WHAT EVIDENCE DO WE HAVE TO START EVIDENCE-BASED DRUGS IN HOSPITAL?Dr. Nadia GiannettiMedical Director, Heart Failure and Heart Transplant ProgramChief Division of CardiologyMcGill University Health Centre

WHAT EVIDENCE DO WE HAVE TO START EVIDENCE-BASED DRUGS IN HOSPITAL?Dr. Nadia GiannettiMedical Director, Heart Failure and Heart Transplant ProgramChief Division of CardiologyMcGill University Health Centre Conflict of Interest•Funding, honoraria or research with the following companies:•Novartis•Servier•Amgen•Pfizer•Boehringer Ingelheim•Astra Overview•Review the limitations of current heart failure management•Discuss the risks and benefits of in-hospital initiation of heart failure therapy•Review the evidence to support in-hospital initiation of heart failure therapy The limitations of current heart failure management•We know that medical therapy can reduce heart failure hospitalizations, CV death and total mortality in patients with heart failure McMurray NEJM 2014SwedbergLancet 2010 The limitations of current heart failure management•Despite this, we know from multiple registries that medical therapy is under prescribed QUALIFY registryCCS.ca 2015 CHAMP registryJACC2018 Why is there under-prescription of medical therapy?•Multi-factorial:•Lack of follow-up: some patients are not seen by a physician after a heart failure presentation•Majority who are seen in follow-up are seen by their family MD•Majority wait weeks to months before they are seen in follow-up•Physician inertia•Patient preference which may be due to lack of understanding How can we improve the use of appropriate medical therapy?•We can start during the hospitalization period when the patient is under our care, where we can provide education•What evidence do we have to support this? How important is medical therapy during a heart failure hospitalization? Medical therapy during hospitalization Can we initiate novel therapy during hospitalization?: TIRATION sudy ACEi, angiotensin converting enzyme inhibitor; ADHF, acute decompensated heart failure; ARB, angiotensin receptor blocker; b.i.d, twice daily; HF, heart failure; OMT, optimal medical treatment for HF; sac/val, sacubitril/valsartan Pascual-Figalet al. ESC Heart Failure DOI: 10.1002/ehf2.12246 Treatment epoch 10 weeks’ duration starting at randomization1–3 days’screening epoch 16 weeks’ follow-up epoch Open-labelSac/val50 mg à100 mg b.i.d. à200 mg b.i.d.orSac/valà100 mg à200 mg b.i.d.as per label and at investigator discretion Open-labelSac/val50 mg à100 mg b.i.d. à200 mg b.i.d.orSac/valà100 mg à200 mg b.i.d.as per label and at investigator discretionOMT continued throughout the study (excluding ACEi/ARB) Any OMT as per treating physicianOMT continued throughout the study (excluding ACEi/ARB) Patient stabilized 3 strata OMT but ACEi/ARB naïve pts PRE-discharge initiation POST-discharge initiation 36 h ACEiwashout Hospital admission for ADHF ACEi+ OMT ARB + OMT Randomization to PRE-or POST-discharge 36 h ACEiwashout Open-label Sac/valat tolerated dose Discharge Down-titration or temporary discontinuation of sac/valis allowed in all groups at any time max. 2 weeks Any OMT as per treating physician Most Common Serious Adverse Events* *≥0.5% of patients in any group**Fischer’s Exact Test, full analysis set [VAL…0,80,6 7 0,600,80 1,20,60,600,40,40,8 7,7 00,60,60,61,4 0,20,40,8 0123456789 HyperkalemiaHypotensionCardiacfailureNon-cardiac chest painPneumoniaAcute kidney injuryCOPD P=1.000P=0.687P=0.725 P =0.717 P=0.249 Proportion of patients (%)P=0.124P=1.000P=0.124P=0.789P=0.624P=1.000P=0.062 Atrial fibrillationVentriculartachycardiaRespiratory tract infectionRenal failurePulmonary edema Pre-discharge initiation (n = 497)Post-discharge initiation (n = 496) 11 Safe to initiate therapy pre-discharge N EnglJ Med 2019; 380:539-548 PIONEER-HF Study Design *Target DoseHF, Heart Failure. EF, Ejection FractionVelazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa1812851 Sacubitril/valsartan 97/103 mg twice daily*Enalapril10 mg twice daily*vsIn-hospital initiation Hospitalized with Acute Decompensated HF with Reduced EFWhile hospitalized •Evaluate biomarker surrogates of efficacy•Evaluate safety and tolerability•Explore clinical outcomes Study Drug for 8 weeks PIONEER-HF•Hospitalized for Acute Decompensated Heart Failure (ADHF)•LVEF ≤40% within the last 6 months•NT-proBNP ≥1600pg/mL or BNP ≥400 pg/mL* •While hospitalized:•SBP ≥100 mmHg in prior 6h; no symptomatic hypotension•No increase in IV diuretics in prior 6h •No IV vasodilators in prior 6h•No IV inotropes in prior 24h Key Entry Criteria *At screeningA complete list of inclusion and exclusion criteria has been previously published at Velazquez et al. Am Heart J 198 (2018) 145-151LVEF, Left Ventricular Ejection Fraction. NT-proBNPN-terminal pro–Brain Natriuretic Peptide. BNP, Brain Natriuretic Peptide. SBP, Systolic Blood Pressure. IV, IntravenousVelazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa1812851 PIONEER-HFPrimary endpoint: •Time-averaged proportional change in NT-proBNP from baseline at 4 and 8 weeksSafety•Worsening renal function•Hyperkalemia•Symptomatic hypotension•AngioedemaExploratory Clinical Outcomes•Serious Clinical Composite: Death, Hospitalization for HF, LVAD or listing for cardiac transplant Study Endpoints* *A more complete list of PIONEER study endpoints has been previously published at Velazquez et al. Am Heart J 198 (2018) 145NT-proBNPN-terminal pro–Brain Natriuretic Peptide. HF, Heart Failure. LVAD, Left Ventricular Assist Device. HF, Heart FailureData on File: PIONEER-HF Protocol, Novartis Pharmaceutical Corp; October 2018Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa1812851 PIONEER-HFBaseline Characteristics Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa181285116 Sacubitril/Valsartan(n=440)Enalapril (n=441)Age (years) 61 (50.5, 71)63 (54, 72)Women (%) 25.730.2Black (%) 35.935.8Prior HF diagnosis (%)67.763.0LVEF,median (25th, 75th)0.24 (0.18, 0.30)0.25 (0.20, 0.30)Systolic pressure, median (25th, 75th)mm Hg118 (110, 133)118 (109, 132)NT-proBNPmedian (25th, 75th)pg/mL at randomization 2883 (1610, 5403)2536 (1363, 4917)ACEi/ARB therapy (%)47.348.5Beta-adrenergic blockers (%)59.659.6 MED/ENT/0380 PIONEER-HFBaseline Characteristics Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa181285117 Sacubitril/Valsartan(n=440)Enalapril (n=441)Age (years) 61 (50.5, 71)63 (54, 72)Women (%) 25.730.2Black (%) 35.935.8Prior HF diagnosis (%)67.763.0LVEF,median (25th, 75th)0.24 (0.18, 0.30)0.25 (0.20, 0.30)Systolic pressure, median (25th, 75th)mm Hg118 (110, 133)118 (109, 132)NT-proBNPmedian (25th, 75th)pg/mL at randomization 2883 (1610, 5403)2536 (1363, 4917)ACEi/ARB therapy (%)47.348.5Beta-adrenergic blockers (%)59.659.6 PIONEER-HFBaseline Characteristics Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa181285118 Sacubitril/Valsartan(n=440)Enalapril (n=441)Age (years) 61 (50.5, 71)63 (54, 72)Women (%) 25.730.2Black (%) 35.935.8Prior HF diagnosis (%)67.763.0LVEF,median (25th, 75th)0.24 (0.18, 0.30)0.25 (0.20, 0.30)Systolic pressure, median (25th, 75th)mm Hg118 (110, 133)118 (109, 132)NT-proBNPmedian (25th, 75th)pg/mL at randomization 2883 (1610, 5403)2536 (1363, 4917)ACEi/ARB therapy (%)47.348.5Beta-adrenergic blockers (%)59.659.6 PIONEER-HFPrimary Endpoint 19 100-10-20Percent Change from Baseline -30-40-50-60-70 Week since RandomizationBaselineWeek 1Week 2Week 3Week 4Week 5Week 6Week 7Week 8 HR 0.71 (95% CI 0.63, 0.80) P<0.001Enalapril Sacubitril/Valsartan Time-average proportional change of NT-proBNPfrom baseline* *Percentage (%) change from baseline to mean of weeks 4 and 8Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa1812851 Endpoint Nr.(%)Sacubitril/Valsartan (n=440)Enalapril (n=441)RR Sac/Val vs Enalapril(95% CI)Compositeof serious clinical events *41 (9.3)74 (16.8)0.54 (0.37 to 0.79)Death 10 (2.3)15 (3.4)0.66 (0.30 to 1.48)Re-hospitalization for HF35 (8.0)61 (13.8) 0.56 (0.37 to 0.84)Requirement of LVAD1 (0.2)1 (0.2) 0.99 (0.06 to 15.97)Inclusion on list for heart transplantation 0 0 n/a PIONEER-HFExploratory Clinical Endpoints Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa1812851 20 *Exploratory Serious Clinical Composite endpoint consisted of death, rehospitalizationfor heart failure, implantation of a left ventricular device, and inclusion on the list of patients eligible for heart transplantation PIONEER-HF 21 Study Limitations Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa1812851 •The study was powered for changes in NTproBNPand interpretation of secondary and exploratory endpoints should be viewed with caution•Safety data were collected for only 12 weeks, therefore adverse events that take longer to transpire may not have appeared in this study. Safety information should be interpreted in the context of prior trials with longer duration•In-hospital initiation included 2 placebo doses in the sacubitril/valsartan group and 6 hours of mandatory observation after the 3rddose of study medication in both arms, which may have prolonged length of stay•The 8 week double-blind study duration could limit the ability to fully assess long-term outcomes such as death, cardiac transplantation, and LVAD implantation Effect of HR upon normal and Failing LV During hospitalization•Beta-blockerson BBs: not stop after admission, with reduction in doses if necessary (based on clinical and hemodynamic condition of patients). BBs were uptitratedevery 48 h in both groups No BBs before admission: BBs were started at low doses (carv: 3,125 mg/12 h or 6.25 mg/12 h, bisop: 1.25 to 2.5 mg/day) once the patient was stabilized, in both groups. •Ivabradine: added to BBs at initial dose of 5 mg bid after and uptitratedevery 48 h until a dose of 7.5 mg bid based on HRAfter discharge•BBs: uptitrationcontinued at the 14 and 28 days visits in both groups•Ivabradine:uptitrationto target dose of 7, 5 mg bid at 14 daysHidalgo et al. IntJ Cardiol2016;217:7-11. Hidalgo et al. Int J Cardiol2016;217:7-11. Early Co-administration of Ivabradine and β-blockers During Hospitalization is Safe and May Improve HF Parameters (effects at 12 months) 28 Initiation of ivabradinepre-dischargeimprovethe likelywoodto takethe medicationas recommended(PRIME-HF)Six months after hospitalization, the patients whose physicians were asked to initiate ivabradine prior to discharge:ØWere far more likely to be using ivabradine (40.4 percent vs. 11.5 percent)ØHad a greater reduction in heart rate •10 bpm vs. 0.7 bpm•average heart rate 77 bpm vs 86 bpmØHad not reduced their dose of beta-blockersØDid not develop abnormally low blood pressure or heart ratehttps://newsroom.heart.org/news/few-people-with-heart-failure-take-guideline-recommended-drug-especially-if-not-started-while-hospitalized?preview=fe3e Is early initiation worth it? How quickly does medical therapy work? PARADIGM –HF trial (NEJM 2014); SHIFT Trial (LANCET 2010) Summary •Heart failure has a high morbidity and mortality, with a high re-admission rate•Medical therapy can reduce all of the above with benefits achieved early on•Medical therapy is under-utilized •Is there another way to approach these patients? •Is there a better window of opportunity to get patients onto GDMT?•In well selected patients, can initiate therapy and titration in hospital