Abbott ABSORB BVS Manual De Usuario página 5

isozymes; absorption and subsequent elimination of everolimus may be influenced by drugs that
affect these pathways. Formal drug interaction studies have not been performed with the
ABSORB BVS System. Therefore, due consideration should be given to the potential for both
systemic and local drug interactions in the vessel wall, when deciding to place the ABSORB BVS
in a subject taking a drug with known interaction with everolimus.
6.8 Pregnancy
This product (the ABSORB BVS System) and everolimus have not been tested in pregnant or
nursing women or in men intending to father children. Effects on the developing fetus have not
been studied. While there is no contraindication, the risks and reproductive effects are unknown
at this time.
7.0 ADVERSE EVENTS
7.1 Observed Adverse Events
Adverse events observed in the ABSORB clinical trials that are related to the key clinical
outcomes of death, cardiac death, myocardial infarction (Q-wave and non-Q-wave), target lesion
revascularization (by PCI or coronary artery bypass graft), scaffold thrombosis, and ischemia-
driven MACE (composite of cardiac death, MI, ID-TLR) are presented in
Table 3. All other adverse events are included in Section 7.2.
7.2 Potential Adverse Events
Adverse events that may be associated with percutaneous coronary intervention, treatment
procedures and the use of a coronary scaffold in native coronary arteries include the following,
but are not limited to:
• Abrupt closure • Emergent or non-emergent coronary
• Access site complications artery bypass graft surgery
• Acute myocardial infarction • Fever
• Allergic reaction or hypersensitivity • Hypotension / hypertension
to contrast agent or polymer poly • Infection and pain
(L-lactide) (PLLA), polymer poly (D,L-
• Injury to the coronary artery
lactide) (PDLLA), and drug reactions • Ischemia, myocardial
to antiplatelet drugs or contrast agent • Myelosuppression
• Aneurysm • Nausea and vomiting
• Arterial perforation • Palpitations
• Arterial rupture • Pericardial effusion
• Arteriovenous fistula
• Peripheral vascular or nerve injury
• Arrhythmias, including atrial and
• Pulmonary edema
ventricular • Pseudoaneurysm
• Bleeding complications, which may • Renal insufficiency / failure
require transfusion • Restenosis of scaffolded segment
• Cardiac arrest
• Shock
• Cardiac, pulmonary, or renal failure
• Stroke / cerebrovascular accident
• Cardiac tamponade
and TIA
• Coronary artery spasm • Total occlusion of coronary artery
• Coronary or scaffold embolism • Unstable or stable angina pectoris
• Coronary or scaffold thrombosis • Vascular complications which may
• Death require additional intervention
• Dissection
• Distal emboli (air, tissue or
thrombotic)
Adverse events associated with daily oral administration of everolimus include the following,
but are not limited to:
• Abdominal pain • Liver function test abnormal
• Acne • Lymphocele
• Anemia • Myalgia
• Angioneurotic edema • Nausea
• Coagulopathy • Pain
• Diarrhea • Pancreatitis
• Edema • Pericardial effusion
• Hemolysis • Pleural effusion
• Hemolytic uremic syndrome • Pneumonia/Pneumonitis
• Hepatic disorders • Pulmonary alveolar proteinosis
• Hepatitis • Pyelonephritis
• Hypercholesterolemia • Rash
• Hyperlipidemia • Renal tubular necrosis
• Hypertension • Sepsis
• Hypertriglyceridemia • Surgical wound complication
• Hypogonadism male • Thrombocytopenia
• Infection • Thrombotic thrombocytopenic
• Interstitial lung disease purpura
• Venous thromboembolism
• Jaundice
• Vomiting
• Leukopenia
8.0 CLINICAL INVESTIGATIONS OF ABSORB BVS SYSTEM
8.1 ABSORB Clinical Trial
The ABSORB clinical investigation is a prospective, single-arm, open-label, multicenter,
international clinical study to evaluate safety and performance of the BVS in coronary
arteries. The study was designed to enroll up to 30 patients (Cohort A) followed by
approximately 80 patients (Cohort B) in approximately 10 clinical sites in Europe and Asia
Pacific region.
Eligible Criteria: Patients at least 18 years of age with evidence of angina, myocardial ischemia,
or a positive functional test; female patients with childbearing potential with a negative pregnancy
test within 7 days prior to the index procedure; and patients who signed an informed consent
prior to enrollment. Angiographic inclusion criteria included: Nominal vessel diameter of 3.0 mm;
lesion length ≤ 8 mm by visual estimation extended to ≤ 14 mm for the 3.0 x 18 mm scaffold; %
diameter stenosis (%DS) of ≥ 50% and < 100%; TIMI flow of ≥ 1. Key angiographic exclusion
criteria included: aorto-ostial location; left main location within 2 mm of the origin of the LAD
or LCX; excessive tortuosity; extreme angulation (≥ 90°); heavy calcification; restenotic from
previous intervention; target vessel containing thrombus; other clinically significant lesions in the
target vessel or side branch.
Treatment Strategy: Predilatation of the target lesion was mandatory. Planned overlapping BVS
disallowed. Any bailout must be done with overlapping a XIENCE V stent of appropriate length,
®
and if not available, a CYPHER sirolimus-eluting stent; bailout with BVS was not permitted.
Postdilatation was performed at operator discretion, but only using balloons sized to fit within the
boundaries of the scaffold.
Antiplatelet Regimen: Subjects not on chronic antiplatelet or aspirin therapy had to receive a
loading dose of clopidogrel bisulfate ≥ 300 mg and aspirin ≥ 300 mg 6 to 72 hours prior to the
index procedure, but no later than 1 hour after the procedure. All patients were required to receive
anticoagulation and other therapy during scaffold implantation according to the standard of care
at the clinical site. All patients were to be maintained on 75 mg clopidogrel bisulfate daily for a
minimum of 6 months and ≥ 75 mg of aspirin daily for the length of the clinical investigation
(5 years). Patients who developed sensitivity to clopidogrel bisulfate were to be switched to
ticlopidine hydrochloride at a dose in accordance with standard hospital practice.
8.2 ABSORB Cohort A
8.2.1 Methodology and Current Status
A total of 30 patients in Cohort A were enrolled between March 7, 2006 and July 18, 2006 at four
clinical sites in Europe and New Zealand.
The Gen 1.0 BVS devices were implanted in patients with a single de novo native coronary artery
lesion. Enrollment started with the 3.0 x 12 mm size. The 3.0 x 18 mm size became available
later on and was used in only 2 patients in Cohort A.
Clinical follow-up through 30, 180, 270 days, 1 year, 18 months, 2 years and 3 years, and
angiographic, IVUS, IVUS-VH, palpography, OCT data at 180 days and 2 years are currently
available. MSCT data at 18 months and coronary vasomotor test data at 2 years are also
available. All other follow-up is ongoing. Patients will be followed through 5 years.
8.2.2 Clinical Outcome at 3 Years
At 3 years, the ischemia-driven MACE (Major Adverse Cardiac Event, defined as the
composite endpoint of cardiac death, MI or ischemia-driven TLR) rate was 3.6% (Table 3).
There was only one non-Q-wave myocardial infarction (peak troponin 2.21 μg/L) related
to the treatment of a non-flow-limiting stenosis (QCA diameter stenosis 42%) of a BVS
implanted 46 days earlier, in a patient who had one episode of angina at rest without
electrographic evidence of ischemia. For a perceived safety reason, the polymeric scaffold
was covered by a drug-eluting metallic stent. No new MACE was recorded between 6
months and 3 years. No instances of scaffold thrombosis arose according to the protocol or
the Academic Research Consortium definitions.
Table 3: Clinical Outcome at 3 Years
6 Months 12 Months
30 Patients 29 Patients†
Cardiac Death
0% 0%
(%)
3.3% (1)* 3.4% (1)*
MI (%)
Q-Wave MI 0% 0%
Non Q-Wave MI 3.3% (1)* 3.4% (1)*
Ischemia-driven
0% 0%
TLR (%)
by PCI 0% 0%
by CABG 0% 0%
Ischemia-driven
MACE, (cardiac
3.3% (1)* 3.4% (1)*
death, MI or
ischemia-driven
TLR, %)
Scaffold
0% 0%
thrombosis (%)
Data are % (number of patients). MI = myocardial infarction. TLR = target lesion
revascularization. PCI = percutaneous intervention. CABG = coronary artery bypass graft.
MACE = major adverse cardiac events.
†One patient officially withdrew from the study, but his vital status and clinical follow-up are
made available through his referring physician. One patient died from a noncardiac cause
706 days postprocedure. *Same patient. This patient also underwent a TLR, not qualified as
Ischemia-driven TLR (diameter stenosis = 42%)
8.2.3 Angiographic, IVUS, and OCT Outcomes at 180 days and 2 Years
QCA results were collected from baseline, postprocedure, 180 days and 2 years. The 180-day data
demonstrated an acceptable in-scaffold late loss of 0.43 ±0.37 mm possibly driven by bioactive
remodeling or mechanical late recoil. At 2 years, this increased to 0.48 ±0.28 mm.
The 180-day grey-scale intravascular ultrasound (IVUS) analysis showed a significant reduction in
the average lumen area (6.04 ±1.12 mm after procedure vs. 5.19 ±1.33 mm
2
p < 0.001). The vessel area remained constant between baseline and 180-day follow-up
(13.49 ±3.74 mm 2 vs. 13.79 ±3.84 mm 2 ), demonstrating the absence of significant expansive
or constrictive remodeling. At 2 years, the main observation provided by Grey-scale IVUS was
the increase in minimal luminal area and average luminal area/volume together with a significant
decrease in plaque area/volume between 6 months and 2 years.
The 180-day OCT group (n = 13) provided a total of 671 apparent struts for visual evaluation,
which showed that 93% of struts evaluated were well apposed to the vessel wall, and 99% of the
struts were covered by tissue. The serial OCT group (n = 7) had serial data postprocedure, at 180
days and at 2 years (intention-to-treat population). The number of apparent struts decreased from
403 at baseline to 368 at 180 days and to 264 at 2 years follow-up (34.5% reduction over two
years), all well covered and apposed to the vessel wall. Preclinical analysis directly comparing
pre-explantation OCT to post-explantation histology indicates there is no correlation between the
presence or absence of OCT-visible features (apparent struts) and the presence or absence of
polylactide polymer in the vessel. Hence, visual OCT features (apparent struts) are not always
indicative of lack of resorption, but absence of the apparent struts by OCT confirms resorption. The
lumen shape was regular with smooth, well delineated borders in all cases, and no intraluminal
tissue was observed. Importantly, minimal and mean luminal area decreased significantly between
postprocedure and 180 days, but enlarged between 180 days and 2 years.
8.2.4 Vasomotor Function Results at 2 Years
Vasomotor function proximal, within, and distal to the treated (scaffolded) segments at 2 years,
was evaluated with either the endothelium-independent vasoconstrictive methylergonovine
maleate (Methergine, Novartis, Basel, Switzerland), or the endothelium-dependent vasoactive
agent acetylcholine (Ovisot, Daiichi-Sankyo, Tokyo, Japan), depending on local practice.
In the Methergine group (n = 7), significant vasoconstriction was observed in proximal and
scaffolded segments (Figure 1). After nitroglycerin, the three segments (proximal, scaffolded,
and distal) dilated significantly with their diameters returning to their baseline values (Figure 1).
In the acetylcholine group (n = 9), 5 patients had vasodilation of at least 3% in mean luminal
diameter. Nitrates induced a significant vasodilatation in the scaffolded and distal segments.
These results suggested the restoration of vasomotor function in the treated segments at 2 years
when the BVS has resorbed.
Paired comparisons between the different time points were done by a Wilcoxon's signed rank
test for continuous variables.
2 Years 3 Years
Figure 1: Results of acetylcholine and Methergine testing in proximal, scaffolded, and
28 Patients† 28 Patients†
distal segments
8.2.5 Discussion
0% 0%
In this prospective, single-group, open-label study, the BVS demonstrated acute success and
safety following the first 30 days after implantation: 100% procedure success; 94% device
3.6% (1)* 3.6% (1)*
success; and successful revascularization of the target lesion evident from postprocedure
0% 0%
angiographic and IVUS analyses. The excellent clinical safety persists through 3 years with
3.6% (1)* 3.6% (1)*
no cardiac deaths, no ischemia-driven target lesion revascularizations or scaffold thrombosis
recorded, and only one non-Q-wave myocardial infarction by 3 years. Despite the discontinuation
0% 0%
of thienopyridine drugs, no scaffold thrombosis occurred, and no additional clinical target lesion
restenosis was evident by 3 years.
0% 0%
The use of multiple imaging modalities yielded several important findings. At 180 days, an
0% 0%
acceptable angiographic in-scaffold late loss of 0.43 mm was seen; this was higher than
previously observed in XIENCE V at 6 months (SPIRIT FIRST), possibly driven by bioactive
remodeling or mechanical late recoil. The IVUS results showed low intrascaffold neointimal
3.6% (1)* 3.6% (1)*
hyperplasia: 5.32% in-scaffold volume obstruction, 4.09 mm
confirmed a positive drug effect in inhibiting restenosis.
At 2 years, angiographic results showed an acceptable 2-year in-scaffold late loss of 0.48 mm
0% 0%
with minimal changes from 6 months (0.43 mm) to 2 years. By contrast, both the IVUS and OCT
data showed late luminal enlargement from 6 months to 2 years. The contrasting findings in late
lumen dimensional changes between angiography and intracoronary imaging await confirmation
in future clinical studies.
At 2 years, reduction in molecular weight and mass had occurred to such an extent that
echogenicity was lost and that struts were no longer recognizable by intravascular ultrasound,
leaving behind few IVUS-visible features. OCT-visible features related to vessel healing were
present in some patients. One third of patients showed no OCT-visible features at 2 years. In these
patients, OCT showed an optically homogeneous vessel wall structure that, taken together with the
documented restoration of both endothelial and non-endothelial dependent vasomotion, suggests
healing of the artery.
8.3 ABSORB Cohort B
8.3.1 Methodology and Current Status
Based upon the strong safety profile observed for the Gen 1.0 BVS in Cohort A, Cohort B of the
ABSORB trial was initiated on March 19, 2009 to evaluate the Gen 1.1 BVS in a prospective,
at 180-day,
2
open-label, multicenter registry. Subjects with up to two de novo native coronary artery lesions
in separate epicardial vessels with visually estimated nominal vessel diameters of 3.0 mm and
lesion(s) length ≤ 14 mm were enrolled, and received a single 3.0 x 18 mm Gen 1.1 BVS per
lesion treated. Twelve clinical sites located in Europe, Australia, and New Zealand participated
in this study.
Enrollment of 101 patients (45 patients in Group 1, and 56 patients in Group 2) in Cohort B was
completed on November 6, 2009. As of August 2010, the baseline, 30-day, and 180-day clinical
results for 101 patients from the full Cohort B are available. Further, 9-month clinical data, as
well as 6-month angiographic and IVUS results for the patients in Group 1 are available. All other
follow-up is ongoing. Patients will be followed through 5 years.
8.3.2 Clinical Outcomes for Cohort B Group 1 and Full Cohort B
Table 4 shows clinical outcomes up to 270 ±14 days in Group 1 (45 patients), and up to
180 ±14 days for the full Cohort B (101 patients), all intent-to-treat populations.
Table 4: Hierarchical Clinical Outcomes for Cohort B (ITT Population)
Cardiac Death (%)
MI (%)
Q-Wave MI
Non Q-Wave MI
Ischemia-driven
TLR (%)
by PCI
by CABG
3 in-scaffold neointimal volume. This
Cohort B, Group 1 Full Cohort B
(N = 45) (N = 101)
30 ±7 180 ±14 270 ±14 30 ±7 180 ±14
Days Days Days Days
0% 0% 0% 0%
2.2% (1) 2.2% (1) 2.2% (1) 2.0% (2) 3.0% (3)
0% 0% 0% 0%
2.2% (1) 2.2% (1) 2.2% (1) 2.0% (2) 3.0% (3)
0% 2.2% (1) 2.2% (1) 0% 2.0% (2)
0% 2.2% (1) 2.2% (1) 0% 2.0% (2)
0% 0% 0% 0%
Days
0%
0%
0%
5