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AGGIORNAMENTI IN TEMA DI TERAPIE DI DISLIPIDEMIE Mauro Vannucci V° CONGRESSO NAZIONALE, Riccione 15-17 Maggio 2015.

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Presentazione sul tema: "AGGIORNAMENTI IN TEMA DI TERAPIE DI DISLIPIDEMIE Mauro Vannucci V° CONGRESSO NAZIONALE, Riccione 15-17 Maggio 2015."— Transcript della presentazione:

1 AGGIORNAMENTI IN TEMA DI TERAPIE DI DISLIPIDEMIE Mauro Vannucci V° CONGRESSO NAZIONALE, Riccione Maggio 2015

2 Eventi coronarici (%) Studi con statine in prevenzione primaria: riduzione eventi ed LDL-col “on trial” C-LDL (mg/dL) O’Keefe et al. JACC, 2004 WOSCOPS-P AFCAPS-P 175 y = x – R 2 = p = WOSCOPS-S AFCAPS-S ASCOT-P ASCOT-S Gli eventi sembrano azzerarsi per un C-LDL di 55 mg/dL

3 Eventi coronarici (%) Studi con statine in prevenzione secondaria: riduzione eventi ed LDL-col “on trial” C-LDL (mg/dL) O’Keefe et al. JACC, S-P LIPID-P 150 y = x – R 2 = p = HPS-P HPS-S Gli eventi sembrano azzerarsi per un C-LDL di 30 mg/dL S-S CARE-P CARE-S PROVET-IT-PR PROVET-IT-AT LIPID-S

4 Adattata e modificata da : LaRosa JC et al. N Engl J Med 2005;352:e-version LDL-C achieved mg/dL (mmol/L) WOSCOPS – Placebo AFCAPS - Placebo ASCOT - Placebo AFCAPS - RxWOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Placebo LIPID - Rx 4S - Placebo CARE - Rx LIPID - Placebo CARE - Placebo HPS - Rx (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Event rate (%) 6 Secondary Prevention Primary Prevention Rx - Statin therapy PRA – pravastatin ATV - atorvastatin 200 (5.2) PROVE-IT - PRA PROVE-IT – ATV TNT – ATV10 TNT – ATV80 THE LOWER THE BETTER Jupiter Ros

5 Aderenza terapeutica: il fattore di rischio occulto Furio Colivicchi, Maurizio G. Abrignani, Massimo Santini G Ital Cardiol 2010 In uno studio condotto nell’ASL di Treviso dal 1994 al 2003 su oltre soggetti che avevano ricevuto una prescrizione di statina, il tasso di interruzione è stato del 50% nel primo anno. Nel Lazio abbiamo osservato un elevato tasso di interruzione del trattamento con statine che va dal 25% nei primi 3 mesi dalla dimissione dopo una sindrome coronarica acuta, al 40% dopo 1 anno da un ictus27, al 50% entro 1 anno dalla prima prescrizione in una popolazione di diabetici afferenti a strutture ambulatoriali.

6 Riduzione progressiva della persistenza dei trattamenti farmacologici raccomandati dalle linee guida durante il follow-up in pazienti con pregresso IMA Dati del registro SIMG - Health Search – J Cardiovasc Med 2009

7 Cause di interruzione della terapia con statine riferite dai pazienti Colivicchi F, et al. Stroke 2007; 38: Effetti collaterali riferiti Dispepsia (52%) Astenia (18%) Cefalea (17%) Mialgie (11%) Incremento asintomatico delle transaminasi (1%) Incremento asintomatico del CK totale (1%) Assenza di reazioni avverse maggiori “Troppe pastiglie”

8 Poluzzi E et al. Br J Clin Pharm 2007; 63: L’aderenza alla terapia con statine tende a ridursi nel tempo: dati della ASL di Ravenna

9 Association between switching and MACEs Colivicchi F, et al. Int J Cardiology 2011; 152:56-60

10 Nissen S. JAMA 2006 Recent Coronary IVUS Progression Trials MedianChange In Percent Atheroma Volume (%) Mean Low-Density Lipoprotein Cholesterol (mg/dL) REVERSALpravastatin REVERSALatorvastatin CAMELOTplacebo A-Plusplacebo ACTIVATEplacebo ASTEROIDrosuvastatin r 2 = 0.95 p<0.001

11 Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of patients from 76 randomized trials Statin therapy reduced:  All-cause mortality (RR 0.90)  Cardiovascular disease mortality (RR 0.80)  Fatal myocardial infarction (RR 0.82)  Non-fatal MI (RR 0.74)  Revascularization (RR 0.76)  Fatal and non-fatal strokes (RR 0.86) E.J. MILLS et al, Q J Med 2011

12 Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of patients from 76 randomized trials E.J. MILLS et al, Q J Med 2011

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14 Target LDL-C Rischio molto alto < 70 mg/dL(1.8 mmol/L) oppure, se il target non si riesce a raggiungere, riduzione ≥ 50% del LDL-C rispetto al basale se il target non si riesce a raggiungere, riduzione ≥ 50% del LDL-C rispetto al basale Rischio alto < 100 mg/dL (2.5 mmol/L) Rischio moderato < 115 mg/dL (3.0 mmol/L) Linee Guida ESC 2012 Target della terapia con statine Presenza di almeno un fattore di rischio rilevante (per esempio dislipidemie familiari severe) Diabete mellito (tipo 1 o tipo 2) ma senza fattori di rischio CV concomitante o danno d’organo IRC moderata (GFRe 30–59 mL/min/1.73 m 2 ) Calcolo del rischio a 10-anni SCORE ≥ 5% e < 10% per patologia cardiaca fatale ACS - CAD documentata – MCV documentata SCORE > 10%

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16 European Heart Journal (2011) 32, 1769–1818 Recommendations for treatment targets for LDL-C RECOMMENDATIONSClassLevel In patients at VERY HIGH CV risk (established CVD, type 2 diabetes, type 1 diabetes with target organ damage, moderate to severe CKD or a SCORE level ≥ 10%) the LDL-C goal is < 1.8 mmol/L (less than ~ 70 mg/dL) and/or ≥ 50% LDL-C reduction when target level cannot be reached. IA In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level ≥ 5 to < 10%) an LDL-C goal < 2.5 mmol/L (less than ~ 100 mg/dL) should be considered. IIaA In subjects at MODERATE risk (SCORE level > 1 to ≤ 5%) an LDL-C goal 1 to ≤ 5%) an LDL-C goal < 3.0 mmol/L (less than ~ 115 mg/dL) should be considered.IIaC La riduzione di LDL-C necessaria per il raggiungimento del target spesso in questa categoria di pazienti è ≥ 50 %

17 Recommendations for treatment of dyslipidaemia in the elderly RecommendationsClassLevel Treatment with statins is recommended for elderly patients with established CVD in the same way as for younger patients.IB Since elderly people often have comorbidities and have altered pharmacokinetics, it is recommended to start lipid-lowering medication at a low doe and then titrate with caution to achieve target lipid levels which are the same as in the younger subjects. IC Statin therapy may be considered in elderly subjects free of CVD, particularly in the presence of at least of at least one other CV risk factor besides age.IIbB

18 Recommendation to begin with a global risk assessment using the Pooled Cohort Equations to estimate 10-year ASCVD Risk (other risk assessment algorithms include the European SCORE, PROCAM, or Framingham scores) Preventive cardiology efforts begin with assessment of cardiovascular disease risk

19 What’s New in the Cholesterol Guideline? 1)Focus on ASCVD reduction: 4 Statin Benefit Groups 2)New Perspective on LDL-C and/or Non-HDL-C Treatment Goals 3)Emphasis on the Clinician-Patient Risk Discussion 4)Global Risk Assessment for Primary Prevention 5)Safety Recommendations Critical questions addressed the evidence for LDL-C and non-HDL-C goals primary and secondary prevention and the evidence for reduction in ASCVD events in relation to cholesterol lowering drugs available

20 WHAT’S SIMILAR TO ATP III? – Emphasis on lifestyle measures as crucial – Focus on treatment of LDL cholesterol (LDL-C) – Greatest intensity of treatment for patients at highest risk – Preference for statins over other medications lowering LDL-C (although this is greater in the new ACC/AHA Guideline)

21 4 STATIN BENEFIT GROUPS Clinical ASCVD Clinical ASCVD LDL–C >190 mg/dL, Age >21 years LDL–C >190 mg/dL, Age >21 years Primary prevention – Diabetes: Age years, LDL–C mg/dL Primary prevention – Diabetes: Age years, LDL–C mg/dL Primary prevention - No Diabetes ≥ 7,5% 10-year Primary prevention - No Diabetes ≥ 7,5% 10-year ASCVD risk, Age years, LDL–C mg/dL, ASCVD risk, Age years, LDL–C mg/dL, These identified statin benefit groups to not imply that other groups (e.g., those outside the specified age ranges) will not benefit and should not be treated

22 INDIVIDUALS NOT IN A STATIN BENEFIT GROUP  In those for whom a risk decision is uncertain:  These factors may inform clinical decision making: Family history of premature ASCVDFamily history of premature ASCVD Elevated lifetime risk of ASCVDElevated lifetime risk of ASCVD LDL–C ≥160 mg/dLLDL–C ≥160 mg/dL hs-CRP ≥2.0 mg/Lhs-CRP ≥2.0 mg/L Coronary artery calcium (CAC) score ≥300 Agaston unitsCoronary artery calcium (CAC) score ≥300 Agaston units Ankle brachial index (ABI)<0.9Ankle brachial index (ABI)<0.9 Their use still requires discussion between clinician and patient

23 Summary of Statin Initiation Recommendations to Reduce ASCVD Risk (Revised Figure)

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25 Ray KK et al. Eur Heart J 2014

26 L’impatto della strategia ACC/AHA dovrebbe essere considerato alla luce del gran numero di soggetti nella popolazione che sarebbero destinati al trattamento con statine per tutta la vita a partire dall’età di 40 anni Per la popolazione europea si continua a raccomandare l’utilizzo delle tabelle SCORE o di tabelle nazionali calibrate sullo SCORE. La riduzione del rischio in generale deve essere personalizzata per ogni paziente, e questa pratica può essere più specifica se vengono definiti degli obiettivi. FIRE and Forget….. the patient !!

27 The results of the EUROASPIRE III survey show that despite the clear evidence of the benefits of lipid-lowering treatment in secondary prevention, many coronary patients with dyslipidaemia are still inadequately treated and a significant number of patients on lipid-lowering therapy is still not reaching the treatment goals. Almost half of all coronary patients did not reach the LDL-C goal of 2.5 mmol/L and about the same percentage did not reach the total cholesterol goal of 4.5 mmol/L Atherosclerosis 2013

28 Conoscendo la riduzione percentuale necessaria per raggiungere il target terapeutico, è possibile individuare quale opzione terapeutica consente di ottenerla.

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35 CONCLUSIONS IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES:Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES:Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dL at 1 year) YES:Confirms ezetimibe safety profile  Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events  Results could be considered for future guidelines

36 Target Aderenza Stili di vita Tipo e dose di statina Appropriatezza Prescrittiva Inerzia Terapeutica Continuità Assistenziale

37 G Ital Cardiol 2015;16(1):44-51

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43 Safety of Anacetrapib in Patients with or at Risk for Coronary Heart Disease Christopher P. Cannon, MD, Sukrut Shah, PhD, RPh, Hayes M. Dansky, MD, Michael Davidson, MD, Eliot A. Brinton, MD, Antonio M. Gotto, Jr., MD, DPhil, Michael Stepanavage, MS, Sherry Xueyu Liu, MS, Patrice Gibbons, MS, Tanya B. Ashraf, BA, Jennifer Zafarino, MS, Yale Mitchel, MD, Philip Barter, MD, PhD, for the DEFINE Investigators DEFINE Determining the EFficacy and Tolerability of CEPT INhibition with AnacEtrapib

44 DEFINE Determining the EFficacy and Tolerability of CEPT INhibition with AnacEtrapib Effects on LDL-C and HDL-C

45 l Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-C and Lp(a) with sustained effects over 18 months. l Anacetrapib had an acceptable side-effect profile with no effects on blood pressure, electrolytes or aldosterone. l Within the power of the study, anacetrapib did not exhibit adverse cardiovascular effects seen with a prior CETP inhibitor l The long term safety and efficacy of anacetrapib will now be tested in a large clinical outcomes trial. Cannon CP et al. N Engl J Med 2010;363 (19) online 11/17/2010

46 30,000 patients with occlusive arterial disease in North America, Europe and Asia Background LDL-lowering with atorvastatin Randomized to anacetrapib 100 mg vs. placebo Scheduled follow-up: 4 years Primary outcome: Coronary death, myocardial infarction or coronary revascularization

47 Lipid effects with dalcetrapib * D 48 weeks vs. placebo Stein EA et al. Eur Heart J 2010;31(4):480-8 %change from baseline *p< *p<0.01 *p=0.002 Dalcetrapib 900 mg/day D 24 weeks D 48 weeks Placebo ApoA-IHDL-CLDL-C

48 Dalcetrapib Phase IIb Trial HDL-C Increase at Week 12 placebo n = 73 dalcetrapib 300 mg n = 75 NOTE: Dalcetrapib 600 mg is the dose used in phase III Stein EA. Am J Cardiol. 2009;104:82-91 * * *P < vs placebo * dalcetrapib 600 mg n = 67 dalcetrapib 900 mg n = 72 Change From Baseline (%)

49 Residual CV risk remains problematic despite statin- mediated LDL-C reduction Residual CV risk remains problematic despite statin- mediated LDL-C reduction Low HDL-C is an independent risk factor for CHD Low HDL-C is an independent risk factor for CHD Most clinical trial and observational data suggest that raising HDL-C may reduce CVD Most clinical trial and observational data suggest that raising HDL-C may reduce CVD HDL particles are very heterogeneous in composition and function, not all HDL may be anti-atherogenic HDL particles are very heterogeneous in composition and function, not all HDL may be anti-atherogenic Many new HDL-C raising treatments are in development Many new HDL-C raising treatments are in development CETP inhibitors greatly raise HDL-C levels, but their effect on HDL function and clinical outcomes remains in question CETP inhibitors greatly raise HDL-C levels, but their effect on HDL function and clinical outcomes remains in question CEPT

50 Residual CVD risk exists despite intense statin monotherapy Low HDL-C predicts high CVD risk; high HDL-C is protective Low HDL-C predicts high CVD risk; high HDL-C is protective Existing HDL raising therapies have inconsistent effects Existing HDL raising therapies have inconsistent effects Investigational drugs to raise HDL-C and reduce CVD risk Investigational drugs to raise HDL-C and reduce CVD risk – CETP inhibitors – PPAR agonists, APO A1 agonists, delipidating agents, etc. But clinical trials have not yet proven that: But clinical trials have not yet proven that: – HDL is a causal factor vs biomarker of risk – Raising HDL-C reduces CVD risk Revisiting the HDL Hypothesis

51 Don’t give up on HDL, researchers plead At a session on the subject, Dr Alan Tall (Columbia University, New York) summarized the situation: Hughs S, Jun, 2012 "The HDL hypothesis is certainly under attack. And there have been a lot of setbacks. But we mustn't throw the baby out with the bathwater. I think we need a new, modified HDL hypothesis."

52 Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort Cederberg H(1), Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M. Diabetologia May; 58(5):

53 STATINS AND DIABETES RISK 1) Meta-analysis of 170,255 patients from 76 randomized clinical trials show overall a 9% increased risk for development of incident diabetes among statin users (Sattar, Lancet 2010) 1) Meta-analysis of 170,255 patients from 76 randomized clinical trials show overall a 9% increased risk for development of incident diabetes among statin users (Sattar, Lancet 2010) 2) Increased risk of diabetes only seen in those with multiple risk factors; obesity, elevated triglycerides, glucose, and hypertension are more strongly related than statins to development of diabetes 2) Increased risk of diabetes only seen in those with multiple risk factors; obesity, elevated triglycerides, glucose, and hypertension are more strongly related than statins to development of diabetes 3) Many persons on statins have pre-diabetes to begin with; statins may accelerate the progression to diabetes, but on average diabetes occurs 5 weeks later in those on placebo. 3) Many persons on statins have pre-diabetes to begin with; statins may accelerate the progression to diabetes, but on average diabetes occurs 5 weeks later in those on placebo. 4) For every case of diabetes associated with statin use, approximately 5- 9 cardiovascular events are prevented 4) For every case of diabetes associated with statin use, approximately 5- 9 cardiovascular events are prevented 5) Most experts contend the benefits outweigh the risks regarding increases in glucose / A1c. 5) Most experts contend the benefits outweigh the risks regarding increases in glucose / A1c.

54 Statins and diabetes risk: how real is it and what are the mechanisms? Jennifer G. Robinson Statins are associated with a modest excess risk of type 2 diabetes mellitus in individuals at risk for diabetes. Statins are associated with a modest excess risk of type 2 diabetes mellitus in individuals at risk for diabetes. Multiple mechanisms have been proposed for statin-associated diabetes, primarily related to increased insulin resistance and decreased insulin secretion. Multiple mechanisms have been proposed for statin-associated diabetes, primarily related to increased insulin resistance and decreased insulin secretion. Diabetes is diagnosed on average 2–4 months earlier in statin-treated patients compared with untreated patients, and is therefore unlikely to have any more adverse consequences in the long term than diabetes occurring in patients who did not receive statins. Diabetes is diagnosed on average 2–4 months earlier in statin-treated patients compared with untreated patients, and is therefore unlikely to have any more adverse consequences in the long term than diabetes occurring in patients who did not receive statins. The cardiovascular risk reduction benefits far outweigh the potential for adverse effects in all but the very lowest risk individuals. The cardiovascular risk reduction benefits far outweigh the potential for adverse effects in all but the very lowest risk individuals. Curr Opin Lipidol Jun;26(3):228-35


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