JOURNAL CLUB

26-5-2017

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.

• 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.

• 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.

METHODS

TRIAL DESIGN AND OVERSIGHT

• TRUE-AHF was a randomized, double-blind,parallel-group, placebo-controlled, event-driven trial.

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.

• 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.

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

• 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

• 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 dyspneaat 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

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 rehospitalizationfor 6 months and for the occurrence of death for the entire duration of the trial.

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

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.

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.

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 prespecifiedcovariates.

RESULTS

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.

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.

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.

• 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.

• 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.

• 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.

CONCLUSIONS

• Ularitide reduced cardiac-wall stress more markedly than placebo, as indicated by more rapid reduction in NT-proBNPlevels.

• 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.

HEART NOVEMBER 2016

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.

• 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 tofremains unknown.

• Trial’s primary objective was to determine whether the presence and extent of fqrs predict all-cause mortality in adults with tof.

METHODS

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

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)

• 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).

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.

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.

RESULTS

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.

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 withsevere fQRS (n=123)

• 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)

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.

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.

• 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.

• 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.

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 fQRSduring follow-up to assess whether fQRS can both mediate and reflect disease progression.

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.

• 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).