Updates from the World of Cardiology: Cardiometabolic Risk Mechanistic approaches to management Eveline Oestreicher Stock, MD Assistant Professor Cardiovascular Prevention Center University of California, San Francisco
Paving th the R Road A Ahead: N New C Clinical G Guidelines “Knowing is not enough, we must apply. Willing is not enough, we must do.” Goethe
How w would y you d design gn t trustworthy g guidelines? s? • To advise clinicians? • To advise healthcare systems? • Insurers? • “One size fits all?” • Concise • Clear • Evidence based • Flexible • Universal • Best advice for the greatest number of patients and advice to individuals
ACC/AHA enlisted 10 other stakeholder organizations, including NLA Ensure best practices, consensus, and distribution of the recommendations Merits and shortcomings to be discussed at a later meeting
Ta Takeaway • The American College of Cardiology (ACC) synthesized the guidelines into 10 key take-home messages • ACC also has created a hub of related resources for clinicians and patients: https://www.acc.org/guidelines/hubs/blood-cholesterol
Why this matters? • The latest cholesterol guidelines call for combining atherosclerotic cardiovascular disease (ASCVD) risk score with “risk enhancer” factors to personalize decision-making • The new recommendations introduce some necessary complexity
Key messa ssages • Outlines critical role of lifestyle intervention (message #1) • Reminds clinicians on importance of clinician-patient risk discussion (message #6) • Reinforces assessment of response and adherence to therapy (message #10) • Other messages - specific, content-driven recommendations with review of supporting evidence
Key messa ssages • Take-homes 2-5 (risk assessment not needed) • Identifies 4 main categories of risk: • Clinical ASCVD • LDL- C ≥ 190 mg/dl • DM • Primary prevention with moderate ASCVD risk • Acknowledges there is a range of ASCVD among patient in those categories • Suggests evidence-based criteria for enhancing stratification: • ApoB, Lp(a) and coronary artery calcium scoring (CAC) – “hidden pearls” • Hope Guidelines will lead to greater utilization of these important risk markers
Key messages • Reinforce importance of treatment thresholds • Give clinicians (patients and payers) clear recommendations for when there is strong enough evidence to intensify pharmacotherapy • Many clinical questions remain • We need to continue to support rigorous clinical scientific investigation Remind us of critical importance of healthy lifestyle • Emphasis on communication with our patients • Need for long term support for long term therapy
Mechanisms of Atherosclerosis: Mechanistic Targets • Atherogenic lipoproteins : ApoB, Lp(a), TG rich lipoproteins (VLDL) • Inflammation • Reverse cholesterol transport (Efflux – HDL function)
Lipid Targets - ASCVD
Lipid Targets – LDL-C Hypothesis Major vascular events avoided per 1000 Vascular deaths avoided per 1000 5-year 5-year risk of risk of major major vascular vascular event event LDL cholesterol reduction (mmol/L) LDL cholesterol reduction (mmol/L) with statin treatment with statin treatment Lancet. 2012 Aug 11; 380(9841): 581 – 590.
Lipid targets : LDL-C lowering • > 30 years of large scale clinical trials to confirm the role of LDL- cholesterol (LDL-C) reduction • Lovastatin - commercially available in 1987 • Landmark 1994 Scandinavian Simvastatin Survival Study (4S) - LDL-C lowering reduces major ASCVD events • Statin drugs to date : “single most important advance in the therapeutic armamentarium against CVD” • Despite statins aprox 60- 70% of ASCVD events occur in statin treated patients – “Residual CV risk”
Lipid Targets Pharmacy 2018 , 6 (1), 10.
Lipid Targets – Ezetimibe
Lipid Targets – Ezetimibe Major atherosclerotic events: 13.4% vs 11.3% • Non-fatal MI Rate reduction 17% (95% CI 6 - 26%) • Coronary death Log-rank p=0.0021 • Non-hemorrhagic stroke • Arterial revascularization Lancet. 2011 Jun 25;377(9784):2181 - 92. doi: 10.1016/S0140- 6736(11)60739 -3. Epub 2011 Jun 12.
Lipid Targets – Ezetimibe Conclusions • No reduction in mortality • Beneficial in reducing major atherosclerotic events • Safe in patients with renal impairment • NNT = 48 over median 4.9 years
Lipid Targets – Ezetimibe
Lipid Targets – Ezetimibe Conclusions • No reduction in mortality • Further reduction in LDL (12.8 mg/dL) reduced the proportion of major vascular events by 7.2% • NNT = 55 over median 6 years
Lipid Targets – PCSK9 inhibitor
Lipid Targets – PCSK9 inhibitor • 62.5 years old N=27,564 • 81% previous MI on statins • 19% nonhemorrhagic stroke • 13% peripheral artery disease • 80% hypertension Evolocumab* Placebo • 36% Diabetes • 28% current smoker 13,784 13,780 • LDL range 80- 109 mg/ dL , median 92 mg/ dL *140 mg q2 weeks OR 420 mg every month per patient preference N Engl J Med. 2017 May 4;376(18):1713 - 1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.
Lipid Targets – PCSK9 inhibitor Conclusions • No reduction in mortality • Effective in preventing future myocardial infarction • 2 injections per month or 1 subcutaneous infusion per month • NNT = 63 over median 26 months
Lipid Targets – PCSK9 inhibitor
Lipid Targets – PCSK9 inhibitor • 58 years old • 29% diabetes • 82% previous MI • 24% current smoker • 64% hypertension Hospitalized LDL >70 mg/ dL >40 years old with ACS* 1-12 on atorva or months prior rosuva ACS*: acute coronary syndrome (myocardial infarction or unstable angina) Alirocumab subcut injection q2 weeks N Engl J Med. 2018 Nov 29;379(22):2097 - 2107. doi : 10.1056/NEJMoa1801174. Epub 2018 Nov 7.
Lipid Targets – PCSK9 inhibitor Conclusions • No reduction in mortality • Effective in preventing future myocardial infarction, hospitalizations due to unstable angina, and revascularization • Results similar to FOURIER trial • NNT = 64 over median 2.8 years
Lipid Targets – Ongoing Research Pt characteristics UCSF (N=54) FOURIER ODYSSEY Male 63% 75% 75% Caucasian 77% 85% 79% Diabetes 22% 37% 29% HTN 51% 80% 66% Current tobacco smoker 2% 28% 24% Prior MI* 26% 81% 82% *Not all patients at UCSF had an event prior to starting PCSK9 inhibitors, but most of FOURIER & ODYSSEY patients had an event prior to being enrolled
Lipid Targets – Ongoing Research Figure 1. Percent change in LDL-C from baseline
Lipid Targets
Lipid Targets Table 2. Scenario analysis of MACE prevented and corresponding costs Simulation of Simulation of Evolocumab in Ezetimibe in ezetimibe in evolocumab in FOURIER IMPROVE-IT Variable FOURIER IMPROVE-IT NNT – 1 year (95% CI) 104 110 95 124 Cost of annual therapy per patient $6,540 $88 $6,540 $88 Cost to prevent one major adverse $678,981 $9,627 $620,218 $10,870 cardiovascular event (95% CI) Am J Cardiol. 2019 Jan 23. pii: S0002- 9149(19)30113 -4. doi : 10.1016/j.amjcard.2019.01.021.
Future Directions – EPA
Future Directions – EPA • Secondary prevention trial (70%) N = 4089 vs 4090 Results • Significant difference in cardiovascular death ( p=0.03 ) • NNT = 21 over median 4.9 years • Potential / viable treatment option
Future Directions – Bempedoic acid • Cholesterol biosynthesis inhibitor • Inhibits adenosine triphosphate citrate lyase (ACL)—2 steps upstream from HMG-CoAR Bempedoic acid is converted to its active moiety by ACSVL1 (not present in skeletal muscle) • • BPA and BPA+ezetimibe are in phase III clinical trials, hoping to apply for NDA in 2019 https://www.esperion.com/development/. Accessed March 8, 2019.
Contribution of Atherogenic Lipoproteins: LDL-C lowering • Studies with ezetimibe and PCSK- 9 inhibitors have confirmed - lower LDL-C is associated with reduced ASCVD events, regardless of the agent used and proportional to the degree of LDL-C lowering • Even with aggressive LDL-C reduction, vascular events continue to occur at an alarming rate, suggesting that there are additional important factors at play • Reiteration of the value of comprehensive risk reduction in the care of our patients
Role of Inflammation in the Development of Atherosclerotic Plaque Different stages of the inflammatory process involve specific mediators/ (orange boxes) – drugs targets (white boxes) Graphic created by Dr. Thomas Dayspring (modified )
Residual risk of MACE remains following cholesterol reduction Control Intervention 40 35 30 MACE (%) 25 20 15 10 5 0 Statin High-dose Ezetimibe PCSK9 statin inhibitor SSSS PROVE-IT IMPROVE-IT FOURIER
On-treatment inflammation is a determinants of residual risk PROVE-IT IMPROVE-IT
Relationship of plasma levels of IL-6 to future risks of cardiovascular disease in 25 prospective epidemiologic cohorts For each SD increase in log IL-6, there is a 25% increase in risk of future vascular events (95%CI 1.19-1.32). Adapted from Eur Heart J 2014;35:578-89
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