11/28/18 1 Late - Breaking Cardiology Trials from 2018 David J. Cohen, M.D., M.Sc. Director, Cardiovascular Research Saint - Luke’s Mid America Heart Institute Professor of Medicine University of Missouri - Kansas City Disclosures Grant Support/Drugs – Daiichi - Sankyo - Merck – Astra - Zeneca Grant Support/Devices – Edwards Lifesciences - Abbott Vascular – Medtronic - Boston Scientific – CSI - Corvia – V - Wave Medical Consulting/Advisory Boards – Medtronic - Edwards Lifesciences DJC: 11/18
Transcript
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Late-Breaking Cardiology Trials from 2018
David J. Cohen, M.D., M.Sc.
Director, Cardiovascular ResearchSaint-Luke’s Mid America Heart Institute
Professor of MedicineUniversity of Missouri-Kansas City
Disclosures
Grant Support/Drugs– Daiichi-Sankyo - Merck– Astra-Zeneca
Grant Support/Devices– Edwards Lifesciences - Abbott Vascular– Medtronic - Boston Scientific– CSI - Corvia– V-Wave Medical
1. Age ≥45 years with established CVD (Secondary Prevention Cohort) or ≥50 years with diabetes with ≥1 additional risk factor for CVD (Primary Prevention Cohort)
2. Fasting TG levels ≥150 mg/dL and <500 mg/dL*
3. LDL-C >40 mg/dL and ≤100 mg/dL and on stable statin therapy (± ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization
Key Inclusion Criteria – REDUCE-IT
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One or more of the following:1. Documented coronary artery disease
• Multi vessel CAD (≥50% stenosis in ≥2 major epicardial coronary arteries – with or without
antecedent revascularization
• Prior MI
• Hospitalization for high-risk non-ST-segment elevation acute coronary syndrome with
ST-segment deviation or biomarker positivity
2. Documented cerebrovascular or carotid disease
• Prior ischemic stroke
• Symptomatic carotid artery disease with ≥50% carotid arterial stenosis
• Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis
• History of carotid revascularization
3. Documented peripheral artery disease
• Ankle-brachial index <0.9 with symptoms of intermittent claudication
• History of aorto-iliac or peripheral artery intervention
Inclusion Criteria for 2° Prevention Cohort
1. Diabetes mellitus requiring medication AND
2. ≥50 years of age AND
3. ≥1 additional risk factor for CVD• Men ≥55 years and women ≥65 years• Cigarette smoker or stopped smoking within 3 months• Hypertension (≥140 mmHg systolic OR ≥90 mmHg diastolic) or on antihypertensive medication; • HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women • hsCRP >3.0 mg/L • Renal dysfunction: Creatinine clearance >30 and <60 mL/min • Retinopathy• Micro- or macroalbuminuria• ABI <0.9 without symptoms of intermittent claudication
Inclusion Criteria for 1° Prevention Cohort
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CONSORT Diagram
Screened
N=19,212
Randomized
N=8179(43% of screened)
Icosapent Ethyl
N=4089 (100%)Placebo
N=4090 (100%)
Completed Study N=3684 (90.1%) Completed Study N=3630 (88.8%)
Countries 11Sites 473
Incl./Excl. criteria not met 10,429Withdrawal of consent 340Adverse event 13Primary Prevention category closed 4Death 5Lost to follow-up 108Enrollment closed 3Other 135
Early Discontinuation from Study N=405 (9.9%)
Actual vs. potential total follow-up time (%) 93.6%Known vital status 4083 (99.9%)
Early Discontinuation from Study N=460 (11.2%)
Actual vs. potential total follow-up time (%) 92.9%Known vital status 4077 (99.7%)
Screen Fails N=11,033*
*4 patients presented 2 screen failure reasons.
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018. Median trial follow up duration was 4.9 years.
Key Baseline CharacteristicsIcosapent Ethyl
(N=4089)Placebo(N=4090)
Age (years), Median (Q1-Q3) 64.0 (57.0 - 69.0) 64.0 (57.0 - 69.0)Female, n (%) 1162 (28.4%) 1195 (29.2%)Non-White, n (%) 398 (9.7%) 401 (9.8%)Westernized Region, n (%) 2906 (71.1%) 2905 (71.0%)CV Risk Category, n (%)
Icosapent Ethyl Triglyceride <150 mg/dL vs Placebo
Icosapent Ethyl Triglyceride ≥150 mg/dL vs Placebo
Icosapent Ethyl Triglyceride <150 vs ≥150 mg/dL
0 1 2 3 4 50
20
40
60
80
90
70
50
30
10
100
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
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REDUCE-IT: Why is it Important?
• Suggests a new approach to primary and secondary coronary
prevention– including ¯’d CV mortality-- in a particularly challenging
group of patients
• One of the few approaches to CV risk prevention to show benefit in
primary prevention in diabetic patients
• Opens the door for new research into mechanisms of benefit, which
may lead to further advances in CV prevention
REDUCE-IT: Why is it Controversial?
• Findings conflict with many previous trials of n-3 fatty acids including the NIH-sponsored VITAL trial
• Mechanism of benefit unclear– High dose of EPA?
– Unique property of icosapent ethyl preparation?
– Benefit seems to be of baseline TG level and of achieved level of TG reductionà ? Other properties of EPA (antiarrhythmic, anticoagulant, antiinflammatory)
• Ongoing trials (STRENGTH, RESPECT-EPA) should help clarify some of these issues
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• TRED-HF
TRED-HF: Background
• Many patients who present with dilated cardiomyopathy make a full recovery with guideline-directed medical therapy with normalization of LV function, biomarkers, and symptoms
• These patients often ask whether lifelong therapy is necessary– Cost and inconvenience of medications
– Medication side effects
– Interest in becoming pregnant
• No high quality, prospective data on the feasibility of medication withdrawal in this population
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Study Objectives
• Determine the feasibility of phased withdrawal of HF medications in patients with recovered dilated cardiomyopathy
• Assess the safety of this approach with respect to symptoms and HF-related events
• Identify predictors of ability/inability to withdraw therapy
TRED-HF
Inclusion/Exclusion Critera
Prior diagnosis of dilated CMP with LVEF <40% at diagnosis
Subsequent full recovery• LVEF >50%• Normal LVEDV index• NT-pro-BNP <250 ng/L• Asymptomatic/NYHA Class I
• Sustained arrhythmia• Resting HR, Exercise time, VO2 max, KCCQ
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BaselineCharacteristics
Therapy Withdrawal (n=25) Control (n=26)DemographicsMedian age (IQR), yrs 54 (46,64) 56 (45,64)Men, n (%) 16 (64) 18 (69)Previous cardiovascular historyTime since initial DCM diagnosis, months 63 (36,112) 41 (20, 91)LVEF at initial diagnosis, % 28 (20,33) 25 (19,33)Time since LVEF>50%, months 28 (8,45) 20 (6,44)Previous moderate alcohol excess, n (%) 8 (32) 9 (35)Previous atrial fibrillation, n (%) 8 (32) 4 (15)AetiologyIdiopathic, n (%) 20 (80) 15 (58)Familial, n (%) 3 (12) 4 (15)Environmental insult, n (%) 2 (8) 7 (27)Medications at enrolmentACE inhibitor /ARB, n (%) 25 (100) 26 (100)Beta-blocker, n (%) 21 (84) 24 (92)Mineralocorticoid receptor antagonist, n (%) 12 (48) 12 (46)Loop diuretic, n (%) 3 (12) 3 (12)Clinical characteristics at enrolmentHeart rate, beats per minute 62 (58,74) 70 (60,75)Systolic blood pressure, mmHg 123 (117,133) 127 (117,134)Diastolic blood pressure, mmHg 72 (68,80) 76 (70,80)NT-pro-BNP, ng/l 72 (44,147) 75 (37,133)CMR variables at enrolmentLVEDVi, ml/m2 86 (66, 91) 80 (70,91)LVEF, % 62 (55, 66) 60 (55,61)
Halliday BP, et al. Lancet 2018
Results: Primary EndpointTRED-HF
Primary Endpoint: Relapse
6 month event rates 44% vs. 0%P= 0.0001
• Only 50% of pts completed therapy withdrawal without re-initiation of rx
• Relapse rate similar in crossover population (30%)
• No death, MACE, or HF hospitalization
• 3 pts had AF, no VT
• After re-initiation of therapy, all pts were asymptomatic and 17/20 had EF >50%
Halliday BP, et al. Lancet 2018
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Results: Secondary EndpointsTRED-HF
Halliday BP, et al. Lancet 2018
Change in LVEF
Control Withdrawal
Change in NT-pro-BNP
• Other Changes
• Significant increase in HR (13 bpm)
• Significant decrease in KCCQ-OS (5 pts)
Predictors of RelapseTRED-HF
Halliday BP, et al. Lancet 2018
Characteristic Hazard Ratio (95% CI) P-Value
Age (per 10 yrs) 1.6 (1.0 to 2.4) 0.031
# of HF medications 0.004
1 or 2 reference
3 3.7 (1.3 to 10.6)
4 4.8 (1.1 to 20.2)
Log NT-pro-BNP, ng/L 1.8 (1.1 to 2.8) 0.016
Global radial strain 0.55 (0.34 to 0.90) 0.018
* Univariate analysis (exploratory)
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Summary/Conclusions
• In patients with dilated cardiomyopathy who appear to have “recovered”, withdrawal of guideline-directed therapy resulted in relapse in ~40% of cases within 6 months
– Likely to be even greater in medium- and long-term
• Based on these findings, withdrawal of therapy should not usually be attempted, until predictors of relapse are more clearly defined
• If withdrawal of therapy is attempted, careful monitoring of multiple parameters (LVEF, LVEDVi, NT-pro-BNP, symptoms) is required.
– Cardiac MRI may be particularly useful given its reproducibility and precision
TRED-HF
Why is this trial important?
• Demonstrates that for many patients with dilated cardiomyopathy, clinical and mechanistic improvement represents “remission” rather than true recovery
• Demonstrates that not every meaningful clinical trial needs to be a 10,000 patient, industry sponsored megatrial
– 50 patient, single center trial run by a small group of careful, committed investigators
TRED-HF
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Conclusions
• In patients with dilated cardiomyopathy who appear to have “recovered”, withdrawal of guideline-directed therapy resulted in relapse in ~40% of cases within 6 months–Likely to be even greater in medium- and long-term
• Based on these findings, withdrawal of therapy should not usually be attempted, until predictors of relapse are more clearly defined
• If withdrawal of therapy is attempted, careful monitoring of multiple parameters (LVEF, LVEDVi, NT-pro-BNP, symptoms) is required. MRI may be particularly useful given its reproducibility and precision
• Demonstrates that not every meaningful clinical trial needs to be a 10,000 patient, industry sponsored megatrial
– 50 patient, single center trial run by a group of careful, committed investigators
