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E. Magnus Ohman, MD ...

E. Magnus Ohman, MD

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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  • 92% of patients with angina were taking ≥1 antianginal medications <br />
  • The evidence for residual cardiovascular risk has been well documented. Sachdeva et al published a landmark analysis from AHA’s Get with The Guidelines CAD Program and database that documented that over 50% of CAD patients hospitalized for acute coronary events had LDL-C &lt; 100 mg/dL, and close to 20% had LDL-C &lt; 70 mg/dL. For patients without a history of heart disease, 72.1% had LDL-C &lt; 130 mg/dL and over 40% had LDL-C &lt; 100 mg/dL. This adds further support to the concept that there is an opportunity to better manage these “at-risk” patients <br />
  • ?? Make the final line ‘Thus, less expert …” and make it a subheading of the previous (‘Develop rec…’) rather than giving it the same priority <br />
  • 2nd bullet: add words: ‘…(IE) criteria for published clinical trial reports for each CQ’ <br />
  • The initial analysis between LDL-C levels and CHD event rates in the major clinical trials seemed to suggest a linear relationship between cholesterol and coronary events. The AVERT trial, however, brings this direct association into question. In this trial, atorvastatin 80 mg reduced LDL-C levels by 46% to a mean LDL-C of 77 mg/dL. Despite this aggressive lipid-lowering in AVERT, the treatment coronary event rate was 13.4%. This rate is greater than that of CARE in which LDL-C was lowered to 98 mg/dL and LIPID in which LDL-C was lowered 25% more than placebo. Therefore, extremely low LDL-C levels may not produce greater clinical benefit. <br />
  • Place question mark at end of ‘intolerance to recommended dose of statin therapy’ in gray diamond text box on right <br />

The New Cholesterol Guidelines Presentation Transcript

  • 1. E. Magnus Ohman, MB, FRCPI, FESC, FACC Professor of Cardiovascular Medicine The Kent and Siri Rawson Director, Program for Advanced Coronary Disease Associate Director, Duke Heart Center Duke University Medical Center Duke Clinical Research Institute Durham, North Carolina The New Cholesterol Guidelines
  • 2. Personal disclosures:Personal disclosures: Research grantsResearch grants Eli Lilly, Daiichi-Sankyo, Gilead Sciences.Eli Lilly, Daiichi-Sankyo, Gilead Sciences. ConsultantConsultant AstraZeneca, Abiomed, Gilead Sciences, JanssenAstraZeneca, Abiomed, Gilead Sciences, Janssen Pharmaceutical, The Medicines Company, Merck,Pharmaceutical, The Medicines Company, Merck, Liposcience, Pozen Medical, WebMD, and BoerhingerLiposcience, Pozen Medical, WebMD, and Boerhinger IngelheimIngelheim Institutional disclosure for DCRI at www.dcri.duke.edu/research/coi.jspInstitutional disclosure for DCRI at www.dcri.duke.edu/research/coi.jsp The New Cholesterol Guidelines
  • 3.  A 63 year old Professor of Psychology concernedA 63 year old Professor of Psychology concerned about statinsabout statins  Prior history of Atrial Fibrillation (Chicago, IL)Prior history of Atrial Fibrillation (Chicago, IL)  Diagnosed in 1998Diagnosed in 1998  Normal stress echo in 2005Normal stress echo in 2005  A Fib ablation in 7/2008, A Flutter ablation inA Fib ablation in 7/2008, A Flutter ablation in 10/200810/2008  Repeat stress echo normal in 2012Repeat stress echo normal in 2012  Hyperlipidemia diagnosed in 2010Hyperlipidemia diagnosed in 2010 A Patient Coming for Second Opinion Regarding Primary Prevention
  • 4.  A 63 year old Professor of Psychology concernedA 63 year old Professor of Psychology concerned about statinsabout statins  Hyperlipidemia diagnosed in 2010Hyperlipidemia diagnosed in 2010  No family history of CADNo family history of CAD  No prior history of CAD, CVD or PVDNo prior history of CAD, CVD or PVD  Non-smokerNon-smoker  BMI 25.2BMI 25.2  Normal BPNormal BP A Patient Coming for Second Opinion Regarding Primary Prevention
  • 5.  A 63 year old Professor of Psychology concernedA 63 year old Professor of Psychology concerned about statinsabout statins  Hyperlipidemia diagnosed in 2010Hyperlipidemia diagnosed in 2010  2012: TC 211, TG 155, HDL 40, LDL 1402012: TC 211, TG 155, HDL 40, LDL 140  Recommended diet + statin (refused Rx)Recommended diet + statin (refused Rx)  2013: TC 208, TG 154, HDL 45, 132 (diet alone)2013: TC 208, TG 154, HDL 45, 132 (diet alone) A Patient Coming for Second Opinion Regarding Primary Prevention Should he be treated with a statin ?
  • 6. 2012 - A Year Of Controversy: Statins for All, None, or Some? Blaha MJ, Nasir K, Blumenthal RS. JAMA 2012;307:1489–90. Redberg RF, Katz MH. JAMA 2012;307:1491–2. June 2012: JAMA
  • 7. 2013 - Another Year Of Controversy ?
  • 8.  A brief update on guideline methodologyA brief update on guideline methodology  The Institute of Medicine reportThe Institute of Medicine report  The new methodology for guidelinesThe new methodology for guidelines  Investigation on residual riskInvestigation on residual risk  Key concepts in the new preventionKey concepts in the new prevention guidelinesguidelines The New Cholesterol Guidelines
  • 9. Tricoci P et al. JAMA 2009 Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Level of Evidence A 4.9 4.9 19 11 9.7 0.3 (1/320) 23.6 6.1 6.4 22.9 12 13.5 15.3 26.4 11.7 0 10 20 30 Radionuclide imaging Pacemaker CABG PCI VA/SCD Valvular disease UA/NSTEMI SV arrhythmia Stable angina Secondary prevention Perioperative STEMI PAD Heart failure AF
  • 10. 26.3 58.2 20 47.8 58.5 70.6 29.6 56.5 54.5 8.3 32 47.2 25.1 54.3 58.6 0 10 20 30 40 50 60 70 80 Radionuclide imaging Pacemaker CABG PCI VA/SCD Valvular disease UA/NSTEMI SV arrhythmia Stable angina Secondary prevention Perioperative STEMI PAD Heart failure AF Tricoci P et al. JAMA 2009 Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Level of Evidence C
  • 11. Jacobs, et al, JACC 2013
  • 12. Frequency of Applying Guidelines For Managing Patients Q2. How frequently do you apply clinical practice guidelines in managing patients? (n=203) but do not use them • More than 8 out of 10 cardiologists (83%) apply clinical practice guidelines for managing patients in most or every case.
  • 13. Q3. Which of the following guidelines/publications do you find most useful in clinical practice? Select all that apply. (n=203) Most Useful Guidelines/Publications In Clinical Practice Research & Quality evidence reports for Clinical Health & Excellence Task Force (USPTF) Guidelines society guidelines Practice Guidelines CardioSurve 47% AHA, et al. 68% • When compared against the major guidelines/publications, the ACCF/AHA Guidelines were found to be the most useful to cardiologists in clinical practice.
  • 14. Q9. Which of the following views on guidelines most closely mirrors your opinions? (n=92) Level of Evidence C and Guidelines • More than 2 out of 3 cardiologists (71%) believe that guidelines should provide broad insight, including both strong evidence and consensus of expert opinion in an integrated, topic-specific document. Total (n=92) Total Dr. J (Limit on Level of Evidence C) 24% - Much more like Dr. J 16% - Somewhat more like Dr. J 8% Neither 4% Total Dr. K (Broad Insight) 71% - Much more like Dr. K 36% - Somewhat more like Dr. K 35% Do not know 1% Dr. J: Thinks that guidelines are too long and should focus on evidence-based recommendations, limiting those based on level of evidence C (consensus) or moving them to a separate section or document. Dr. K: Thinks that guidelines should provide broad insight, including both strong evidence and consensus of expert opinion in an integrated, topic-specific document.
  • 15. Q9. Which of the following views on guidelines most closely mirrors your opinions? (n=103) Class IIb and Guidelines • The majority of cardiologists (66%) think that guidelines should provide broad insight, including relatively weak recommendations addressing measures with less benefit or harm that might be applicable in special situations. Total (n=103) Total Dr. Q (Eliminate Class IIb recommendations ) 30% - Much more like Dr. Q 18% - Somewhat more like Dr. Q 12% Neither 3% Total Dr. R (Broad insight) 66% - Much more like Dr. R 39% - Somewhat more like Dr. R 27% Do not know 1% Dr. Q: Thinks that guidelines should provide guidance to clinicians only when there is evidence that a test or treatment has clear benefit or harm and should eliminate Class IIb recommendations. Dr. Q thinks that weak recommendations based on opinion should be separated from guidelines and expressed in other formats. Dr. R: Thinks that guidelines should provide broad insight, including relatively weak recommendations addressing measures with less benefit or harm that might be applicable in special situations.
  • 16. Q9. Which of the following views on guidelines most closely mirrors your opinions? (n=108) Incorporating Costs and Guidelines • Nearly 3 out 4 cardiologists (74%) believe that physicians have a responsibility to help society provide optimal care for all patients and guidelines should incorporate available information about cost/resource utilization to educate providers, payers, and patients about the value of various strategies. Total (n=108) Total Dr. X (Not incorporate costs) 20% - Much more like Dr. X 7% - Somewhat more like Dr. X 13% Neither 4% Total Dr. Y (Incorporate costs) 74% - Much more like Dr. Y 39% - Somewhat more like Dr. Y 35% Do not know 2% Dr. X: Believes that physicians should focus on the interests of individual patients under their care without regard to the availability or distribution of finite resources and that cost/resource use and value considerations should not guide recommendations. Dr. Y: Believes that physicians have a responsibility to help society provide optimal care for all patients and guidelines should incorporate available information about cost/ resource utilization to educate providers, payers, and patients about the value of various strategies.
  • 17.  A brief update on guideline methodologyA brief update on guideline methodology  The Institute of Medicine reportThe Institute of Medicine report  The new methodology for guidelinesThe new methodology for guidelines  Investigation on residual riskInvestigation on residual risk  Key concepts in the new preventionKey concepts in the new prevention guidelinesguidelines The New Cholesterol Guidelines
  • 18. CVD mortality rates declining 7.0 4.7 3.4 18.2 13.0 11.1 0 5 10 15 20 1971-1986 1976-1992 1988-2000 Cohort follow-up period Annual deaths (per 1000) No diabetes Diabetes Gregg EW et Al. Ann Intern Med. 2007;147. N = 26,057 NHANES participants National Health and Nutrition Examination Surveys
  • 19. Evidence of Residual CVD Risk • 136,905 hospitalizations for (non-CHF) CAD and lipids w/in 24 hrs of admit (at 541 hospitals) • Over 50% of patients with LDL-C <100 mg/dL and 17.6% with LDL-C <70 mg/dL • For patients without h/o CAD, 72.1% with LDL-C <130 mg/dL and 41.5% with LDL-C <100 mg/dL Sachdeva A, et al. Am Heart J 2009; 157:111-7.e2. From AHA’s Get with The Guidelines (GWTG) CAD Program and database; 2000-2006.
  • 20.  A brief update on guideline methodologyA brief update on guideline methodology  The Institute of Medicine reportThe Institute of Medicine report  The new methodology for guidelinesThe new methodology for guidelines  Investigation on residual riskInvestigation on residual risk  Key concepts in the new preventionKey concepts in the new prevention guidelinesguidelines The New Cholesterol Guidelines
  • 21. *Ex-Officio Members. ACC/AHA Blood Cholesterol Guideline Panel Members Neil J. Stone, MD, MACP, FAHA, FACC, Chair Jennifer G. Robinson, MD, MPH, FAHA, Vice Chair Alice H. Lichtenstein, DSc, FAHA, Vice Chair Anne C. Goldberg, MD, FACP, FAHA Conrad B. Blum, MD, FAHA Robert H. Eckel, MD, FAHA, FACC Daniel Levy, MD* David Gordon, MD* C. Noel Bairey Merz, MD, FAHA, FACC Donald M. Lloyd-Jones, MD, ScM, FACC, FAHA J. Sanford Schwartz, MD Patrick McBride, MD, MPH, FAHA Sidney C. Smith, Jr, MD, FACC, FAHA Karol Watson, MD, PhD, FACC, FAHA Susan T. Shero, MS, RN* Peter W.F. Wilson, MD, FAHA Acknowledgements Methodology Members Karen M. Eddleman, BS Nicole M. Jarrett Ken LaBresh, MD Lev Nevo, MD Janusz Wnek, PhD National Heart, Lung, and Blood Institute Glen Bennett, M.P.H. Denise Simons-Morton, MD, PhD
  • 22. NHLBI Charge to the Expert Panel Evaluate higher quality randomized controlled trial (RCT) evidence for cholesterol-lowering drug therapy to reduce ASCVD risk  Use Critical Questions (CQs) to create the evidence search from which the guideline is developed • Cholesterol Panel: 3 CQs • Risk Assessment Work Group: 2 CQs • Lifestyle Management Work Group: 3 CQs  RCTs and systematic reviews/meta-analyses of RCTs independently assessed as fair-to-good quality  Develop recommendations based on RCT evidence •Less expert opinion than in prior guidelines
  • 23. Systematic Review Process • The Expert Panel constructed CQs relevant to clinical practice. • The Expert Panel identified (a priori) inclusion/exclusion (I/E) criteria for each CQ. • An independent contractor developed a literature search strategy, based on I/E criteria, for published clinical trial reports for each CQ. • An independent contractor executed a systematic electronic search of the published literature from relevant bibliographic databases for each CQ. • The date for the overall literature search was from January 1, 1995 through December 1, 2009. • However, RCTs with the ASCVD outcomes of MI, stroke, and cardiovascular death published after that date were eligible for consideration until July 2013.
  • 24. NHLBI Grading the Strength of Recommendation Grade Strength of Recommendation* A Strong recommendation: There is high certainty based on evidence that the net benefit is substantial. B Moderate recommendation: There is moderate certainty based on evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate. C Weak recommendation: There is at least moderate certainty based on evidence that there is a small net benefit. D Recommendation against: There is at least moderate certainty based on evidence that it has no net benefit or that risks/harms outweigh benefits. E Expert opinion (“There is insufficient evidence or evidence is unclear or conflicting, but this is what the Panel recommends.”) Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the Panel thought it was important to provide clinical guidance and make a recommendation. Further research is recommended in this area. N No recommendation for or against (“There is insufficient evidence or evidence is unclear or conflicting.”) Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, and the Panel thought no recommendation should be made. Further research is recommended in this area.
  • 25. Type of Evidence Quality Rating* • Well-designed, well-executed† RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomes. • MAs of such studies. Highly certain about the estimate of effect. Further research is unlikely to change the Panel’s confidence in the estimate of effect. High • RCTs with minor limitations‡ affecting confidence in, or applicability of, the results. • Well-designed, well-executed nonrandomized controlled studies§ and well-designed, well-executed observational studies║. • Meta-analyses of such studies. Moderately certain about the estimate of effect. Further research may have an impact on the Panel’s confidence in the estimate of effect and may change the estimate. Moderate • RCTs with major limitations. • Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results. • Uncontrolled clinical observations without an appropriate comparison group (e.g., case series, case reports). • Physiological studies in humans. • Meta-analyses of such studies. Low certainty about the estimate of effect. Further research is likely to have an impact on the Panel’s confidence in the estimate of effect and is likely to change the estimate. Low Quality Rating the Strength of Evidence
  • 26. Evidence based medicine rating scale Class 0: things I believe Class 0a: things I believe despite the available data Class 1: randomized, controlled clinical trials (RCCTs) that agree with what I believe Class 2: other prospectively collected data Class 3: expert opinion Class 4: RCCTs that don't agree with what I believe Class 5: what you believe that I don't
  • 27. Guideline Scope • Focus on treatment of blood cholesterol to reduce ASCVD risk in adults • Emphasize adherence to a heart healthy lifestyle  See Lifestyle Management Guideline • Identify individuals most likely to benefit from cholesterol-lowering therapy  4 statin benefit groups • Identify safety issues
  • 28. CTT Lancet 2010;376:1670-81 Statins Across LDL Levels: 2010 CTT No evidence of effect modification!
  • 29. CTT Lancet 2012 Statin Therapy in Low-Risk Patients
  • 30. CTT Lancet 2012 Statin Therapy in Low-Risk Patients No effect on cancer incidence or cancer mortality
  • 31. Statin Benefit Groups • Clinical ASCVD • LDL–C >190 mg/dL without secondary cause • Primary prevention/Diabetes: Age 40-75 years, LDL–C 70- 189 mg/dL • Primary prevention/No Diabetes: Age 40-75 years, LDL–C 70-189 mg/dL, ASCVD risk ≥7.5%* *Requires risk discussion with clinician before statin prescription. Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator.
  • 32. Individuals Not in a Statin Benefit Group  In those not clearly in a statin benefit group, additional factors may inform treatment decision- making: • Family history of premature ASCVD • Elevated lifetime risk of ASCVD • LDL–C ≥160 mg/dL • hs-CRP ≥2.0 mg/L • Subclinical atherosclerosis  CAC score ≥300 or ABI<0.9  Discussion of potential for ASCVD risk reduction benefit, potential for adverse effects, drug-drug interactions, and patient preferences
  • 33. New Perspective on LDL–C & Non-HDL–C Goals • Lack of RCT evidence to support titration of drug therapy to specific LDL–C and/or non-HDL–C goals • Strong evidence that appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit • Quantitative comparison of statin benefits with statin risk • Nonstatin therapies – did not provide ASCVD risk reduction benefits or safety profiles comparable to statin therapy
  • 34. 210 Correlation Between CHD Events and LDL-C Levels Opie et al.,Lancet 2006; 367: 69–78
  • 35. 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
  • 36. 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.
  • 37. 4 Statin Benefit Groups IA IA IB IA IIaB
  • 38. 4 Statin Benefit Groups (con’t) *10-year ASCVD Risk Calculator online IA IA
  • 39. Primary Prevention Global Risk Assessment • To estimate 10-year ASCVD risk  New Pooled Cohort Risk Equations  White and black men and women • More accurately identifies higher risk individuals for statin therapy  Focuses statin therapy on those most likely to benefit  You may wish to avoid initiating statin therapy in high- risk groups found not to benefit (higher grades of heart failure and hemodialysis)
  • 40. Safety • RCTs & meta-analyses of RCTs used to identify important safety considerations • Allow estimation of net benefit from statin therapy o ASCVD risk reduction versus adverse effects • Expert guidance on management of statin-associated adverse effects, including muscle symptoms • Advise use of additional information including pharmacists, manufacturers prescribing information, & drug information centers for complex cases
  • 41. Clinical ASCVD Initiating Statin therapy
  • 42. Statin-Treated Individuals Nonstatin Therapy Considerations
  • 43. Statin Therapy: Monitoring Response and Adherence
  • 44. ‡In those already on a statin, in whom baseline LDL–C is unknown, an LDL–C <100 mg/dL was observed in most individuals receiving high-intensity statin therapy in RCTs.
  • 45.  A 63 year old Professor of Psychology concernedA 63 year old Professor of Psychology concerned about statinsabout statins  Hyperlipidemia diagnosed in 2010Hyperlipidemia diagnosed in 2010  2012: TC 211, TG 155, HDL 40, LDL 1402012: TC 211, TG 155, HDL 40, LDL 140  Recommended diet + statin (refused Rx)Recommended diet + statin (refused Rx)  2013: TC 208, TG 154, HDL 45, 132 (diet alone)2013: TC 208, TG 154, HDL 45, 132 (diet alone) A Patient Coming for Second Opinion Regarding Primary Prevention Should he be treated with a statin ?
  • 46.  A 63 year old Professor of Psychology concernedA 63 year old Professor of Psychology concerned about statinsabout statins  Hyperlipidemia diagnosed in 2010Hyperlipidemia diagnosed in 2010  2012: TC 211, TG 155, HDL 40, LDL 1402012: TC 211, TG 155, HDL 40, LDL 140  Recommended diet + statin (refused Rx)Recommended diet + statin (refused Rx)  2013: TC 208, TG 154, HDL 45, 132 (diet alone)2013: TC 208, TG 154, HDL 45, 132 (diet alone) A Patient Coming for Second Opinion Regarding Primary Prevention Framingham Risk Score (10-year CHD risk): 10% (12 points)
  • 47.  A 63 year old Professor of Psychology concernedA 63 year old Professor of Psychology concerned about statinsabout statins  Hyperlipidemia diagnosed in 2010Hyperlipidemia diagnosed in 2010  2012: TC 211, TG 155, HDL 40, LDL 1402012: TC 211, TG 155, HDL 40, LDL 140  Recommended diet + statin (refused Rx)Recommended diet + statin (refused Rx)  2013: TC 208, TG 154, HDL 45, 132 (diet alone)2013: TC 208, TG 154, HDL 45, 132 (diet alone) A Patient Coming for Second Opinion Regarding Primary Prevention Lipid Sub-fraction Analysis: LDL-Particle # 1815 (high risk) Small LDL-P # 793 (75th % risk) LDL size 20.9 (large)
  • 48.  The cholesterol guidelines is using a newThe cholesterol guidelines is using a new methodology not previously used by themethodology not previously used by the ACC/AHAACC/AHA  More like evidence reviewMore like evidence review  Limited recommendation outsideLimited recommendation outside clinical trialsclinical trials  For secondary prevention the approachFor secondary prevention the approach is greatly simplifiedis greatly simplified  Most of the controversy has been in theMost of the controversy has been in the area of primary preventionarea of primary prevention The New Cholesterol Guidelines