Hot Topics from AHA Scientific Sessions 2018 - Comments from ACCA

PRINCESS Trial— Pre-hospital Resuscitation Intra-arrest Cooling Effectiveness Survival Study

(Presented at AHA Scientific Sessions, late-breaking clinical trials, Sunday 11 November 2018)

The PRINCESS trial was a European multicenter randomized nonblinded trial run in 7 European countries from 2010 to 2018. In total 677 bystanders witnessed adult Out of Hospital Cardiac arrest patients were randomized to usual care or to TRANSNASAL EVAPORATIVE COOLING starting already during the resuscitation attempt. Both groups received targeted temperature management at the hospital. The intervention was safe. The time to target temperature (<34C) was significantly shortened by the intervention (101 vs 182 minutes, p<0-001), but the primary endpoint (CPC 1-2; Cerebral Performance Category 1-2 mean good cerebral outcome) at 90 days) was not statistically different between the groups (16,6% vs 13,3%, p=0.26).

The author also reported a secondary endpoint even though the study was neutral: Among VT/VF patients only they observed significantly more patient survived with a CPC 1 (not including CPC 2) in the intervention group (45 out of 138) compared with the control group (27 out of 135), p=0.02. The study is not published yet.

ACCA's comment by Christian Hassager

This long-awaited trial is very important. Two previous +1000 patient trials testing prehospital cooling were neutral, but this trial may indicate that very rapid cooling could be beneficial.

The trial was neutral on its primary outcome and can therefore only be read as a phase II trial with interesting indications. The original design paper (BMC Emerg Med 2013 Nov 25;13:21) reported 836 needed patients and on clinicaltrials.gov the authors wrote in 2011, that they planned to enrol 900 patients.

It will be interesting to hear why the trial was stopped at 677 patients once the paper is out.

PIONEER-HF trial - Angiotensin Receptor-Neprilysin Inhibition in Patients Hospitalized With Acute Decompensated Heart Failure: Primary Results of the PIONEER-HF Randomized Controlled Trial

(Presented at AHA Scientific Sessions, late-breaking clinical trials, Sunday 11 November 2018)

The PIONEER-HF trial was designed to assess the efficacy and safety of sacubitril/valsartan in the setting of acute heart failure (AHF). Patients were randomized between 24 hours and 10 days after presentation, to receive sacubitril/valsartan (n=440) or enalapril (n=441) for 8 weeks.

The primary outcome was the time-averaged reduction in NT-proBNP. Main characteristics of patients included: roughly 30% of patients had de novo- HF; mean left ventricular ejection fraction (LVEF) was 25%; median
baseline NT-proBNP was 4800 pg/ml.

A significant reduction of the primary outcome measure was observed in favor of sacubitril/valsartan (-46.7% versus -25.3%, hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.63-0.81, p < 0.001). A significant reduction in terms of rehospitalization for HF was also observed. The trial was not powered to detect differences in mortality between the two groups.

ACCA's comment by Alessandro Sionnis

Altogether this trial strengthens the role of sacubitril/valsartan in the acute cardiac care setting. A significant reduction in NT-proBNP was noted in the first week after randomization and a reduction in rehospitalization for HF was observed during follow-up.

Nevertheless, a larger trial adequately powered to detect clinical endpoints is warranted.

EARLY — Optimal Timing of Intervention in Non-ST-elevation Acute Coronary Syndromes Without Pretreatment

(Presented at AHA Scientific Sessions, late-breaking clinical trials, Sunday 11 November 2018)

The goal of the EARLY trial was to assess the safety and efficacy of a very early invasive strategy compared with a delayed invasive strategy in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) at intermediate or high-risk who were naïve from P2Y12 inhibitors.

Of a total of 1,142 patients screened, 709 were enrolled and randomized 1:1 to very early invasive approach (ie within 2 hours) (n = 346) versus a delayed invasive strategy (12-72 hours) (n = 363) and followed for 30 days. At baseline, 44% of patients were on aspirin and 21% were receiving a P2Y12 inhibitor.

The mean GRACE score was 122. At coronary angiography, 19% had no significant disease, 23% three-vessel
disease and 75% underwent percutaneous coronary intervention (3% coronary artery bypass grafting).

The primary endpoint of cardiovascular (CV) death or recurrent ischemia at 30 days, for very early vs. delayed invasive, was 4.4% vs. 21.3% (p < 0.001) with no significant effect on CV death (0.6% vs. 1.1%, p = 0.69) and a substantial reduction in symptoms of ischemia: 4.1% vs. 20.7%, p < 0.001. No significant differences were observed on the MI component (1.2% vs. 0.8%, p = 0.72) nor Bleeding Academic Research Consortium (BARC)-defined bleeding ≥3: 0.3% vs. 0.8%, p = 0.62.

ACCA's comment by Sergio Leonardi

The results of this relatively small, randomized controlled trial suggest that a very early invasive strategy is superior to a delayed invasive strategy in improving symptoms of recurrent ischemia among patients presenting NSTE-ACS with intermediate or high-risk who were naïve from P2Y12 inhibitors. Notably, no
differences in “hard” clinical endpoints, including CV death or MI were observed. Also, despite the design of the study was focused on patients naïve from P2Y12 inhibitors, one out five patients (21%) were receiving it at the time of randomization.

Therefore – while awaiting the publication of the manuscript – these intriguing findings appear to require confirmatory observations.

Door to Unload (DTU) Trial — Mechanically Unloading the Left Ventricular and Delaying Reperfusion in Patients with Anterior ST-segment Elevation Myocardial Infarction: The Door to Unload Pilot Trial

(Presented at AHA Scientific Sessions, late-breaking clinical trials, Sunday 11 November 2018)

The Door to Unload (DTU) trial was a pilot study (n=50) to assess the safety and feasibility of left ventricular unloading using the Impella CP ® device in patients with acute anterior STEMI. Patients were randomized to either left ventricular (LV) unloading and immediate coronary reperfusion by PCI or LV-unloading and delayed (30 minute) coronary reperfusion by PCI (femoral or radial access was used for PCI, Impella was inserted via a 14 french femoral sheath). The Impella CP ® was explanted after a minimum of 3 hours of LV-support. Patients with cardiogenic shock were excluded.

The primary outcome of MACCE (major cardiovascular and cerebrovascular adverse events) and the safety outcomes of difference in infarct size normalized as percent of total LV-mass (determined by cardiac MRI) did not differ between the immediate reperfusion group and the delayed reperfusion group. While there was a trend towards a reduced myocardial area at risk in patients with ST-segment elevation >6mm in sum, the authors present this as the rational for a future pivotal study. The pivotal study will assess immediate reperfusion without Impella®-support compared to LV-unloading and a delayed (30min) reperfusion strategy in patients with first time anterior STEMI.

ACCA's comment by Ingo Ahrens

 The concept of left ventricular unloading in order to reduce infarct size has come a long way. Some animal studies suggest that unloading before reperfusion may reduce infarct size. Overall there is currently no reason to abandon the “time is muscle”-dogma in the acute treatment of patients with STEMI admitted for primary PCI. However, the Impella® LV-support system is rapidly inserted via femoral access and the authors have demonstrated the feasibility of their strategy in STEMI patients.

It remains to be determined whether LV-unloading does indeed reduce infarct size and improves clinical outcome in patients with first time anterior STEMI.

The Neuroprotect trial

 (Presented at AHA Scientific Sessions, late breaking clinical trials, Sunday November 11th 2018)

The Neuroprotect trial was performed in two centers in Belgium. 112 survivors of out-of-hospital cardiac arrest, who were unconscious at hospital admission, were randomly assigned (stratified by the presence of a shockable rhythm) to early goal directed hemodynamic optimization (EGDHO) – targeting a higher mean arterial blood pressure (85-100mmHg) in post-cardiac arrest patients during the first 36 hours after hospital admission – vs. standard care. During the 36-hours interventional period, patients assigned to EGDHO received higher doses of norepinephrine and had higher MAP’s. This resulted in significant improvement of cerebral oxygenation during the first 12 hours and was paralleled by significantly higher cerebral perfusion.

However, this did not result in a reduction of the primary outcome – the percentage of irreversibly damaged anoxic voxels on DW-MRI was 16% in the interventional arm and 12% in the control arm (p = 0.09). Applying EGDHO did not reduce length of ICU stay or duration of mechanical ventilation. The percentage of patients with favorable neurological outcome tended to be somewhat higher in the interventional arm although this did not reach statistical significance at ICU discharge and at 180 days.

ACCA's comment by Marek Gierlokta

Unconscious patients after resuscitated cardiac arrest are still a challenge for the ICCU team as safe and effective neuroprotective therapies remain extremely limited. This new concept of targeting a higher mean arterial blood pressure does not provide evidence for its use. Anyway, EGDHO improved cerebral perfusion and oxygenation, providing for the first time the proof of concept for this therapy and allowing further studies to be initiated.

T-TIME — A Randomized, Double Blind, Placebo-Controlled, Parallel Group, Multicenter Clinical Trial of Low-Dose Adjunctive Alteplase During Primary PCI (T-TIME)

 (Presented at AHA Scientific Sessions, late breaking clinical trials, Sunday November 11th 2018)

The study addressed patients undergoing PCI for acute STEMI due to a proximal, midvessel occlusion of a major coronary artery presenting up to 6 hours after symptom onset. Patients were randomized to either a placebo infusion or to a 10-mL or 20-mL dose of alteplase delivered after reperfusion but prior to stent implantation.

T-Time had enrolled 440 patients by the time it was stopped for futility. For the primary outcome of microvascular obstruction (MVO) on contrast-MRI between days 2 and 7 postprocedure, there was no difference between groups who underwent placebo infusion compared with the 20-mL infusion, as measured by % LV mass (2.3% vs 3.5%, P=0.32). The 10-mL dose was associated with a slight uptick in LV mass (2.6%) as compared with placebo, but this difference, was not statistically significant.

Patients who presented within 4 to 6 hours after symptoms, as compared to within 0 to 2 hours or 2 to 4 hours, had more microvascular obstruction.

Repeat imaging at 3 months again found no differences between placebo and alteplase groups.

ACCA's comment by Antonia Sambola

There are a number of trial-related factors that may have influenced study outcomes, including some heterogeneity in the timing of alteplase infusion and the sequence of procedures, as well as the 30% use of thrombus aspiration.

However, the results do not support this therapeutic strategy. Microvascular obstruction remains common, affecting half of all patients with STEMI, but there remains no therapy to prevent or treat this problem.

The study is not published yet.