Adverse Impacts of Severe ASCVD Is PCSK9 Inhibition the Key to Improving Patient Outcomes? Educational Objectives At the conclusion of this activity, participants should be able to: Evaluate the extent of residual CVD risk to which high-risk Adverse I m pacts of Severe ASCVD: patients are exposed Analyze the potential strengths and weaknesses of new I s PCSK9 I nhibition the Key approaches to reduce CVD risk to I m proving Patient Outcom es? Incorporate insights about new LDL-lowering agents in combination with statin therapy into more comprehensive clinical treatment strategies Eliot A. Brinton, MD, FAHA, FNLA President, Utah Lipid Center Discuss strategies to improve the knowledge, skills, or Salt Lake City, Utah performance of the healthcare team Past President, American Board of Clinical Lipidology ARI C Study: Relationship of LDL-C to CHD 4.50 Adjusted for age and race 10-year follow-up Relative Risk of CHD 2.85 Women Elevated LDL-C n=6907 Cardiovascular Pathobiology 1.80 Men n=5432 1.15 0.75 80 100 120 140 160 180 LDL-C (mg/dL) Sharrett AR et al. Circulation. 2001;104:1108–1113. I m pact of Hypercholesterolem ia Mutation Support for LDL Causality in ASCVD Status on CAD According to LDL-C Level Four Compelling Lines of Evidence: Observational data Interventional data Genetic studies Experimental data LDL Cholesterol Category (mg/dL) FH mutations included loss ‐ of ‐ function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH ASCVD = atherosclerotic cardiovascular disease Khera AV et al. J Am Coll Cardiol. 2016;67:2578-2589. 1
Adverse Impacts of Severe ASCVD Is PCSK9 Inhibition the Key to Improving Patient Outcomes? Unadjusted Rates of CHD Death or Nonfatal MI per 1 0 0 0 Person-years and Underlying Observed Event Num bers in Men and W om en w ith FH LDL-C Reduction: Cardiovascular Benefits Perak AM et al. Circulation. 2016;134:9-19. Mean Attained LDL-C on Statin Therapy and Genetically and Pharm acologically Mediated Risks of Secondary Cardiovascular Events Reduction of LDL-C Low ers Risk of CHD Ference BA et al. J Am Coll Cardiol. 2015;65:1552-1561. Boekholdt SM et al. J Am Coll Cardiol. 2014;64:485-494. LDL-C and Atherosclerotic Patients w ho Achieve Very Low LDL-C Levels have Low er Risk For MACE Cardiovascular Disease Cumulative LDL arterial burden is a central determinant for the initiation and progression of atherosclerotic cardiovascular When LDL-C is disease reduced to 50 The lower the LDL-C level attained by agents that primarily target mg/dL or lower, the LDL receptors, the greater the clinical benefit risk for CV events Both relative and absolute risk reduction relate to the magnitude is reduced by of LDL-C reduction more than half. Lowering LDL-C in individuals at high cardiovascular risk earlier rather than later appears advisable, especially in those with familial hypercholesterolemia Boekholdt SM et al. J Am Coll Cardiol. 2014;64:485-494. Eur Heart J. 2017 Apr 24. doi: 10.1093/eurheartj/ehx144. [Epub ahead of print]. 2
Adverse Impacts of Severe ASCVD Is PCSK9 Inhibition the Key to Improving Patient Outcomes? CHD Events Are Reduced Proportional to LDL-C Low ering w ith Statins ACS and Other Secondary Prevention Trials 30 y = 0.1629x ∙ 4.6776 R² = 0.9029 4S ‐ P 25 P <0.0001 Statins: The Gold Standard 20 CHD Events (%) HPS ‐ P LIPID ‐ P 4S ‐ S 15 for LDL-C Reduction HPS ‐ S A2Z 20 CARE ‐ P A2Z 80 TNT 10 LIPID-S 10 IDEAL A80 TNT 80 IDEAL S20/40 PROVE ‐ IT ‐ AT CARE ‐ S PROVE ‐ IT ‐ PR 5 0 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dL) Updated from O’Keefe J et al. J Am Coll Cardiol. 2004;43:2142-2146. High, Moderate, and Low -intensity 2 0 1 3 ACC/ AHA Guideline: Treatm ent of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults Statin Therapy Used in Clinical Trials Low-intensity statins are recommended only in patients with history of or at High-intensity Moderate-intensity Low-intensity risk for adverse drug effects Statin Therapy Statin Therapy Statin Therapy Moderate-to-high-intensity statins recommended for patients with clinical Daily dose lowers LDL-C, Daily dose lowers LDL-C, Daily dose lowers LDL-C, on average, by on average, by on average, by ASCVD and those with diabetes approximately ≥ 50% approximately 30% to <50% approximately <30% Atorvastatin 40*-80* mg Atorvastatin 10* (20**) mg Simvastatin 10** mg High-intensity statins recommended for patients with LDL-C >190 mg/dL Rosuvastatin 20*-40** mg Rosuvastatin (5**) 10* mg Pravastatin 10*-20* mg Simvastatin 20*-40* mg Lovastatin 20* mg Did not find evidence to support LDL-C thresholds or targets of therapy. No Pravastatin 40* (80**) mg Fluvastatin 20**-40** mg evidence was found that titration or combination drug therapy to achieve Lovastatin 40* mg Pitavastatin 1** mg Fluvastatin XL 80** mg specific LDL-C or non-HDL-C levels or percent reduction improved ASCVD Fluvastatin 40 mg BID* outcomes. No dose titration recommended. Pitavastatin 2-4** mg Monitor LDL-C to assess compliance and response to therapy *Statins demonstrated reduction in major CVD events ** FDA-approved doses not tested in clinical trials FD HDL-C = high-density lipoprotein cholesterol Stone NJ et al. Circulation. 2014;129(25 Suppl 2):S1-45. Stone NJ et al. Circulation. 2014;129(25 Suppl 2):S1-45. Goff DC et al. Circulation. 2014;129(25 Suppl 2):S49-73. Goff DC et al. Circulation. 2014;129(25 Suppl 2):S49-73 Statin Therapy: Monitoring Therapeutic ASCVD Statin Benefit Groups Response and Adherence LDL Testing LDL Testing LDL Testing No LDL Testing LDL Testing Stone NJ et al. Circulation . 2013;129:S49-S73. Stone NJ et al. Circulation . 2013;129:S49-S73. 3
Adverse Impacts of Severe ASCVD Is PCSK9 Inhibition the Key to Improving Patient Outcomes? NLA Recom m endations: I nitiate Therapy Based on Risk and Lipid Levels and Treat to Specific Goal Initiate Drug Therapy Treatment Goal Risk Criteria Non ‐ HDL ‐ C (LDL ‐ C) Non ‐ HDL ‐ C (LDL ‐ C) Category (mg/dl) (mg/dl) Low • 0 ‐ 1 major RF* >190 (>160) <130 (<100) • At least 2 major RF and 10 ‐ year risk Moderate >160 (>130) <130 (<100) Residual CHD Risk <10%* • At least 2 major RF and 10 ‐ year risk High >130 (>100)# <130 (<100) Despite Statin Therapy >10% • At least 3 RF • DM with 0 ‐ 1 other RFs and no end organ damage • CKD stage 3 or 4 • LDL ‐ C >190 mg/dl Very High • Established ASCVD >100 (>70)# <100 (<70) • DM with at least 2 other RFs or end organ damage *Consider other risk markers # Consider moderate or high intensity statin in patient with ASCVD or DM regardless of baseline lipid levels www.lipid.org Change in LDL-C Major Statin Trials: Despite Benefit, on Statin and MACE Event Rates Substantial Residual CV Risk Rem ains On ‐ treatment LDL ‐ C (mg/dL) 117 112 97 93 140 115 55 Placebo No Reduction/Increase <50% Reduction ≥ 50% Reduction CHD events occur in patients treated with statins 80 12 11.2 MACE Event Rate / 1000 Person ‐ Years : Only 23% ‐ 43% risk reduction across all studies 70 11 Patients Experiencing Major CHD Events, % 28.0 60 Placebo 10 50 9.2 Statin (High Intensity Statin) 40 Change in LDL ‐ C (%) 9 30 19.4 8 20 6.7 15.9 10 7 12.3 13.2 0 11.8 6 10.9 10.2 ‐ 10 4.8 8.7 7.9 ‐ 20 5 6.8 5.5 ‐ 30 4 ‐ 40 1.4 0.8 ‐ 50 3 ‐ 60 2 4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/ JUPITER 7 Greatest risk ‐ 70 TexCAPS 6 1 ‐ 80 n 4444 9014 4159 20,536 6595 6605 17,802 ‐ 90 0 0 1200 2400 3600 4800 6000 7200 High Risk Secondary Primary Individual Observations (N=7856) 1 4S Group. Lancet. 1994;344:1383-1389. 5 Shepherd J et al. N Engl J Med. 1995;333:1301-1307. 2 LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 6 Downs JR et al. JAMA. 1998;279:1615-1622. 3 Sacks FM et al. N Engl J Med. 1996;335:1001-1009. Ridker PM et al. Eur Heart J. 2016. doi:10.1093/eurheartj/ehw046. 7 Ridker PM et al. N Engl J Med . 2008;359:2195-2207. 4 HPS Collaborative Group. Lancet . 2002;360:7-22. Statin I ntolerance and Statin-Treated CHD Patients Achieving LDL-C < 1 0 0 m g/ dL and < 7 0 m g/ dL Risk of Coronary Events Cumulative Incidence for Recurrent MI, CHD Events, and All-Cause Mortality As Percent of All As Percent of All As Percent of All Treated Patients Treated High ‐ Risk Patients Treated CHD Patients 80 75.5 70.1 71.0 70 Administrative Claims Data 2003 ‐ Sept 2010 Electronic Medical Records 2003 ‐ Sept 2010 60 Ntl. Health & Nutrition Exam. Survey 2007 ‐ 2008 51.4 49.3 Patients (%) 50 43.6 37.9 40 30.9 30.5 30.5 28.4 30 24.8 23.7 22.1 19.0 20 14.3 13.2 10.3 10 0 High ‐ Risk CHD CHD Patients CHD Patients CHD Patients CHD Patients Patients Patients at LDL ‐ C Goal at LDL ‐ C Goal at LDL ‐ C Goal at LDL ‐ C Goal (<100 mg/dL) (<70 mg/dL) (<100 mg/dL) (<70 mg/dL) A Study of 105,329 Medicare beneficiaries who began a moderate ‐ or high ‐ intensity statin dosage after hospitalization for MI Serban MC et al. J Am Coll Cardiol. 2017;69:1386-1395. Jones PH et al. J Am Heart Assoc . 2012; doi 10.1161/JAHA.112.001800. 4
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