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Primary Prevention: Progress but a long way to go

Primary Prevention: Progress but a long way to go . Lawrence J. Fine, MD, DrPH , FAHA Division of Cardiovascular Sciences NHLBI/NIH November 16, 2013 Disclosures: None SHAPE Symposium. When I was a glimmer in my parent’s eye the March of Dimes had a mission to eradicate polio .

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Primary Prevention: Progress but a long way to go

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  1. Primary Prevention: Progress but a long way to go Lawrence J. Fine, MD, DrPH, FAHA Division of Cardiovascular Sciences NHLBI/NIH November 16, 2013 Disclosures: None SHAPE Symposium

  2. When I was a glimmer in my parent’s eye the March of Dimes had a mission to eradicate polio

  3. When I was a child …. March of Dimes had to change

  4. Declining Annual Change First MI or Death Due CHD (ARIC study – adjusted for changes in biomarkers) Rosamond Circ 2012

  5. Trends in LDL in Men and Women 1988-2010

  6. Better Control of Risk Factors and Treatment of MI 10 mm Delta No Change 1988 to 1999

  7. Avoidable Deaths from Heart Dsease, Stroke, and Hypertensive Disease – United States, 2001 -2010 MMWR September 6, 2013 Deaths due to lack of preventive health care or timely and effective medical care can be considered avoidable Look at CVD mortality for those < 75 years old Nearly one fourth of all CVD death avoidable 56% of the avoidable deaths in those < 65 ( important target for primary prevention )

  8. Number of Avoidable Deaths from CVD deaths – United States, 2001 -2010 MMWR 9/6/2013 Schieb L et al.

  9. Rates of Avoidable Deaths Data Illustrates Murray’s Eight Americas: new perspectives on U.S. health disparities. Asian men 47

  10. Eight Americas: new perspectives on U.S. health disparities. Murray CJ, et al. 2005 AJP The Eight Americas Study divides the U.S. population into eight distinct groups with different mortality experience. Life expectancy for males is 8 is 21 years lower than life expectancy for females. To tackle disparities in the United States, public health will need to increase its focus on chronic diseases in young and middle-aged Americans. In particular, if blood pressure and cholesterol are confirmed as major contributors to current mortality patterns, innovative strategies …unique individual and population approaches need to be explored.

  11. Individuals Genes, Cells, Organs Influences on Health Physical and Socio-political Environment Communities Organizations Family Adapted from: The future of the public’s health in the 21st century. Institute Of Medicine, 2002, and other sources.

  12. “Getting warm …. warmer.”

  13. Challenges of Many Research Opportunities and Few Dollars Gaps in our knowledge are increasing being recognized coupled with calls for higher quality studies for decision making In addition, RCT’s which involve primary prevention of CVD are increasing challenging because of falling event rates

  14. Recommended SBP Goals in 2013 ESH/ESC HTN Guidelines < 80 yrs

  15. Research Needs 2013 ACC/AHA Cholesterol Guideline Outcomes of RCT’s to evaluate statins for primary prevention in adults over 75 RCTs to evaluate alternate treatment strategies for CVD risk reduction such as titration to specific goals vs. fixed dose in high risk patients.

  16. What the possible solutions to this dilemma ? • ? More funds • Disruptive technologies • Big data and better studies of observational data sets • More efficient trials where possible.

  17. International Symbol for Don’t Rock the Boat

  18. Original ArticleComparative Effectiveness of Revascularization Strategies William S. Weintraub, M.D., Maria V. Grau-Sepulveda, M.D., M.P.H., Jocelyn M. Weiss, Ph.D., M.P.H., Sean M. O'Brien, Ph.D., Eric D. Peterson, M.D., M.P.H., Paul Kolm, Ph.D., Zugui Zhang, Ph.D., Lloyd W. Klein, M.D., Richard E. Shaw, Ph.D., Charles McKay, M.D., Laura L. Ritzenthaler, M.B.A., Jeffrey J. Popma, M.D., John C. Messenger, M.D., David M. Shahian, M.D., Frederick L. Grover, M.D., John E. Mayer, M.D., Cynthia M. Shewan, Ph.D., Kirk N. Garratt, M.D., Issam D. Moussa, M.D., George D. Dangas, M.D., and Fred H. Edwards, M.D. N Engl J Med Volume 366(16):1467-1476 April 19, 2012

  19. Study Overview • A large PCI registry and a large CABG registry were linked to claims records, with data adjusted for propensity score, to compare clinical outcomes. • Patients selected for CABG had a long-term survival advantage over those selected for PCI.

  20. Propensity Scores for Coronary Artery Bypass Grafting (CABG) in the Percutaneous Coronary Intervention (PCI) and CABG Populations. Weintraub WS et al. N Engl J Med 2012;366:1467-1476

  21. Rates of Survival in the CABG and PCI Populations, from an Analysis Adjusted with the Use of Inverse Probability Weighting. RR for CABG vs. PCI at 2yrs = .79 ( 0.76-.82) Weintraub WS et al. N Engl J Med 2012;366:1467-1476

  22. Another Disruptive Technology The Randomized Registry Trial —(Lauer and D’Agostino NEJM 2013) With the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial... The investigators designed a large-scale trial to answer an important clinical question and carried it out at remarkably low cost by building on the platform of an already-existing high-quality observational registry

  23. Lauer et al With this clever design, which leveraged clinical information that was already being gathered for the registry and for other preexisting databases, the investigators were.., to enroll thousands of patients in little time, .., to obtain accurate follow-up with minimal effort, and to report their findings, all for less than the amount of a typical modular R01 grant

  24. Original ArticleThrombus Aspiration during ST-Segment Elevation Myocardial Infarction Ole Fröbert, M.D., Ph.D., Bo Lagerqvist, M.D., Ph.D., Göran K. Olivecrona, M.D., Ph.D., Elmir Omerovic, M.D., Ph.D., Thorarinn Gudnason, M.D., Ph.D., Michael Maeng, M.D., Ph.D., Mikael Aasa, M.D., Ph.D., Oskar Angerås, M.D., Fredrik Calais, M.D., Mikael Danielewicz, M.D., David Erlinge, M.D., Ph.D., Lars Hellsten, M.D., Ulf Jensen, M.D., Ph.D., Agneta C. Johansson, M.D., Amra Kåregren, M.D., Johan Nilsson, M.D., Ph.D., Lotta Robertson, M.D., Lennart Sandhall, M.D., Iwar Sjögren, M.D., Ollie Östlund, Ph.D., Jan Harnek, M.D., Ph.D., and Stefan K. James, M.D., Ph.D. N Engl J Med Volume 369(17):1587-1597 October 24, 2013

  25. Study Overview • The infrastructure of an established PCI registry was used to conduct a randomized trial comparing manual thrombus aspiration before PCI with PCI alone in patients with STEMI. • There was no significant difference between the two groups in mortality at 30 days.

  26. Kaplan–Meier Curves for Death from Any Cause and Hospitalization Due to Reinfarction. Fröbert O et al. N Engl J Med 2013;369:1587-1597

  27. End Points According to Randomization Status and Treatment Group. Death rate in trial is 3% vs. 10.5% in those not randomized – even in this setting. Fröbert O et al. N Engl J Med 2013;369:1587-1597

  28. Current Funding Notices: RFA-HL-14-019 (UH2/UH3) & RFA-14-020 (R01): • Low-Cost, Pragmatic, Patient-Centered Randomized Controlled Intervention Trials • Pragmatic RCTs seek to determine the effectiveness of an intervention in a real world setting.  Trials must leverage existing clinical practice settings and/or existing electronic resources such as registries for the conduct of clinical trials.  Trials must include features such as randomization at the point of patient care; data collection integrated into or obtained from routine clinical records or similar existing electronic resources; minimal eligibility criteria, and interventions delivered as part of routine clinical care.

  29. Thank You (Incomplete List) Mike Lauer Joni Snyder Paul Sorlie Authors of articles that I used.

  30. Enrollment, Randomization, and Follow-up. Fröbert O et al. N Engl J Med 2013;369:1587-1597

  31. Hazard Ratios for the Primary End Point in Subgroups of Patients. Fröbert O et al. N Engl J Med 2013;369:1587-1597

  32. Baseline Characteristics of the Patients According to Randomization Status and Treatment Group. Fröbert O et al. N Engl J Med 2013;369:1587-1597

  33. Conclusions • Routine thrombus aspiration before PCI as compared with PCI alone did not reduce 30-day mortality among patients with STEMI.

  34. Kaplan–Meier Estimates of the Incidence of Outcome Events in the Total Study Population. Estruch R et al. N Engl J Med 2013;368:1279-1290

  35. Is SPRINT the last of its kind?

  36. FDA’s Mini-Sentinel Disruptive Technology Curtis L et al. Pharmacoepi Drug Safety. 2012; 21(S1): 21-31

  37. Seminal, High-Impact Findings “Whether or not the correction of these abnormalities once they are discovered will favorably alter the risk of development of disease, while reasonable to contemplate and perhaps attempt, remains to be demonstrated…” Annals Internal Med 1961;55:33-50

  38. Two perspectives When It Comes to Trials, Do We Get What We Pay For? P.J. Devereaux, M.D., Ph.D., and Salim Yusuf, M.B., B.S., D.Phil. The larger (and more expensive) trials evaluating clinical end points provide much more definitive and clinically meaningful assessments of the effect of interventions. Although these findings suggest value for money when it comes to large, more expensive trials that are focused on clinical end points, there is a need to conduct large, definitive trials more efficiently at reduced costs. Simplifying large trials and eliminating the enormous bureaucracy and wasteful regulations that exist would make trials more affordable and would facilitate more rapid evaluation of many additional hypotheses in large and more definitive trials

  39. Increasing External Validity “ Although the best way to control for treatment-selection bias is to conduct a randomized trial, such trials often have limited power to evaluate subgroups and the results may not be generalizable, since patients and centers are often highly selected. Nonrandomized, observational data from clinical databases can complement data from clinical trials, because observational data, if they are from a larger and more representative population, may better reflect real-world practice.” NEJM 2012

  40. Unmeasured confounder could it explain the difference? • As an example of a potential unmeasured confounder, suppose that patient frailty (yes or no) could be assessed in our study. If frailty was waspresent in 10% of the patients in the CABG group (green curved line) but in 35% of patients in the PCI group (x axis), and if frailty increased the risk of death by a factor of slightly more than two (hazard ratio, 2.09), then frailty alone could itself account for the observed difference in mortality between the study groups.. NEJM 2012

  41. Effect of Unmeasured Confounding Factors. Weintraub WS et al. N Engl J Med 2012;366:1467-1476

  42. Another Disruptive Technology The Randomized Registry Trial — The Next Disruptive Technology in Clinical Research? (Lauer and D’Agostino NEJM 2013) What good are trials if, they can be used to answer only a tiny fraction of our important clinical questions? Enter the registry-based randomized trial. With the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial,.., a new paradigm has emerged that can potentially release us from the circular (and expensive) trap of the randomized-versus-registry debate. The TASTE investigators designed a large-scale trial to answer an important clinical question and carried it out at remarkably low cost by building on the platform of an already-existing high-quality observational registry

  43. Lauer et al With this clever design, which leveraged clinical information that was already being gathered for the registry and for other preexisting databases, the investigators were able to quickly identify potential participants, to enroll thousands of patients in little time, .. avoid filling out long case-report forms, to obtain accurate follow-up with minimal effort, and to report their findings, all for less than the amount of a typical modular R01 grant

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