Disclosures

1. Benefits of Natriuretic Peptide Guided Heart Failure Therapy for Patients With Chronic Left Ventricular Systolic DysfunctionResults of the Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study James L. Januzzi, Jr, MD, Shafiq U. Rehman, MD, Asim A. Mohammed, MD, Anju Bhardwaj, MD, Linda Barajas, RN, Justine Barajas, Han-Na Kim, MD MPH, Aaron L. Baggish, MD, Rory B. Weiner, MD, Annabel Chen-Tournoux, MD, Jane E. Marshall, RDCS, Stephanie A. Moore, MD, William D. Carlson, MD, Gregory D. Lewis, MD, Jordan Shin, MD, Dorothy Sullivan, ANP, Kimberly Parks, DO, Thomas J. Wang, MD, Shawn A. Gregory, MD, Shanmugam Uthamalingam, MD, and Marc J. Semigran, MD Heart Center, Massachusetts General Hospital Boston, Massachusetts

2. Disclosures • Dr. Januzzi: • Grant support: Roche Diagnostics, Siemens Diagnostics, Critical Diagnostics • Consulting: Roche Diagnostics, Critical Diagnostics • Speaking: Roche Diagnostics, Siemens Diagnostics, Ortho Clinical Diagnostics • No other authors have disclosures to report

3. Introduction • Despite great success in development of therapies for chronic heart failure (HF), affected patients nonetheless suffer significant morbidity and mortality. • Standard of care (SOC) management for chronic HF includes use of therapies based on symptoms, signs, and achievement of a maximal medical program. • Although such an approach is standard, titration of therapies remains sub-optimal, and even when optimal, higher risk patients may go unrecognized. • This has led to greater interest in alternative means to monitor patients with HF, in an effort to “guide” therapy.

4. Introduction • Concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP), are strongly associated with the presence and severity of HF, and are markedly prognostic in affected patients. • Values of NT-proBNP often fall in response to therapy change, and such a fall in NT-proBNP is associated with more favorable outcomes. • It remains unclear whether “guiding” HF therapy with NT-proBNP is beneficial. • Clinical trials of guided therapy (with heterogeneous inclusion criteria and patient demographics) have returned mixed results.

5. Methods American Heart Journal, 2010 Investigator-initiated, prospective, randomized controlled trial Sponsored in part by Roche Diagnostics, Inc Clinical Trials.Gov NCT00351390

6. Inclusion/Exclusion Criteria

7. Patient with Class II-IV symptoms, EF  40%, recent HF event Randomization echocardiogram Standard of Care + NT-proBNP Minnesota Living With HF Questionnaire quarterly Standard of Care Minnesota Living With HF Questionnaire quarterly Therapy adjusted to achieve optimal drug targets PLUS NT-proBNP  1000 pg/mL Visits q3 months Extra visits as needed for treatment goals Therapy adjusted to achieve optimal drug targets Visits q3 months Extra visits as needed for treatment goals Close-out echocardiogram Total cardiovascular events assessed Study Design

8. 1 endpoint Total cardiovascular events* Worsening HF† HF hospitalization ACS Ventricular arrhythmia Cerebral ischemia Cardiovascular death 2 endpoints Quality of life Changes in echo parameters LV ejection fraction LVESVi LVEDVi Endpoints *Assessed using generalized estimating equations †Requiring at least 2 from the following: symptoms of congestion or falling cardiac output, signs of new congestion on exam, use of “bail out” decongestive therapy, or rising NT-proBNP in the un-blinded arm

9. PROTECT Study Results

10. 151 consented and randomized Standard of care plus NT-proBNP (N=75) Standard of care alone (N=76) 6 elective withdrawals 6 elective withdrawals 75 analyzed 0 excluded 76 analyzed 0 excluded Study flow

11. Baseline characteristics

12. HF therapy: Baseline

13. SOC NT-proBNP Office visits* *908 visits overall; mean follow-up 10 ± 3 months Median number of visits: NT-proBNP 6.0 vs SOC 5.0; P =.05 P = .001 5 visits 6-7 visits ≥8 visits 1-4 visits Visit number

14. HF therapy: Follow-up Rates of achievement of ≥50% of goal dose were higher in NT-proBNP arm for ACEi/ARBs (56.5% versus 50.8%) and β blockers (53.4% versus 41.9%).

15. HF therapy: Titration *Limited number of observations

16. NT-proBNP Concentrations P = .40 for SOC baseline versus NT-proBNP baseline

17. NT-proBNP Concentrations P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL

18. P =.009 SOC NT-proBNP *Logistic OddsNT-proBNP= 0.44 (95% CI= .22-.84; P =.019) *Adjusted for age, LVEF, NYHA Class, and eGFR Primary Endpoint 100 events 58 events

19. SOC NT-proBNP NB: 3 of 4 CV deaths in NT-proBNP arm occurred after elective withdrawal from study P =.72 P =.41 P =.52 Individual Endpoints NB: 0 cerebral ischemia events in either arm P =.002 P =.001

20. NT-proBNP (N=75) Standard-of-care (N=76) Kaplan-Meier Analysis 1.0 Log rank P =.03 0.8 0.6 Event free survival 0.4 0.2 0 0 73 146 219 292 365 Days from enrollment

21. SOC NT-proBNP Age and outcomes Mean number of events P =.008 P =.005 Age < 75 years Age ≥ 75 years *No interaction between age and NT-proBNP guided care was found (P =.11)

22. SOC NT-proBNP Safety P =.72 P =.70 P =.32 P =.08 P =.47 Hypo or hyperkalemia Acute renal failure Dizziness Hypotension Syncope Adverse events

23. Minnesota Living with Heart Failure Questionnaire NT-proBNP patients had larger QOL improvements than SOC, and were more likely to have large (≥10 point) improvements in their MLWHF scores

24. SOC (N= 56) P =.06 P =.01 NT-proBNP (N=60) P <.001 P =.008 Selected echo results LV end-systolic volume index LV end-diastolic volume index LVEF Absolute  LVEF Relative 

25. PROTECT: Limitations • Small size • Primary endpoint uses cumulative events • Effect of NT-proBNP guidance mainly on worsening HF and HF hospitalization • Caregivers and patients un-blinded to NT-proBNP results • Suspension of the study at interim increases the risk for Type I error

26. PROTECT: Summary • Against a background of excellent overall medical care, addition of NT-proBNP measurement with a goal to reduce and maintain values 1000 pg/mL: • Was achieved in a large % of subjects • Resulted in favorable patterns in medication application • Was well-tolerated

27. PROTECT: Summary • NT-proBNP guided care was superior to SOC management for the reduction of total cardiovascular events. • Particular effects on worsening HF and HF hospitalization • Comparable benefits seen in elderly patients • Compared to SOC, NT-proBNP guided care was associated with more significant improvements in both QOL and echo parameters.

28. PROTECT: Conclusion • If duplicated in larger cohorts, therapy guided by NT-proBNP concentrations may represent a new paradigm for HF care.

29. Benefits of Natriuretic Peptide Guided Heart Failure Therapy for Patients With Chronic Left Ventricular Systolic DysfunctionResults of the Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study Slides available at www.cardiosource.com James L. Januzzi, Jr, MD, Shafiq U. Rehman, MD, Asim A. Mohammed, MD, Anju Bhardwaj, MD, Linda Barajas, RN, Justine Barajas, Han-Na Kim, MD MPH, Aaron L. Baggish, MD, Rory B. Weiner, MD, Annabel Chen-Tournoux, MD, Jane E. Marshall, RDCS, Stephanie A. Moore, MD, William D. Carlson, MD, Gregory D. Lewis, MD, Jordan Shin, MD, Dorothy Sullivan, ANP, Kimberly Parks, DO, Thomas J. Wang, MD, Shawn A. Gregory, MD, Shanmugam Uthamalingam, MD, and Marc J. Semigran, MD

30. Number of office visits* *908 visits overall; mean follow-up 10 ± 3 months 12 P = .05 9 Number of visits 6 3 0 SOC (N=76) NT-proBNP (N=75)

31. Achieved NT-proBNP Concentrations of NT-proBNP at the end of the study

32. Events as a function of NT-proBNP P <.001 1000 pg/mL 1001-2000 pg/mL 2001-3000 pg/mL >3000 pg/mL Achieved NT-proBNP value

33. P =.03 SOC NT-proBNP Mean Number of Events/Patient 1.3 events 0.77 events

34. P =.04 SOC NT-proBNP % of Patients with Events 48.6% 29.3%

35. Safety

36. Differences in characteristics between subjects in each arm were assessed using χ2 test, Student's t test or Wilcoxon rank sum test. Comparison of event rates between study arms was performed with use of generalized estimating equations (GEE). A logistic β-coefficient, adjusted for age, LVEF, NYHA Class, and eGFR was calculated for the effect of NT-proBNP guidance. Kaplan-Meier analysis performed to analyze time to first event as a function of treatment allocation. Associations between treatment strategy and treatment-related serious adverse events were examined, after adjustment for relevant baseline covariates. Parametric and non-parametric tests were used to examine secondary objectives, including effects of NT-proBNP guided HF care on QOL, as well as echo parameters. Interim analysis performed upon enrollment of 151st subject for assessment of primary endpoint. Statistics

37. Differences in characteristics between subjects in each arm were assessed using χ2 test, Student's t test or Wilcoxon rank sum test. Comparison of event rates between study arms was performed with use of generalized estimation equations (GEE). A logistic β-coefficient, adjusted for age, LVEF, NYHA Class, and eGFR was calculated for the effect of NT-proBNP guidance. Kaplan-Meier analysis performed to analyze time to first event as a function of treatment allocation. Associations between treatment strategy and treatment-related serious adverse events were examined, after adjustment for relevant baseline covariates. Parametric and non-parametric tests were used to examine secondary objectives, including effects of NT-proBNP guided HF care on QOL, as well as echo parameters. Interim analysis performed upon enrollment of 151st subject for assessment of primary endpoint. Statistics