U N I V E R S I T Ä T S M E D I Z I N B E R L I N Hypertonie und Herzinsuffizienz Univ.-Prof. Dr....

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Hypertonie und Herzinsuffizienz

Univ.-Prof. Dr. Burkert Pieske

Department of Internal Medicine and Cardiology

Charité University Medicine, Campus Virchow Klinikum

and

Department of Internal Medicine and Cardiology,

German Heart Center Berlin, Germany

[email protected]

www.cvk-kardiologie.de

www.dhzb.de

Update ESC und EuroPCR 20157.10.2015

Hot Line Clinical Trials ESC 2015

1. Hypertonie

2. Herzinsuffizienz

Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease 2 (CUPID 2) study

A Phase 2b Trial Investigating the Efficacy and Safety of the Intracoronary Administration of AAV1/SERCA2a in Patients with Advanced Heart Failure.

SERCA2a deficiency is pivotal for the progression of Heart Failure

ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD) J Am Coll Cardiol. 2008;51:1112-1119;

ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)

SERCA2a deficiency is pivotal for the progression of Heart Failure

J Mol Cell Cardiol. 2007;42:852-861; Byrne M, et.al. Gene Ther. (24 Jul 2008); Surg Clin N Am 84 (2004) 141–159

CUPID 2 - Main Inclusion and Exclusion Criteria

Inclusion• 18-80 years of age• Diagnosis of NYHA Class II-IV chronicHF due to ischemic or non-ischemiccardiomyopathy• LVEF ≥ 0.35• Optimal tolerated stable medicaltherapy for ≥30 days• Elevated natriuretic peptide or historyof HF-related hospitalization within 6months of enrollment• <1:2 or equivocal anti-AAV1neutralizing antibody

Exclusion• Hypertrophic, restrictive and obstructivecardiomyopathy; acute myocarditis;amyloidosis; discrete LV aneurysm• Cardiac surgery, PCI, valvuloplasty or IVtherapy for HF within 30 days prior toscreening• Surgically implanted LVAD• Significant liver or renal impairment (>3xULN; GFR ≤20 mL/min/1.73 m2)• History of cancer within the past 5 years• Active infection

Greenberg B, Yaroshinsky A, Zsebo KM, et al. J Am Coll Cardiol HF 2014;2:84.92ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)

Primary Efficacy Endpoint: Time to recurrent HF-related hospitalizations and ambulatory WHF in presence of terminal events (all-cause death, transplant, dMCS)

Secondary Efficacy Endpoint: Time to first terminal event (all-cause death, transplant, dMCS)

Exploratory Endpoints: NYHA class, NT-proBNP, 6MWT & KCCQ QOL

Safety Endpoints: Disposition, clinical events; AEs including procedure-related AEs; changes in medications, vital signs & weight, physical exam, 12-lead ECG, ICD & lab parameters; time to CV-related death

CUPID 2 - Endpoints

Greenberg B, Yaroshinsky A, Zsebo KM, et al. J Am Coll Cardiol HF 2014;2:84.92ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)

Design of a Phase 2b Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Advanced Heart Failure: The CUPID 2 Trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b)

JCHF. 2014;2(1):84-92. doi:10.1016/j.jchf.2013.09.008

CUPID 2 – Study design

CUPID 2 – Patient population flow chart


CUPID 2 – Patient characteristics


CUPID 2 – Primary Endpoints


Of the 232 recurrent events that qualified as primary endpoints, 128 were in the placebo group and 104 were in the AAV1/SERCA2a group

Treatment with AAV1/SERCA2a failed to improve the rate of recurrent events (HR, 0·93; 95% confidence interval [CI] 0·53 to 1·65; p=0·81)

CUPID 2 – Secondary Endpoints


Of the 65 terminal events that qualified as secondary endpoints, 29 were in the placebo group and 36 were in the AAV1/SERCA2a group

Treatment with AAV1/SERCA2a failed to improve time to first terminal event (HR, 1·27; 95% CI 0·72 to 2·24; p=0·40)

CUPID 2 failed to support the hypothesis that AAV1/SERCA2a at the dose used has clinicalbenefits in patients with moderate to severeheart failure and reduced ejection fraction

CUPID 2 – Summary

Effect of implanted device-based impedance monitoring with telemedicine alerts on mortality and morbidity in heart failure: results

from the OptiLink HF study

Does Intrathoracic Impedance Monitoring with an Automatic Wireless Telemedicine Notification Compared to Standard Clinical Assessment Reduces All-cause Death or Cardiovascular Hospitalizations?

OptiLink HF: Inclusion Criteria

ESC London 2015 - Hotline Session; Heart Failure

ICD Indication according to SCD-HeFTChronic Heart Failure (HF), NYHA II – III, LVEF <= 35%, Optimized Medical Therapy (OMT)

CRT-ICD Indication according to the ESC Guidelines (2008) Chronic Heart Failure (HF), only NYHA III, LVEF <= 35%, QRS >= 120msec , LVEDD >= 55mm

Optimized Medical Therapy (OMT)


Additional inclusion criteria


OptiLink HF Study Design

Brachmann J, et al. Eur J HF. 2011;13(7):796-804.

Telemedicine guided intervention

OptiLink HF: Primary endpoint all cause death or CV hospitalisation


Treatment of Sleep-Disordered Breathing With Predominant Central Sleep Apnoea by adaptive Servo Ventilation in Patients With Heart

Failure and Reduced Ejection Fraction (SERVE-HF)

Adaptive Servo-Ventilation (ASV)• ASV is a non-invasive ventilatory therapy that supports inspiration whenbreathing amplitude is reduced and ensures sufficient respiration whenrespiratory effort is absent (variable IPAP)

• Upper airway patency is ensured by provision of end-expiratory pressure(fixed or variable EPAP)

• Although algorithms employed by different ASV devices vary slightly, theprinciple of treatment is the same: back-up rate ventilation with adaptivepressure support

Cowie et al. Eur Cardiol Rev 2015.

• 91 centres in 11 countries (Germany, France, UK, Sweden, Australia,Denmark, Norway, Czech Republic, Finland, Switzerland, Netherlands)• Randomized, parallel, event-driven design• Guideline-based medical management:– Alone (control group)– Plus ASV (Auto Set CS™, ResMed)• ASV titration in hospital (PG or PSG)– Starting at default settings– Expiratory positive airway pressure manually increased to controlobstructive sleep apnoea (OSA) and maximum pressure supportincreased to control central sleep apnoea (CSA)


SERVE-HF: Design

• Primary composite endpoint:– Time to first event of all-cause death, life-saving cardiovascularintervention*, or unplanned hospitalization for worseningchronic HF• Secondary endpoints:– As for primary endpoint, but cardiovascular vs all-cause death– As for primary endpoint, but all-cause vs unplanned hospitalization forworsening chronic HF– Time to death (all-cause)– Time to cardiovascular death– Change in NYHA class– Change in 6MWD– Quality of life


SERVE-HF: Endpoints

Inclusion Criteria• Age ≥22 years• Chronic stable HF (ESC guidelines,no hospitalization within 4weeks)• LV systolic dysfunction– LVEF ≤45%• NYHA class III or IV– Or NYHA class II with ≥1hospitalization for HF in previous24 months• Predominant CSA (AHI >15/h with≥50% central events and centralAHI ≥10/h)

Exclusion Criteria• Significant COPD• Oxygen saturation <90% at restduring the day• Current use of positive airwaypressure therapy• Cardiac surgery orresynchronization therapy withinthe previous 6 months• TIA or stroke in previous 3months• Significant valvular heart disease• Contraindications to ASV



Primary Endpoint: Neutral


All cause death


Cardiovascular death

Randomized Trial of Benznidazolefor Chronic Chagas CardiomyopathyBENznidazole Evaluation For Interrupting Trypanosomiasis(BENEFIT Trial)

BENEFIT

Study Design

BENEFIT Trial Flow and Adherence

Baseline Characteristics

Primary Outcome

Primary Outcome Components

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Hypertonie und Herzinsuffizienz Univ.-Prof. Dr....

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