Primary Unloading and Delayed Reperfusion in ST-Elevation Myocardial Infarction. The STEMI-DTU Pivotal trial.

Heart Failure (HF) is a leading cause of mortality, morbidity and poses a heavy
financial burden on healthcare systems and societies. In 2012, the total cost
for HF in the US was estimated to exceed $30 billion, with over $20 billion in
direct medical costs. It is projected that by 2030, the total cost for HF in
the US will increase to nearly $70 billion1,2. Survival after the diagnosis of
HF has improved over the past decade, yet mortality at 5-years remains over 50%
and the absolute number of deaths attributed to HF has not changed over the
past 20 years due to an overall increase in the incidence and prevalence of HF.
The two most preventable causes of HF are hypertension and acute myocardial
infarction (AMI).
Despite efforts to reduce cardiovascular risk factors, AMI remains a leading
cause of morbidity and mortality, with an annual incidence of over 805,000 in
the United States. Over the past 3 decades, early revascularization strategies
and the introduction of effective systems of care for AMI management have
reduced early mortality associated with AMI. However, despite timely
reperfusion, 25% and 75% of patients experiencing their first AMI will develop
HF within 1 and 5 years respectively. The inevitable loss of viable myocardium
and subsequent scar among the survivors of AMI forces additional load on the
remaining cardiac muscle to maintain an adequate cardiac output (CO). To
achieve this, the heart must alter its structure and function (remodel) to
increase the strength of contraction. While initially adaptive, ultimately this
remodeling process becomes maladaptive and leads to worsening cardiac function,
arrhythmias, and HF. One explanation for these poor outcomes is that
reperfusion of ischemic myocardium can accelerate cardiomyocyte death and
microvascular damage through a process referred to as myocardial
Ischemia-Reperfusion Injury (IRI)9. These data suggest that despite
improvements in the treatment of AMI, progression to HF remains an unsolved and
major health problem. There is a need for new approaches aimed at IRI to
promote myocardial salvage and limit myocardial damage in the setting of AMI.
Recent reports have highlighted the need for improved in-hospital treatment
strategies in AMI by showing that reducing the time to reperfusion below 90
minutes, known as the Door to Balloon (DTB) time, does not further reduce
mortality from AMI. Despite the success in reducing system delays, patients
continue to sustain significant myocardial damage in AMI. Since myocardial
infarct size directly correlates with the development of HF, reducing the size
of an infarct is expected to translate into reduced incidence of HF and
improved long-term survival.
Abiomed recently completed a multi-center, two-arm feasibility study, with 50
patients, to test the safety and feasibility of Primary Unloading and
mechanical pre-conditioning in patients presenting with anterior ST-Segment
Elevation Myocardial Infarction (STEMI). In this multicenter, prospective,
randomized exploratory safety and feasibility trial, 50 patients with anterior
STEMI were assigned to either LV unloading followed by immediate PCI (U-IR) or
LV Unloading and a 30 minutes delay - while maintaining LV Unloading - prior
PCI (U-DR). All patients were treated using the Impella CP®. The primary safety
outcome was a composite of major adverse cardiovascular and cerebrovascular
events at 30 days. Efficacy parameters included the assessment of infarct size
by using cardiac magnetic resonance imaging. The results have been published in
Circulation. The DTU Safety and Feasibility Pilot study showed that all fifty
patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective
mean door-to-balloon times of 72 versus 97 minutes. Major adverse
cardiovascular and cerebrovascular event rates were not statistically different
between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In
comparison with the U-IR group, delaying reperfusion in the U-DR group did not
affect 30-day mean infarct size measured as a percentage of LV mass (15±12%
versus 13±11%, U-IR versus U-DR, P=0.53). From these results, the authors
concluded that LV unloading using the Impella CP device with a 30-minute delay
before reperfusion is feasible within a relatively short time period in
anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety
signals that would preclude proceeding to a larger pivotal study of LV
unloading before reperfusion. An appropriately powered pivotal trial comparing
LV unloading before reperfusion to the current standard of care is required.
In the current submission we propose the second phase of our approach: Two-Arm,
Multi-Center Randomized Controlled study to evaluate the impact of primary
unloading and a thirty-minute delay-to-reperfusion using the IMPELLA CP® in
patients presenting with Anterior STEMI on Infarct size and a composite of
clinical end-points compared to the current standard of care using PPCI alone.

Demonstrate that primary Left Ventricular unloading and a thirty-minute
delay-to-reperfusion, when compared to the control cohort, treated according to
the current standard of care treatment of Anterior STEMI, has the following
effects:

1. Reduction in Infarct Size
2. Reduction in the Incidence of Heart Failure-related clinical events
3. An acceptable safety profile

A prospective, multicenter, randomized, controlled open-label two-arm trial
with an adaptive design.

Prior to randomization, all patients will undergo Iliac & femoral angiograms,
LVEDP measurement and an LV gram - to rule out contraindication for Impella CP®
placement. (An alternate method, such as bedside Echo, may be used in lieu of
LV Gram; however, LVEDP measurement will still be necessary.)
Subjects randomized to the treatment arm, will undergo Impella CP® placement
through a femoral arterial sheath and the Impella device will be activated to
unload the left ventricle. The femoral arterial sheath will be placed using
large bore access best practices (Appendix C). Coronary angiography will be
performed no earlier than 30 minutes from Impella CP® placement.
Subjects randomized to the treatment arm will be supported at a Performance
Level of P-8 or highest level attainable, for 4-24 hours with the Impella CP®
device. The P Level can be lowered in the events of suction or other AIC
console alarms. Once an alarm has been resolved, the P-Level will be raised to
the highest level possible without causing a suction alarm. Systolic
hypertension and/or tachycardia will be treated with recommended targets for
heart rate (HR) <=80 bpm and systolic blood pressure (SBP) <=130 mmHg.
[Appendix D provides Recommended Pharmacologic Therapy to Achieve SBP and HR
Targets]
Subjects randomized to both the treatment and control arms will be treated
based on the contemporary AHA/ACC/SCAI and ESC practice guidelines for STEMI
management using primary PCI, both during their index admission and over the
duration of the follow-up period.
Weaning from Left Ventricular support and removal of the Impella CP®
The subject will return to the catheterization laboratory for device and sheath
removal. The criteria for weaning from Impella CP® support will be the
following:
1. A minimum of 4 hours of support is required (operators are encouraged to
support at the highest P-level possible given subject*s condition and fluid
status).
2. The device may be left in for up to 24 hours. If it is left in for greater
than 24 hours due to hemodynamic instability, this meets the definition of
Cardiogenic shock. If it is left in for greater than 24 hours for another
reason, this is a protocol deviation.
3. The subject tolerates 30 minutes of support at P-3 prior to device removal
without hemodynamic instability, defined as sustained systolic BP <90 mmHg for
longer than 30 minutes or the need for inotropes/pressors to maintain a
systolic BP >90mmHg for longer than 30 minutes.
4. ACT/PTT/Anti-Xa levels show normalization of anticoagulation prior to
Impella removal
5. The facility/healthcare team is prepared for safe weaning and removal of the
device in the catheterization laboratory
In the event these criteria are not met, the operator may decide to continue
with a longer duration of Impella support. This will not be considered a
protocol deviation, unless duration is >24 hours for any reason other than
hemodynamic instability.
If clinically appropriate, any additional coronary intervention or
revascularization planned for the index admission, should be performed after
the 3-5-day CMR has been completed.

The risks and burden associated with participation essentially are the risks
usually encountered with venapunction and blood collection, and potential risk
associated with contrast dye. Other risks are associated with the heart
catheterization that is part of Standard of care.