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The Impact of the New Prevention Guidelines on Clinical Practice and Research

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Christie M. Ballantyne, MD ...

Christie M. Ballantyne, MD
Baylor College of Medicine

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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  • Place question mark at end of ‘intolerance to recommended dose of statin therapy’ in gray diamond text box on right <br />
  • Figure 2 Study design of the SOLID-TIMI 52 trial. EC , Enteric coated. <br /> O&apos;Donoghue ML, Braunwald E, White HD, Serruys P, Steg PG, Hochman J, Maggioni AP, Bode C, Weaver D, Johnson JL, Cicconetti G, Lukas MA, Tarka E, Cannon CP. Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J. 2011 Oct;162(4):613-619.e1. doi: 10.1016/j.ahj.2011.07.018. Epub 2011 Sep 15. PubMed PMID: 21982651. <br />
  • Figure 1 Simplified flow diagram of CIRT. Clinically stable patients with a history of MI in the past 5 years and either type 2 diabetes or the metabolic syndrome will enter a 5- to 6-week active run-in period with escalating doses of methotrexate (advanci... <br />
  • Cholesterol isolation from gallstones in 1784 <br /> Endo A. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 484–93. <br /> Akira Endo and isolation of compactin in 1973 <br /> Endo A. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 484–93. <br /> Brown & Goldstein awarded Nobel Prize in 1985 <br /> Endo A. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 484–93. <br /> 4S study <br /> Scandinavian Simvastatin Survival Study Group. Lancet 1994; 344: 1383–9. <br /> Fenofibrate <br /> 1European Medicines Agency. Questions and answers on the review of medicines containing fibrates (EMA/643808/2010 rev 1) [available from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Fibrates/human_referral_000247.jsp&mid=WC0b01ac05805c516f] <br /> FDA approval for hypertriglyceridemia in 1993; FDA approval for reducting LDL-C, TGs, TC and ApoB levels and increasing HDL-C levels in patients with primary HC or mixed dyslipidemia in 1999 (2Goldfine AB et al. New Engl J Med 2011; 365: 481–4.) <br /> Gemfibrozil <br /> 1European Medicines Agency. Questions and answers on the review of medicines containing fibrates (EMA/643808/2010 rev 1) [available from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Fibrates/human_referral_000247.jsp&mid=WC0b01ac05805c516f] <br /> 3Cunningham ML et al. PPAR Res 2010; 2010: pii: 681963. <br /> Lovastatin <br /> 4European Medicines Agency. Public consultation on the list of Union Reference Dates and frequency of submission of Periodic Safety Update Reports [available at www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2012/04/WC500125001.xls] <br /> 5Tobert JA. Nat Rev Drug Discov 2003; 2: 517–26. <br /> Ezetimibe <br /> 6UK Medicines Information Monograph 3/02/07: Ezetimibe [available from http://www.ukmi.nhs.uk/NewMaterial/Secure/ezetimibe%20final%20RGB.pdf] <br /> 7Drugs@FDA@: Ezetimibe [available from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=021445&DrugName=ZETIA&ActiveIngred=EZETIMIBE&SponsorApplicant=MSD%20INTL%20GMBH&ProductMktStatus=1&goto=Search.DrugDetails] <br />
  • Cholesterol isolation from gallstones in 1784 <br /> Endo A. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 484–93. <br /> Akira Endo and isolation of compactin in 1973 <br /> Endo A. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 484–93. <br /> Brown & Goldstein awarded Nobel Prize in 1985 <br /> Endo A. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 484–93. <br /> 4S study <br /> Scandinavian Simvastatin Survival Study Group. Lancet 1994; 344: 1383–9. <br /> Fenofibrate <br /> 1European Medicines Agency. Questions and answers on the review of medicines containing fibrates (EMA/643808/2010 rev 1) [available from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Fibrates/human_referral_000247.jsp&mid=WC0b01ac05805c516f] <br /> FDA approval for hypertriglyceridemia in 1993; FDA approval for reducting LDL-C, TGs, TC and ApoB levels and increasing HDL-C levels in patients with primary HC or mixed dyslipidemia in 1999 (2Goldfine AB et al. New Engl J Med 2011; 365: 481–4.) <br /> Gemfibrozil <br /> 1European Medicines Agency. Questions and answers on the review of medicines containing fibrates (EMA/643808/2010 rev 1) [available from http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Fibrates/human_referral_000247.jsp&mid=WC0b01ac05805c516f] <br /> 3Cunningham ML et al. PPAR Res 2010; 2010: pii: 681963. <br /> Lovastatin <br /> 4European Medicines Agency. Public consultation on the list of Union Reference Dates and frequency of submission of Periodic Safety Update Reports [available at www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2012/04/WC500125001.xls] <br /> 5Tobert JA. Nat Rev Drug Discov 2003; 2: 517–26. <br /> Ezetimibe <br /> 6UK Medicines Information Monograph 3/02/07: Ezetimibe [available from http://www.ukmi.nhs.uk/NewMaterial/Secure/ezetimibe%20final%20RGB.pdf] <br /> 7Drugs@FDA@: Ezetimibe [available from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=021445&DrugName=ZETIA&ActiveIngred=EZETIMIBE&SponsorApplicant=MSD%20INTL%20GMBH&ProductMktStatus=1&goto=Search.DrugDetails] <br />

The Impact of the New Prevention Guidelines on Clinical Practice and Research The Impact of the New Prevention Guidelines on Clinical Practice and Research Presentation Transcript

  • The Impact of the New PreventionThe Impact of the New Prevention Guidelines on Clinical Practice andGuidelines on Clinical Practice and ResearchResearch Christie M. Ballantyne, MDChristie M. Ballantyne, MD Center for Cardiovascular Disease PreventionCenter for Cardiovascular Disease Prevention Methodist DeBakey Heart & Vascular CenterMethodist DeBakey Heart & Vascular Center Baylor College of MedicineBaylor College of Medicine Houston, TexasHouston, Texas
  • • Grant/Research Support:Grant/Research Support: Abbott, Amarin, Amgen, Eli Lilly,Abbott, Amarin, Amgen, Eli Lilly, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer,Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi-Synthelabo, NIH, AHA (all paid toRegeneron, Roche, Sanofi-Synthelabo, NIH, AHA (all paid to institution, not individual)institution, not individual) • Consultant:Consultant: Abbott Diagnostics, Aegerion, Amarin, Amgen,Abbott Diagnostics, Aegerion, Amarin, Amgen, Arena, Cerenis, Esperion, Genentech, Genzyme, Kowa,Arena, Cerenis, Esperion, Genentech, Genzyme, Kowa, Merck, Novartis, Pfizer, Resverlogix, Regeneron, Roche,Merck, Novartis, Pfizer, Resverlogix, Regeneron, Roche, Sanofi-SynthelaboSanofi-Synthelabo Christie M. Ballantyne, MDChristie M. Ballantyne, MD Financial DisclosureFinancial Disclosure
  • Case 1 • 53-year-old white man with a family history of premature CHD; his father died of MI at age 50. He has a history of hypertension, which has been treated for 6 years, as well as a history of high cholesterol for as long as he can remember. He is a nonsmoker who walks 30 min 3 times a week. • PE: BMI 28.6 kg/m2 , waist 40", BP 136/88 mm Hg • Current meds: lisinopril 20 mg/HCTZ 12.5 mg, ASA 81 mg, atorvastatin 80 mg
  • According to the new ACC/AHA guidelines, should you check his lipid profile? a.Yes b.No c.Unsure Audience Response Question
  • Monitoring and Follow-up ✔ Adherence to a heart-healthy lifestyle - Optimal adherence to improve lipid profile ✔ Measure lipids regularly; 3-12 weeks after start, then 4-12 months as appropriate to check adequacy of statin Rx - Consider secondary causes - If high risk and inadequate response, consider nonstatin Rx ✔ Review safety issues at each visit with history and labs, if appropriate - For example, some may require CK, FBS, HbA1C ✔ Review adherence to statin at each visit Maximally tolerated statin intensity to keep LDL-C low
  • Lab Results • Glucose 110 mg/dL • TC 204 mg/dL • HDL-C 35 mg/dL • non-HDL-C 169 mg/dL • TG 200 mg/dL • LDL-C 128 mg/dL • Lp(a) 310 nmol/L (ULN < 75 nmol/L) • ALT 48 IU/L (ULN 44 IU/L) • AST 30 IU/L (ULN 40 IU/L)
  • ASCVD Risk Estimate (Pooled Cohort Equations) • 10-year ASCVD risk: 9.8% • Lifetime ASCVD risk: 50.0% http://www.cardiosource.org/en/Science-And-Quality/Practice-Guidelines-and-Quality- Standards/2013-Prevention-Guideline-Tools.aspx
  • Does this information influence your care of the patient? a.Yes b.No c.I agree Audience Response Question
  • Lipid Profile 1. Assess compliance 2. Consider intensifying therapy with lifestyle and drugs 3. Screen family members
  • Questions to Consider • He says he is compliant and does not miss his medications; he has 4 children and does not know their cholesterol values • How does this information influence your care of the patient? • What do you do now?
  • Case 1: Follow-up • After being instructed to exercise more and lose weight and after being told that evidence no longer supports a benefit in setting a target LDL-C level or adding a second drug, he was seen by his family practitioner who ordered some other tests that he is concerned about. – LDL-P 1,880 nmol/L – Small LDL-P 1,020 nmol/L – Apo B 105 mg/dL – Coronary calcium score 677
  • What is your response to his question as to whether he may benefit from additional therapy? a.There is evidence that additional therapy may be of benefit b.There is no evidence to support additional therapy at this time c.I’m unsure d.What is LDL-P??????? Audience Response Question
  • Questions to Consider • Do we have any evidence that adding another therapy targeting lipoproteins would provide additional benefit? – Epidemiology – Genetics – Clinical trials
  • Follow-up 4-12 wk and thereafter as indicated Reinforce continued adherence Follow-up 3-12 mo Management of statin intolerance (Table 8, Rec 8) Follow-up 4-12 wk Follow-up lipid panel—see if anticipated response Yes Yes No No Reinforce improved adherence Increase statin intensityǂ OR Consider addition of nonstatin drug therapy Anticipated therapeutic response? Reinforce medical adherence Reinforce adherence to intensive lifestyle changes Exclude secondary causes of hypercholesterolemia (Table 6) Intolerance to recommended dose of statin therapy Less-than-anticipated therapeutic response
  • Case 2 • A 62-year-old black woman with a history of hypertension and diabetes who had PCI and stent 6 weeks ago is seen in follow-up. She has been walking on a regular basis after discharge and now complains of sore muscles in her legs and back • PE: BMI 32 kg/m2 , waist 39" • Current meds: metformin 1,000 mg BID, amlodipine 10 mg, losartan 100 mg/HCTZ 12.5 mg, ASA 81 mg, clopidogrel 75 mg, atorvastatin 80 mg
  • Lab Results • TC 155 mg/dL • HDL-C 50 mg/dL • non-HDL-C 105 mg/dL • TG 150 mg/dL • LDL-C 75 mg/dL • CK 650 U/L (ULN 200 U/L)
  • Case 2: Follow-up • Her atorvastatin is reduced to 10 mg. She continues to walk and complain of sore muscles, but there may be some improvement. Follow-up lipids at 8 weeks: – LDL-C 100 mg/dL – TG 200 mg/dL – HDL-C 50 mg/dL – CK 440 IU (ULN 200 U/L)
  • Do you feel that her lipids are optimally treated? a.Yes b.No c. Unsure d.What do you mean by optimally? e.Lipids are not important, it’s all about inflammation Audience Response Question
  • Which of the following would you consider to be the best option? a.Increase atorvastatin to 40 mg b.Change to rosuvastatin 10 mg c.Change to pravastatin 10 mg d.Add ER niacin and titrate to 2,000 mg e.Add ezetimibe 10 mg f.Add colesevelam 625 mg 3 po BID g.Chelation therapy Audience Response Question
  • Intensity of Statin Therapy *Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. †Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al). ‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. High-, Moderate- and Low-Intensity Statin Therapy (used in the RCTs reviewed by the Expert Panel)* High-Intensity Statin Therapy Moderate-Intensity Statin Therapy Low-Intensity Statin Therapy Daily dose lowers LDL-C, on average, by approximately ≥ 50% Daily dose lowers LDL-C, on average, by approximately 30% to < 50% Daily dose lowers LDL-C, on average, by < 30% Atorvastatin (40†)-80 mg Rosuvastatin 20 (40) mg Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20-40 mg‡ Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 2-4 mg Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg
  • Question to Consider How would you discuss this with the patient?
  • What is the Optimal LDL-C?What is the Optimal LDL-C? ARICARIC LDL-C QuintilesLDL-C Quintiles RelativeRiskforIncidentCHDRelativeRiskforIncidentCHD mmol/Lmmol/L mg/dlmg/dl (median)(median) Adjusted for age and race, 12-year follow-up; N=12,339Adjusted for age and race, 12-year follow-up; N=12,339 Sharrett AR et al.Sharrett AR et al. CirculationCirculation 2001;104:1108-1113.2001;104:1108-1113. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 1 2 3 4 5 2.272.27 8888 2.932.93 113113 3.403.40 131131 3.943.94 152152 4.844.84 187187 WomenWomen 0.0 0.5 1.0 1.5 2.0 2.5 3.0 1 2 3 4 5 MenMen 2.452.45 9595 3.103.10 120120 3.553.55 137137 4.044.04 156156 4.784.78 185185
  • ATP I 1988 ATP II 1993 ATP III 2001 ATP III Update 2004 Exclusive focus on LDL-C Risk assessment guides therapy Lower LDL-C threshold for therapy initiation in high- risk patients Lower LDL-C threshold for therapy initiation in very- high-risk patients Strong support for resins, niacin Goal LDL-C reduced for CHD (≤100 mg/dL) LDL-C goal <100 mg/dL for CHD equivalent Optional LDL-C goal <70 mg/dL for CVD + multiple/severe risk or ACS Statins, fibrates not first line Statins included in "major drugs," fibrates for mixed HPL Non-HDL-C and metabolic syndrome as secondary targets Optional LDL-C goal <100 mg/dL for moderately high-risk primary prevention Evolution of lipid managementEvolution of lipid management guidelinesguidelines Low- to moderate- dose monotherapy High-dose statin, increased combination therapy Moderate- to high-dose statin
  • Risk category LDL-C Non-HDL-C Goal Initiation level for TLC Consideration level for drug therapy Goal Very high risk: CHD + other risk factors <70 (optional) ≥100 ≥100 (<100: consider drug options) <100 High risk: CHD or CHD risk equivalents (10-yr risk >20%) <100 (optional: <70) ≥100 ≥130 (100–129: drug optional) <130 Moderately high risk: 2+ risk factors (10-yr risk 10–20%) <130 (optional: <100) ≥130 ≥130 <160 Moderate risk: 2+ risk factors (10-yr risk <10%) <130 ≥130 ≥160 <160 Lower risk: 0–1 risk factor <160 ≥160 ≥190 (160–189: LDL-C– lowering drug optional) <190 Grundy SM et al.Grundy SM et al. CirculationCirculation 2004;110:227–2392004;110:227–239 Updated ATP III LDL-C and non-HDL-C goals andUpdated ATP III LDL-C and non-HDL-C goals and cutpoints for therapycutpoints for therapy
  • 0% 5% 10% 15% 20% 25% 30% 0.0 0.5 1.0 More vs. Less (5 trials) Statin vs. control (21 trials)  PROVE­IT   TNT   IDEAL   SEARCH   A to Z  CTT meta analysis: Proportional reduction in MAJOR VASCULAR EVENTS versus absolute LDL-C reduction Proportional reduction in vascular event rate (95% CI) Mean LDL cholesterol difference between treatment groups (mmol/L) 22% (20%-24%) risk reduction per mmol/L P<0.0001 CTT Collaboration, Lancet 2010
  • Why Not Continue to Treat to Target? Major difficulties: 1.Current RCT data do not indicate what the target should be 2.Unknown magnitude of additional ASCVD risk reduction with one target compared to another 3.Unknown rate of additional adverse effects from multidrug therapy used to achieve a specific goal 4.Therefore, unknown net benefit from treat-to-target approach
  • Failed Trials of More-Intensive Therapy ofFailed Trials of More-Intensive Therapy of lipids in High-Risk Patients with CHD tolipids in High-Risk Patients with CHD to Reduce Atherothrombotic EventsReduce Atherothrombotic Events 1.1. Addition of niacin to statin—no benefit in AIM-Addition of niacin to statin—no benefit in AIM- HIGH and HPS2-THRIVEHIGH and HPS2-THRIVE 2.2. Addition of fibrate to statin—no benefit inAddition of fibrate to statin—no benefit in ACCORDACCORD 3.3. Addition of CETP to statin – harm withAddition of CETP to statin – harm with torcetrapid, no benefit with dalcetrapibtorcetrapid, no benefit with dalcetrapib
  • HPS II: baseline lipids on statin-based therapy Mean (SD) baseline mg/dL mmol/L Total cholesterol 128 (22) 3.32 (0.57) Direct-LDL 63 (17) 1.64 (0.44) HDL 44 (11) 1.14 (0.29) Triglycerides* 125 (74) 1.43 (0.84) *64% fasted for >8 hours 30Armitage J, ACC 2013
  • Effect of ERN/LRPT on major cardiovascular events 0 1 2 3 4 Years of follow-up 20 15 10 5 0 Patientssufferingevents(%) 15.0% 14.5% Placebo ERN/LRPT Logrank P=0.29 Risk ratio 0.96 (95% CI 0.90–1.03) 31 ERN/LRPT = Extended release Niacin/Laropiprant Armitage J, ACC 2013
  • Randomized allocation Risk ratio & 95% CI Het or trend χ² (uncorrected p value)PlaceboERN/LRPT (12,835)(12,838)Age (years) < 65 740 (11.4%) 786 (12.2%) 0.00 (p=0.98)≥ 65 <70 392 (13.9%) 367 (13.1%) ≥ 70 564 (15.9%) 605 (17.0%) Sex Male 1397 (13.2%) 1485 (14.0%) 3.21 (p=0.07)Female 299 (13.4%) 273 (12.3%) Region Europe 832 (11.3%) 913 (12.4%) 3.61 (p=0.06)China 864 (15.8%) 845 (15.5%) Statin-based therapy Simvastatin 40 mg 945 (14.0%) 949 (14.0%) 1.28 (p=0.26)Ezetimibe/simvastatin 751 (12.4%) 809 (13.3%) All 1696 (13.2%) 1758 (13.7%) 3.5% SE 3.3 reduction 1.0 1.20.8 ERN/LRPT better Placebo better MVE by age, sex, region and statin- based therapy 32 MVE = Major vascular events Armitage J, ACC 2013
  • Randomized allocation Risk ratio & 95% CI Het or trend Χ² (uncorrected p value)PlaceboERN/LRPT (12835)(12838) HDL cholesterol <35 (0.9) 388 (15.8%) 399 (16.3%) 0.20 (p=0.66)≥35 <43 560 (13.7%) 546 (13.5%) ≥43 (1.1) 748 (11.9%) 813 (12.8%) LDL cholesterol <58 (1.5) 724 (14.7%) 679 (13.8%) 5.91 (p=0.02)≥58 <77 685 (12.4%) 761 (13.7%) ≥77 (2.0) 287 (12.0%) 318 (13.5%) All 1696 (13.2%) 1758 (13.7%) 3.5% SE 3.3 reduction 1.0 1.20.8 ERN/LRPT better Placebo better mg/dL (mmol/L) Triglycerides <89 (1.0) 541 (13.2%) 563 (13.4%) 0.66 (p=0.42)≥89 <151 694 (12.8%) 712 (13.2%) ≥151 (1.7) 461 (13.9%) 483 (14.8%) Major cardiovascular events by baseline lipids 33Armitage J, ACC 2013
  • Should we be treating inflammation?Should we be treating inflammation? 1.1. Lp-PLALp-PLA22 inhibitorinhibitor 2.2. sPLAsPLA22 inhibitorinhibitor 3.3. IL-1IL-1ββ mAbmAb 4.4. Low-dose methotrexateLow-dose methotrexate
  • STABILITY Trial Study Design 15,828 patients randomized Patients with chronic CHD (prior MI >1 mth, prior coronary revascularization, multivessel CAD) Darapladib 160mg daily Placebo Median follow-up 3.7 years, 1588 events Primary endpoint: composite of CV death, MI, strokePrimary endpoint: composite of CV death, MI, stroke Secondary endpoints: major coronary events, total coronary eventsSecondary endpoints: major coronary events, total coronary events Enrichment criteria: ≥60 years of age, diabetes mellitus, low HDL, current smoking, significant renal dysfunction, polyvascular disease Optimized guideline-recommended treatment Design paper reference: White H, et al. Am Heart J 2010;160:655-61.
  • Primary Endpoint: Time to First Occurrence of CV Death, MI, Stroke Placebo events = 819 (10.4%) Darapladib events = 769 (9.7%) HR = 0.94 (95% CI, 0.85 - 1.03) P-value = 0.199 STABILITY Investigators. N Engl J Med 2014 [Epub ahead of print].
  • Time to First Occurrence Major Coronary Events (CHD Death, MI, Urgent Coronary Revascularization) Placebo events = 814 (10.3%) Darapladib events = 737 (9.3%) HR = 0.90 (95% CI, 0.82 - 1.00) P-value = 0.045 STABILITY Investigators. N Engl J Med 2014 [Epub ahead of print].
  • Adverse Events Placebo (N=7890) Darapladib (N=7912) Any serious adverse event 44% 43% Any adverse event leading to study drug discontinuation 14% 20% Cancer New cancer 6.7% 6.4% Adjudicated new GI cancer 1.3% 1.3% Renal Effects Serious adverse events of renal failure 1.1% 1.5% eGFR Change from baseline treatment difference (ml/min/1.73m2 ) End of treatment (n=14820) 1 month after treatment end (n=2650) -2.5 (-3.0, -2.1) -0.1 (-1.4, 1.1) STABILITY Investigators. N Engl J Med 2014 [Epub ahead of print].
  • Conclusions Darapladib in patients with stable CHD followed for 3.7 years on a background of optimal medical therapy resulted in  No significant reduction in the incidence of the primary composite endpoint of CV death, MI or stroke  A signal of efficacy on the pre-specified coronary-specific secondary endpoints of major coronary events and total coronary events with nominal significance (p<0.05)  A safety profile that was well characterized STABILITY Investigators. N Engl J Med 2014 [Epub ahead of print].
  • O'Donoghue ML et al. Am Heart J 2011;162-613-619.e1 Stabilization of Plaques Using Darapladib–Stabilization of Plaques Using Darapladib– Thrombolysis In Myocardial Infarction 52 (SOLID-Thrombolysis In Myocardial Infarction 52 (SOLID- TIMI 52) DesignTIMI 52) Design
  • Vascular Inflammation Suppression to TreatVascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 WeeksAcute Coronary Syndrome for 16 Weeks (VISTA-16)(VISTA-16) • Background:Background: – High secretory phospholipase AHigh secretory phospholipase A22 (sPLA(sPLA22) levels are) levels are associated with increased risk for CVD events andassociated with increased risk for CVD events and increased levels noted in atherosclerotic plaquesincreased levels noted in atherosclerotic plaques – Varespladib is a nonspecific pan-sPLAVarespladib is a nonspecific pan-sPLA22 inhibitor whichinhibitor which reduces sPLAreduces sPLA22 levels by 90% and has favorable effects onlevels by 90% and has favorable effects on LDL-C and hs-CRPLDL-C and hs-CRP • Design:Design: – Double-blind RCT in 5145 patients randomized toDouble-blind RCT in 5145 patients randomized to varespladib or placebo within 96 hours of ACSvarespladib or placebo within 96 hours of ACS Nicholls SJ et al.Nicholls SJ et al. JAMAJAMA 2014;311:252-262.2014;311:252-262.
  • VISTA-16VISTA-16 • Results:Results: – Trial stopped early for futility and possible harm after 212Trial stopped early for futility and possible harm after 212 primary endpoints (CV mortality, nonfatal MI, nonfatal stroke,primary endpoints (CV mortality, nonfatal MI, nonfatal stroke, unstable angina with ischemia requiring hospitalization) in 6.1%unstable angina with ischemia requiring hospitalization) in 6.1% varespladib (V) vs 5.1% placebo (P) (HR 1.25 [95% CI 0.97–varespladib (V) vs 5.1% placebo (P) (HR 1.25 [95% CI 0.97– 1.61]) with significant increase in MI (1.61]) with significant increase in MI (HR 1.66 [95% CI 1.16HR 1.66 [95% CI 1.16–– 2.39])2.39]) – Modest beneficial effects on LDL-C (V:Modest beneficial effects on LDL-C (V: 69.1 mg/dL, P: 73.869.1 mg/dL, P: 73.8 mg/dLmg/dL) and hs-CRP (V:) and hs-CRP (V: 1.4 mg/L, P: 1.5 mg/L1.4 mg/L, P: 1.5 mg/L) at week 16) at week 16 • Conclusion:Conclusion: – sPLAsPLA22 inhibition with varespladib does not work to reduce CVDinhibition with varespladib does not work to reduce CVD events post ACS!events post ACS! Nicholls SJ et al.Nicholls SJ et al. JAMAJAMA 2014;311:252-262.2014;311:252-262.
  • Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation of hsCRP (> 2 mg/L) Randomized Canakinumab 150 mg SC q 3 months Randomized Placebo SC q 3 months Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death Randomized Canakinumab 300 mg SC q 3 months Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Secondary Endpoints: Total Mortality, New Onset Diabetes, Other Vascular Events Exploratory Endpoints: DVT/PE; SVT; hospitalizations for CHF; PCI/CABG; biomarkers 43 Randomized Canakinumab 50 mg SC q 3 months Ridker PM et al. Am Heart J 2011;162:597-605.
  • Everett BM et al.Everett BM et al. Am Heart JAm Heart J 2013;166:199-207.e15.2013;166:199-207.e15. CIRT DesignCIRT Design
  • If inflammation is not yet aIf inflammation is not yet a target of therapy, how about fortarget of therapy, how about for risk stratification?risk stratification?
  • Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive Cardiology, Association of Black Cardiologists, Preventive Cardiovascular Nurses Association and WomenHeart: The National Coalition for Women With Heart Disease 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
  • Overview: Statin Benefit Groups Secondary Prevention LDL-C ≥ 190 mg/dL Diabetes 40 to 75 yrs LDL-C 70-189 mg/dL Primary Prevention 40 to 75 yrs LDL-C 70-189 mg/dL ASCVD Risk ≥ 7.5 % High Risk Groups Statin Rx not automatic, requires clinician-patient discussion Rx: Optimal benefit with high-intensity statins Use moderate-intensity if age > 75 or can’t tolerate high intensity
  • Individuals Not in a Statin Benefit Group • In those for whom a risk decision is uncertain, these factors may inform clinical decision making in the context of clinician-patient discussion: – LDL-C ≥160 mg/dL – Elevated lifetime risk of ASCVD (below added from risk assessment guideline) – Family history of premature ASCVD – hs-CRP ≥ 2.0 mg/L – Coronary artery calcium score ≥ 300 Agatston units – Ankle brachial index (ABI) < 0.9
  • How do we move forwards?How do we move forwards? 1.1. Improved algorithms and methods for assessingImproved algorithms and methods for assessing thethe absoluteabsolute 10 year and life time risk for all CV10 year and life time risk for all CV events ( MI, stroke, revasc, CHF, arryhthmiasevents ( MI, stroke, revasc, CHF, arryhthmias and DM) and theand DM) and the modifiablemodifiable riskrisk 2.2. Use of human genetics to accelerate targetUse of human genetics to accelerate target identification and pathways with greater chancesidentification and pathways with greater chances
  • 50 Cholestyramine (MK-135) reported to reduce serum total cholesterol in humans by ~20%3 1959 Development of lipid-lowering therapies 1970 1975 1980 1985 1990 1995 2000 2005 First statin (lovastatin) approved in the EU7 and USA8 1987 Gemfibrozil approved in the EU4 1981 Gemfibrozil approved in the USA6 1982 Fenofibrate approved in the EU4 1975 Fenofibrate approved in the USA5 1993 Ezetimibe approved in the EU10 and USA11 2002 Cholesterol first isolated from gallstones1 1784 Akira Endo isolates compactin (mevastatin), paving the way for new methods of blocking HMG-CoA reductase1 1973 Michael Brown and Joseph Goldstein awarded the Nobel Prize for research into cholesterol metabolism1 1985 The 4S study demonstrated a reduction in risk of mortality with statin treatment9 1994 HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A Niacin first shown to lower plasma cholesterol in normal and hyper-cholesterolemic subjects2 1955 1 Endo A. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 484–93; 2 Altschul R, et al. Arch Biochem 1955; 54: 558–9; 3 Bergen SS, et al. Proc Soc Exp Biol Med 1959; 102: 676–9; 4 European Medicines Agency. Questions and answers on the review of medicines containing fibrates (EMA/643808/2010 rev 1); 5 Goldfine AB, et al. New Engl J Med 2011; 365: 481–4; 6 Cunningham ML, et al. PPAR Res 2010; 2010: pii: 681963; 7 European Medicines Agency; Public consultation on the list of Union Reference Dates and frequency of submission of Periodic Safety Update Reports; 8 Tobert JA. Nat Rev Drug Discov 2003; 2: 517–26; 9 Scandinavian Simvastatin Survival Study Group. Lancet 1994; 344: 1383–9; 10 UK Medicines Information Monograph 3/02/07: ezetimibe; 11 Drugs@ FDA: ezetimibe.
  • 51 Drug discovery for lipid-modifying therapy in the 20th and 21st centuries 20th Century •SLOW •Empiric process •Many failures, few successes 21st Century •Focus on human genetics •Rare and common variants used to identify key biological pathways •Use of biotechnology to reduce time from target identification to therapeutic trials in humans • Target identification: epidemiology + Mendelian randomisation and human genetics • Time period between target identification and proof of concept in man reduced • Target identification: epidemiology and animal studies primarily • Long gap between target selection and proof-of-concept studies in humans
  • 52 ARIC LDL-C quintiles What is the optimal LDL-C? ARIC, Atherosclerosis Risk in Communities study; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol Adapted from Sharrett AR, et al. Circulation 2001; 104: 1108–13. RelativeriskforincidentCHD mmol/L mg/dL (median) Adjusted for age and ethnicity, 12-year follow-up (N=12,339) WomenMen 2.27 88 2.93 113 3.40 131 3.94 152 4.84 187 2.45 95 3.10 120 3.55 137 4.04 156 4.78 185
  • 53 Associations with LDL-C CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; SNP, single-nucleotide polymorphism Adapted from Ference BA, et al. J Am Coll Cardiol 2012; 60: 2631–9.
  • 54 Associations with CHD CHD, coronary heart disease; CI, confidence interval; OR, odds ratio; RRR, relative risk reduction; SNP, single-nucleotide polymorphism Adapted from Ference BA, et al. J Am Coll Cardiol 2012; 60: 2631–9.
  • 55 Linear effect on CHD (per unit lower LDL-C) CHD, coronary heart disease; CI, confidence interval; LDL-C, low-density lipoprotein; RRR, relative risk reduction Adapted from Ference BA, et al. J Am Coll Cardiol 2012; 60: 2631–9.
  • 56 ARIC HDL-C quintiles What is the optimal HDL-C? ARIC, Atherosclerosis Risk in Communities study; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol Adapted from Sharrett AR, et al. Circulation 2001; 104: 1108–13. RelativeriskforincidentCHD mmol/L mg/dL (median) Adjusted for age and ethnicity, 12-year follow-up (N=12,339) WomenMen 1.01 39 1.25 48 1.44 56 1.69 65 2.09 81 0.80 31 0.97 38 1.11 43 1.27 49 1.60 62
  • 57 HDL, high-density lipoprotein Voight BF, et al. Lancet 2012; 380: 572–80.
  • 58 Of 15 variants that alter HDL-C, 6 also affect MI risk HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; MI, myocardial infarction Voight BF, et al. Lancet 2012; 380: 572–80.
  • 59 Human genetics – LDL vs HDL • LDL is a straightforward target, common and rare genetic variants are associated with CHD in the expected direction • HDL is much more complex, most variants are NOT associated with CHD unless also associated with changes in LDL-C or TGs CHD, coronary heart disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride
  • 60 Disorders with low LDL-C 1. Abetalipoproteinemia (MTP): autosomal recessive; very low total cholesterol, diarrhea, steatorrhea 2. Familial hypobetalipoproteinemia (apoB): autosomal co-dominant; near or total absence of plasma apoB and LDL-C, low VLDL and CM after fatty meal, variable presentation 3. Primary bile acid malabsorption (ileal apical sodium-dependent bile acid transporter): autosomal recessive; low plasma LDL-C, elevated fecal bile acid excretion, diarrhea, steatorrhea 4. PCSK9 deficiency (proprotein convertase subtilisin/kexin type 9): autosomal recessive; very low LDL-C (1st percentile), normal phenotype apoB, apolipoprotein B; CM, chylomicrons; LDL-C, low-density lipoprotein cholesterol; MTP, microsomal triglyceride transfer protein; PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low-density lipoprotein Rahalkar AR, et al. Mol Genet Metab 2008; 93: 282–94.
  • 61 Recent development of lipid-lowering therapies 2000 2002 2004 2006 2008 2010 2012 2013 Ezetimibe approved in the EU2 and USA3 2002 Colesevelam (a BAS) approved in the US1 2000 Colesevelam approved in the EU4 2004 Publication of Phase I clinical trial data for alirocumab (an anti- PCSK9 mAb)5 Mar 2012 Publication of Phase I clinical trial data for AMG 145 (an anti-PCSK9 mAb)7 Nov 2012 Lomitapide (a MTP inhibitor) approved in the USA8 Dec 2012 First publication of Phase III clinical trial data for anacetrapib (a CETP inhibitor)6 Aug 2012 Mipomersen (an antisense oligonucleotide inhibitor of ApoB-100 synthesis) approved in the USA9 Jan 2013 Lomitapide approved in the EU8 Aug 2013 BAS, bile acid sequestrant; 9 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337195.htm; ApoB, apolipoprotein B; CETP, cholesterol ester transfer protein; mAb, monoclonal antibody; MTP, microsomal triglyceride transfer protein; PCSK9, proprotein convertase subtilisin/kexin type 9 1 Sonnett TE, et al. Clin Ther 2009; 31: 245–59; 2 UK Medicines Information Monograph 3/02/07: ezetimibe; 4 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000512/WC500025675.pdf; 5 Stein EA, et al. N Engl J Med 2012; 366: 1108–18; 6 Gotto AM & Moon JE. Expert Rev Cardiovasc Ther 2012; 10: 955–63; 7 Dias CS, et al. J Am Coll Cardiol 2012; 60: 1888–98; 8 http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5374; Mutations inMutations in PCSK9PCSK9 gene cause ADHgene cause ADH1111 20032003 Mutations inMutations in PCSK9PCSK9 gene cause ADHgene cause ADH1111 20032003 11 Abifadel M, et al. Nat Genet 2003; 34: 154–6. Polymorphism atPolymorphism at CETPCETP locuslocus associated withassociated with HDL-C and ApoBHDL-C and ApoB levelslevels1010 19891989 Polymorphism atPolymorphism at CETPCETP locuslocus associated withassociated with HDL-C and ApoBHDL-C and ApoB levelslevels1010 19891989 10 Kondo I, et al. Clin Genet 1989; 35: 49–56; ADH, autosomal dominant hypercholesterolemia; 3 Drugs@ FDA: ezetimibe;
  • 62 Conclusions: 21st century drug development • Better target identification – Multiple targets recently identified from common and rare disease variants in humans • Speed of drug development greatly enhanced by advances in biotechnology – mAbs – Antisense technology and siRNA – More rapid small-molecule therapeutic screens mAb, monoclonal antibody; siRNA, small interfering RNA
  • How do we move forwards?How do we move forwards? 1.1. Select patients for clinical trials who haveSelect patients for clinical trials who have highhigh modifiablemodifiable risk related to the mechanism ofrisk related to the mechanism of action of the drug, not just high risk. Example ofaction of the drug, not just high risk. Example of HPS II Thrive versus PCSK9 trialsHPS II Thrive versus PCSK9 trials 2.2. Use of bimarkers, genetics, metabolomics andUse of bimarkers, genetics, metabolomics and imaging to help identify patients with modifiableimaging to help identify patients with modifiable risk and the therapies which may benefit suchrisk and the therapies which may benefit such patientspatients
  • How do we move forwards?How do we move forwards? 1.1. New methods of testing approaches such asNew methods of testing approaches such as treat to target versus high efficacy statin, ietreat to target versus high efficacy statin, ie comparative effectives trials done in the realcomparative effectives trials done in the real world setting using large health care networksworld setting using large health care networks