Natriuretic Peptide Guided Therapy for Heart Failure

Transcription

1 Natriuretic Peptide Guided Therapy for Heart Failure Michael Felker, MD, MHS Associate Professor of Medicine Director of Heart Failure Research Duke Clinical Research Institute

2 Disclosures Research Grants and/or Consulting from: Roche Diagnostics BG Medicine Corthera Cytokinetics Amgen Otsuka NHLBI

3 Uses of Biomarkers Diagnosis: Establishing a cause of undifferentiated symptoms Screening: Looking for disease in asymptomatic persons Risk stratification: Assessing the future risk of adverse outcomes Guiding therapy: Triage, therapy selection or titration Surrogate endpoint: drug development Fundamental insights: Research Mark, Felker New Eng J Med 2004

4 Natriuretic Peptides and Prognosis in Chronic HF: Data from Val-HeFT Anand, I. et al, Circ 2003

5 Change in BNP Over Time and Outcomes: Data from VALHeFT Mortality 25% 23% 13% 8% N=3740 Latini, R. Am J Med 2006

6 Change in NTproBNP over Time and Outcomes Mason et al, JACC 2008

7 Therapies with Effects on NP Levels in HF Therapy Diuresis ACE-I ARB -blockers Aldosterone antagonists BiV pacing Exercise Rate control of AF BNP infusions Effect on BNP/NT-proBNP May transiently, then N-BNP, BNP then

8 Rationale for Natriuretic Peptide Guided Therapy Decreases in NP levels over time associated with favorable outcomes All proven effective HF therapies decrease NP levels Will a strategy of titrating therapy to specific NP targets improve outcomes?

9 How Should we Apply our Current Therapies in Chronic HF? Current guidelines: Therapy should be up-titrated to targets from clinical trials or the maximally tolerated dose An alternate hypothesis: Therapy should be up-titrated based upon the personalized physiologic response of each individual patient

10 Examples from other Areas of Medicine HIV/Hepatitis viral load Diabetes mellitus HbA1C Hypertension Blood pressure Hyperlipidemia LDL Anticoagulation INR Heart failure?

11 Event free (%) Chronic HF Therapy Guided by BNP Cardiovascular events Heart failure or death NT-proBNP Clinical NT-proBNP Clinical N = P = P = Time after randomisation (days) Time after randomisation (days) Troughton Lancet 2000

12 Event free survival % Treatment modifications (n) BNP guided HF therapy: STARS-BNP STARS BNP BNP Control 60 Clinical group BNP group P < T (days) Diuretics ACEI BB Spiro Other Jourdain, JACC 2007

13 NT-proBNP and HF Outcomes: TIME-CHF 499 subjects with systolic HF, recent event, randomized to NT-proBNP versus Standard HF management 18 month follow up: Endpoint Overall <75 years 75 years Hosp-free survival 0.92 ( ) 0.76 ( ) 1.06 ( ) Survival 0.68 ( ) 0.38 ( ) ( ) HF hosp-free survival 0.66 ( ) ( ) ( ) 1 P =.008; 2 P =.01; 3 P =.002 Brunner-LaRoca, JAMA 2009

14 BATTLESCARRED Mortality N = 364 Richards, AHA 2008

15 Mortality (%) BATTLESCARRED Mortality in Patients <75yrs NT-proBNP Clinical Usual Care * *P=.048 for NTproBNP vs Clinical P=.02 for NT-proBNP vs Usual care 1-Year 2-Years 3-years Richards, AHA 2008

16 NTproBNP vs. Disease Management vs. Usual Care % Pts on optimal therapy Hosp free Survival Berger et al. JACC 2010

17 Biomarker Guided Therapy and All-Cause Mortality Adjusted HR = 0.69 ( ) N = 1627 Felker GM et al. Am Heart J 2009

18 Biomarker Guided Therapy and All-Cause Mortality Porapakkham, P. Arch Int Med 2010

19 GAPS IN EVIDENCE: Does tailoring therapy according to plasma natriuretic peptide levels reduce morbidity and mortality?

20 What is the Evidence to-date? Multiple small trials (largest N = 499) Suggestive meta-analyses Showing a treatment effect on morbidity and mortality in well treated chronic heart failure patients requires significantly larger study Stage is set for Phase III trial

21 Unanswered Questions Does it really work? Is there a disconnect between mortality benefit and morbidity benefit? Is there an differential effect in elderly patients vs. young patients? What is the correct target? Is there an impact on other endpoints? (HRQOL, cost) How does it work?

22 GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment: The GUIDE-IT Study GUIDE-IT is an robustly powered, randomized controlled trial of NTproBNP guidance vs. usual care in high risk HF patients Currently under review by US NHLBI Planned to begin enrollment in 2011

23 Hospitalization for heart failure LVEF 40 within 12 months NTproBNP > 2000 pg/ml or BNP > 400 pg/ml during index hospitalization Randomized within 2 weeks of hospital discharge Screening Randomization Usual Care N= 550 Biomarker Guided NTproBNP < 1000 pg/ml N=550 Follow up: 2 wks, 6 wks, 3 months, then Q3 month for mos Follow-up Additional 2 week follow up after changes in therapy Primary endpoint: Time to CV death or first HF hospitalization Endpoints Secondary Endpoints: All-cause mortality Total days alive and out of hospital during follow-up CV mortality or CV hospitalization Safety Health related quality of life Resource utilization, costs, cost-effectiveness

24 1-Year Mortality (%) Rationale for NTproBNP Target 40 NTproBNP 972 pg/ml Decile of NT-proBNP Januzzi, Archives Int Med 2006

25 GUIDE IT Endpoints Primary Endpoint Time to cardiovascular death or first heart failure hospitalization Secondary Endpoints Total days alive and out of hospital over follow up Time to all-cause mortality Time to death or rehospitalization (all cause) HRQOL Resource use, costs and cost effectiveness Global rank score based on death, hospitalization, and quality of life Changes in adherence and self-management

26 Possible Quality of Life Effects More intensive (BNP-guided) therapy may be associated with improved functional status and well-being relative to usual care More intensive medical therapy could also have unintended consequence of making patients feel worse rather than better

27 Possible Economic Effects Fewer rehospitalizations and unscheduled ED/clinic visits with BNP-guided Rx may produce important cost savings Very aggressive Rx in pursuit of a BNP target might also induce complications that increase costs

28 Plasma, DNA, Imaging Biobank Leveraging Trial as a Platform for Discovery Carefully phenotyped patients Rigorous assessment of outcomes in all domains (clinical, quality of life, economic) Randomized biomarker driven treatment Serial banked plasma samples DNA Imaging

29 Other Biomarker Guided Hypotheses Should we use serial natriuretic peptide measurements to make decisions about hospital discharge in ADHF patients?

30 Death or readmission (%) BNP at Discharge: Failure to decrease BNP Predicts Readmission or Death Pre-discharge BNP >350 pg/ml Pre-discharge BNP <350 pg/ml Follow up (days) Logeart JACC 2004

31 In the final analysis, the benefits of BNP guidance cannot be greater than the benefits of the drugs for which the assay would provide for use. Packer, Circulation 2003

32 The use of biomarkers must augment clinical judgment, not replace it