CCS 2016 Guideline Update: Management of Dyslipidemia for Prevention of Cardiovascular Disease in Adults

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2. CCS 2016 Guideline Update: The Management of Dyslipidemia For The Prevention of Cardiovascular Disease in the Adult 

3. Outline

4. Introduction and Overview of What’s New

5. GRADE Process Followed Formulated PICO question  Literature Search  Study Selection  Individual Study Review x2 panelists  GRADE Checklist for QA x2 panelists

6. Approach to Risk Management Who, how when to screen? How to evaluate risk? When to initiate treatment? Monitoring and surveillance?

7. Evidence Profile Example PICO QUESTION: Are CV outcomes (including non-fatal MI, cardiac death, ischemic stroke, revascularization or hospitalization for acute coronary syndromes) reduced in subjects with CKD, of any severity, treated with a lipid-lowering agent compared another agent or placebo? Evidence Search: PubMed, Embase, Cochrane Library with a focus on 2011-2015. Key words included: chronic kidney disease, cholesterol lowering medications, statins, cardiovascular outcomes. Search outcomes were compared with 2014 Cochrane review on “Statins for people with CKD not on dialysis”.

8. Who to Screen

9. How to Screen RECOMMENDATIONS • We recommend non-fasting lipid and lipoprotein testing which can be performed in adults in whom screening is indicated as part of a comprehensive risk assessment to reduce CVD events (Strong Recommendation, High Quality Evidence). • We suggest that for individuals with a history of triglyceride levels >4.5 mmol/L that lipid and lipoprotein levels be measured fasting (Conditional Recommendation, Low Quality Evidence). Practical tip: Compared to fasting lipid values, there will be minimal change with non-HDL-C, a slight decrease in LDL-C and small increase in triglyceride concentrations when individuals do not fast.

10. Changes in Postprandial Lipids in Normal Populations Langsted A et al., Circulation 2008. Fasting and nonfasting lipid levels influence of normal food intake on lipoids, lipoproteins, apolipoproteins and cardiovascular risk prediction Cross-sectional study of fasting versus nonfasting lipid levels in Copenhagen General Population Study and Copenhagen City Heart Study Siddhu D and Naugler C. Arch Int Med 2012. Fasting time and lipid levels in a community-based population Cross-sectional study of 209180 individuals tested from 1 to 16 hours postprandially In both studies, non-HDL-C, and apo B varied little between fasting and nonfasting TG levels increased up to 20% (0.3-0.4 mM) and LDL-C was lower by up to 10% (0.2-0.3 mM)

11. Benefits of Non-fasting Lipids Patient convenience – no need to go to lab early in the morning and fasting; no need for retesting if not fasting Reduced wait times and reduced early morning patient burden in clinical laboratories Safety – prevention of hypoglycemic episodes in diabetics Enhances compliance and avoids delay in lipid screening and follow up tests Enhanced predictive value for CVD and mortality of nonfasting lipids Identification of high remnants/insulin resistance Removal of need to perform fasting blood work generally HbA1c is accepted as a diagnostic test and follow up test by CDA and ADA that does NOT have to be accompanied by a fasting glucose High fasting glucose usually results in HbA1c test

12. When to Consider Pharmacological Treatment in Risk Management RECOMMENDATIONS • Statin indicated conditions: We recommend management that includes statin therapy in high risk conditions including clinical atherosclerosis, abdominal aortic aneurysm, most diabetes mellitus, chronic kidney disease (age >50 years) and those with LDL-C ≥5.0 mmol/L to lower the risk of CVD events and mortality (Strong Recommendation, High Quality Evidence). • Primary prevention: • We recommend management that does not include statin therapy for individuals at low risk (modified FRS < 10 %) to lower the risk of CVD events (Strong Recommendation, High Quality Evidence). • We recommend management that includes statin therapy for individuals at high risk (modified FRS ≥ 20%) to lower the risk of CVD events (Strong Recommendation, High Quality Evidence). • We recommend management that includes statin therapy for individuals at intermediate risk (IR; modified FRS 10-19%) with LDL-C ≥3.5 mmol/L to lower the risk of CVD events. Statin therapy should also be considered for IR persons with LDL-C <3.5 mmol/L but with apo B ≥1.2 g/L or non-HDL-C ≥4.3 mmol/L or in men ≥50 and women ≥60 years of age with ≥1 CV risk factor (Strong Recommendation, High Quality Evidence).

13. Pharmacological Treatment Indications & Targets * consider LDL-C < 1.8 mmol/L for subjects with ACS within last 3 months;** statins indicated as initial therapy

14. Monitoring, Surveillance & Targets RECOMMENDATIONS • We recommend a treat-to-target approach in the management of dyslipidemia to mitigate CVD risk (Strong Recommendation, Moderate Quality Evidence). • Statin Indicated Conditions • We recommend a target LDL-C consistently <2.0 mmol/L or >50% reduction of LDLC for individuals for whom treatment is initiated to lower the risk of CVD events and mortality (Strong Recommendation, Moderate-Quality Evidence). Alternative target variables are apoB <0.8 g/L or non-HDL-C <2.6 mmol/L (Strong Recommendation, Moderate Quality Evidence). • We recommend a >50% reduction of LDL-C for patients with LDL-C > 5.0 mmol/L in individuals for whom treatment is initiated to decrease the risk of CVD events and mortality (Strong Recommendation, Moderate Quality Evidence). • Primary prevention conditions warranting therapy (All risk groups): • We recommend a target LDL-C consistently <2.0 mmol/L or >50% reduction of LDLC in individuals for whom treatment is initiated to lower the risk of CVD events (Strong Recommendation, Moderate Quality Evidence). Alternative target variables are apoB <0.8 g/L or non-HDL-C <2.6 mmol/L (Strong Recommendation, Moderate Quality Evidence).

15. Non-Statin Therapy RECOMMENDATIONS • We recommend ezetimibe as second-line therapy to lower LDL-C in patients with clinical cardiovascular disease if targets are not reached on maximally tolerated statin therapy (Strong Recommendation, High Quality Evidence). • We recommend that niacin not be added to statin therapy for CVD prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence). • We recommend that fibrates not be added to statin therapy for CVD event prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence). Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: 10.1016/j.cjca.2016.07.510

16. Non-Statin Therapy RECOMMENDATIONS • We suggest that bile acid sequestrants be considered for LDL-C lowering in high risk patients who remain above target despite statin +/- ezetimibe therapy (Conditional Recommendation, Low Quality Evidence). • We suggest the use of PCSK9 inhibitors (evolocumab, alirocumab) to lower LDL-C for patients with heterozygous familial hypercholesterolemia whose LDL-C remains above target despite maximally tolerated statin therapy (Conditional Recommendation, Moderate Quality Evidence). • We suggest that Evolocumab be added to background therapy in patients with homozygous familial hypercholesterolemia and continued if LDL-C lowering is documented (Conditional Recommendation, Moderate Quality Evidence). • We suggest that PCSK9 inhibitors be considered to lower LDL-C for patients with atherosclerotic cardiovascular disease in those not at LDL-C goal despite maximally tolerated statin +/- ezetimibe therapy (Conditional Recommendation, Moderate Quality Evidence). • We suggest lomitapide and mipomersen* may be considered exclusively in patients with homozygous familial hypercholesterolemia (Conditional Recommendation, Moderate Quality Evidence). • *not approved in Canada Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: 10.1016/j.cjca.2016.07.510

17. Major Changes Since the 2012 Update Provide better guidance to clinicians for the assessment of risk, screening and appropriate treatment of dyslipidemia for the prevention of cardiovascular disease Lipid screening for both men and women ≥ 40 years of age and inclusion of screening for women with a history of hypertensive diseases of pregnancy Use of non-fasting lipid determinations for initial screening and follow-up Expansion of CKD definition for high risk and harmonization with K-DIGO guidelines

18. Major Changes Since the 2012 Update Broader treatment recommendations for those in the intermediate risk category More explicit recommendations for health behaviour changes Greater emphasis about discussion with patients about their preferences (shared decision making) New recommendations about non-statin drug use

19. Risk Assessment

20. Among over 180,000 participants, only 10% knew both their BP and lipid levels

21. Among 10,120 Individuals Treated for Dyslipidemia (Average age 63 years, 55% female) • 27% CVD, 24% diabetes, 64% taking HTN meds • 58% were overweight (BMI > 27), • 75 % were sedentary (weekly METS<720), • 12% smoked • 72% reported optimal (100%) adherence with lipid meds during the previous month

22. Each patient carries his own doctor inside him. They come to us not knowing that truth. We are at our best when we give the doctor who resides within each patient a chance to go to work.” Albert Schweitzer (1875-1965) F Charatan, BMJ. 2004 Jun 12; 328(7453): 1426.

23. How Do We Get the Doctor in Each Patient to Go to Work ?

24. The Challenge… Lack of Interest The Solution… Engage the Patient

25. Intrinsic Motivation

26. 2016 Recommendations We recommend that a cardiovascular risk assessment be completed every 3 to 5 years for men and women age 40 to 75. A risk assessment may also be completed whenever a patient’s expected risk status changes. Options include using the 10 Year Risk (Framingham Model) or Cardiovascular Age (Cardiovascular Life Expectancy Model). (Strong Recommendation, High Quality Evidence)

27. Knowing One’s Cardiovascular Age (CVage) Improves Lipid Management Among Individuals at Increased Risk The larger one’s “Age Gap” (CVage-Actual Age), the greater the effect The positive impact of the risk profile increases with increasing age gap (p<0.04) after adjustment for baseline LDL-C, TC/HDL lipid targets, and statin dosage . Arch Intern Med. 2007;167(21):2296-230

28. A novel programme to evaluate and communicate 10-year risk of CHD reduces predicted risk and improves patients’ modifiable risk factor profile. Benner, Erhardt, Flammer, et al. J Clin Pract, Oct 2008, 62, 10, 1484–1498 *Included 3 Educational Phone Calls at 6,12,18 wks Knowing One’s Cardiovascular Risk* Improves Both BP and Lipids After 24 wks Among Moderate Risk (FHS >10%) Individuals with HTN

29. Clinical Impact of Heart Age >10yr Risk >UC RCT comparing the impact of communicating Heart Age, 10 yr FHS risk and UC among 3,153 primary care patients in Spain. After 12 mo., both the FHS Risk and the Heart Age groups demonstrated significant decreases in their risk scores at compared to the control group, with the improvement being of a greater magnitude in the Heart Age group. Effectiveness of the Heart Age tool for improving modifiable cardiovascular risk factors in a Southern European population: a randomized trial. A A Lopez-Gonzalez, A Aguilo, M Frontera, et al., European Journal of Preventive Cardiology 2015, Vol. 22(3) 389–396

30. Methods: Randomly assigned 9,361 persons with a SBP of 130 mmHg or higher and an increased cardiovascular risk (FHS 15%), to a SBP target of <120 mmHg (IC) or a target of <140 mmHg (SC). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Results:At 1 year, mean SBP was 121 mmHg (IC) group and 136 mmHg (SC). Intervention stopped after a median follow-up of 3.26 years with fewer outcomes in the IC group than in the SC group: (HR=0.75; 95% CI 0.64 to 0.89; P<0.001). (Ignoring heart failure, the HR=0.81 in favor of intensive control.) Extrapolating the Results of SPRINT

31. Average Sprint Male SC (mmol/L) 4.91 1.16 3.10 IC RR= 0.82 (NNT=19) ∆ Age Gap= 1.1 yrs chiprehab.com

32. Older High Risk Male SC (mmol/L) 4.91 1.16 3.10 IC RR= 0.83 (NNT=15) ∆ Age Gap= 0.9 yrs chiprehab.com

33. Younger Low Risk Male SC (mmol/L) 4.91 1.16 3.10 IC RR= 0.81 (NNT=77) ∆ Age Gap= 1.5 yrs chiprehab.com

34. The Incidence and Determinants of Primary Nonadherence With Prescribed Medication in Primary Care: A Cohort Study.Robyn Tamblyn, PhD; Tewodros Eguale, MD, PhD; Allen Huang, MD; Nancy Winslade, PharmD; and Pamela Doran, MSc, Ann Intern Med. 2014;160(7):441-450. Why Should We Spend the Extra Time and Effort To Discuss a Patient’s CV Risk? Objective: To estimate the incidence of medication nonadherence in primary care. Design: A prospective cohort of 15,961 patients in Quebec and all their incident prescriptions from electronic health records between 2006 and 2009. Results:Overall, 31.3% of the 37,506 incident prescriptions written for 15,961 patients were not filled.

35. “Drugs don’t work in people who don’t take them.” – C. Everett Koop Adherence With Statin Therapy in Elderly Patients… Jackevicius, Mamdani and Tu, University of Toronto “Increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.” Haynes et al., World Health Organization, 2003

36. CIHR Community Pharmacy Study Recruitment: March 2016 • Over 2 weeks 25,000+ MHC visitors check their CVage Comprehensive:1.5% Basic: 1% Nil: 97.5% 1.5% = 400+ participants over 2 weeks!

38. 2016 Recommendations We recommend that a cardiovascular risk assessment be completed every 3 to 5 years for men and women age 40 to 75. A risk assessment may also be completed whenever a patient’s expected risk status changes. Options include using the 10 Year Risk (Framingham Model) or Cardiovascular Age (Cardiovascular Life Expectancy Model). • The results should be shared with the patient to support shared decision making and improve the likelihood that they will reach lipid targets. (Strong Recommendation, High Quality Evidence)

39. Trials and Targets

40. CTT: Reduction in MVE by Baseline Risk Cholesterol Treatment Trialists’ (CTT) Collaborators.Lancet 2012; 380: 581–90.

41. CTT: Reduction in MVE by Baseline LDL-C per 1 mmol/L LDL-C Lowering Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet 2010; 376: 1670–81.

42. In-Trial Achieved LDL-C On-Statin LDL-C Levels and Risk for Major Cardiovascular Events 40 1.00 • Meta-analysis of 8 statin trials (n=38,153): • >40% did not reach LDL-C target (<1.8 mmol/L) on high dose statin 30 0.75 Percent of Patients ( ) HR for Major CV Events ( ) 0.50 20 0.25 10 0 1.3 2.6 3.9 5.2 6.5 Achieved On-statin LDL Levels • Patients achieving LDL-C <1.3 mmol/L are at lower CVD risk than those achieving an LDL-C of 1.9 to <2.6 mmol/L Boekholdt et al. J Am Coll Cardiol.2014;64(5):485-495.

43. Yusuf S. N Engl J Med 2016;374:2021-31.

44. Yusuf S. N Engl J Med 2016;374:2021-31.

46. IMPROVE-IT Study Design Patients stabilized post ACS ≤ 10 days: LDL-C 1.3–3.2 mmol//L (or 1.3–2.6 mmol/L if prior lipid-lowering Rx) Standard Medical & Interventional Therapy N=18,144 Uptitrated to Simva 80 mg if LDL-C >2 mmol/L (adapted per FDA label 2011) Simvastatin 40 mg Ezetimibe / Simvastatin 10 / 40 mg Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (≥ 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

47. IMPROVE-IT LDL-C and Lipid Changes *mg/dL Median Time avg 1.8 vs. 1.4 mmol/L Cannon CP. N Engl J Med 2015;372: 2387-97.

48. IMPROVE-IT Primary Endpoint — ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke HR 0.936 CI (0.887, 0.988) p=0.016 Simva - 34.7 2742 events NNT= 50 EZ/Simva - 32.7% 2572 events Cannon CP. N Engl J Med 2015;372: 2387-97.

49. IMPROVE-IT: Lowering LDL-C with a non-statin agent reduces CV Events Individual Cardiovascular Endpoints and CVD/MI/Stroke- On Cannon CP, et al. AHA, Chicago, Nov 2014.

50. IMPROVE-IT Clinical Benefit vs. LDL-C Lowering IMPROVE-IT CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.