ECG in CRT patients & novel HF therapies · 2016. 4. 9. · Dominant R in lead V1 corresponds to a...

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Δημήτριος M. Κωνσταντίνου Ειδικός Καρδιολόγος, MD, MSc, PhD, CCDS Πανεπιστημιακός Υπότροφος ECG in CRT patients & novel HF therapies

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Transcript of ECG in CRT patients & novel HF therapies · 2016. 4. 9. · Dominant R in lead V1 corresponds to a...

  • Δημήτριος M. Κωνσταντίνου

    Ειδικός Καρδιολόγος, MD, MSc, PhD, CCDS

    Πανεπιστημιακός Υπότροφος

    ECG in CRT patients & novel HF therapies

  • Dr. Konstantinou has received grants from Medtronic®

  • Is identification of LV pacing site feasible from

    surface ECG analysis?

    J Electrocardiol 2014;47(2):202-11

  • Baseline ECG

    AF, LBBB, QRSd=160ms

    2013 ESC guideline

  • Dominant R in lead V1 corresponds to a LV lead position towards the free wall Predominately -ve QRS complex in lead aVF (i.e. superior axis) indicates an inferolateral position Early transition to a predominately -ve QRS complex in chest leads is suggestive of an apical position

    Post-CRT

  • Quadripolar LV leads introduce additional layers of complexity…

  • BiV pacing

    Baseline ECG

  • Cardiol J 2011;18(6):610-24

    LV only pacing

  • LV pacing does not necessarily results in a -ve QRS in lead I

    When LV pacing is performed from the basis of the LV, especially in dilated and leftward displaced hearts, the activation spreads from basis to apex and from right to left, resulting a +ve QRS in lead I

    Journal of Atrial Fibrillation 2015;7(6)

    A very basal LV lead position can produce a prominent R wave in I lead

  • Suboptimal (i.e.

  • Baseline ECG

  • Post-CRT

    BiV paced beats Pseudofusion beats

  • Post AVJ ablation

  • Baseline ECG

  • Pseudofusion BiV PVC

    PVCFusion

    Post-CRT

  • Baseline ECG Post-CRT

    Which of the QRS complexes represent biV pacing and which are the result from fusion?

  • “The marked narrowing of the QRS complex in lead V1 strongly suggests ventricular fusion with the intrinsic QRS complex rather than QRS narrowing from satisfactory BiV pacing...”

    Ann Noninvasive Electrocardiol 2005;10:231-55

  • SR, 1st degree AV block (PR=220ms)LBBB (QRSd=140ms)

    Baseline ECG

  • Paced QRSd=160msQRS morphology

    Lead I: rsLeads II, III, avF: QS

    Lead V1: Rsr’

    Why QRS doesn’t get narrower?

    Post-CRT

  • Some fusion may not be detrimental after all

    • The effect of the underlying PR interval duration may be explained in terms of “concealed resynchronization”

    • Ventricular activation in patients with a normal PR interval may have resulted from fusion of electrical wave fronts coming from the right bundle branch and the impulse from the LV electrode

    • Hemodynamic response may thereby be superior as detrimental effects of RV apical stimulation are avoided

    • The wider QRS width during BiV pacing in patients with a long PR interval supports this hypothesis

    Pacing Clin Electrophysiol 2005;28:754-61

  • Please note that devices work better in medically

    optimized patients!

    Device based therapy is only the fifth step in HF treatment

    algorithm!!!

    2012 ESC guideline

  • Emerging Heart Failure Therapies

  • Novel Targets in Heart Failure

    SNS

    RAAS

    VasoconstrictionBlood pressure

    Sympathetic toneAldosteroneHypertrophy

    Fibrosis

    Ang II AT1R

    HFrEFSYMPTOMS & PROGRESSION

    Epinephrine

    Norepinephrineα1, β1, β2receptors

    VasoconstrictionRAAS activity

    VasopressinHeart rate

    Contractility

    RAAS inhibitors

    (ACEI, ARB, MRA)

    β-blockers

    Natriuretic peptide

    system

    VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

    NPRs NPs

    1. McMurray et al. Eur Heart J 2012;33:1787–847Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte.

    Cardiovascular Pathology 2012;365–371; Schrier & Abraham. N Engl J Med 1999;341:577–85

    The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1

    Benefits of β-blockers indicate that the SNS also plays a key role1

  • Vasorelaxation

    Blood pressure

    Sympathetic tone

    Aldosterone levels

    Fibrosis

    Hypertrophy

    Natriuresis/diuresis

    Inactive

    fragments

    ANP, BNP, CNP, othervasoactive peptides*

    AT1 Receptor

    Vasoconstriction

    Blood pressure

    Sympathetic tone

    Aldosterone

    Fibrosis

    Hypertrophy

    Angiotensinogen(liver secretion)

    Ang I

    Ang II

    RAAS

    LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks AT1 receptors (via valsartan)

    LCZ696

    Sacubitril (AHU377; pro-drug)

    InhibitingEnhancing

    LBQ657(NEP inhibitor)

    OH

    OHN

    O

    HO

    O

    Valsartan

    N

    NHN

    N

    N

    O

    OH

    O

    *Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNPLevin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42;

    Schrier & Abraham N Engl J Med 1999;341:577–85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9;Feng et al. Tetrahedron Letters 2012;53:275–6

  • PARADIGM-HF: The most geographically diverse trial in patients with HFrEF

    1. McMurray et al. Eur J Heart Fail. 2014;16:817–25; 2. McMurray et al. Eur J Heart Fail 2013;15:1062–73

    8442 patients were randomized at 985 sites in 47 countries

  • Characteristic*LCZ696 (n=4187)

    Enalapril (n=4212)

    Age, years 63.8 ± 11.5 63.8 ± 11.3

    Women, n (%) 879 (21.0) 953 (22.6)

    Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1)

    LV ejection fraction, % 29.6 ± 6.1 29.4 ± 6.3

    NYHA functional class, n (%)II III

    2998 (71.6)969 (23.1)

    2921 (69.3)1049 (24.9)

    SBP, mmHg 122 ± 15 121 ± 15

    Heart rate, beats/min 72 ± 12 73 ± 12

    NT pro-BNP, pg/mL (IQR) 1631 (885–3154) 1594 (886–3305)

    BNP, pg/mL (IQR) 255 (155–474) 251 (153–465)

    History of diabetes, n (%) 1451 (34.7) 1456 (34.6)

    Treatments at randomization, n (%)

    Diuretics 3363 (80.3) 3375 (80.1)

    Digitalis 1223 (29.2) 1316 (31.2)

    β-blockers 3899 (93.1) 3912 (92.9)

    Mineralocorticoid antagonists 2271 (54.2) 2400 (57.0)

    ICD 623 (14.9) 620 (14.7)

    CRT 292 (7.0) 282 (6.7)

    PARADIGM-HF: baseline characteristics

    *mean ± standard deviation, unless statedMcMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

  • Primary endpoint:

    Death from CV causes or first hospitalization for HF

    McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

    Hazard ratio = 0.80 (95% CI: 0.73–0.87)P=0.0000004

    Days since randomizationNo at riskLCZ696 4187 3922 3663 3018 2257 1544 896 249Enalapril 4212 3883 3579 2922 2123 1488 853 236

    Cu

    mu

    lati

    ve p

    rob

    abili

    ty

    1.0

    0.6

    0.4

    0.2

    0

    0 180 360 540 720 900 1080 1260

    Enalapril

    LCZ696

  • In the PARADIGM-HF trial, CV causes accounted for 81% of all deaths

    Sudden death, 36%

    Presumed sudden death, 3%

    Worsening HF; 21%

    Fatal MI; 4%

    Fatal stroke, 4%

    Presumed CV death, 10%

    Other CV death, 2%

    Unknown; 4%Non-CV death,

    15%

    45% of CV deaths

    26% of CV deaths

    Desai et al. Eur Heart J 2015; epub ahead of print: DOI:10.1093/eurheartj/ehv186

    ACEI=angiotensin-converting-enzyme inhibitor; ARNI=angiotensin receptor neprilysin inhibitor; CV=cardiovascular; HF=heart failure; MI=myocardial infarction; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure

  • • Resuscitated sudden deaths* occurred in 16 patients receiving LCZ696 versus 28 patients receiving enalapril (HR 0.57, 95% CI: 0.31–1.04, p=0.07). Further, LCZ696 significantly reduced the risk of combined resuscitated and non-resuscitated sudden deaths by 22% when compared with enalapril (HR 0.78, 95% CI: 0.66–0.92, p=0.002)

    LCZ696 significantly reduced the number of sudden cardiac deaths compared with enalapril

    Desai et al. Eur Heart J 2015; epub ahead of print: DOI:10.1093/eurheartj/ehv186;

    Data on file. Clinical Study Protocol CLCZ696B2314

    Hazard ratio = 0.80 (95% CI: 0.68–0.94) p=0.008

    Enalapril

    LCZ696

    0 180 360 540 720 900 1,080 1,260

    0

    0.02

    0.04

    0.06

    0.08

    0.10

    Days since randomizationNo. at riskLCZ696 4,187 3,891 2,478 1,005Enalapril 4,212 3,860 2,410 994

    Cu

    mu

    lati

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    f ev

    ent

    *Resuscitated sudden deaths were defined as successful resuscitation following cardiac arrest

    CI=confidence interval; HR=hazard ratio

  • The LCZ696 treatment effect for sudden cardiac death was not influenced by the presence of implantable defibrillator devices

    Desai et al. Eur Heart J 2015; epub ahead of print: DOI:10.1093/eurheartj/ehv186

    Sudden cardiac death n (%)

    Hazard ratio, LCZ696 vs enalapril(95% CI)

    p-value for interaction

    ICD 525 (93.6%) 0.82 (0.69–0.98)

    0.17+ICD 36 (6.4%) 0.49 (0.25–0.98)

    CI=confidence interval; ICD=implantable cardioverter defibrillator; vs=versus

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