POPULATION PRECISION MEDICINE AND SECONDARY PREVENTION OF HEART FAILURESean A. ViraniMD, MSc, MPH, FRCPC, FCCSChief of Cardiology | Providence HealthcarePhysician Program Director | The Heart Centre | St. Paul’s HospitalAssociate Professor of Medicine | UBCPast-President | Canadian Heart Failure Society

POPULATION PRECISION MEDICINE AND SECONDARY PREVENTION OF HEART FAILURESean A. ViraniMD, MSc, MPH, FRCPC, FCCSChief of Cardiology | Providence HealthcarePhysician Program Director | The Heart Centre | St. Paul’s HospitalAssociate Professor of Medicine | UBCPast-President | Canadian Heart Failure Society Disclosures•Grants/research support: Abbott, Bayer, BI, Medtronic, Novartis, Otsuka, Servier•Consulting and speaker fees: Abbott, Amgen, AstraZeneca, BI, Medtronic, Novartis, Pfizer, Servier, Takeda, •Other: None •I willNOT discussoff-label use. Can we resolve …•Precision medicine•Tailoring a treatment strategy based on patient specific factors •Population health•The health outcomes of a group of individuals, including the distribution of such outcomes within the group Tailoring treatment for mortality benefitA few examplesPrognostic FactorsRiskScoresHospitalizationNatriuretic PeptidesCo-morbidity Clinical FactorsHeartRateBlood PressureEtiologyQRS DurationRenalFunction and K+AnemiaMcDonald M et al. Can J Cardiol33(11):1434-1449 Case: Patient Johan Hulette•50ish year old male with ischemic cardiomyopathy, LVEF 28%•Status post-surgical and percutaneous revascularization•Complex co-morbidities including CKD•Persistent NYHA III symptoms with marked fatigue and postural lightheadedness•Recent hospitalization for AHF with volume overload•Diuretics adjusted but the admitting team did not think there was anything additional to add/change to his baseline treatment to improve “hard outcomes”•Clinically euvolemicat discharge with BNP of 2100 •HF therapies•bisoprolol 2.5 mg pood, ramipril2.5 mg pood, spironolactone 12.5 and furosemide 80 mg pood•ICD for primary prevention•Notable patient characteristics•HR 75 in NSR•BP 90/50 with no postural drop•eGFR 40•K+ 5.4•QRS duration of 115ms Q1 –Precision Medicine•What can you do to further customize his therapies? A.Nothing –he’s on optimally tolerated medical therapy (OTMT)B.I would “push” his RAASiand beta-blockers to target doses and cautiously monitor his blood pressure, renal function and K+C.I would increase his diuretic given the BNP was 2100D.I would add ivabradine CCS HF Guideline Recommendations•Recommendation 27: We recommend preferentially using the specific drugs at target dosesthat have been proven to be beneficial in clinical trials as optimal medical therapy. If these doses cannot be achieved, the maximally tolerated dose is acceptable[Table 11] (Strong Recommendation, High Quality Evidence). •Practical Tip: If a drug with proven mortality or morbidity benefits does not appear to be tolerated by the patient(eg, low blood pressure, low heart rate or renal dysfunction), other concomitant drugs, including diuretics, with less proven benefit should be carefully re-evaluated to determine whether their dose can be reduced or the drug discontinued. Ezekowitz et al. Can J Cardiol33(11):1342-1433 HR atbaseline(bpm)HR70 -< 721.0072 -< 751.1575 -< 801.3380 -< 871.80≥ 872.341.02.03.00.51.52.53.5CV MortalityandHF Hospitalization The higher the HR …the higher the risk of CV mortality and HF hospitalization Böhmet al. Lancet 2010; 376: 886-94 Risk increases by:3% per 1-bpm increase in HR16% per 5-bpm increase in HR Early impact of HR at discharge:High discharge HR is associated with worse outcomesHeart rate at discharge (bpm)40-6061-7071-8081-90>90Patients (%)14.6%23.9%28.9%18.7%13.9%Hazardratio for30-day mortality1.06Referent1.211.701.88 p-value0.720Referent0.185<0.001<0.001Habalet al. CircHeart Fail. 2014 Jan 1;7(1):12-20 SHIFT TrialPrespecifiedEndpointsHeartrate attrial entry≥ 70 bpm≥ 77 bpmPrimaryendpointCV deathor hospitaladmission for worseningHF18% (p<0.0001)25% (p<0.0001)MortalityendpointsAll-cause mortality -19% (p=0.0074)Cardiovascularmortality-19% (p=0.0137)DeathfromHF 26% (p=0.014) 39% (p=0.0017)OtherendpointsAll-cause hospitaladmission 11% (p=0.003)18% (p=0.0002)AnyCV hospitaladmission15% (p=0.0002)21% (p<0.0001)Hospitaladmission for worseningof HF26% (p<0.0001)31% (p<0.0001) Swedberget al. Lancet 2010; 376: 875-85 Meta-regression: Evaluating the effect of individual covariates on mortality in beta-blocker trialsPotential ModifierTrials, nPatients, nRatio of Relative Risks (95% CI)p ValueBaseline heart rate1917 9811.07 (0.88-1.32) per 5 beats/min0.47Heart rate reduction*1717 8310.82 (0.71-0.94) per 5 beats/min0.006b-blocker dose1717 6601.02 (0.93-1.10) per increment0.69Mean baseline SBP1717 5161.00 (0.73-1.35) per 20 mmHg0.99Mean SBP reduction105 4621.02 (0.87-1.20) per 2 mmHg0.78Agent 2118 773--- ---Carvedilol------Reference---Bisoprolol------1.05 (0.82-1.35)0.68Metoprolol------1.03 (0.77-1.38)0.85Atenolol------0.89 (0.29-2.76)0.83Bucindolol------1.36 (1.09-1.69)0.009Nebivolol------1.30 (0.99-1.71)0.056 adapted from McAlisteret al. Ann Intern Med 2009; 150 (11): 784-94 Screening Randomization Follow-up Endpoints High-Risk Heart Failure with Reduced EFLVEF ≤40 within 12 monthsHF event (hospitalization, ED visit, outpatient IV diuretics) within prior 12 mosNT-proBNP > 2000 pg/mL within prior 30 days Usual CareN=550 Primary endpoint:Time to CV death or first HF hospitalizationSecondary 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 Biomarker-GuidedNT-proBNP < 1000 pg/mLN=550 Follow up:2 wks, 6 wks, 3 months, then Q3 month for 12–24 mos Additional 2-week follow-up after changes in therapy 446 405 376 355 331 315 293 272 254 242 225 218 202 185 175 166 152 135 128 128 128 100 93 85 78 448 401 381 359 330 301 278 263 257 243 227 210 199 185 175 169 153 138 138 138 115 104 90 90 77 Number at risk Biomarker-guided Usual care 0 2 4 6 8 10 12 14 16 18 20 22 24 0.00 0.10 0.20 0.30 0.40 0.50 0.60 Probability of HF hospitalization or CV death P value = 0.875 HR (CI) = 0.983 (0.791, 1.222) Usual care: 15 (7, 24) Biomarker-guided: 15 (7, 24) Duration of follow-up: Median (25th, 75th) Months since randomization Usual Care Biomarker-Guided GUIDE-IT: Primary EndpointTime to CV death or HF Hospitalization Case: Patient Johan Hulete–Part II•You initiate ivabradine at the first post-discharge visit•Before you can up-titrate the dose or follow-up with the patient, he re-presents to hospital with AHF•Apparently, he was unable to afford his medications •In hospital, he is diuresedand discharged home•There are no changes to his HF therapies •After his second admission, he is referred to the HF Clinic at discharge•Follow-up appointment within 2 weeks per CCS Companion Recommendations •Discharge Summary•“Hopefully the HF Clinic can help ensure a seamless transition to the community … and the patient would benefit from the multidisciplinary team approach” Q2 –Population Health•What provider type(s) are essential for a multidisciplinary HF clinic (assuming they are working within their scope of practice)? i.e. what is the gold standard? A.NurseB.Physician and nurseC.Physician, nurse and nurse practitionerD.Physician, nurse, nurse practitioner and pharmacistE.Physician, nurse, nurse practitioner, pharmacist and dieticianF.Depends on the size of the community and available services CCS HF Guideline Recommendations•Recommendation 175:We recommend that specialized outpatient HF clinicsor disease management programs provide access to an interprofessionalteamideally including a physician, a nurse, and a pharmacist with experience and expertise in HF (Strong Recommendation, High Quality Evidence). •Recommendation 176:We recommend that all patients with recurrent HF hospitalizations, irrespective of age, multimorbidity, or frailty, should be referred to a HF disease management program (Strong Recommendation, High Quality Evidence). Ezekowitz et al. Can J Cardiol33(11):1342-1433 Supporting the Patient Journey:Defining the Optimal Model for HF Care in Canada•Define each level of HF care by provider type and the core competencies associated with each role (i.e. level of training, scope of practice).•Describe the key services and resources (human and structural) that must be in place at each level of care as well as the toolsnecessary to support optimal patient care at each stage (e.g. care plans/protocols, educational resources, quality assurance strategies)•Describe how and what should travel with patients between levels (hubs) of care to provide seamless transitional careand to optimize the patient and provider experience of care. Precision Public Health:Precision medicine and population health•Precision public health is providing the right interventionto the right population at the right time•More accurate methods for measuring disease severity allows for development of precision and targeted policies for programs that are tailored to each population’s unique characteristics•Dr. Milan Khoury(Director, Office of Public Health Genomics at the CDC) •Population and public health policy is based on process improvementthat direct resources to those at highest risk•Precision medicine approaches help us identify those at high risk, while clinical trials help us to understand whether we can modify their outcomes