Λιπίδια θεραπευτική αντιμετώπιση με βάση τα νεώτερα δεδομένα

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1 Πρόληψη στεφανιαίας νόσου Λιπίδια θεραπευτική αντιμετώπιση με βάση τα νεώτερα δεδομένα «Ιπποκράτειες Ημέρες Καρδιολογίας» 31 Μαρτίου 2017 Φωτεινή Λαζαρίδου Καρδιολόγος ΕΑ ΓΝ Αγιος Παύλος, Θεσσαλονίκη

2 Σύγκρουση συμφερόντων: καμμία

6 The USPSTF recommends using the ACC/AHAPooled Cohort Equations to calculate 10-year risk of CVD events. The ACC and AHA recommend statin use in asymptomatic adults aged 40 to 75 years without a history of CVD who have an LDL-C level of 70 to 189 mg/dl if they also have diabetes (use of moderate- to high-dose statins is recommended, depending on the patient s 10-year CVD event risk) or an estimated 10-year CVD event risk of 7.5%or greater (Pooled Cohort Equations risk calculator* -* overestimation of CV risk in European population and possible for Amarican population as well). Οι ESC/EAS: υπολογισμός του συνολικού καρδιαγγειακού κινδύνου (SCORE), της τιμής στόχου για την LDL-C με βάση το συνολικό κίνδυνο, του ποσοστού ελάττωσης της LDL-C, επιλογή στατίνης και επί αποτυχιας επίτευξης στόχου LDL-C, συνδυασμός με χρήση εζετιμίμπης

8 Μόνο οι ασθενείς με σοβαρή ΧΝΝ (GFR<30ml/min/1.71m2) παραμένουν στην κατηγορία πολύ υψηλού κινδύνου, ενώ αυτοί με μέτρια ΧΝΝ (GFR 30-59ml/min/1.71m2) μεταπίπτουν στην ομάδα υψηλού κινδύνου Κατηγορία πολύ υψηλού κινδύνου παραμένουν οι διαβητικοί ασθενείς τύπου ΙΙ με βλάβη οργάνων στόχων (πρωτεϊνουρία) ή σημαντική υπερλιπιδαιμία ή σημαντικά υψηλή ΑΠ ΟΙ διαβητικοί τύπου ΙΙ χωρίς επιπλέον παράγοντες κινδύνου παραμένουν στην ομάδα υψηλού κινδύνου Οι διαβητικοί τύπου Ι χωρίς επιπλέον παράγοντες κινδύνου μεταπίπτουν στην ομάδα μετρίου ή και χαμηλού κινδύνου

10 aaa SCORE overestimates risk in older people. * *Illustrative charts in subjects older than 65 years of age. To convert the risk of fatal CVD to risk of total (fatal + nonfatal) hard CVD, multiply by 3 in men and 4 in women, and slightly less in old people. The SCORE chart is for use in people without overt CVD, diabetes, chronic kidney disease, familial hypercholesterolaemia or very high levels of individual risk factors because such people are already at highrisk and need intensive risk factor advice.

11 Neither routine assessment of circulation or urinary biomarkers, nor carotid ultrasound for intima media thickness (IMT) screening are recommended for CVD risk assessment stratification 2016 European Guidelines on cardiovascular disease prevention in clinical practice

12 gjgh Another approach in young people is to use CV risk age. Risk age is recommended for helping to communicate about risk, especially to younger people with a low absolute risk but a high relative risk. It is not currently recommended to base treatment decisions on risk age.

Γυναίκα 60 ετών, με ολική χοληστερόλη 280 mg/dl, μη καπνίστρια και χωρίς υπέρταση, έχει συνολικό

13 Θεραπευτική παρέμβαση με φάρμακα προτείνεται σε score από 5% και πάνω και μόνο αν αποτύχουν πρώτα τα υγιεινοδιαιτητικά μέτρα. Γυναίκα 60 ετών, με ολική χοληστερόλη 280 mg/dl, μη καπνίστρια και χωρίς υπέρταση, έχει συνολικό κίνδυνο (score) μόνο 2% και επομένως δε χρειάζεται καμία φαρμακευτική αγωγή Ανδρας με ολική χοληστερόλη 190 mg/dl, καπνιστής και υπερτασικός, έχει score κινδύνου 21%, δηλαδή 10 φορές μεγαλύτερο

16 Fasting or non fasting

17 Non-HDL-C is used as an estimation of the total amount of atherogenic lipoproteins in plasma (VLDL, VLDL remnants, intermediate-density lipoprotein (IDL), LDL, Lp(a)) and relates well to apob levels. Non-HDL-C = TC - HDL-C. Some recent guidelines recommend non-hdl-c as a better risk indicator than LDL-C Non-HDL-C should be used as a secondary target when the LDL-C goal is reached. Goals for non-hdl-c are easily calculated as LDL-C goals plus 0.8 mmol/l (30 mg/dl). Based on epidemiological data, levels of HDL-C associated with increased risk for men are <1.0 mmol/l (40 mg/dl) and for women are <1.2 mmol/l (48 mg/dl). In a number of meta-analyses, TGs has been shown to be an independent risk factor

22 No level of LDL-C below which benefit ceases or harm occurs has been defined the European Task Force retains a goal approach to lipid management and treatment goals are defined, tailored to the total CV risk level. There is also evidence suggesting that lowering LDL-C beyond the goals that were set in the previous EAS/ESC guidelines is associated with fewer CVD events. Therefore, it seems appropriate to reduce LDL-C as low as possible, at least in patients at very high CV risk.

26 Statins in primary prevention Ελάττωση απόλυτου και σχετικού κινδύνου στην πρωτογενή πρόληψη : (WOSCOPS, AF/TEXCAPS, ASCOT LLA, JUPITER: καρδιαγγειακών συμβαμάτων NNT40-90)

the CV risk, the lower the CV event rate The higher the CV risk, the

27 Στατίνες στην πρωτογενή πρόληψη CCT Μετααναλύσεις cholesterol treatment trialist CTT (27 trials, RR ~20% in low and high risk pts) The lower the CV risk, the lower the CV event rate The higher the CV risk, the greater the benefit with statin use and LDL reduction Lancet 2012;378:

reduction for each reduction of LDL-C of 1.

28 The risk of major coronary events was reduced by 23% and the risk of stroke was reduced by 17% per 1 mmol/l (40 mg/dl) LDL-C reduction for each reduction of LDL-C of 1.0 mmol/l, the relative risk reduction was 10% for all-cause mortality and 20% for CVD mortality

29 Statins in primary prevention Cochrane review 2013 (19 trials, 56937pts, (14trials: higher risk HTN, DM, microalbuminuria) Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins. Authors conclusions : The totality of evidence now supports the benefits of statins for primary prevention. The individual patient data metaanalyses now provide strong evidence to support their use in people at low risk of cardiovascular disease Statin use: reduction RR 95% CI All cause mortality combined fatal and non-fatal CVD combined fatal and non-fatal CHD events reduced by 14% reduced by 27% reduced by 22% combined fatal and non-fatal stroke revascularisation rates Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD

30 Adverse effects of statins Statins might increase the incidence of diabetes (greater risk for older and pts with other risk factors for diabetes) More potent statins at higher doses are associated with a greater risk for diabetes development Pitavastatin does not increase the incidence of diabetes Possible renal complications (proteinuria with all statins). A recent Cochrane analysis of renal function failed to identify any beneficial effects of statins on creatinine clearance, but no harmful effects were seen either. Combinations of statins and fibrates: can increase the risk of myopathy. Because the risk is higher with gemfibrozil, this combination should be avoided, and it seems lower with fenofibrate, bezafibrate, and ciprofibrate

33 What if targets not achieved with statins? Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol and has the effect of lowering LDL-C levels by 20% in monotherapy or in addition to a statin. The findings from the IMPROVE-IT trial support the use of ezetimibe as a second- line therapy if LDL-C target levels are not reached with maximum tolerated doses of statin The guidelines summarize the positive findings of the IMPROVE-IT trial. This study determined that a < 70 mg/dl reduction in LDL-C is beneficial, with no additional adverse effects, even when the active agent is not a statin

The new clinical guidelines review the potential combinations of these drugs: statins with cholesterol absorption inhibitors (ezetimibe) (IIa B recommendation), statins with bile acid sequestrants

34 The new clinical guidelines review the potential combinations of these drugs: statins with cholesterol absorption inhibitors (ezetimibe) (IIa B recommendation), statins with bile acid sequestrants (resins) (IIb C recommendation), resins with cholesterol absorption inhibitors, and statins with phytosterols; however, no clinical trials have found fewer cardiovascular events with these last 2 combinations. What if targets not achieved with statins? The main innovations are the increased levels of evidence awarded to combination statin +ezetimibe therapy after the results of the IMPROVE-IT trial, the IIb C recommendation for combination PCSK9 inhibitors when LDL-C targets are not reached with maximum tolerated doses of statins, with or without ezetimibe combination, and the abandonment of the recommendation to add nicotinic acid to combination therapy.

35 DRUGS FOR THE TREATMENT OF HYPERTRIGLYCERIDEMIA This edition of the guidelines stresses on the role played by TGs as a cardiovascular risk factor, with a greater association with the nonfasting TG level than the fasting TG level. Prior to any intervention: analysis of possible causes of the TG elevation and an evaluation of overall cardiovascular risk. The main objective is to reduce LDL-C due to cardiovascular risk Statins are the drug of choice, although the recommendation strength has decreased (class IIa, level B); if a reduction below 200 mg/dl cannot be achieved, fenofibrate should be added (class IIa, level C). There is evidence that omega-3 fatty acids can reduce TG levels but not cardiovascular events or mortality. REDUCE-IT with 8000 participants and STRENGTH with participants are trying to evaluate the efficacy of these fatty acids in reducing cardiovascular events. Omega-3 fatty acids are generally safe, although they can increase bleeding in individuals taking aspirin/clopidogrel J Am Coll Cardiol. 2013;61: Lancet. 2014;384:

36 According to the EAS consensus document, mild to moderate HTG is defined as TGs >1.7 mmol/l (150 mg/dl) and <10 mmol/l (880 mg/dl); TGs >10 mmol/l is defined as severe HTG.

37 DRUGS AFFECTING HDL-C LEVELS After disheartening results with torcetrapib, evacetrapib, and dalcetrapib, the guidelines stress that there is no clear evidence that a HDL increase boosts cardiovascular risk prevention. The only study still underway is the REVEAL trial of anacetrapib (in phase III), which hopes to show the efficacy and safety of a HDL-C increase. The guidelines lack clear recommendations for the HDL-C values indicating pharmacological therapy initiation, as well as an algorithm specifying values and treatment steps for HTG and low HDL-C, in particular

38 Management of dyslipidemias in different clinical settings: FCH, FH Familial combined hyperlipidemia (FCH) (prevalence of at least 1 in 100), and familial hypercholesterolemia (FH),(prevalence of 1 in 250 to 300), are calculated to be the cause of up to 40% of cases of premature coronary heart disease. FCH is characterized by high levels of LDL-C and/or TGs and is frequently associated with type 2 diabetes, hypertension, and central obesity Heterozygous FH is a frequent genetic cause of premature cardiovascular disease that affects half of a given family The clinical criteria for the diagnosis (index case) of genetic dyslipidemias: elevated LDL-C levels in subjects and their family members, premature coronary heart disease, and xanthomas

39 FH and PCSK9 inhibitors PCSK9 inhibitors, can be an alternative for certain patients with FH. These drugs are very effective and reduce LDL-C levels by an additional 60% in patients under treatment with statins. Because studies of cardiovascular morbidity and mortality are required, the use of these inhibitors should be limited to patients with FH and highly elevated cardiovascular risk, those with LDL-C levels far from the objectives despite maximum lipid-lowering therapy, and those unable to tolerate statin

42 Extreme risk : diabetic pt + CAD Target: LDL-C 55mg/dl, non-hdl-c 80mg/dl

43 Elderly patients The main differences from previous recommendations are an increased weight of the evidence in favor of statin use in the same way as in younger patients in secondary prevention (I A), a lowered recommendation for lipid-lowering agent titration in elderly people (from I C to IIa C), and an evaluation of the use of statins in primary prevention if patients have classic associated cardiovascular risk factors (from IIb B to IIa B).

51 ευχαριστώ

Factors modifying interpretation of SCORE risks Subjects in need of reclassification are those belonging to the intermediate CV risk group.

54 Factors modifying interpretation of SCORE risks Subjects in need of reclassification are those belonging to the intermediate CV risk group. Therefore the use of methods to detect these markers should be of interest in that group (class IIa, level of evidence B). * Cut-off values that should be used in considering these markers as modifiers of total CV risk are CAC score >400 Agatston units, ABI <0.9 or >1.40, aortic pulse wave velocity of 10 m/s and the presence of plaques on carotid ultrasonography. * Some factors such as a high HDL-C or apoa1 and a family history of longevity can also reduce risk. * Neither routine assessment of circulation or urinary biomarkers, nor carotid ultrasound for intima media thickness (IMT) screening are recommended for CVD risk assessment stratification** * 2016 ESC/EAS guidelines for the management of dyslipidaemias Controversy: the documentation of preclinical CVD based on imaging, such as significant plaque on coronary angiography or carotid ultrasound, classifies patients in the very high-risk category, with need of appropriate lipid-lowering therapy!!! ** **2016 European Guidelines on cardiovascular disease prevention in clinical practice

55 2016 European Guidelines on cardiovascular disease prevention in clinical practice HDL-C is not recommended as a therapeutic target, but is a strong independent risk factor when values are <1.0 mmol/l (40mg/dl) in men and <1.2 mmol/l (48mg/dl) in women

56 LP(a) the measurement of lipoprotein(a) [Lp(a)] levels should be considered in selected cases at high risk, such as: (1) premature CVD; (2) familial hypercholesterolaemia; (3) a family history of premature CVD and/or elevated Lp(a); (4) recurrent CVD despite optimal statin treatment; and (5) 5% 10-year risk of fatal CVD according to SCORE. The risk is considered significant for Lp(a) 50 mg/dl, but no randomised controlled trial has yet demonstrated that the reduction of Lp(a) levels is associated with a reduction of cardiovascular events ESC/EAS guidelines for the management of dyslipidaemias

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