true ahf and fragmented qrs in adult pts with tof

1. JOURNAL CLUB
26-5-2017

3. INTRODUCTION
• Acute presentation with new-onset heart failure and rapid
worsening of preexisting heart failure - most common causes
of hospitalization worldwide.
• The disorder in each case is characterized by intravascular
volume expansion and ventricular distention, which may
cause myocardial injury in the absence of coronary artery
disease or occlusion.
• The first few hours after the initial presentation with acute
heart failure may represent a period of substantial myocardial
vulnerability, which is characterized by rapid increases in
cardiac-wall stress.

4. • Patients with acute heart failure have elevated levels of N-
terminal pro–brain natriuretic peptide (NT-proBNP) and
cardiac troponin, thus mimicking features of an acute
coronary syndrome.
• These observations have led to the hypothesis that very early
short term interventions that attenuate cardiac-wall stress
may reduce myocardial injury during a critical period and have
favorable long-term effects.

5. • In the Trial of Ularitide Efficacy and Safety in Acute Heart
Failure (TRUE-AHF), investigators examined whether the
prompt administration of the natriuretic peptide ularitide in
doses sufficient to reduce myocardial-wall stress would
reduce the long-term risk of cardiovascular death in patients
with acute heart failure.
• Ularitide, a chemically synthesized analogue of the naturally
occurring vasodilator urodilatin, was selected as the study
drug because it had been associated with hemodynamic and
clinical benefits in two previous randomized clinical trials.

6. METHODS

7. TRIAL DESIGN AND OVERSIGHT
• TRUE-AHF was a randomized, double-blind,parallel-group,
placebo-controlled, event-driven trial.

8. INCLUSION CRITERIA
• Men and women between the ages of 18 and 85 years with
following features:
1) An unplanned emergency department visit or hospitalization
for acute heart failure,
2) Dyspnea at rest that had worsened during the previous
week,
3) Evidence of heart failure on chest radiography,
4) Blood BNP level of more than 500 pg per milliliter or an NT-
proBNP level of more than 2000 pg per milliliter,
5) Possibility of initiating the study drug within 12 hours after
the initial clinical evaluation.

9. • Patients who continued to have dyspnea at rest for at least 2
hours after the intravenous administration of at least 40 mg of
furosemide (or the equivalent) and who had a SBP between
116 mm Hg and 180 mm Hg were eligible for randomization.

10. EXCLUSION CRITERIA
• USE OF MEDICATIONS OR INTERVENTIONS
a) Change in the rate of ongoing intravenous infusions within 2
hours before randomization.
b) Treatment with intravenous dobutamine at a dose > 5
μg/kg/min or use of any drug for support of blood pressure
at the time of randomization.
c) Treatment with intravenous levosimendan, milrinone or any
other phosphodiesterase inhibitor within 7 days before
randomization
d) Treatment with intravenous nesiritide within 30 days before
randomization
e) Requirement for mechanical circulatory support

11. • PRESENCE OF CERTAIN CARDIAC CONDITIONS
a) Clinically suspicion of an acute mechanical cause of acute
heart failure (e.g., papillary muscular rupture)
b) Clinical diagnosis of acute coronary syndrome fulfilling 2/3
criteria: (a) prolonged chest pain at rest or an accelerated
pattern of angina; (b) ECG changes indicative of ischemia or
myocardial injury; (c) serum troponin > 3 times upper limit
of normal
c) Planned coronary revascularization procedure (PCI/CABG)
within 5 days of randomization
d) Known active myocarditis, obstructive hypertrophic
cardiomyopathy, congenital heart disease, restrictive
cardiomyopathy, constrictive pericarditis or uncorrected
clinically significant primary valvular disease

12. • ASSOCIATED NONCARDIAC CONDITIONS
a) Creatinine clearance < 30 mL/min/1.73 m2 at screening
b) Patients with severe hepatic impairment
c) Acute or chronic respiratory disorder (e.g., severe COPD) or
primary pulmonary hypertension sufficient to cause dyspnea
at rest
d) Anemia (hb < 9 g/dL or a hematocrit < 25%)
e) Known systemic inflammatory response (e.g., vasculitis) or
suspected infections (e.g., pneumonia, acute hepatitis, active
infective endocarditis, SIRSor sepsis)
f) Body temperature ≥ 38°C prior to randomization.
g) Terminal illness other than heart failure with an expected
survival <180 days

13. PROCEDURES
• Patients underwent randomization in a 1:1 ratio in a double-
blind manner to receive a continuous intravenous infusion of
either ularitide at a dose of 15 ng per kilogram of body weight
per minute or matching placebo for 48 hours.
• Investigators used a patient global assessment to inquire
about changes in symptoms of heart failure at 6, 24, and 48
hours after the initiation of the study infusion .
• Levels of NT-proBNP and high-sensitivity troponin T were
assessed before the start of the infusion and after 48 hours.
• At 48 hours, the study-drug infusion was stopped.
• Patients were followed for the occurrence of rehospitalization
for 6 months and for the occurrence of death for the entire
duration of the trial.

14. PRIMARY AND SECONDARY OUTCOMES
The trial had two primary outcomes:
a) Cardiovascular death over the entire duration of the trial
b) Clinical course of patients during the first 48 hours, assessed
by a hierarchical clinical composite end point

16. SECONDARY ENDPOINTS
 Length of stay of index hospitalization in hours after start of
study drug infusion up to 30 days.
 Length of stay in intensive care during the first 120 hours
following the start of the study drug infusion.
 Number of events of persistent or worsening heart failure
requiring a specified intervention from the start of the study
drug infusion to 120 hours.
 Proportion of patients with persistent or worsening heart
failure and requiring a specified intervention from the start
of study drug infusion to 120 hours.

17.  Rehospitalization for heart failure within 30 days after initial
hospital discharge.
 Change of N-terminal pro-brain natriuretic peptide (NT-pro
BNP) at 48 h of treatment compared to baseline.
 Change in serum creatinine from baseline through 72 hours
 Combined all-cause mortality or cardiovascular
rehospitalization through day 180 after start of study drug
infusion, including patients still hospitalized at day 30.

18. STATISTICAL ANALYSIS
• The sample size was based on the primary efficacy analysis of
cardiovascular mortality, which was tested at a two-sided
significance level of 0.04.
• Investigators evaluated time-to-event data with Kaplan–Meier
estimates and used Cox proportional-hazards models to
calculate hazard ratios, 96% confidence intervals, and two-
sided P values for the risk of cardiovascular death, using age,
sex, baseline SBP(<140 mm Hg vs. ≥140 mm Hg), time from
the first clinical evaluation until the initiation of the study-
drug infusion (≤6 hours vs. >6 hours)as prespecified
covariates.

19. RESULTS

21. BIOMARKERS OF DRUG RESPONSE
The mean decrease in SBP in the ularitide group was greater by 6.8 mm Hg at 6 hours
and by 3.9 mm Hg at 48 hours than in the placebo group (P<0.001 for both
comparisons); these between-group differences dissipated over a period of 72 to 120
hours.

23. SAFETY
• Patients in the ularitide group were more likely than those in
the placebo group to have hypotension and to discontinue
treatment because of it.

24. DISCUSSION
• In the TRUE-AHF trial, ularitide exerted its expected short-
term hemodynamic effects.
• The drug produced systemic vasodilation (as evidenced by
decreases in SBP), which was accompanied by decreases in
NT-proBNP levels (reflecting a reduction in cardiac-wall
stress).
• Both the hematocrit and serum creatinine levels increased
during the infusion, pointing to hemoconcentration and to
aggressive decongestion; these effects were paralleled by a
decrease in the rate of in hospital heart-failure events during
the infusion.

25. • A reduction in cardiac-wall stress that is achieved rapidly after
clinical presentation might be expected to reduce myocardial
necrosis, preserve ventricular function, maintain clinical
stability, and reduce the long-term risk of cardiovascular
death.
• Even though the time from clinical evaluation to
pharmacologic intervention was shorter than in previous
studies, and despite evidence of meaningful cardiac
decongestion, the long-term risk of cardiovascular death was
not reduced among patients who received ularitide.

26. • Trial findings differed from those of the RELAX-AHF trial, in
which treatment with the vasodilator serelaxin (at a median
of 7 hours after clinical evaluation) led to decreases in NT-
proBNP levels and in rates of in-hospital worsening of heart
failure, reductions that were followed by decreases in
cardiovascular mortality.
• In the RELAX-AHF trial, the reported survival benefits may
have been due to chance, since investigators did not
adjudicate in-hospital heart failure events, the trial was not
designed to reliably evaluate the risk of cardiovascular death,
and the reduced risk of death was least apparent among
patients who received very early therapy.

27. • Hypotension was an expected side effect of ularitide.
• In other large-scale trials involving patients with acute heart
failure, hypotension that was reported before the initiation of
the infusion or during the infusion was associated with
unfavorable effects on morbidity and mortality, which
suggests that hypotension may limit the benefits of any
reduction in cardiac-wall stress.

28. CONCLUSIONS
• Ularitide reduced cardiac-wall stress more markedly than
placebo, as indicated by more rapid reduction in NT-proBNP
levels.
• However, in an intention-to-treat analysis,the drug did not
reduce myocardial injury (as indicated by cardiac troponin T
levels), did not affect a clinical composite end point, and did
not influence disease progression, as shown by the lack of
effect on cardiovascular mortality.

29. HEART NOVEMBER 2016

30. INTRODUCTION
• In patients with tetralogy of Fallot (TOF), right ventricular (RV)
dysfunction is thought to contribute to late complications and
has been related with QRS duration.
• Severe QRS prolongation has been widely recognised as a risk
factor for mortality in adults with TOF.
• However, sensitivity of QRS >180 ms for mortality was lower
than 50% in recent studies.
• In patients with coronary artery disease, the fragmentation of
QRS (fQRS) complexes has been identified as an independent
predictor of cardiac events.

31. • Recent studies revealed that fqrs is strongly related with
regional rv dysfunction and myocardial fibrosis in adult
patients with tof.
• Myocardial fibrosis is associated with deterioration of
myocardial contractility, and may serve as a substrate for
arrhythmias.
• However, the prognostic significance of fqrs in adults with tof
remains unknown.
• Trial’s primary objective was to determine whether the
presence and extent of fqrs predict all-cause mortality in
adults with tof.

32. METHODS
• Investigators used the prospective Dutch nationwide
congenital corvitia (CONCOR) registry to identify patients with
TOF, in one of the six participating centres.

33. ELECTROCARDIOGRAM
• The standard 12-lead ECG (25 mm/s, 10 mm/mV) at time
closest to CONCOR inclusion was retrieved.
• All ECGs were analysed by a single observer blinded to patient
characteristics and clinical data.
• The rhythm, rate, morphology and duration of QRS were
determined.
• QRS complexes were assessed on the presence of
fragmentation on each lead. Most patients had right bundle
branch block (RBBB).
• In these patients, QRS fragmentation was defined as ≥3 R-
waves/ notches in the R/S complex (more than typical 2 in
RBBB) in ≥2 contiguous leads (right sided/septal: aVR, V1, V2;
anterior: V2–V5; lateral: I, aVL, V5, V6; or inferior: II, aVF, III)

35. • In paced QRS and premature ventricular complexes, QRS
fragmentation was defined as ≥3 notches in the R/S complex.
• In patients with QRS <120 ms, QRS fragmentation was defined
as an additional R wave (R’) or notch in the nadir of the S
wave.
• Extent of fQRS was classified as none, moderate (2–4 leads
with fQRS) or severe (5–12 leads).

36. OUTCOME VARIABLES
• The primary outcome variable was all-cause mortality.
• The secondary outcome was clinical ventricular arrhythmia (VA).
• Hospital databases were reviewed for clinical VA, which was
defined as:
I. Documented (eg, on Holter or pacemaker) symptomatic and/or
recurrent non-sustained ventricular tachycardia (VT), requiring
intervention such as cardioversion or ablation therapy.
II. Documented sustained VT, lasting ≥30 s or requiring
cardioversion.
III. Ventricular fibrillation or out-of-hospital cardiac arrest, with
successful resuscitation.

37. STATISTICAL ANALYSIS
• Categorical data were described as numbers with percentage.
• Continuous data were described as median with IQR or mean
with SD, as appropriate.
• Differences on baseline variables were assessed using
independent samples t-test, χ2 test or Wilcoxon rank-sum
test, as appropriate.

38. RESULTS

40. PRIMARY ENDPOINT
• During a median follow-up duration of 10.7 years, 46 patients
died.
• Causes of death were: heart failure in 20 (43%), sudden
cardiac in 10 (22%), perioperative in 1 (2%), vascular in 3 (7%),
non-cardiac in 8 (17%) and unknown in 4 (9%).
• Deceased patients were older, more likely had a previous
shunt procedure, had more ECG abnormalities and had many
other complications prior to inclusion.

41. Ten-year survival was 97.9% in patients without fQRS (n=414), 92.5%
in patients with moderate fQRS
(n=257) and 81.4% in patients with
severe fQRS (n=123)

43. • A risk model was constructed in
which 1 point was attributed for
each class of fQRS (0–2 points), 1
for each decade older age (1 for
age 30–40, 2 for age 40–50 and
so on), 1 for previous shunt and 1
for pacemaker.
• The ten-year survival ranged from
100% in patients without any
points (n=201) to 52% in patients
with ≥6 points (n=19)

45. SECONDARY ENDPOINT
• Clinical VAs occurred in 35 patients.
• In the multivariable analysis, extent of fQRS, atrial fibrillation
on ECG and QRS duration >180 ms remained predictive for
clinical VA.

46. DISCUSSION
• This is the first study to demonstrate the QRS fragmentation
in adult patients with TOF.
• The extent of fQRS strongly predicted both all-cause mortality
and clinical VAs in multivariable models.
• The analysis of fQRS on a standard 12-lead ECG is easily
performed, is inexpensive and may be implemented in risk
stratification for adult patients with TOF.

47. • A potential substrate for life-threatening VAs is myocardial
fibrosis, which may be caused by previous surgery and
childhood cyanosis, and is proposed to negatively affect
myocardial function.
• Investigators hypothesise that fibrotic scars may serve as
substrates for VT and cause fragmented QRS complexes by
delayed or zigzag conduction, similar to causing late potentials
that may be identified on signal-averaged ECGs in TOF.
• Considering RV outflow tract fibrosis is most typically found
in adult patients with TOF, patients with RBBB may have the
most suitable conduction to identify RV fibrosis by fQRS.
• However, investigators found QRS fragmentation remained
predictive for mortality in the subgroups, such as patients
without RBBB configuration.

48. • QRS duration >180 ms had a sensitivity of only 28%, was
inferior to fQRS in predicting mortality.
• These findings indicate that patients with shorter,
fragmented, QRS complexes have higher mortality risk
compared with patients with longer, unfragmented, QRS
complexes.
• Long-term prospective follow-up data were used to create a
simple mortality risk score for adults with TOF.
• High-risk patients could be referred for additional risk
assessment (gadolinium-enhanced CMR imaging), to identify
those patients who should be referred for ICD implantation
for primary prevention.

49. LIMITATIONS
• All obtained ECGs were analysed retrospectively by a single
observer blinded to clinical outcomes.
• CONCOR database did not acquire echocardiographic or CMR
imaging data and signal-averaged ECGs were not performed.
• No data on RV myocardial fibrosis were collected.
• Finally, investigators did not investigate changes of fQRS
during follow-up to assess whether fQRS can both mediate
and reflect disease progression.

50. KEY MESSAGES
• WHAT IS ALREADY KNOWN ON THIS SUBJECT?
• Adults with tetralogy of Fallot are at risk for life-threatening
arrhythmias and mortality.
• QRS duration is used in risk stratification despite limited
sensitivity to predict these outcomes.
• The fragmentation of QRS complexes is related with
myocardial fibrosis and may improve risk stratification.

51. • WHAT MIGHT THIS STUDY ADD?
• The extent of QRS fragmentation is superior to QRS duration
in predicting all-cause mortality.
• In addition, this easily measured parameter is also a predictor
of ventricular arrhythmias.
• HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE?
• Clinicians should assess QRS fragmentation on standard 12-
lead ECGs.
• The extent of QRS fragmentation can guide risk stratification
and help select high-risk patients for additional risk
assessment (including more costly and invasive
investigations).