How might biomarkers and other strategies help establish adequacy of care?

How might biomarkers and other strategies help establish adequacy of care? James L. Januzzi, Jr, MD, FACC, FESC Hutter Family Professor of Medicine, Harvard Medical School Cardiology Division, Massachusetts General Hospital Cardiometabolic Trials/Trial Design, Harvard Clinical Research Institute

Disclosures I disclose the following relationships with industry that are relevant to my talk: Employee of Harvard Clinical Research Institute Grants: Roche Diagnostics, Singulex, Prevencio Consulting and/or CEC/steering committee participation: Roche Diagnostics, Critical Diagnostics, Amgen, Novartis, Pfizer, Merck, Contravir, Boeringer- Ingelheim, Phillips, General Electric I will discuss off-label use of biomarkers

Topics Establishing need for improvement in adequacy of care Defining a biomarker Data for hemodynamic/pressure biomarkers Data for circulating biomarkers

Heart Viability Natural History of Chronic and Acute Heart Failure Normal heart Initial myocardial injury Chronic heart failure 5 million in the US 10 million in Europe Death First Acute Decompensated Heart Failure (ADHF) episode: Pulmonary edema ER admission Cost of final 2 yrs of life: $156K 75% for hospitalizations during last 6 months Later ADHF episodes: Rescue therapy ICU admission Initial phase Last year Gheorghiade M. Am J Cardiol. 2005;96(suppl 6A):1-4G.

Repeat Hospitalizations Predict Mortality 1 st hospitalization: 30-day mortality = 12% 1-year mortality = 34% Setoguchi S, et al. Am Heart J. 2007;154:260-266.

Patients (%) Baseline Quality of Outpatient HF Care Conformity with Quality Measures at Baseline 100 90 80 70 60 50 40 30 79.8 86.2 34.4 CRT-P only 68.6 CRT-D 37.7 6.3 ICD only 48.8 31.7 61.8 20 31.4 10 17.2 0 ACEI / ARB Beta-Blocker Aldosterone (N = 11,165/ (N = 11,868/ Antagonist 13,987) 13,772) (N = 987/ 2827) Anticoagulation for Atrial Fibrillation (N = 2910/ 4244) CRT (CRT-D / CRT-P) ICD / CRT-D HF Education (N = 580 /1540) (N = 4799/ 9830) (N = 9373/15,177)

Use of Guideline Recommended Therapies at Baseline, 12, and 24 Months Longitudinal p=<0.001 p=0.001 p=0.001 p=<0.001 p=0.001 p=0.778 p=0.546 p=0.001 p=<0.001 p=<0.001 p=0.001 p=0.001 p=<0.001 p=<0.001 The P-values for 12 and 24 month outcomes are compared to baseline.

What is a biomarker? NIH definition: a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. WHO definition: any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease. The measured response may be functional and physiological, biochemical at the cellular level, or a molecular interaction. Examples of biomarkers include everything from non-invasively measured pulse and blood pressure, basic chemistries and more complex laboratory tests of blood and other tissues, imaging, and invasively determined physiologic measurements.

Biomarkers from devices Heart rate Activity CRT pacing % PVCs NSVT AF/AFL burden Impedance Invasive Non-invasive Filling pressures

Impedance and HF Management Management trials using invasive impedance monitors have been negative (e.g.dot-hf 1 ; 79% increase in HF hospitalization), neutral (e.g. Opti-Link HF 2 ), or trending positive (LIMIT-CHF 3 ; with improved QOL but no impact on HF hospitalization). A recent report of non-invasive lung impedance guided HF care suggested significant reduction in HF hospitalization (67 vs 158; P <.001) and deaths (42 vs 59 deaths; hazard ratio 0.52, 95% confidence interval 0.35-0.78, P =.002 )3. 1 Circulation. 2011 Oct 18;124(16):1719-26. 2 Eur Heart J. 2016 Mar 16. pii: ehw099. [Epub ahead of print] 2 Europace. 2016 Mar;18(3):428-35. 3 J Card Fail. 2016 Apr 4. pii: S1071-9164(16)30008-2. [Epub ahead of print]

Estimating pulmonary artery diastolic pressure A strong correlation (r = 0.84) has been shown to exist between epad and actual pulmonary artery pressures measured under a variety of physiological conditions. Studies using epad to manage patients with HF have returned suggestive results, but larger studies are needed. Bourge R et al, J Am Coll Cardiol. 2008;51(11):1073-1079.

Wireless Pulmonary Artery Hemodynamic Monitoring in Chronic Heart Failure 550 patients with NYHA class III HF with both preserved and reduced LVEF and previous hospital admission were randomly assigned to management with a wireless implantable hemodynamic monitoring system or to a control group for at least 6 months. 100.0% 90.0% 80.0% 70.0% 60.0% 50.0% In 6 months, 83 heart-failurerelated hospitalizations were reported in the treatment group (n=270) compared with 120 in the control group (n=280). 40.0% 30.0% 20.0% 10.0% 0.0% 29% relative risk reduction HR = 0.71 (0.55-0.92), p = 0.009 Treatment Control 0 90 180 270 360 450 540 630 No. at Risk Treatment270 226 202 169 130 104 84 62 Control 280 223 186 146 113 80 57 39 Abraham WT, et al. Lancet. 2011;377(9766):658-666.

Wireless Pulmonary Artery Hemodynamic Monitoring in Chronic Heart Failure Doses of all categories of med classes were adjusted more in the PAP guided group, notably including diuretics and RAAS agents. Constanzo MR et al, JACC Heart Fail. 2016;4(5):333-344.

Proportion Surviving Guided Therapy Combined Analyses: Mortality Meta analysis of publication data Pooled patient data from all available trials Study ID OR (95% CI) % Weight BNP-guided therapy Anguita Beck de Silva STARBRITE STARS-BNP UPSTEP Subtotal (i-squared = 0.0% p = 0.823) 1.00 (0.23, 4.43) 2.05 0.45 (0.04, 5.39) 0.74 0.32 (0.03, 3.19) 0.87 0.61 (0.23, 1.64) 4.68 0.95 (0.54, 1.68) 13.94 0.81 (0.52, 1.28) 22.27 1.00 0.95 HR=0.59 [0.41-0.84], p<0.001 NT-proBNP-guided therapy BATTLESCARRED Berger PRIMA PROTECT SINGAL-HF TIME-CHF Troughton Subtotal (i-squared = 0.0%, p = 0.692) 0.95 (0.53, 1.70) 13.27 0.64 (0.26, 1.16) 13.25 0.72 (0.45, 1.14) 21.22 0.66 (0.18, 2.43) 2.66 0.98 (0.33, 2.89) 3.92 0.67 (0.42, 1.05) 22.32 0.13 (0.62, 1.12) 0.96 0.72 (0.56, 0.91) 77.73 0.90 0.85 0.80 0.75 BNP-guided Clinically-guided Overall (i-squared = 0.0%, p = 0.896) NOTE: Weights are from random effects analysis 0.74 (0.60, 0.91) 100.00 0.70.015 1 Better Treatment 66.6 Better Control 0.0 0.5 1.0 1.5 2.0 Years Savarese G, et al. PLoS ONE. 2013;8:e58287. Troughton RW, et al. Eur Heart J. 2013.

Natriuretic peptides to guide HF care: Caveats For HFrEF only In trials suggesting benefit of biomarker-guided care: Biomarkers led to more up-titration of therapies, more adjustment of life-saving GDEM (rather than diuretics) and significant separation was seen in NP values between guided and non-guided arms. This may mean biomarkers may not be as needed in those already receiving aggressive, excellent care. Some patients do not respond; this is more likely related to severity of HF and/or comorbidities 1 limiting application of GDEM. 1 Brunner-Larocca HP, et al, Eur J Heart Fail. 2015;17(12):1252-61.

Topics Establishing need for improvement in adequacy of care Defining a biomarker Data for hemodynamic/pressure biomarkers Data for circulating biomarkers

Conclusion Adequacy of HF care is a pivotal component to reduce hospitalization and prolong life. There is a need for improvement in achievement of GDEM in patients with HF. Hemodynamic/filling pressure or circulating biomarkers are useful for predicting risk, and may be useful to improve GDEM in patients with HF, but more data are needed. As most trials examining use of tools to guide HF care (invasive or non-invasive) are small, vulnerable to play of chance, and depend heavily on care delivered in the usual care arm, understanding when guided therapy may be of benefit will be important.