2017 Cardiovascular Summit for Primary Care Thursday 30th & Friday 31st March Crowne Plaza, Dublin

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1 2017 Cardiovascular Summit for Primary Care Thursday 30th & Friday 31st March Crowne Plaza, Dublin 2016 ESC Guidelines on Cardiovascular Risk and elevated lipids Carlos Brotons Sardenya Primary Health Care Centre Biomedical Research Institute Sant Pau Barcelona, Spain

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3 ESC/EAS Guidelines on the management of dyslipidaemias Treatment scheme 1. Evaluate the total CV risk of the subject 2. Involve the patient with decisions on CV risk management 3. Identify the LDL-C goal for that risk level 4. Calculate the % of LDL-C reduction required to achieve that goal 5. Choose a statin and a dose that could provide this reduction 6. Response to statin treatment is variable, therefore up-titration of the dose may be required 7. If the highest tolerated statin dose does not reach the goal, consider drug combinations 8. In addition, a reduction 50% in LDL-C should be achieved in very high and high risk patients

4 ESC/EAS Guidelines on the management of dyslipidaemias Treatment scheme 1. Evaluate the total CV risk of the subject 2. Involve the patient with decisions on CV risk management 3. Identify the LDL-C goal for that risk level 4. Calculate the % of LDL-C reduction required to achieve that goal 5. Choose a statin and a dose that could provide this reduction 6. Response to statin treatment is variable, therefore up-titration of the dose may be required 7. If the highest tolerated statin dose does not reach the goal, consider drug combinations 8. In addition, a reduction 50% in LDL-C should be achieved in very high and high risk patients

5 ESC/EAS Guidelines on the management of dyslipidaemias Treatment scheme 1. Evaluate the total CV risk of the subject 2. Involve the patient with decisions on CV risk management 3. Identify the LDL-C goal for that risk level 4. Calculate the % of LDL-C reduction required to achieve that goal 5. Choose a statin and a dose that could provide this reduction 6. Response to statin treatment is variable, therefore up-titration of the dose may be required 7. If the highest tolerated statin dose does not reach the goal, consider drug combinations 8. In addition, a reduction 50% in LDL-C should be achieved in very high and high risk patients

6 ESC/EAS Guidelines on the management of dyslipidaemias Treatment scheme 1. Evaluate the total CV risk of the subject 2. Involve the patient with decisions on CV risk management 3. Identify the LDL-C goal for that risk level 4. Calculate the % of LDL-C reduction required to achieve that goal 5. Choose a statin and a dose that could provide this reduction 6. Response to statin treatment is variable, therefore up-titration of the dose may be required 7. If the highest tolerated statin dose does not reach the goal, consider drug combinations 8. In addition, a reduction 50% in LDL-C should be achieved in very high and high risk patients

7 Systolic blood pressure 8 SCORE chart: 10-year risk fatal cardiovascular disease (CVD) in population at high CVD risk Women Men Non-smoker Smoker Age Non-smoker Smoker SCORE % and over 10%-14% 5%-9% 3%-4% 2% 1% <1% 10-year risk of fatal CVD in populations at High CVD risk Cholesterol(mmol/L) mg/dl European Heart Journal doi: /eurheartj/ehv272

8 Systolic blood pressure 9 SCORE chart: 10-year risk of fatal cardiovascular disease (CVD) population at low CVD risk Women Men Non-smoker Smoker Age Non-smoker Smoker SCORE % and over 10%-14% 5%-9% 3%-4% 2% 1% <1% 10-year risk of fatal CVD in populations at Low CVD risk Cholesterol(mmol/L) mg/dl European Heart Journal doi: /eurheartj/ehv272

9 12 Risk function without high-density lipoprotein-cholesterol (HDL-C) for women in populations at high cardiovascular disease risk, with examples of the corresponding estimated risk when different levels of HDL-C are included. Non-smoker Age Smoker Without HDL 4.4 HDL HDL HDL HDL Without HDL HDL 0.8 HDL HDL HDL Without HDL 4.2 HDL HDL HDL HDL Without HDL HDL 0.8 HDL 1.0 HDL 1.4 HDL Without HDL 2.4 HDL HDL HDL HDL Without HDL HDL 0.8 HDL HDL HDL Without HDL HDL 0.8 HDL HDL HDL Systolic blood pressure (mmhg) Total Cholesterol (mmol/l) European Heart Journal doi: /eurheartj/ehv272

10 13 Risk function without high-density lipoprotein-cholesterol (HDL-C) for men in populations at high cardiovascular disease risk, with examples of the corresponding estimated risk when different levels of HDL-C are included. Non-smoker Age Smoker Without HDL HDL 0.8 HDL 1.0 HDL 1.4 HDL Without HDL HDL HDL HDL HDL Without HDL HDL 0.8 HDL 1.0 HDL 1.4 HDL Without HDL HDL HDL HDL HDL Without HDL HDL 0.8 HDL 1.0 HDL 1.4 HDL Without HDL HDL HDL HDL HDL Without HDL HDL 0.8 HDL 1.0 HDL 1.4 HDL Without HDL HDL HDL HDL HDL Systolic blood pressure (mmhg) Total Cholesterol (mmol/l) Without HDL HDL HDL HDL HDL European Heart Journal doi: /eurheartj/ehv272

11 ESC/EAS Guidelines on the management of dyslipidaemias CV risk categories 2011 ESC Dyslipidaemias guidelines Recommendation VERY-HIGH CV risk: - Documented CVD - DM or type-1 DM with TOG - GFR <60 mg/ml/1.72 m 2-10 year risk SCORE 10% HIGH CV risk: - Markedly elevated single risk factor - 10 year risk SCORE 5% and <10% MODERATE CV risk: - 10 year risk SCORE 1% and <5% LOW CV risk: - 10 year risk SCORE <1% 2016 ESC Dyslipidaemias guidelines Recommendation VERY-HIGH CV risk: - Documented CVD - DM with TOG or with a major CV risk factor - GFR <30 mg/ml/1.73 m 2-10 year risk SCORE 10% HIGH CV risk: Markedly elevated single risk factor in particular cholesterol >8 mmol/l (>310 mg/dl) (e.g. in FH) or BP 180/110 mmhg year risk SCORE 5% and <10% - GFR mg/ml/1.73 m 2 MODERATE CV risk: - 10 year risk SCORE 1% and <5% LOW CV risk: - 10 year risk SCORE <1%

12 ESC/EAS Guidelines on the management of dyslipidaemias Lipid analyses 2011 ESC Dyslipidaemias guidelines Recommendation Class Level LDL-C is the primary target for treatment TC should be considered as a treatment target if other are not available Non-HDL-C should be considered as a secondary treatment target in combined DLP, DM, MS and CKD ApoB should be considered as a secondary treatment target HDL-C is not recommended as a target for treatment ApoB/ApoAI or non-hdl-c/hdl- C ratios are not recommended treatment targets I IIa IIa IIa III III A A B B A B 2016 ESC Dyslipidaemias guidelines Recommendation Class Level LDL-C is the primary target for treatment TC should be considered as a treatment target if other are not available Non-HDL-C should be considered as a secondary treatment target ApoB should be considered as a secondary treatment target only if available HDL-C is not recommended as a target for treatment ApoB/ApoAI or non-hdl-c/hdl- C ratios are not recommended treatment targets I IIa IIa IIa III III A A B B A B

13 ESC/EAS Guidelines on the management of dyslipidaemias Treatment targets 2011 ESC Dyslipidaemias guidelines Recommendation Class Level VERY-HIGH CV risk: LDL-c goal <70 mg/dl (1.8 mmol/l) and/or 50% reduction when target cannot be reached HIGH CV risk: LDL-c goal <100 mg/l (2.5 mmol/l) MODERATE CV risk: LDL-c goal <115 mg/dl (3.0 mmol/l) I IIa IIa A A C 2016 ESC Dyslipidaemias guidelines Recommendation Class Level VERY-HIGH CV risk: LDL-c goal <70 mg/dl (1.8 mmol/l) and/or 50% reduction if baseline is mg/dl ( mmol/l) HIGH CV risk: LDL-c goal <100 mg/l (2.6 mmol/l) or 50% reduction if baseline is mg/dl ( mmol/l) MODERATE CV risk: LDL-c goal <115 mg/dl (3.0 mmol/l) I I IIa B B C

14 27 Treatment goals for low-density lipoprotein- cholesterol (LDL-C) Examples Patient A Patient B Patient C Patient D Patient E Patient F Very high-risk, LDL-C >1.8 mmol/l (>70 mg/dl) on statin: the goal is still <1.8 mmol/l (70 mg/dl). High-risk, LDL-C >2.6 mmol/l (>100 mg/dl) on statin: the goal is still <2.6 mmol/l (100 mg/dl). Very high-risk, LDL-C mmol/l ( mg/dl) not on pharmacological therapy: the goal is at least a 50% reduction. High-risk, LDL-C mmol/l ( mg/dl) not on pharmacological therapy: the goal is at least a 50% reduction. Very high-risk, LDL-C >3.5 mmol/l (135 mg/dl) not in pharmacological therapy: the goal is <1.8 mmol/l (70 mg/dl). High-risk LDL-C >5.2 mmol/l (200 mg/dl) not in pharmacological therapy: the goal is <2.6 mmol/l (100 mg/dl).

15 ESC/EAS Guidelines on the management of dyslipidaemias Drug combinations 2011 ESC Dyslipidaemias guidelines 2016 ESC Dyslipidaemias guidelines Recommendation: Class Level Prescribe statin up to the highest recommended dose or highest tolerable dose to reach the goal I A Recommendation: Class Level Prescribe statin up to the highest recommended dose or highest tolerable dose to reach the goal I A

16 LDL % 34 A systematic review and meta-analysis of the therapeutic equivalence of statins A10 A20 A40 A80 F20 F40 F80 L10 L20 L40 L80 P10 P20 P40 S10 S20 S40 S80 R5 R10 R20 R40 P1 P2 P4 ATOR FLUVA LOVA PRAVA SIMVA ROSU PITA Weng TC, et al. J Clin Pharm Ther. 2010;35; Mukhtar RY, et al. Int J Clin Pract. 2005;59(2):

17 35 Percentage reduction of low-density LDL-C requested to achieve goals as a function of the starting value Starting LDL-C Reduction to reach LDL-C goal, % mmol/l ~ mg/dl < 1.8 mmol/l (~ 70 mg/dl) < 2.6 mmol/ (~ 100 mg/dl) < 3 mmol/l (~ 115 mg/dl) >6.2 > 240 > 70 > 60 > < < < 22

18 ESC/EAS Guidelines on the management of dyslipidaemias Drug combinations 2011 ESC Dyslipidaemias guidelines Recommendation Class Level 2016 ESC Dyslipidaemias guidelines Recommendation Class Level If statin intolerance, ezetimibe or bile acid sequestrants, or these combined, should be considered IIa C If statin intolerance, ezetimibe or bile acid sequestrants, or these combined, should be considered IIa C If goal is not reached, statin combination with a cholesterol absorption inhibitor, bile sequetran acid or nicotinic acid may be considered IIb B If goal is not reached, statin combination with a cholesterol absorption inhibitor should be considered Statin combination with a bile acid sequestrant may be considered IIa IIb B B

19 ESC/EAS Guidelines on the management of dyslipidaemias Drug combinations Recommendation Class Level Very high risk patients, with persistent high LDL-C despite treatment with maximal statin dose, in combination with ezetimibe or in patients with statin intolerance a PCSK9 inhibitor may be considered IIb C

20 ESC/EAS Guidelines on the management of dyslipidaemi Treatment of tryglicerides 2011 ESC Dyslipidaemias guidelines Recommendation Class Level Fibrates drug of choice I B Considerd nicotinic acid IIa B Nicotinic acid +laropiprant IIa C Statin+Nicotinic acid IIa A Statin+Fibrate IIa C N-3 fatty acids IIa B Fibrate+n-3 fatty acids IIb B 2016 ESC Dyslipidaemias guidelines Recommendation Class Level Treatment considered in high risk patients and TG >2.3 mmol/l (200 mg/dl) Statins considered as the first drug of choice for reducing CVD risk in high risk individuals with hypertriglyceridaemia In high risk patients with TG >2.3 mmol/l despite treated with statin, fenofibrate considered in combination with statins IIa I IIb B A C

21 ESC/EAS Guidelines on the management of dyslipidaemi Drugs affecting HDL 2011 ESC Dyslipidaemias guidelines Recommendation Class Level 2016 ESC Dyslipidaemias guidelines Recommendation Class Level Nicotinc acid is the most efficent drug to raise HDL- C and should be considered IIa A Statins and fibrates raise HDL-C with similar magnitude and these drugs may be considered IIb B Statins and fibrates raise HDL-C with similar magnitude and these drugs may be considered IIb B The efficacy of fibrates to increase HDL-C may be attenuated in people with type 2 diabetes IIb B The efificacy of fibrates to increase HDL-c may be attenuated in people with type 2 diabetes IIb B

22 ESC/EAS Guidelines on the management of dyslipidaemias Familial hypercholesterolemia Clinical diagnosis and screening using the Dutch Lipid Clinic Network diagnostic criteria Genetic cascade screening of family members Cholesterol lowering treatment should be initiated as soon as possible PCSK9 antibodies have recently been registered for use in FH patients. Efficiently lower LDL-C by up to 60% on top of the statin. There are no randomized controlled studies with clinical endpoints and therefore the use of the drugs still should be restricted (FOURIER TRIAL recently published). Should be considered in patients with FH: 1. Very high risk due to the presence of CVD 2. Family history of CAD at very young age 3. LDL-C level far from goal even on maximal other therapy 4. FH patients who cannot tolerate statins 5. FH patients with high Lp(a).

23 Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolaemia 42 Criteria 1) Family history First-degree relative with known premature (men: <55 years; women: <60 years) coronary or vascular disease, or First-degree relative with known LDL-C above the 95 th percentile. 1 First-degree relative with tendinous xanthomata and/or arcus cornealis, or children <18 years of age with LDL-C above the 95 th percentile. 2 2) Clinical history Patient with premature (men: <55 years; women: <60 years) coronary artery disease 2 Patient with premature (men: <55 years; women: <60 years) cerebral or peripheral vascular disease 1 3) Physical examination Tendinous xanthomata 6 Arcus cornealis before age 45 years 4 4) LDL-C levels LDL-C 8.5 mmol/l (325 mg/dl) 8 LDL-C mmol/l ( mg/dl) 5 LDL-C mmol/l ( mg/dl) 3 LDL-C mmol/l ( mg/dl) 1 5) DNA analysis Functional mutation in the LDLR, apob or PCSK9 gene 8 Choose only one score per group, the highest applicable Diagnosis (diagnosis is based on the total number of points obtained) A definite FH diagnosis requires >8 points A probable FH diagnosis requires 6 8 points ww.escardio.org/guidelines w A possible FH diagnosis requires 3 5 points European Heart Journal doi: /eurheartj/ehv272 Points

24 ESC/EAS Guidelines on the management of dyslipidaemias The elderly 2011 ESC Dyslipidaemias guidelines Recommendation Class Level Treatment with statins is recommended for older adults with established CVD in the same way as for younger patients It is recommended lipidlowering medication at a lower dose and then titrated to targets Statin therapy may be considered in older adults free from CVD, in the presence of HT, smoking, DM or dyslipidaemia. I I IIb B C B 2016 ESC Dyslipidaemias guidelines Recommendation Class Level Treatment with statins is recommended for older adults with established CVD in the same way as for younger patients Lipid-lowering medication should be started at a lower dose and then titrated to targets Statin therapy should be considered in older adults free from CVD, in the presence of HT, smoking, DM or dyslipidaemia. I IIa IIa A C B

25 ESC/EAS Guidelines on the management of dyslipidaemias ACS patients or PCI Recommendation Class Level Initiate or continue high dose statins early after admission in all ACS patients without contraind. or intolerance, regardless of initial LDL-C values If LDL-C target is not reached, with the highest tolerable statin dose, ezetimibe should be considered in combination with statins in post-acs. If LDL target is not reached with the highest tolerable statin dose and/or ezetimibe, PCSK9 inhibitors may be considered on top of lipid-lowering therapy; or alone or in combination with ezetimibe in statin intolerant patients or in whom a statin is contraindicated Lipids should be re-evaluated 4 6 weeks after the ACS to assess LDL-C target (70 mg/dl or a reduction of at least 50% and whether there are any safety issues; the therapy dose should then be adapted accordingly. Routine short pretreatment or loading with high-dose statin before PCI should be considered in elective PCI or in NSTE-ACS. I IIa IIb IIa IIa A B C C A

26 ADVERSE EFFECTS OF STATIN RISKS Myopathy Diabetes Increase of liver enzymes BENEFITS CV diseases prevention Increased survival

27 Statins and potential side effects Musculoskeletal complaints Risk of diabetes Gastro-intestinal discomfort Fatigue Liver enzyme elevation Peripheral neuropathy Insomnia Neurocognitive symptoms

28 Statins and potential side effects Musculoskeletal complaints Risk of diabetes

29 Statin associated muscle symptoms: 7 29% of patients complain of statin associated muscle symptoms. Incidence of Myopathy (CK.10 ULN), is 1 per per year with a standard statin dose (e.g. simvastatin 40 mg daily). Incidence of Rhabdomyolysis (CK.40 ULN) with statin therapy is 1 in per year. Stroes ES et al. European Heart Journal (2015) 36,

30 Muscle-related symptoms occurred with the various regimens of studies: The Prediction of Muscular Risk in Observational Conditions (PRIMO study) Fluvastatin XL 40 mg 5.1% Pravastatin 40 mg 10.9% Rosuvastatin 5-40 mg 12.7% Atorvastatin 40 to 80 mg 14.9% Simvastatin 40 to 80 mg 18.2% Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients the PRIMO study. Cardiovasc Drugs Ther 2005; 19:

31 RISK FACTORS FOR STATIN-INDUCED MYOPATHY: ENDOGENOUS Advanced age (>65 y) Low BMI and frailty Renal dysfunction Hepatic dysfunction Hypothyroidism

32 RISK FACTORS FOR STATIN-INDUCED MYOPATHY: EXOGENOUS Alcohol consumption Heavy exercise Drugs afecting the cytochrom P450 system (fibrates, verapamil/diltiazem,amiodarone, digoxin, warfarin, anti-infective agents)

33 ESC/EAS Guidelines on the management of dyslipidaemias Algorithm for treatment of muscular symptoms during statin treatment

34 HOW TO RELIEVE STATIN MUSCLE SYMPTOMS EFFECTS Take a brief break from statin therapy 2-4 weeks washout period Symptoms improved Second statin at usual or starting dose

35 HOW TO RELIEVE STATIN SIDE EFFECTS Second statin at usual or starting dose Symptoms Re-ocurred 1. Low dose third efficacious statin 2. Efficacious statin with alternate day or once/twice weekly dosing regimen

36 HOW TO RELIEVE STATIN SIDE EFFECTS Consider other cholesterol-lowering medications. Ezetimibe reduces LDL-C by 15 20%, in combination of with fluvastatin/pravastatin reduce LDL-C by 46% Bile acid sequestrants can reduce LDL-C levels by 15 25%, in combination with ezetimibe can reduce LDL-C by 30 35%.

37 HOW TO RELIEVE STATIN SIDE EFFECTS Consider other cholesterol-lowering medications. Fenofibrate can lower LDL-C by 15 20% in patients with high baseline levels who do not have concomitant hypertriglyceridaemia. Unlike gemfibrozil, there is no increased risk of rhabdomyolysis when fenofibrate is added to a statin.

38 Statins and potential side effects musculoskeletal complaints risk of diabetes

39 Association between statin therapy and incident diabetes mellitus in 13 major cardiovascular trials. Statin therapy was associated with a 9% increased risk for incident DM (OR 1.09, 95% CI ) Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:

40 The use of statins in people at risk of developing diabetes mellitus: Evidence and guidance for clinical practice The diabetogenic effects of statins appear to be dose-related. (OR 1.12, 95% CI ). (OR 0.84, 95% CI ). Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:

41 Risk of diabetes Clinical guide for GPs 1. Avoid changes for patients with existing coronary heart disease and for high-risk primary prevention patients. 2. Consider less-intensive statins for lower-risk patients, those with risk factors for DM, or individuals concerned with new-onset diabetes. 3. Consider the addition of a nonstatin option to the less-intensive statin to achieve additional LDL-C reduction. Statin-associated Diabetes Mellitus: Review and Clinical Guide Backes JM et al. South Med J. 2016;109(3):

42 Risk of diabetes Clinical guide for GPs 4. Choose concomitant antihypertensive agents wisely. Hypertension is a common comorbidity associated with dyslipidemia, agents such as β- blockers and thiazide diuretics, increase New-onset Diabetres by 22% to 43%. Risk of diabetes 5. Emphasize therapeutic lifestyle changes: healthy diet and regular physical activity provide marked reductions in New-Onset Diabetes.