ACCP Cardiology PRN Journal Club

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PGY2 Cardiology CHI Baylor St. Luke’s Medical Center, Houston, TX Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study Ellen B. Yin, Pharm.D. PGY2 Cardiology CHI Baylor St. Luke’s Medical Center, Houston, TX August 27, 2015 2010

Disclosure Presenters have no conflicts to report related to financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation

Background Chronic HF affects roughly 2-3% of the population ↓ Morbidity and Mortality Chronic HF affects roughly 2-3% of the population Treatment with beta-blockers Benefits of beta-blockers in HFrEF Likely linked to HR lowering properties Meta-analysis of 23 trials Every HR reduction of 5 beats/min with beta-blocker treatment 18% reduction (CI 6%-29%) in risk of death Concerns of beta-blockers in HFrEF Decrease in myocardial contractility Effect on peripheral vasculature Effect on airways -Chronic heart failure results in many readmissions  problem when moving towards penalization for 30-day readmissions -Attenuates the effect of energy starvation of the myocardium -Use of beta-blocker remain suboptimal in due to contraindications and side effects -Heart rate remains increased in most patients treated with beta-blockers ----- -Peripheral vasoconstriction, unopposed alpha effects, claudication; theoretically but not a lot in literature Swedberg K, et al. Lancet. 2010;376: 875-885; McAlister F, et al. Ann Intern Med. 2009; 150:784-794.

Background: Ivabradine Specific inhibitor of the If current in the sinoatrial node No other known action on other channels Does not modify myocardial contractility and intracardiac conduction -Specific inhibitor of the If current in the sinoatrial node -Selectively inhibits the If current, which is the primary modulator of diastolic depolarization, the pacemaker current, at the SA node -Delays phase 4 depolarization resulting in bradycardia -Ivabradine reduces the frequency of sinoatrial pacemaker potentials by blocking HCN channels and hence reducing the slope of diastolic depolarization -No action on other channels in the heart or vascular system -No action on other known channels -Does not modify myocardial contractility and intracardiac conduction -Action is atypical use and rate-dependence type, increased the modulation of the channel at higher heart rates: when heart rate is les than 50-60 bpm the action of ivabradine on HCN channels is very poor: patients do not experience extreme bradycardia -Channel opens during repolarization and is closed during depolarization: interaction between drug and the binding site is dependent on the rate of closing/opening of the channel; related to heart rate (use dependency property) -Slow sodium inflow in phase 4, fast Ca/Na inflow once hit -40, hit +10 K channel open and cause outflow to hyperpolarize ----- -Blue line normal, yellow line ivabradine Swedberg K, et al. Lancet. 2010;376: 875-885

Background: BEAUTIFUL Trial Design Randomized, double-blind, placebo-controlled, parallel-group, multicenter, international with intention-to-treat analysis Purpose To determine whether lowering HR with ivabradine reduces CV death and morbidity in patients with CAD and left ventricular systolic dysfunction Patients N=10917; N=5392 in pre-specified subgroup with HR ≥ 70 bpm Aged ≥ 55 years, CAD, LVEF ≤ 40%, sinus rhythm, resting HR ≥ 60 bpm Treatment Ivabradine 5 mg BID with target dose of 7.5 mg BID Standard CV treatment for CAD and HF; 87% on beta-blockers Median follow-up of 19 months (IQR 16-24) -Shift trial is not the first trial that examined ivabradine, similar trial was done in patients with coronary disease and LV systolic dysfunction -Large study, well designed trial looked at coronary disease and LVEF -BEAUTIFUL ended Dec 2006; SHIFT started Oct 2006 -There were almost 11000 patients in the study with about 50%; most patients were on beta-blockers --- Fox K, et al. Lancet. 2008; 372:807-816

Ivabradine vs. Placebo; Hazard Ratio Outcome Ivabradine vs. Placebo; Hazard Ratio P-Value Primary composite endpoint: CV death or admission to hospital for MI or new-onset or worsening HF Total population Subgroup HR ≥ 70 bpm 15.4% vs 15.3%; 1.00 (CI 0.91-1.10) 17.2% vs 18.5%; 0.91 (CI 0.81-1.04) 0.94 0.17 Mortality endpoints: All-cause death CV death 10.4% vs 10.1%; 1.04 (CI 0.92-1.16) 12.3% vs 12.0%; 1.02 (CI 0.87-1.19) 8.6% vs 8.0%; 1.07 (CI 0.94-1.22) 10% vs 9.8%; 1.02 (CI 0.86-1.21) 0.55 0.82 0.32 Heart failure endpoints: Admission to hospital for HF 7.8% vs 7.9%; 0.99 (CI 0.86-1.13) 9.9% vs 10.1%; 0.97 (CI 0.82-1.15) 0.85 0.76 Coronary endpoints: Admission to hospital for MI Coronary revascularization 3.6% vs 4.2%; 0.87 (CI 0.72-1.06) 3.1% vs 4.9%; 0.64 (CI 0.49-0.84) 2.8% vs 3.4%; 0.83 (CI 0.67-1.02) 2.8% vs 4.0%; 0.70 (CI 0.52-0.93) 0.16 0.001 0.078 0.016 -No significantly different outcomes -Only reduced secondary endpoints in patients with HR > 70 bpm; admission to hospital for fatal and non-fatal MI and coronary revascularization -Reduction in HR with ivabradine does not improve cardiac outcomes in all patients with stable CAD and LV systolic dysfunction, but could be used to reduce the incidence of CAD outcomes in subgroup of patients who have HR of greater than 70 bpm -Wanted to look at a study examining patient with HR > 70 bpm Fox K, et al. Lancet. 2008; 372:807-816

SHIFT: Design & Purpose To assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure Study Design International, multicenter, randomized, double-blind, placebo-controlled, parallel group study Ivabradine vs placebo given on top of standard heart failure treatment regimen Funding Servier, France Swedberg K, et al. Lancet. 2010;376: 875-885.

SHIFT: Inclusion and Exclusion Inclusion Criteria Exclusion Criteria Age ≥ 18 years Sinus rhythm with resting HR ≥ 70 bpm NYHA Class II, III, IV for ≥ 4 weeks, in stable clinical condition Previous admission for worsening heart failure within previous 12 months LVEF ≤ 35%, documented within previous 3 months Recent (<2 months) myocardial infarction or recent or scheduled coronary revascularization Pacemaker with atrial or ventricular pacing > 40% of the time, or with stimulation threshold at the atrial or ventricular level ≥ 60 bpm Atrial fibrillation or flutter Symptomatic hypotension Congenital heart disease Sick sinus syndrome, sinoatrial block, second and third atrio-ventricular block Patients on non-dihydropyridine calcium channel blockers, class I antiarrhythmics, strong inhibitors of CYP3A4 , selected QT prolonging products -Sinus rhythm with resting heart rate ≥ 70 bpm (measured on EKG after 5-mins rest on two consecutive visits) Swedberg K, et al. Lancet. 2010;376: 875-885.

SHIFT: Procedure HR ≥ 60 bpm Titrate dose up to max of 7.5 mg BID Starting dose 5 mg BID, then down-titrated to 2.5 mg, maintained at 5 mg, or uptitrated to 7.5 mg BID Run-In Matching placebo, twice daily Selection Inclusion at D0 D14 visit D28 visit M4 visit Follow-up visits, every 4 months M48 visit -14-day run-in period to confirm inclusion and exclusion data -Follow-up every 4 months with dose titration -Treated for 12-48 months -Study treatment given on top of background CV therapy optimized in accordance with contemporary guidelines recommendations: ACE/ARB, beta-blocker, diuretic, and aldosterone antagonist -Stratified according to center and beta-blocker use HR ≥ 60 bpm Titrate dose up to max of 7.5 mg BID HR 50 - 60 bpm Keep same dose HR ≤ 50 bpm or symptomatic bradycardia Titrate dose down or stop therapy if already taking 2.5 mg BID Swedberg K, et al. Lancet. 2010;376: 875-885.

SHIFT: Endpoints Primary Endpoint Composite of CV death or hospital admission for worsening HF Secondary Endpoint Primary outcome for patients receiving at least 50% of the target daily dose of a beta-blocker Readmission: All-cause, any CV, worsening HF Mortality: All-cause, any CV, HF Changes in functional capacity based on NYHA classification Swedberg K, et al. Lancet. 2010;376: 875-885.

SHIFT: Statistical Analysis Survival analysis done on a time-to-first event basis with an intention-to-treat principle Time-to-event curves estimated with Kaplan-Meier method Cox’s proportional hazards model adjusted for baseline beta-blocker intake used to estimate treatment effect Power: Assuming an annual incidence rate of the primary composite endpoint of 14% in the placebo group Sample size of 6500 patients needed for 90% power to find 15% relative risk reduction with 1600 first events Swedberg K, et al. Lancet. 2010;376: 875-885.

SHIFT: Baseline Characteristics N=3241 in Ivabradine group; N=3264 in placebo group Average age 60.4 years (11% > 75 years) 76% male, 89% white HR 79 bpm, BP 122/75 mmHg, LVEF 29% 49% NYHA class II, 50% class III, 2% class IV 68% ischemic cause of HF 89% on beta-blockers, 83% on ACE/ARB, 22% cardiac glycoside, 4% on CRT/ICD -Results based on 6505 patients (met sample size) -Groups were well balanced -Average age 60.4 (11% of patients aged > 75 yrs) -Mainly men (76%) and white (89%) -Mean heart rate 79.9 bpm, LVEF 29% -68% ischemic HF, equally distributed between NYHA II and III -RAAS 91% of patients, beta-blocker 89% of patients Swedberg K, et al. Lancet. 2010;376: 875-885.

Results: Beta-Blocker Use -56% patients on beta-blockers treated with at least 50% of target doses by ESC guidelines (recommended by the guidelines, not approved) -26% at target doses -Reasons for not receiving target doses were hypotension and fatigue -11% did not receive beta-blockers because of COPD, asthma, hypotension Swedberg K, et al. Lancet. 2010;376: 875-885.

Results: Heart Rate Reduction Median duration of follow-up: 22.9 months Mean dose of ivabradine 6.5 mg BID at 1 year Heart rate fell by 10.9 bpm at 28 days and 9.1 bpm at 1 year -BEAUTIFUL trial, ivabradine reduced HR by 6 bpm at 12 months, corrected for placebo -Ivabradine fell by a mean of 15.4 bpm compared with pretreatment Swedberg K, et al. Lancet. 2010;376: 875-885.

Results: Primary and Secondary Endpoints Number Needed to Treat: 26 -26 patients would need treatment for 1 year to prevent one CV death or 1 hospital admission for worsening HF -Effect mainly driven by hospital admissions for worsening HF -CV deaths not significantly reduced in ivabradine group but deaths due to HF did fall significantly -Hospital admissions significantly reduced -NYHA class (P=0.001) and patient-reported global assessment (P=0.0005) improved in patients significantly -Subgroup of patients taking at least 50% of target daily dose of beta-blocker, effects of ivabradine consistent with overall findings though less marked; the primary composite endpoint (HR 0.90; 95% CI 0.77-1.04; P=0.155); significantly reduced hospital admission by 19% Swedberg K, et al. Lancet. 2010;376: 875-885.

Results: Subgroup Analysis -Results consistent across the subgroups -Patients with higher HR did benefit from ivabradine which is similar to what the BEAUTIFUL trial saw Swedberg K, et al. Lancet. 2010;376: 875-885.

Results: Adverse Events -21% withdrawals in patients assigned to ivabradine and 19% assigned to placebo (P=0.017) -Adverse events similar between groups -Symptomatic and asymptomatic bradycardia more frequent in ivabradine group than in patients taking placebo -Other adverse events include visual symptoms (phosphenes/blurred vision) (If chanel similar to Ih channel in eye) --- -introduce SIGNIFY a little Swedberg K, et al. Lancet. 2010;376: 875-885.

Study Conclusions Ivabradine significantly reduced major risks associated with heart failure In patients treated with ivabradine, relative risk of cardiovascular death or hospital admission for heart failure fell by 18% Shows importance of heart-rate reduction for improvement of clinical outcomes in heart failure -Finding mainly result of favorable effect on heart failure events (death or hospital admission for heart failure) which became apparent within 3 months of initiation and benefits maintained through course of trial -Effect consistent across all presepcified subgroups, although less striking in subgroup with baseline HR lower than median Swedberg K, et al. Lancet. 2010;376: 875-885.

Discussion: Patients and Outcomes Significant difference mainly due to the favorable effect on heart failure events CV and all-cause deaths were not significantly reduced May not benefit patients with a HR < 77 bpm 56% of patients achieved at least 50% of target beta-blocker Primary event rate per year was fairly higher in placebo group (18% per year) compared with what was assumed for power analysis (14% per year) -Subgroup of patients receiving at least 50% of target dose of beta-blocker, effects on CV outcomes were not significant apart from hospital admission for HR -56% of patients achieved at least 50% of target beta-blocker dose but may mirror clinical practice more closely although event risk in patients was fairly high (18% per year in placebo group) despite background therapy; lower rate event in subgroup of patients receiving beta-blockers (13% per year) -Power analysis assumed average yearly incidence of primary composite endpoint of 14% in placebo group (maybe background treatment wasn’t optimized in this study?) Swedberg K, et al. Lancet. 2010;376: 875-885.

Discussion: Patients and Outcomes -Leading reason for failure to reach target dose was hypotension, although mean entry SBP was 122 mmHg -HR of patients included were similar to patients naïve to beta-blockers -SBP value similar to the baseline pretreatment BP in selected recent outcome trials of beta-blockers -Calls into question whether they were truly on maximally tolerated doses of beta-blockers -Patients receiving 50% or more of target beta-blocker doses at baseline had no significant benefit from ivabradine for the primary endpoint, although there was a modest reduction in HF hospitalizations; raises question of whether there would be any benefit if beta-blockers were titrated to near target doses Leading reason for failure to reach target dose was hypotension HR of patients included similar to patients naïve to beta-blockers Teerlinik JR. Lancet. 2010; 376:875-886

Discussion: Adverse Events Patients on ivabradine experienced more events of bradycardia, phosphene-type visual disturbances , atrial fibrillation In SIGNIFY, atrial fibrillation and QT prolongation significant Higher number of withdrawals in the ivabradine group when compared with placebo arm (HR 1.14; 95% CI, 1.02-1.7; P = 0.017) -Higher number of withdrawal in the ivabradine group when compared with the place arm (HR 1.14; 95% CI, 1.02-1.7; P = 0.017); significant number of patients withdrew due to symptomatic and asymptomatic bradycardia -686 (21%) withdrawals in patients assigned to ivabradine and 605 (19%) in those given placebo -SIGNIFY atrial fibrillation, increase Swedberg K, et al. Lancet. 2010;376: 875-885; Fox K, et al. N Engl J Med. 2014; 371 (12) :1091-1099c

Discussion: Current Guidelines Ivabradine approved April 2015 to reduce the risk of hospitalization for worsening HF in CHF with LVEF ≤ 35% with resting HR ≥ 70 bpm  ESC 2012 HF guidelines recommend ivabradine in patients with HR ≥ 70 bpm despite evidence based treatment (Class IIa, Level B) -Indication includes: And either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker -Not in current AHA/ACC guidelines due to recent FDA approval in 2015 (guidelines written in 2013) Corlanor (ivabradine) [package insert]. Thousand Oaks, CA: Amgen Inc.; 2015; McMurray J, et al. Eur Heart J. 2012; 33:1787-1847

Critique Strengths Limitations Study design Based off previous study targeting patients that may benefit from therapy Subgroup analysis Generalizability Limited NYHA Class IV Few patients with ICD or CRT Limited number of elderly patients Did not include any patients from US Medication therapy not optimized Beta-blockers may not have been titrated Used non-recommended beta-blockers Medication compliance not described -Subgroup analysis (patients taking at least 50% of beta-blockers, baseline HR > than median of 77 bpm -Internal validity good, external validity more limited -Many patients with Afib and CHF but drug might not work in Afib due to effect on SA node -Beautiful study, patients with a higher heart rate -Did not include any patients from US; limited minority population

Practical Implications Moving towards HR as possible target of therapy Confirmed importance of titration of beta-blocker therapy Avoid pre-mature initiation of ivabradine Ivabradine may be beneficial in patients who truly cannot tolerate higher doses of beta-blockers and still have elevated HR Patient consideration: compliance, cost Monitor for bradycardia, visual disturbances, atrial fibrillation -Trial showed that rather than ivabradine, the importance of heart-rate reduction in patients with CHF -May be appropriate to target a specific HR in patients with CHF whether that be with beta-blocker titration or addition of ivabradine -Ivabradine may be beneficial in patients who truly cannot tolerate higher doses of beta-blockers: HR still > 77 bpm, symptomatic hypotension, fatigue, COPD/asthma flare -Patient consideration: compliance (another medication added to already medication heavy regimen, patients might stop taking other medications), cost -Cannot be initiated with clinical inertia with beta-blocker -As seen in both SHIFT and BEAUTIFUL, patients with lower HR tended to do better; might be moving towards having HR as possible target of therapy

Acknowledgements Journal Club Mentor: Program Directors: Toni L. Ripley, Pharm.D., BCPS-AQ Cardiology Program Directors: ACCP Cardiology PRN Journal Club Coordinator: Craig Beavers, Pharm.D., FAHA, AACC, BCPS-AQ Cardiology, CACP Maryam Bayat, Pharm.D., BCPS-AQ Cardiology

Ellen B. Yin, Pharm.D. August 27, 2015 Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study Ellen B. Yin, Pharm.D. August 27, 2015

Thank you for attending! If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail.com or craig.beaverspharmd@gmail.com Join us next month when we hear the IMPROVE-IT Trial from Kyle Thorner, PharmD PGY-2 Cardiology at WAKEMED with Dave Dixon, PharmD as mentor