in thrombus formation. 4. There is growing interest in agents that may stabilise the plaque and discourage rupture. Statins are currently being studied in this context.
  • A retrospective analysis of patients with both ST elevation and non-ST elevation ACS included in GUSTO IIb gave similar results. In patients discharged on lipid-lowering therapy, significant reductions in mortality were observed. After adjusting for other variables, the reduction in mortality at 6 months was 52% (risk ratio = 0.48, 95% CI 0.28–0.83, p =0.009). In the PRISM trial, a retrospective analysis showed that the death/MI rate was significantly lower in patients who were continued on background statin therapy. If the statin therapy was withdrawn during the first hours of hospitalisation, cardiac risk did not differ from patients that did not receive statins before or after randomisation. References Aronow HD, Wolski KE, Lauer MS. Marked reduction in mortality with early lipid-lowering therapy after ST and non-ST elevation acute coronary syndromes. Circulation ; 102(18) : II-435. Hamm CW, Heeschen C, Boehm M Role of statins in patients with acute coronary syndromes. Circulation ; 102(18) : II-435.
  • Each year from 1993 to 1999, we prospectively collected data among the first 1000 patients undergoing PCI at Cleveland C. Patients who presented with acute or recent myocardial infarction or cardiogenic shock were excluded from the analysis. Baseline, procedural, and 6-month data of statin-treated and non–statin-treated patients were compared. Propensity score and multivariate survival analysis were used to adjust for heterogeneity between the two groups. Of 5052 patients who completed follow-up, 26.5% were treated with statin at the time of the procedure. Statin therapy was associated with a mortality reduction at 30 days (0.8% versus 1.5%; hazard ratio, 0.53; P 0.048) and at 6 months (2.4% versus 3.6%; hazard ratio, 0.67; P 0.046). After adjusting for the propensity to receive statin therapy before the procedure and other confounders, statin therapy remained an independent predictor for survival at 6 months after coronary intervention (hazard ratio, 0.65; 95% CI, 0.42 to 0.99; P 0.045).
  • University Clinic Essen, Essen, Germany, and the Division of Cardiovascular Diseases Mayo Clinic, Rochester, Minn. stratified 296 consecutive patients who were undergoing stenting of a de novo stenosis according to the preprocedural status of statin therapy (229 statin-treated and 67 control patients). Incidence of periprocedural myocardial injury was assessed by analysis of creatine kinase (CK; upper limit of normal [ULN] 70 IU/L for women, 80 IU/L for men) and cardiac troponin T (cTnT; bedside test; threshold 0.1 ng/mL) before and 6, 12, and 24 hours after the intervention. Relative to control patients, the incidence of CK elevation 3 ULN was more than 90% lower in statin-treated patients (0.4% versus 6.0%, P 0.01). Statin therapy was the only factor independently associated with a lower risk of CK elevation 3 ULN (OR: 0.08, 95% CI: 0.01 to 0.75; P 0.03). The overall incidences of CK and cardiac troponin T elevation were slightly lower in statin-treated than in control patients (14.4% versus 20.9%, P 0.3, and 17.9% versus 22.4%, P 0.5, respectively)
  • Dirk H. Walter, Department of Internal Medicine IV, Division of Cardiology, University of Frankfurt, Frankfurt, Germany Preprocedural CRP levels also appear to be a powerful predictor of both early and late outcome in patients undergoing conventional balloon angioplasty and stent implantation suggesting that preprocedural activation of inflammatory cells may play a role in the modulation of vessel wall responses to the injury induced by balloon angioplasty. 388 consecutive patients undergoing coronary stent implantation. Patients were grouped according to the median CRP level (0.6 mg/dl) and to the presence of statin therapy.
  • Briguori: 451 patients scheduled for elective PCI and not on statins were randomly assigned to either no treatment or to statin treatment. Statin administration was started at least 3 days before the procedure. The type and the dosage of the statin used was as follows: atorvastatin 29% of cases (mean dose = 22 ± 9 mg/day); (2) pravastatin, 29% of cases (mean dose = 32 ± 10 mg/day); (3) simvastatin, 39% of cases (mean dose = 24 ± 9 mg/day); and (4) fluvastatin, 3% of cases (80 mg/day).
  • for measurement of plasma levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin: 38 patients belonged to atorvastatin (40 mg/day) and 38 to the placebo arm. Adhesion molecules were evaluated 7 days before intervention, immediately before PCI, and after 8 and 24 h
  • Further atorvastatin is not only lipid lowering, it is much beyond that. Many ploeiotropic benefits.
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  • Three paradigms are presented which might explain the benefits of statins in reducing the risk of coronary heart disease. Low-density lipoprotein cholesterol (LDL-C) reduction is integral to the efficacy of statins. However, analysis of lipid reductions in WOSCOPS with pravastatin suggest s that clinical benefit seen with pravastatin is not explained by lipid changes alone. Stains may alter one or more lipid subfractions in addition to LDL-C. These might include chylomicrons, small dense LDL-C, very low density lipoprotein remnants, or intermediate-density lipid (IDL). The combined reduction in these multiple lipid particles might explain the difference between predicted and observed event rates in patients receiving pravastatin. In addition, pravastatin has also been shown to have non-lipid effects, ie restored endothelial function, plaque stabilisation, inflammation, or decreased thrombogenicity. Research into these and other additional mechanisms of action is being actively pursued.

14.09.13 high dose statin 14.09.13 high dose statin Presentation Transcript

  • Dr. Rajeev Agarwala Jaswant Rai Speciality Hospital, Meerut. E-mail : rajeev_jrsh@yahoo.co.in High Dose Statin: The Evidence, Choice and Duration of Therapy
  • Collateral Therapeutics Lipid abnormalities Inflammation Coagulation cascade Thrombus
  • 4. Plaque rupture,4. Plaque rupture, cholesterol content,cholesterol content, inflammation (hs-CRP)inflammation (hs-CRP) (statins)(statins) 3. Platelet adhesion/3. Platelet adhesion/ activation/aggregationactivation/aggregation (aspirin, clopidogrel,(aspirin, clopidogrel, GP IIb/IIIa inhibitors)GP IIb/IIIa inhibitors) 2. Activation of clotting2. Activation of clotting cascade – thrombincascade – thrombin (heparin/LMWH)(heparin/LMWH) 1. Downstream from thrombus1. Downstream from thrombus myocardial ischaemia/necrosismyocardial ischaemia/necrosis ((ββ-blockers, nitrates etc)-blockers, nitrates etc) PlateletPlatelet GP IIb/IIIaGP IIb/IIIa receptorreceptor FibrinogenFibrinogen ThrombinThrombin FibrinFibrin clotclot Pathophysiology of ACS and potentialPathophysiology of ACS and potential pharmacological interventionspharmacological interventions
  • GUSTO IIb/PRISM: Early reduction in death/MIGUSTO IIb/PRISM: Early reduction in death/MI in patients on lipid-lowering therapyin patients on lipid-lowering therapy • GUSTO IIbGUSTO IIb – Retrospective analysis of 12,630 ACS patients (Retrospective analysis of 12,630 ACS patients (±±STST elevation)elevation) – 52% reduction in 6-month mortality (RR 0.48, 95%52% reduction in 6-month mortality (RR 0.48, 95% CI 0.28-0.83)CI 0.28-0.83) • PRISMPRISM – Retrospective analysis of 1616 patientsRetrospective analysis of 1616 patients – Death/MI rate at 30 days was significantly lower inDeath/MI rate at 30 days was significantly lower in these patients (these patients (pp<0.01)<0.01) Aronow et al, Hamm et al (AHA 2000)Aronow et al, Hamm et al (AHA 2000)
  • Early Striking Mortality Reduction After ACS by Lipid-lowering Therapy GUSTO IIbGUSTO IIb && PURSUIT, 1993-98PURSUIT, 1993-98 (20,809 patients)(20,809 patients) RIKS-HIA 1995-98RIKS-HIA 1995-98 (19,599 patients)(19,599 patients) Stenestrand et al, JAMA 2001;285:430Stenestrand et al, JAMA 2001;285:430 Aronow et al, Lancet 2001;357Aronow et al, Lancet 2001;357::10631063 Relative risk 0.75Relative risk 0.75 95% CI 0.63-0.8995% CI 0.63-0.89 Log-rank p<0.0001Log-rank p<0.0001 RR 0.75RR 0.75 95% CI 0.63-0.8995% CI 0.63-0.89 p=p=0.0010.001 Statin (n=5528) No statin (n=14071) p<0.0001 RR 0.48RR 0.48 95% CI 0.37­0.6395% CI 0.37­0.63 No LL (n=17156) Lipid-lowering (n=3653)
  • THE EVIDENCE
  • Very early (<24 hrs) statin therapy in patients with ACS associated with reduced mortality Lenderink et al, Eur Heart J 2006;27:1799-1804 HR 0.44HR 0.44 (95% CI 0.31-(95% CI 0.31- 0.64)0.64) 77 HR 0.16HR 0.16 (95% CI 0.08-0.37)(95% CI 0.08-0.37) (n=1426)(n=1426) (n=6771)(n=6771) Euro Heart Survey 2000-01 (10,484 patiens)Euro Heart Survey 2000-01 (10,484 patiens)
  • Early statins and mortality in Euro Heart Survey Lenderink et al, Eur Heart J 2006;27:1799-1804 7-day7-day YESYES (n=1426)(n=1426) NONO (n=6771)(n=6771) Unadjusted HRUnadjusted HR (95%CI)(95%CI) Adjusted HRAdjusted HR (95%CI)(95%CI) STEMISTEMI 0.3%0.3% 3.4%3.4% 0.090.09 (0.02–0.35)(0.02–0.35) 0.170.17 (0.04–0.70)(0.04–0.70) NonSTENonSTE MIMI 0.6%0.6% 1.5%1.5% 0.410.41 (0.15–1.1)(0.15–1.1) 1.01.0 (0.34–2.9)(0.34–2.9) AllAll 0.4%0.4% 2.6%2.6% 0.160.16 (0.08–0.37)(0.08–0.37) 0.340.34 (0.15–0.79)(0.15–0.79) 30-day30-day STEMISTEMI 1.6%1.6% 5.9%5.9% 0.250.25 (0.13–0.47)(0.13–0.47) 0.490.49 (0.25–0.95)(0.25–0.95) NonSTENonSTE MIMI 2.7%2.7% 3.5%3.5% 0.780.78 (0.47–1.3)(0.47–1.3) 1.61.6 (0.95–2.8)(0.95–2.8) AllAll 2.3%2.3% 5.0%5.0% 0.440.44 (0.31–0.64)(0.31–0.64) 0.900.90 (0.60–1.3)(0.60–1.3)
  • STATIN STEMI Study A total 171 patients with STEMI were randomized to 80-mg atorvastatin (n=86) or 10-mg atorvastatin (n=85) arms for pre-treatment before PCI. After PCI, both groups were treated with atorvastatin (10 mg) End points were TIMI frame count, myocardial blush grade, and ST-segment resolution at 90 min after PCI J Am Coll Cardiol Intv 2010;3:332–9
  • STATIN STEMI: Study Design
  • TIMI frame count (in Seconds) Atorvastatin 80 mg Atorvastatin 10 mg 0 5 10 15 20 25 30 35 26.9 31.4 P=0.01 Coronary Perfusion was better and faster in atorvastatin 80 mg group than in atorvastatin 10 mg group J Am Coll Cardiol Intv 2010;3:332–9
  • Mean ST segment resolution Atorvastatin 80 mg Atorvastatin 10 mg 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 61.8 50.6 Average ST segment resolution was better in atorvastatin 80 mg Vs 10 mg group J Am Coll Cardiol Intv 2010;3:332–9
  • Complete ST segment resolution Atorvastatin 80 mg Atorvastatin 10 mg 0 5 10 15 20 25 30 35 40 45 39.5 23.8 p=0.03 More patients achieved complete ST segment resolution in atorvastatin 80 mg Vs 10 mg group J Am Coll Cardiol Intv 2010;3:332–9
  • STATIN- STEMI: ST resolution and MACE Atorvastatin 80 mg is associated with: •Significantly better ST resolution •Trend for lower MACE
  • STATIN STEMI: Conclusion High-dose atorvastatin pre-treatment before PCI improved immediate coronary flow after primary PCI compared with low-dose atorvastatin . J Am Coll Cardiol Intv 2010;3:332–9
  • Statin therapy significantly reduced the risk of the composite primary endpoint J Am Coll Cardiol 2011;58:1664–71
  • Hulten et al, Arch Intern Med 2006
  • Early statin treatment reduces 1-year mortality in AMI survivors Stenestrand U, Wallentin L. JAMA 2001;285:430–436 RR 0.75 (95% CI 0.63-0.89)RR 0.75 (95% CI 0.63-0.89) p 0.001p 0.001 RIKS-HIA database (19,599 patients)RIKS-HIA database (19,599 patients)
  • Statin Therapy and Outcome during Hospitalization for ACS On-statin treatment and ACS presentation in GRACE Spencer et al, Ann Intern Med 2004; 140: 857 - 866 32 52 30 30 38 18 0% 20% 40% 60% 80% 100% No Yes STEMI NSTEMI Unstable Angina
  • Effect of statins on arrhythmia related mortality in STEMI Non-sustaained ventricular tachycardia (NSVT) is an independent factor affecting mortality after ACS* In German ACS registry, data from 3137 patients with STEMI and in-hospital Holter monitoring were analysed for association with statin therapy and NSVT related mortality upto 1 yr NSVT related Mortality was evaluated in presence or absence of statin therapy at discharge * Circulation 1993;87:312–322 Eur Heart J. 2005 Jun;26(11):1078-85.
  • Statin therapy can neutralize effect of non- sustained ventricular tachycardia (NSVT) on mortality in STEMI Not giving statin at time of hospital discharge in STEMI patients, increase NSVT related mortality by 3 times. Eur Heart J. 2005 Jun;26(11):1078-85.
  • VIRHISTAMI Study Objective: To evaluate effect of low Vs high-dose statin on necrotic core in coronary plaques as assessed by intravascular ultrasound - virtual histology 87 STEMI patients were given low Or high dose statin for 12 months duration The plaque component necrotic core (%) was measured at baseline and at 12 months High dose Low dose 0 2 4 6 8 10 12 14 16 14.2 7.6 Reduction in Necrotic Core (%) Only High dose statin was effective for plaque regression in the STEMI patients * Vs Baseline EuroIntervention. 2012 Sep 18. pii: 20110313-03 P=0.29P=0.29* P=0.003*
  • THE DURATION
  • • In a tertiary care hospital in Italy, 1321 ACS patients who were discharged with 80 mg/day atorvastatin were followed up for 1 yr. • Any change in Atorvastatin dose or switch over was recorded. • Patients who continued 80 mg/day for 1 yr were compared to those who reduced atorvastatin dose or switch over to another statin • Primary end point: All cause death, non fatal MI or non fatal stroke “San Filippo Neri” Study, Italy International Journal of Cardiology 152 (2011) 56–60
  • Risk of CV event was inversely proportional to duration of atorvastatin 80 mg/day therapy International Journal of Cardiology 152 (2011) 56–60 “San Filippo Neri” Study, Italy
  • Conclusion • For optimum cardiovascular benefits, Atorvastatin 80 mg/day should be continued for at least 1 yr (except when patient has intolerable ADRs to the drug) • Reducing dose of atorvastatin or switch over to other statins increase the risk of adverse CV events International Journal of Cardiology 152 (2011) 56–60 “San Filippo Neri” Study, Italy
  • And this is not the 1st evidence • Switch over to simvastatin from atorvastatin led to 30% increase in CV events in UK over 1.2 yrs* • Switch over from intensive lipid lowering to moderate therapy (due to change in national policy) tripled the CV events within 6 months in New Zea land and it was reversed by starting intensive therapy * Br J Cardiol 2007;14:280–5 ** Lancet 1998;352:1830–1
  • Effects of the synergistic actions between PCI-statins • Stabilization and regression of atherosclerotic plaque • Prevention of peri-procedural infarct • Prevention of restenosis • Prevention of contrast induced nephropathy • Improvement of slow flow Clin Invest Arterioscl. 2012;xxx(xx):xxx---xxx in press
  • PROVE IT-TIMI 22: treatment effects stratified by PCI for the index ACS event Wiviott et al, Circulation 2006;113:1426 0-4 months0-4 months Trial durationTrial duration Statin treatmentStatin treatment 4 4,7 7,1 10,9 10,19,9 2,8 3,9 0 2 4 6 8 10 12 PCI no PCI PCI no PCI Moderat e (prava 40 mg) I ntensive (at orva 80 mg) p 0.07p 0.07 p 0.01p 0.01 NSNS NSNS
  • Statin therapy at discharge was associated with a significant reduction in 1-year mortality after primary angioplasty for STEMI. Therefore, the use of statins is highly recommended in these patients
  • Statin therapy pre-PCI is an independent predictor of survival Chan et al, Circulation 2002;105:691 6-month mortality of patients pretreated with statins (n= 1337) vs those not statins pretreated (n=3715) at the time of PCI
  • Preprocedural Statin Reduces the Extent of Periprocedural Non-Q- Wave Myocardial Infarction Herrmann et al, Circulation. 2002;106:2180 0 2 4 6 8 10 control on statincontrol on statin 6.0% 0.4% CK > 3XUNL p<0.01p<0.01 n=56 P=0.18, log-rank n=211
  • Statin therapy, inflammation and recurrent coronary events following PCI Walter et al, J Am Coll Cardiol 2001;37:839
  • Pre-PCI statin Rx reduces the incidence of large peri-procedural nonQ-AMI Briguori et al,Briguori et al, Eur Heart JEur Heart J 20042004;; 2525:: 1822–18281822–1828 Pasceri et al, Circulation 2004;110:674Pasceri et al, Circulation 2004;110:674 8,0 5,0 15,6 18,0 0,0 5,0 10,0 15,0 20,0 25,0 Briguoli (n.451) Pasceri (n.153) St at in No st at in OR 0.19OR 0.19 (95% CI 0.05-0.57)(95% CI 0.05-0.57) p = 0.02 OR 0.47OR 0.47 (95% CI 0.26–0.86)(95% CI 0.26–0.86) p = 0.01 PeriproceduralAMI(%)
  • 7-day atorvastatin pretreatment decreases adhesion molecules after PCI Patti et al, J Am Coll Cardiol 2006;48:1560 atorvastatinatorvastatin placeboplacebo
  • Patti et al, J Am Coll Cardiol 2007;49:1272 5%5% p 0.01p 0.01 17%17% 5%5% p 0.01p 0.01 17%17%
  • Atorvastatin Pretreatment Improves Outcomes in Patients With ACS Undergoing Early PCI ARMYDA-ACS Randomized Trial Patti et al, J Am Coll Cardiol 2007;49:1272
  • Atorvastatin Pretreatment Improves Outcomes in Patients With ACS Undergoing Early PCI Results of the ARMYDA-ACS Randomized Trial Patti et al, J Am Coll Cardiol 2007;49:1272
  • Atorvastatin and CIN (contrast-induced nephropathy) in PCI for STEMI patients 161 STEMI patients undergoing emergency PCI were randomized to atorvastatin 80 mg or placebo before PCI All patients received atorvastatin 40 mg/day after PCI The primary end point was incidence of CIN. Cardiology. 2012;122(3):195-202
  • Atorvastatin 80 mg placebo 0 2 4 6 8 10 12 14 16 18 2.6 15.7 CIN (%) P=0.01 Atorvastatin and CIN (contrast-induced nephropathy) in PCI for STEMI patients RESULTS: % patients developing CIN Cardiology. 2012;122(3):195-202 High dose atorvastatin pre-treatment before PCI in STEMI patients significantly reduces CIN
  • THE MECHANISM
  • How can High dose statin produces immediate benefits in STEMI?
  • Pleiotropic benefits • Anti-inflammatory • Anti-oxidant • Improves endothelial function (NO). • Plaque stabilization • Anti-platelet • Fibrinolytic • Anti-proliferative ….Many more •Pleiotropic benefits are dose dependent •Pleiotropic benefits appears much before the lipid lowering effects
  • Potential mechanisms by which statins act rapidly and favorably in ACS Improve endothelial integrity & vasomotion Decrease plaque matrix degradation Reduce plaque inflammation Reduce platelet aggregability and thrombus formation Decrease reperfusion injury
  • • An immediate significant effect of just a single dose of statin has been previously reported Immediate functions of statins Ostadal et al. demonstrated that a single dose of cerivastatin at the time of admission of patients with unstable angina or non-ST elevation MI positively influences the inflammatory parameters CRP and interleukin-6 at 24 hours (Mol Cell Biochem 2003;246:45-50) Romano et al. described that a 24-h treatment with lovastatin and simvastatin induces inhibition of monocyte chemotactic protein-1 (MCP-1) synthesis in mononuclear and endothelial cells in vitro (Lab Invest 2000;80:1095-1100) Statins indeed have beneficial effects on endothelial function by a rapid increase in nitric oxide bioavailability; this effect has been observed as early as 3 hours following statin administration (Laufs et al. Circulation 1998;97:1129-1135)
  • Possible mechanisms of the clinical benefit: Vasodilation of coronary microvessels N=32 pts without CAD randomized to placebo or atorvastatin (single dose of 40 mg) transthoracic doppler evaluation of LAD (baseline and 1 hr) 0 1 2 3 4 Placebo Atorvastatin Before After Coronary flow velocity reserve (hyperemic/basal peak diastolic velocity) P<0.01 Am J Cardiol 2005;96:89 –91
  • • Isolated perfused mouse hearts. • Atorvastatin infused at the initiation of reperfusion. • Results: – Within 5 minutes, Atorvastatin activates • PI3K/Akt signalling pathway. • eNOS phosphorylation • Dose dependent reduction of infarct size.
  • Immediate Antiplatelet and Antioxidant effect of Atorvastatin • Patients with hypercholesterolemia were randomly allocated to a: – Mediterranean diet with low cholesterol intake (<300 mg/d; n=15) or – Atorvastatin (40 mg/d; n=15). • Oxidative stress assessed by serum Nox2 and urinary isoprostanes. • Platelet activation assessed by platelet recruitment, platelet isoprostanes, and thromboxane A(2), platelet Nox2, Rac1, p47(phox), protein kinase C, vasodilator-stimulated phosphoprotein, nitric oxide, and phospholipase A(2). • Oxidative stress and platelet activation were etermined at baseline and after 2, 24, and 72 hours and 7 days of follow-up. Circulation. 2012 Jul 3;126(1):92-103 NOX2: NADPH oxidase
  • • Results: • The atorvastatin-assigned group showed a significant and progressive reduction of urinary isoprostanes and serum Nox2, along with inhibition of platelet recruitment, platelet isoprostanes, Nox2, Rac1, p47(phox), and protein kinase C, starting 2 hours after administration. • Platelet phospholipase A(2) and thromboxane A(2) significantly decreased • Vasodilator-stimulated phosphoprotein and nitric oxide increased after 24 hours. • No changes were observed in the Mediterranean diet group. Circulation. 2012 Jul 3;126(1):92-103 First evidence suggesting that atorvastatin acutely and simultaneously decreases oxidative stress and platelet activation by directly inhibiting platelet Nox2 and ultimately platelet isoprostanes and thromboxane A(2).
  • Early Antiplatelet effect of statin in STEMI Effect of statins on platelets were measured in 120 STEMI patients (80 received statin, 40 did not receive) Platelets were incubated with a statin or placebo for 72 hrs Effect of statins on platelet function under flow conditions and platelet aggregation was studied in vitro by aggregometry. Platelet incubation with statin compared with placebo resulted in a lower aggregate-size (29 ± 9 μm(2) vs. 39 ± 15 μm(2), p<0.01), and lower surface coverage (8.5 ± 4% vs. 12 ± 4%, p<0.01) statin therapy produces antiplatelet effects within 72 hrs in the STEMI patients Platelets. 2011;22(2):103-10.
  • STATINSSTATINS ↓LDL-C reduction ↑HDL-C Reduction in chylomicron and VLDL remnants, IDL, LDL-C Reduce plasma ViscosityReduce plasma Viscosity Altering platelet aggregationAltering platelet aggregation Suppressing ThrombinSuppressing Thrombin Suppress inflammation (↓Suppress inflammation (↓ CRP/IL6) Inhibit M.M.P.CRP/IL6) Inhibit M.M.P. Improve Endothelial functionImprove Endothelial function Up regulate VasodilatorsUp regulate Vasodilators (NO/Prostacyclin)(NO/Prostacyclin)Lumen Lipid core Macrophages Smooth muscle cells Potential mechanisms of benefit of statins in ACS Dissociation Vs Association between lipidDissociation Vs Association between lipid lowering and anti-inflammatory effectslowering and anti-inflammatory effects
  • HIGH DOSE THE SIDE EFFECTS
  • Severe adverse event rates for intensive vs moderate statin therapy (n. 32,279 pts) mod. from Cannon et al, J Am Coll Cardiol 2006;48:438 StandarStandar d dosed dose HighHigh dosedose StandardStandard dosedose HighHigh dosedose StandardStandard dosedose HighHigh dosedose PROVE ITPROVE IT (n=4162)(n=4162) 0%0% 0%0% 0.1%0.1% 0.1%0.1% 1.1%1.1% 3.3%3.3% AA toto ZZ (n=4497)(n=4497) 0%0% 0.1%0.1% 0.04%0.04% 0.4%0.4% 0.3%0.3% 0.8%0.8% TNTTNT (n=10001)(n=10001) 0.06%0.06% 0.04%0.04% 0%0% 0%0% 0.2%0.2% 1.2%1.2% IDEALIDEAL (n=8888)(n=8888) 0.07%0.07% 0.05%0.05% 0%0% 0%0% 0.1%0.1% 1.3%1.3% SPARCLSPARCL (n=4731)(n=4731) 0.1%0.1% 0.1%0.1% 0.1%0.1% 0.1%0.1% 0.4%0.4% 2.2%2.2% RhabdomyolysisRhabdomyolysis CPK >10 xULNCPK >10 xULN AST/ALT >3 xULNAST/ALT >3 xULN
  • LIVER EXPERT PANEL: KEY MESSAGES • There is no proof that statins cause life-threatening liver damage. • Mild asymptomatic elevations in liver enzymes are found in about 3 patients per 1,000 person-years who participate in clinical trials. Elevations are reversible on stopping the statin and do not cause lasting harm. • Liver failure has been reported in 1 person out of 1 million person-years of statin use, as well as in 1 person in 1 million people not taking a statin. • Routine liver function monitoring during statin therapy is not needed. The Task Force recommends that statin manufacturers work with the FDA to remove the requirement for liver function monitoring from prescribing information.
  • Rate of Elevated Liver Enzymes by Statin DoseRate of Elevated Liver Enzymes by Statin Dose CategoryCategory JACCJACCJ Am Coll Cardiol 2007;50:409–18 Drug- and dose-specific effects are more important determinants of liver toxicity than magnitude of LDL-C lowering
  • MUSCLE EXPERT PANEL: KEY MESSAGES • Though all marketed statins have a small potential for inducing muscle side effects, 5 in 100,000 patients taking a statin have muscle complaints and are found to have an increase in muscle enzymes, suggesting muscle injury. This finding is not statistically significant. • 1.5-3.0 percent of patients taking a statin complain of muscle pain, weakness, or cramps. The numbers are similar for patients receiving placebo. • Exercise, trauma, falls, accidents, seizures, infections, chills, and alcohol and drug abuse can cause muscle injury. Physicians should carefully identify and address the risk factors for muscle problems before prescribing a statin. • Rhabdomyolysis, the most serious potential problem associated with statin therapy, occurs in about 2 of 100,000 patients taking a statin. This is rarely life threatening and is reversible when the statin is stopped.
  • Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described Rosuvastatin and atorvastatin dosing decision support algorithm Circ Cardiovasc Genet. 2013;6:400-408
  • Study Trial Population Regimens Durati on (yrs) New DM Cases in Compared Regimens Relative LDL Reduction 4S Previous MI or angina Simvastatin 40 mg 5.4* 198 (9.4%) 36.7% at 12 mos HPS History of CVD Simvastatin 40 mg 5.0 335 (4.6%) 29.4% average in trial ALLHAT -LLT CAD or CAD risk factors Pravastatin 40 mg 4.8 238 (7.9%) 18.1% at 24 mos PROVE-IT- TIMI-22 Recent ACS Atorvastatin 80 mg vs pravastatin 40 mg 2.0 101 (5.9%) vs 99 (5.9%) 22% TNT Stable CAD Atorvastatin 80 mg 5.0 418 (11.0%) 22% IDEAL Previous MI Atorvastatin 80 mg vs simvastatin 20 OR 40 mg 4.8* 240 (6.4%) vs 209 (5.6%) 16% SPARCL Previous stroke or TIA Atorvastatin 80 mg 4.9 166 (8.7%) NA Jupitor healthy persons without hyperlipidemia, elevated high-sensitivity C-reactive protein levels, Rosuvastatin 20 mg 1.9 years 3.0% 50% Meta-Analysis of Impact of Different Types and High Doses of Statins on New-Onset Diabetes Mellitus Am J Cardiol 2013;111:1123e1130
  • THE COMPLIACE
  • % STEMI patients receiving statin at discharge in India and developed countries Kerala ACS registry NCDR action registry 0 10 20 30 40 50 60 70 80 90 100 69 94.5 %STEMIpatientsreceivingstatinatdischarge Circulation. 2011; 124: A9151
  • Statin dosage used in pre-PCI and post-PCI period in patients with UA/NSTEMI and STEMI Clin. Cardiol. 35, 11, 700–706 (2012) High-dose statin treatment is being underused despite extensive evidence for patients with ACS undergoing PCI
  • Difference in High dose statin use in STEMI and UA/NSTEMI in KOREA STEMI NSTEMI/UA 0 5 10 15 20 25 19.6 13.7 %patientsreceivingstatinatdischarge Clin Cardiol. 2012 Nov;35(11):700-6 STEMI NSTEMI/UA 0 5 10 15 20 25 20.1 12.2 %patientsreceivingstatinatdischarge Use of high dose statin before/after PCI was more common in STEMI than in UA/NSTEMI, but still only 1 out of 5 STEMI patients received such therapy in korea P < 0.001; P < 0.001; Pre-PCIPre-PCI 30 days post-PCI
  • Lipid Management High-intensity statin therapy should be initiated or continued in all patients with STEMI and no contraindications to its use. It is reasonable to obtain a fasting lipid profile in patients with STEMI, preferably within 24 hours of presentation. I IIa IIb III I IIa IIb III 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Class I Level of Evidence B
  • ESC 2012 STEMI GUIDELINES
  • High-dose statins in ACS: an intriguing hypothesis • Early benefits derived largely from the anti-inflammatory effects of the drug. • The delayed benefits are lipid- modulated. Nissen S, JAMA 2004;292;1365
  • Conclusions • Benefit of intensive statin therapy is evident in ACS patients who underwent PCI • Pleiotropic effectsPleiotropic effects llikelyikely • Significantly better myocardial perfusion with 80 mg atorvastatin • PProven efficacy in the longroven efficacy in the long--termterm  aabsence of harmbsence of harm ? Fixed doses / dose titration to achieveFixed doses / dose titration to achieve specific goalsspecific goals (lipid / anti-inflammatory)(lipid / anti-inflammatory)