S. HUNT

1. Tenth International Symposium HEART FAILURE & Co. CARDIOLOGY SCIENCE UPDATE FEMALE DOCTORS SPEAKING ON FEMALE DISEASES Milano 9 - 10 aprile 2010 S. HUNT

2. Tenth International SymposiumHEART FAILURE & Co.Milano 9-10 Abrille 2010 Sex Specific Guidelines for Cardiovascular Disease Management: How Close Are We? Sharon A. Hunt, MD Stanford University, California

3. Why create guidelines? Because “Knowledge about HF {and many other conditions} is accumulating so rapidly that individual clinicians may be unable to synthesize new information into effective principles of patient care. Trial data, though valuable, often do not give adequate direction for individual patient management.”* *Adams KF et al HFSA 2006 Guideline Executive Summary

4. …in turn leading to • Over- and under-use of technology and drugs • Wide regional practice variations

5. …further leading, in turn, to A move to create published clinical guidelines over past 10+ years with purpose of (a)codifying and (b)promotingimplementationof evidence-based advances in diagnosis and therapy

6. Basic GL Principles Include… • GL’s should be evidence based • GL’s should be consistent with other GL’s (ACC/AHA, ESC, others) • GL’s focus on information already published in peer-reviewed literature

7. Guidelines should in theory also… Acknowledge specific subsets of the population for whom evidence suggests differing effectiveness of various forms of therapy.

8. In CV disease this isn’t often possible because… Subset analyses usually rely on • Meta-analyses • Post-hoc analyses AND BOTH ARE FLAWED METHODS

9. There is a severe lack of data in all types of trials in CV medicine that enroll adequate numbers of women to allow significant subset analyses. This is despite the fact (in the US) that the NIH established a policy for the inclusion of women in clinical research in1986 that was passed into law when Congress approved the NIH Revitalization Act of 1993.

10. Having said that, the reality is… • Guidelines aren’t always consistent with one another • Many recommendations are really based on “expert consensus” because there simply is no evidence base

11. There is, in fact, increasing consciousness of the need to provide guidance for management of important subsets of patients This consciousness is perhaps best attributed to the data suggesting that improvements in outcomes over time are not evenly distributed between the sexes.

12. Temporal Trends in 5-Year Mortality After the Diagnosis of Heart Failure, Data Stratified by Sex (From analysis of Olmsted County population) Roger, V. L. et al. JAMA 2004;292:344-350.

13. Such data led to investigations to determine whether evidence based therapies are being used equally. Several very large studies have now been done.

14. IMPROVE-HF A prospective cohort study designed to characterize current management of patients with diagnosed HF and LVSD (or prior MI associated with LVSD) in outpatient cardiology practices.* Analyzed 15,381 patients in 167 outpatient practices in the US *Yancy et al. Am Heart J 2009;157:754.

15. . . Patients receiving recommended HF therapy by sex Yancy et al Am Heart J 2009;157:754

16. Thus, in IMPROVE-HFstudy of Guideline-recommended Rx • The use of ACEI or ARB and beta blockers was remarkably similar for men and women • Women less likely to receive ICD/CRT-D implants or HF education

17. OPTIMIZE-HF *A prospective registry and performance improvement program of hospitalized patients withHF Evaluated differences in medical care and patient outcomes by age and gender in 48,612 patients from 259 hospitals in US *Fonarow et al Am J Cardiol 2009;104:107

18. In OPTIMIZE-HF registry • Length of stay was similar for men and women • Both groups experienced similarly high postdischarge mortality and readmission rate.

20. Thus, in OPTIMIZE-HF registry • Appropriate ACEI/ARB and beta blocker use were similar between men and women. • Fewer women had Aldo antagonists Warfarin for AF Discharge instructions

21. This is in contrast to recent UK study and others which have shown lower HF treatment rates in women. .

22. Retrospective survey Of >9,000 hospital Admissions for HF In 2005-6 in UK. Women significantly Less likely to be Prescribed HF meds On discharge Nicol et al Heart 2008;94:172

23. Why the differences in IMPROVE-HF and OPTIMIZE-HF from UK study? Not completely clear, but possibly: • Data were collected for outpatients in IMPROVE-HF, inpatients in others • There was a greater awareness of guideline recommendations in US • There was selection bias in the analyzed outpatient practices and hospitals in IMPROVE-HF and OPTIMIZE-HF

24. In any case… For the moment, Guidelines assign a Class I recommendation that groups of patients, including women, even if underrepresented in clinical trials, should, in the absence of specific evidence to treat otherwise, have clinical screening and therapy in a manner identical to that provided to the broader HF population

25. CONCLUSIONS • Our current HF guidelines are not sex specific because of insufficient data • Review of published reports raises concern that sex differences might exist regarding the degree of benefit of any given therapy for HF. • There continues to be a low rate of sex-specific reporting in CV trials

26. THIS NEEDS TO CHANGE… …although who should accept this responsibility and how it should be enforced remain controversial.

27. . “…it is important to stress that being male or female is a variable that should be dealt with in both basic science and clinical research …differences are unlikely to be due only to sex hormones (but also to differences in gene expression on X and Y chromosomes)” Piro M et al. JACC 2010;55:1057-65 Rome, Italy

28. How close are we to gender-specific guidelines? I think…only as close as we are to designing clinical trials that include sufficient numbers of women to analyze. That may not be very close.