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Cardiovascular risk management: What are the strategic changes ?

Cardiovascular risk management: What are the strategic changes ?. Prof. John Deanfield University College London London, United Kingdom. Death Rates from All Circulatory Disease in England 1993-2011. 180. A fall of 55% since baseline. 160. 140. Target: 40% minimum reduction from

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Cardiovascular risk management: What are the strategic changes ?

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  1. Cardiovascular risk management: What are the strategicchanges? Prof. John Deanfield University College London London, United Kingdom

  2. Death Rates from All Circulatory Disease in England 1993-2011 180 A fall of 55% since baseline 160 140 Target: 40% minimum reduction from 1995-97 120 100 Death / 100,000 population 80 60 40 Immortality Guaranteed by 2026 20 0 1995/7 2003/5 2005/7 2001/3 1993/5 1997/9 2007/9 2009/11 2009/11 1999/2001 Progress target B/L Source: ONS (ICD9 390-459; ICD10 I00-I99)

  3. Treatment of CVD: Residual Risk 100 Statins 40% % CV events Residual Risk 60% 0

  4. CHD Impact of Early vs Late LDL Lowering Mendelian Randomisation Studies of 9 Polymorphisms in 6 Genes Ference J Am Coll Cardiol 2012; 60: 2631–9

  5. Lifetime Risk of Death from CV Disease BerryNEJM 2012; 366: 321-329

  6. Early intervention pays long term dividends

  7. A reasonable next step for ATP IV? ….Consider statins for younger persons, perhaps starting at 30 in those with risk factors that convey high lifetime risk (as opposed to 10 yr risk) for CHD Pletcher JACC 2010; 56: 637-640

  8. Benefits of further lowering of causal factors?

  9. LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9142X or PCSK9679X Allele No Nonsense Mutation (n=3278) 12 50th Percentile 30 P=0.008 20 88% 8 10 Frequency (%) Coronary Heart Disease (%) 0 0 100 200 250 50 150 300 PCSK9142X or PCSK9679X (N=85) 4 28% 30 20 0 No Yes 10 PCSK9142X or PCSK9679X 0 0 100 200 50 150 300 250 Cohen NEJM 2006; 354:1264-72 LDL Cholesterol in Black Subjects (mg/dl)

  10. PCSK9 Monoclonal AB in heFH Patients TC Non-HDL-C ApoB Lp(a) 0 -10 -20 % Change in LDL-C from Baseline -30 -40 -50 -60 Stein Lancet 2012; 380: 29-36

  11. Life Course Blood Pressure and Mortality Harvard Alumni Health Study 10 8 Survival from CVD 6 4 Pre-hypertension Stage 2 hypertension Normal Stage 1 hypertension 2 80 60 40 20 Follow up time (years) Gray JACC 2011; 58: 2396-403

  12. BP Treatment in Type 2 DM 4733 age 62.2 years intensive vs standard BP treatment over 4.7 years ACCORD Study Group NEJM 2010;362:1575-1585

  13. Lifetime Risk from Blood Pressure: NICE Short-term (10-year) riskunderestimates lifetime CV risk of young people with hypertension... Lifetime risk with untreated stage 1 hypertension in this age group could be substantial. Lifetime risk assessments may be a better way to inform treatment decisions and evaluate cost effectiveness of earlier drug therapy.

  14. Evidence for residual risk from other risk factors and pathways Need Treatments for New Targets

  15. Coronary Heart Disease and HDL-C 3.5 3.0 2.5 N = 302,430 Hazard Ratio 2.0 1.5 1.0 0.8 30 40 50 60 70 80 HDL-C (mg/dL) The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000

  16. Dalcetrapib in Patients With Recent ACS Schwartz NEJM 2012; 367: 2089-2099

  17. Failure of molecule -Toxicity • -Potency • Failure of biology • -HDL not on causal pathway • -Wrong pathway for drug • -HDL properties may change • -Wrong stage of disease HDL Trials:Reasons for Failure

  18. HDL : Effects on endothelial NO production in patients with CAD Healthy sCAD P<0.025 30 ACS 20 Endothelial NO production [in % of buffer-treated cells] 10 0 -10 -20 25 mg/ml HDL 50 mg/ml HDL 100 mg/ml HDL Besler C et al. & Landmesser U. J Clin Invest (in press)

  19. DALCETRAPIB 25 dalcetrapib treated 25 placebo-treated Dalcetrapib HDL Function Study PLACEBO 12 wks 36 wks Baseline Serum collection HDL isolation density ultracentrifugation Endothelial Nitric Oxide production ESR spectroscopy Endothelial anti-apoptotic capacity Inhibition of caspase-3 expression Endothelial anti-inflammatory capacity Inhibition of VCAM-1 expression

  20. Dalcetrapib and HDL Function Placebo Dalcetrapib Effect of HDL on NO production Anti-apoptotic capacity of HDL Anti-inflammatory capacity of HDL

  21. Late-stage Drug Development Failure A major productivity limiting barrier Late-stage failure In vitro & in vivo experiments Hunan observational studies Phase I Target identification Molecule development Phase II Phase III Approval Clinical studies Pre-clinical development Cost $4-11B Time Kola & Landis, Nat Rev Drug Disc. 2004 Arrowsmith, Nat Rev Drug Disc, 2011 Bunnage, Nature Chemical Biology, 2011 Arrowsmith, Nature Reviews Drug Disc, 2011 ~12yrs

  22. In Search of Fewer independent Risk Factors Brotman Arch Intern Med. 2005; 165: 138-145

  23. New approaches to refine target validation, safety and efficacy

  24. RCT as an arbiter of molecule efficacy and safety, and target validity Drug intervention Genetics: natural randomisation RCT (Phase III) Mendelian randomisation Sample Population Randomisation Random allocation of alleles Protein target: HMGCR Protein target: HMGCR Placebo HMGCR aa Genotype AA HMG-CoA red inhibitor LDL-C reduced LDL-C unchanged LDL-C unchanged LDL-C reduced HMGCR variant (rs12916) reduce LDL-C by -0.07 mmol/L, and risk of CHD (OR of 0.94; 95%CI: 0.90, 0.98). JACC 2013 CV event rate lower Off target CV event rate higher CV event rate lower CV event rate higher

  25. Finding new indications for existing medications Genetics: natural randomisation Drug intervention (IL6R blocker licensed for Rheumatoid arthritis) Population Sample Random allocation of IL6R alleles Randomisation (Tocilizumab) Protein target: IL6R Protein target: IL6R IL6R aa IL6R AA IL6R- blocker (MAB) Placebo Reduced IL6 signalling IL6 signalling unchanged Reduce IL6 signalling IL6 signalling unchanged RA disease activity higher CV event rate higher RA disease Activity lower CV event rate lower

  26. Finding new indications for existing medications Drug intervention (IL6R blocker licensed for Rheumatoid arthritis) Genetics: natural randomisation Swerdlow, Lancet 2012 Sample Randomisation (Tocilizumab) Protein target: IL6R IL6R- blocker (MAB) Placebo Reduce IL6 signalling IL6 signalling unchanged RA disease activity higher RA disease Activity lower

  27. Harmful effects of first-in-man drugs: On- vs Off-target effects CETP genetic variant recapitulates the effects of pharmacological CETP inhibition on blood lipids, but does not share the BP raising effect of torcetrapib Sample Drug Randomisation CETP genotypes Individuals (studies) Systolic BP Mean Difference (95% CI) B1B2 v B1B1 46,412 (21) -0.27 (-0.64, 0.10) Torcetrapib Control 29,050 (21) B2B2 v B1B1 0.16 (-0.28, 0.60) -2 0 mmHg CETP-inhibition No-CETP inhibition Change in lipid traits No change in lipids BP (Off-target) TRG HDL LDL

  28. CV Risk Management: What is Needed? • Opportunities from novel therapies to reduce residual CV risk • Optimal approach will involve lifetime management of RFs • Better strategies to refine priorotization of new drug targets needed

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