1. Regional Differences in Heart Failure Medication Changes During Acute Heart Failure Hospitalization: Findings From the PROTECT Trial Robert J. Mentz, Gad Cotter, John G. Cleland, Susanna R. Stevens, Karen Chiswell, Beth A. Davison, John R. Teerlink, Marco Metra, Adriaan A. Voors, Mona Fiuzat, Michael M. Givertz, Piotr Ponikowski, Barry M. Massie, and Christopher M. O'Connor

2. Background Clinical trials are increasingly conducted globally – –Shorten timelines – –Reduce costs – –Satisfy regulatory authorities Regional differences in CV trials – including HF – –Baseline patient characteristics – –Outcomes Specific reasons are uncertain Glickman SW, et al. NEJM 2009; Blair JE, et al. JACC 2008

3. Unanswered Question Are there regional differences in medication changes during acute HF hospitalization? Hypothesis International differences exist in the use of HF medications Prior to admission During hospitalization At discharge (or Day 7)

4. PROTECT Trial Placebo-controlled, randomized trial of the adenosine antagonist rolofylline 2,033 patients Admitted with worsening HF & renal dysfunction Included patients regardless of LVEF Enrollment between 2007-2009 173 sites in 17 countries Neutral for primary endpoint of changes in symptoms and signs, clinical status and renal function through day seven – –Rolofylline: increased seizures and strokes Massie, BM et al. NEJM 2010

5. Methods We grouped countries into 6 regions based on international differences in CV clinical trials: – –North America – –Western Europe – –Eastern Europe – –Russia – –Israel – –Argentina In-hospital HF medication changes by region Mentz RJ, et al. Am Heart J 2012; 164(3): 303-12.

6. Enrollment North America = 15% N = 313 Argentina = 3% N = 55 Russia = 14% N = 283 Israel = 16% N = 318 Western Europe = 19% N = 388 2033 patients 17 Countries & 173 Sites Eastern Europe = 33% N = 676

7. Country Contributions Number of Patients (% of region) Eastern Europe (N=676, 33%) Poland354 (52.3) Czech Republic169 (25.0) Romania91 (13.5) Ukraine33 (4.9) Hungary29 (4.3) Western Europe (N=388, 19%) Germany99 (25.5) France85 (21.9) Netherlands65 (16.8) Italy57 (14.7) Belgium45 (11.6) United Kingdom30 (7.7) Sweden7 (1.8) Israel (N=318, 16%)318 (100.0) North America (N=313, 15%) United States276 (88.2) Canada37 (11.8) Russia (N=283, 14%)283 (100.0) Argentina (N=55, 3%)55 (100.0)

8. Baseline Characteristics Results ArgentinaIsraelRussia Eastern Europe Western Europe North America Age, years727669717567 Men39%62%58%68%70%74% Ischemic53%82%86%67%60%63% Prior CABG22%35%2%13%27%38% ICD2%15%0%9%21%44% SBP, mmHg120128130125120114 LVEF, %30 3430 25 LVEF <40% 85%70%69%70% 76% eGFR, mL/ min/1.73 m 2 414254484143 Presented as % or Median Value

9. Baseline Medication Use (%) 2 weeks prior to admission Arg Isr Russ East West NA

10. Inpatient Medication Use (%) Arg Isr Russ East West NA

11. Inpatient LOS & Diuretic Use *Median Diuretic Dose (Furosemide Equivalent) through earliest of Day 7/Discharge Arg Isr Russ East West NA

12. Medication Changes: ACE/ARB 72% 77% 76% 69% 66% 58% 9% 8% 18% 16% 12% 13% 9% 14% 9% 12% 17% From 2 weeks prior to admission to discharge/day 7 *Similar observations in those with documented HFrEF

13. Medication Changes: BB 72%75%45% 78% 79%72% 15% 10% 33% 10% 8% 9% 11%10% 16% 7% 16% 8%

14. Medication Changes: MRA 34% 28% 43% 51% 29%28% 32% 12% 53% 37% 13% 25% 19% 20% 47% 13% 53%

15. Mortality or Hospitalization 30-days from Day 14 Visit (44 days post-randomization) Variable HR95% CI Region (vs. N. America) Russia0.260.080.86 ACE-I or ARB (at discharge)0.610.450.83 MRA (at discharge)0.720.550.94 Multivariable Predictors Other multivariable predictors included: Hospitalization for HF past year, Pulse Pressure, BUN

16. Summary Differences in baseline characteristics across 6 regionsDifferences in baseline characteristics across 6 regions –Age, Gender, HF Etiology –Blood pressure, Renal Function, CABG, ICDs Marked HF medication differencesMarked HF medication differences –Beta-blockers at baseline –MRAs at baseline & discharge Different inpatient strategies and LOSDifferent inpatient strategies and LOS –Inotropes, vasodilators, diuretic dosing –Differential initiation of HF medications

17. Limitations Specific trial entry criteriaSpecific trial entry criteria Lack of consensus on grouping regionsLack of consensus on grouping regions Relatively small regional sample sizes Sites were selected based on operational feasibility not epidemiology

18. Conclusions There were marked differences in patient characteristics across world regions World regions demonstrated differential use of HF medications at baseline with distinct inpatient management strategies and drug initiation These findings should be confirmed in other datasets and explored for a potential role in the differential outcomes across regions

19. Thank you

20. Acknowledgements MentorsMentors –Christopher M. O’Connor –G. Michael Felker –Mona Fiuzat StatisticiansStatisticians –Susanna Stevens –Karen Chiswell

21. Death or CV/Renal Hosp (60 d)

22. 22 Outcome Event Rates by Region

23. Outcomes Adjusted for BUN, past hospitalization for heart failure, sodium, systolic blood pressure, ischemic heart disease, edema, albumin, creatinine, glucose, rales, BMI, ALT, age, NYHA class, respiratory rate, heart rate, and WBC count