Impact of Vascular Reparative Therapy on Vasomotor Function and Myocardial Perfusion: a randomized H215O PET/CT Study

More than three decades ago, percutaneous coronary intervention (PCI) was
introduced as a means to restore myocardial perfusion in the presence of an
obstructive epicardial coronary stenosis. Initially, coronary angioplasty
consisted solely of mechanical dilatation of the stenotic lesion by balloon
inflation. Notwithstanding the clinical groundbreaking success of this
therapeutic avenue, now referred to as *plain old balloon angioplasty* was
associated with feared short-term complications such as elastic recoil,
dissection, and intraparietal hematoma that led to acute coronary occlusion in
a not inconsequential number of patients. (Gruntzig A, Lancet 1978)
Furthermore, angioplasty was associated with re-stenosis of the dilated
coronary segment due to constrictive remodeling and neointimal hyperplasia in
the ensuing months after treatment. The introduction of stenting coronary
lesions with a metallic scaffold dramatically counteracted these aforementioned
acute hazardous complications. (Serruys et al, NEJM 1994) Cytostatic drug
coating of these metallic stents, which inhibit neointimal proliferation,
thereafter largely antagonized the issue of intra-stent re-stenosis. (Morice MC
et al, NEJM 2002) Due to these advances in interventional cardiology, PCI for
stable coronary artery disease (CAD) in the current era is characterized by a
low complication rate and good long-term outcome.
Nonetheless, implantation of a permanent metallic device has several proven and
hypothesized caveats. First, the uncovered and/or malapposed struts of the
endoluminal prosthesis may offset a thrombotic cascade that can result in
subacute or late stent thrombosis. The latter phenomenon is particularly
relevant with drug- eluted stents that interfere with the endothelialization
process thereby demanding prolonged dual anti-platelet therapy. (Finn AV et al,
Circulation 2007) Second, permanent caging of the coronary artery with a rigid
stent alters vessel geometry indefinitely and induces changes in flow, shear
stress, and cyclic strain patterns throughout the cardiac cycle. These
permanent changes may interrupt physiological cellular signaling pathways,
through lack of what is called *mechanotransduction*, and promote the process
of atherosclerosis. (Slager CL et al, Nat Clin Pract Cardiovasc Med 2005)
These issues have propelled the development of a biodegradable scaffold that
instantly and safely treats a stenotic coronary stenosis but thereafter
ultimately dissolves and may facilitate restoration of normal coronary
physiology, abolishing the long-term detrimental effects of a traditional
coronary stent implantation. (Waksman R, J Invasive Cardiol 2006) Indeed,
preliminary studies have revealed that vasomotor function of the neo-intima
gradually returns, as tested by intraluminal administration of acetylcholine,
throughout the degrading process of the scaffold. (Serruys PW, JACC 2011)
Apparently, the newly formed endothelial layer can regain the capacity to
respond to pharmacologically induced stimuli. This form of therapy is therefore
also ambitiously labeled as *vascular reparative therapy* (VRT). (Serruys PW et
al, Eur Heart J 2012)
Eventhough the implantation of these drug-eluting bioresorbable scaffolds (BRS)
appears to be safe in selected cohorts of human subjects, their hypothesized
superiority over conventional drug-eluting stents has yet to be proven.
(Serruys PW et al, Lancet 2009) Currently, randomized trials are ongoing to
further clarify this issue. These trials, however, are predominantly targeted
to document clinical end- points (e.g. target vessel revascularization,
myocardial infarction, and death). Given the low event rate of patients who are
treated by PCI for stable CAD in the current era, such trials demand inclusion
of large numbers of patients to be sufficiently powered to detect potential
differences between treatment strategies and will require long-term follow-up.
These results, therefore, will not become available within the next coming
years. Furthermore, these studies will reveal little about the potential
beneficial physiological aspects of VRT. Ultimately, the primary goal of any
PCI is not to relief the anatomical blockage of a coronary artery per se but to
restore downstream myocardial perfusion. In fact, the level of impairment of
myocardial perfusion reserve is one of the most important independent
prognostic predictors for death in patients with ischemic heart disease.
(Murthy VL et al, Circulation 2011) Consequently, enhancement of flow reserve
and alleviation of significant ischemic burden is associated with a more
favorable prognosis. (Shaw LJ et al, Circulation 2008) In theory, the potential
beneficial effect of VRT on vasomotor function, e.g. by flow mediated coronary
dilatation, could contribute to a more substantial restoration of long-term
myocardial perfusion. Documented late luminal gain by VRT in comparison with
conventional stent implantation may also add to this hypothesized favorable
effect on perfusion. (Onuma Y et al, Circulation 2010) Data to substantiate
these postulated effects are, however, lacking.
Positron emission tomography (PET) enables to noninvasively quantify biological
processes in vivo. In fact, PET in conjunction with the flow tracer
oxygen-15-labeled water (H215O) is considered the gold standard to
noninvasively assess myocardial blood flow (MBF) in man. (Knaapen et al, Basic
Research Cardiol 2009) Moreover, the short physical half-life of this tracer
(120 seconds) allows to perform multiple measurements within a single scanning
session at low radiation burden for the patient. Thus, this imaging technique
allows to study the effects of VRT on downstream myocardial perfusion using
different physiological and pharmacological stimuli.

The objective of the proposed study is to determine the impact of VRT, in
comparison with conventional drug-eluting stenting, on endothelium dependent
vasodilation and maximal hyperemic myocardial perfusion using H215O PET.

Type of study
The study is designed as a single center single-blind randomized clinical trial
and will be conducted at the VU University Medical Center in Amsterdam.

Summary of the study design
Sixty patients accepted for this study will be randomized to implantation of a
drug-eluted stent (Xience Prime) or BRS (Absorb). H215O PET will be performed
one month (reference scan), one year, and three years after the PCI procedure
(resolution of BRS is generally complete within a three year period). The PET
protocol will consist of three MBF measurements: resting MBF, during
endothelial dependent vasodilation provoked by cold-pressor-testing (CPT), and
during (endothelial dependent and independent) maximal vasodilation by infusion
of adenosine intravenously. After three years a control invasive coronary
angiogram will document any potential obstructive coronary lesions that may
affect the MBF measurements.

Duration of the study
Inclusion rate will be 1-2 patients weekly and therefore the inclusion period
is estimated to be one year. The follow-up period is three years, therefore the
entire study will be conducted over a four-year period.

Patients will be randomized to implantation of a drug-eluted stent (Xience
Prime) or BRS (Absorb).

PET/CT scans will be planned one month, one year, and three years after PCI,
each with exposure to an effective dose equivalent of 2 mSv. Every PET/CT will
take approximately one hour inclusive patient preparation. Adenosine will be
infused intravenously during PET/CT, which may induce transient AV-conduction
delay or bronchospasm. Investigator will be present to monitor any adverse
events. Patient will have to place their hand in ice-water for a few minutes
depending on endurence. This might cause unplaesant feelings. The patient is
able to remove their hand from the ice-water at any time.
After three years control angiography will be performed during one day
hospitalization with exposure to an effective dose equivalent of 4mSv,
depending on patient habitus. Risk of caronary angiography is comparable with
clinical control coronary angiography with an event rate of less than 0,5%.
Patient-benefit consists of a potentially improved treatment and close
monitoring of patient treatment and symptoms. There is benefit for good
clinical practice because of an improved determination of indications for BRS.
An other possible benefit will exists of documentation of microvascular
function (PET).