Online appendix for: Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement The Randomized BRAVO-3 Trial Table of contents Trial Organization and committees...........................................2 Investigators............................................................... 3 Trial inclusion and exclusion criteria......................................5 Standardized definitions for study outcomes.................................7 Bleeding scales............................................................7 Cerebrovascular accident scales...........................................11 Myocardial infarction.....................................................11 Vascular access site and access-related complications.....................12 Acute kidney injury (modified RIFLE classification, adapted from Leon et al. 2011 (7)).................................................................12 Adaptive sample-size scheme................................................13 ONLINE TABLE 1 Additional secondary bleeding outcomes at 30 days...........14 ONLINE TABLE 2 Thirty-day mortality rates according to patient complication. ........................................................................... 15 ONLINE TABLE 3 Adjudicated major vascular complications....................16 ONLINE TABLE 4 Adjudicated acute kidney injury at 48 hours and 30 days according to calculated glomerular filtration rate at baseline.............17 ONLINE TABLE 5 Adjudicated endpoints in patients with a baseline calculated glomerular filtration rate less than 30 ml/min.............................18 ONLINE FIGURE 1 Outcomes according to prespecified subgroups...............19 1
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Trial Organization and committees · Web viewNicolas Dumonteil. CHU Rangueil, Toulouse, France Prodromos Anthopoulos, The Medicines Company, Zurich, Switzerland Roxana Mehran, The
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Online appendix for:
Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic
Valve Replacement
The Randomized BRAVO-3 Trial
Table of contents
Trial Organization and committees..............................................................................................................2
ONLINE TABLE 1 Additional secondary bleeding outcomes at 30 days...................................................14
ONLINE TABLE 2 Thirty-day mortality rates according to patient complication.........................................15
ONLINE TABLE 3 Adjudicated major vascular complications...................................................................16
ONLINE TABLE 4 Adjudicated acute kidney injury at 48 hours and 30 days according to calculated glomerular filtration rate at baseline...........................................................................................................17
ONLINE TABLE 5 Adjudicated endpoints in patients with a baseline calculated glomerular filtration rate less than 30 ml/min.................................................................................................................................... 18
ONLINE FIGURE 1 Outcomes according to prespecified subgroups........................................................19
1. New focal neurological deficit with rapid symptom resolution always within 24 hours AND
2. No acute tissue injury on neuroimaging
Stroke meets ALL of the following diagnostic criteria:
1. Rapid onset of a focal or global neurological deficit with at least one sign or symptom c/w stroke
(includes decreased level of consciousness if associated with unequivocal abnormalities on
neuroimaging)
2. Duration more than 24 hours unless there was a therapeutic intervention, confirmatory
neuroimaging or a neurological deficit resulting in death
3. No other identifiable cause for the clinical presentation AND
4. Diagnosis is confirmed by a specialist in neurology or neurosurgery, with neuroimaging or lumbar
puncture (in the case of intracranial hemorrhage).
Myocardial infarctionPeriprocedural myocardial infarction Periprocedural myocardial infarction fulfills ALL three criteria (but is not a confirmed coronary embolus):
1. ≤72 hours after the index procedure
2. New ischemic symptoms or signs (e.g. ventricular arrhythmias, new or worsening heart failure,
new hemodynamic instability), new ST segment changes OR imaging evidence of new loss of
viable myocardium or new wall motion abnormality.
3. Elevated cardiac biomarkers (preferably Creatine Kinase Myocardial Band [CKMB]) as defined
by:
a. At least two samples that are >6 to 8 hours apart with a 20% increase in the second
sample AND a peak value greater than 10x the 99th percentile upper reference limit OR
b. A peak value exceeding 5x the 99th percentile upper reference limit with new pathological
Q waves in at least 2 contiguous leads
Spontaneous myocardial infarction Spontaneous myocardial infarction includes ANY of the following occurring more than 72 hours after the
index procedure (but note a confirmed coronary embolus is specifically excluded):
1. Rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th
percentile upper reference limit, WITH any one of the following:
a. New ischemic ECG changes (new ST-T changes or new Left bundle branch block
[LBBB]) OR
b. New pathological Q waves in 2 or more contiguous leads OR
c. Imaging evidence of new loss of viable myocardium or new wall motion abnormality
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2. Sudden unexpected death due to cardiac arrest, often with symptoms suggestive of myocardial
ischemia AND accompanied by presumably new ST elevation, new LBBB and/or evidence of
fresh thrombus on coronary angiography or autopsy.
3. Pathological findings of an acute myocardial infarction
Coronary embolusMeets the definition criteria for periprocedural or spontaneous myocardial infarction but is due to a
confirmed coronary embolus.
Vascular access site and access-related complications
1. Any thoracic aortic dissection is automatically a major vascular complication.2. Access-related vascular injury – major and minor criteria (only 1 criterion required to qualify)
Major MinorComplicated by death YesBlood transfusion 4 or more units 2–3 unitsLocal treatment Unplanned percutaneous or
3. Distal embolization – major and minor criteria (only 1 criterion required to qualify)Major Minor
Underwent treatment Surgery Embolectomy and/or thrombectomyIrreversible end-organ damage YesResulted in Amputation Yes
4. Failed access site closureMajor Minor
Complicated by death YesBlood transfusion 4 or more unitsUnderwent treatment Percutaneous intervention or surgical correctionIrreversible end-organ damage Yes
Acute kidney injury (modified RIFLE classification, adapted from Leon et al. 2011 (7))
Stage % Rise in creatinine Absolute creatinine increase
1 (Risk) 150–200%OR
≥0.3 mg/dl
2 (Injury) 200–300%OR
>0.3 but <4.0 mg/dl
3 (Failure) ≥300% OR
Serum Cr ≥ 4 mg/dl + Absolute increase >0.5 mg/dl
OR received new renal replacement therapy
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Adaptive sample-size schemeTwo interim analyses were pre-specified and the data safety monitoring board (DSMB) reserved the right
to amend this plan after their periodic monitoring of data during the study, according to the DSMB charter.
Prior to these analyses, the protocol was amended by the executive committee on February 12, 2014,
which changed the primary bleeding endpoint from Bleeding Academic Research Consortium (BARC) ≥3
to BARC ≥3b. The first interim analysis occurred after enrolment of the first 170 randomized patients
(approximately one third of the projected enrolment) and the second after enrolment of 340 randomized
patients (approximately two thirds of the projected enrolment). The first analysis was a blinded
determination of the overall major bleeding rate in the study population. Based on the hypothesized major
bleeding rates of 19% and 10% in the two groups, the expected incidence at the first interim analysis was
14.5% (95% confidence interval 9.7–20.1). If the major bleeding rate for the study population at this initial
analysis fell below the lower 95% confidence bounds for the expected rate (<10%), then allowances could
be made to enrich the study population. This interim look took place on August 31, 2013 and resulted in
the study to continue without any changes.
The second interim analysis was an unblinded determination of the adjudicated major bleeding
rates in each group, observed relative risk reduction, and conditional power. The interim analysis plan
included the alpha spending function and the exact methods used to calculate the adaptive sample size
changes.
Accordingly, the DSMB reviewed summary reports of the second interim analysis on 340
completed patients and the adaptive sample size calculations prepared by independent statisticians and
convened on 22 May 2014 to determine their recommendation. A maximum of 800 patients was specified
in the interim statistical analysis plan as the upper limit of the increase in sample size. On 23 May 2014,
the DSMB issued a recommendation to continue the trial unmodified until the final number of inclusions
(800 patients), according to the interim statistical analysis plan.
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ONLINE TABLE 1 Additional secondary bleeding outcomes at 30 days
ONLINE FIGURE 1 Outcomes according to prespecified subgroups. A. Major bleed (BARC ≥3b) events at 48 h. COPD=chronic obstructive lung disease; GFR= glomerular filtration rate.
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B. Net adverse clinical events at 30 days. COPD=chronic obstructive lung disease; GFR=glomerular filtration rate.
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REFERENCES
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2. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012;60:1438-54.
3. Rao SV, O'Grady K, Pieper KS, et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol 2006;47:809-16.
4. The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-82.
5. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 2004;148:764-75.
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