Conditions: Coronary Artery Disease Ischemic Heart Disease Anticoagulant-induced Bleeding Coronary Syndrome
Keywords: activated clotting time outcomes bleeding
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The purpose of this study is to find the ideal range of the activated clotting time (ACT) during percutaneous coronary intervention (PCI) that is associated with lowering the rate of undesirable medical outcomes

Detailed description:

Arms:
arm 1: ACT target range of 225 to 275 seconds is achieved prior to PCI if no planned glycoprotein IIb/IIIa inhibitor used arm 2: ACT target range of 275 to 325 seconds is achieved prior to PCI if no planned glycoprotein IIb/IIIa inhibitor used arm 3: ACT target range of 325 to 375 seconds is achieved prior to PCI if no planned glycoprotein IIb/IIIa inhibitor used

Interventions: intervention 1: Unfractionated heparin
Intervention descriptions: intervention 1: Administration of unfractionated heparin will be assessed using the activated clotting time

Protocol document:
Prot_SAP_000.pdf: 
 
 
Optimal Target of Activated Clotting Time 
During Percutaneous Coronary Intervention 
and Outcomes: The Randomized OPTIMAL-ACT 
Trial   
 
NCT03772613 
 
January 20, 2020 


Optimal Target of Activated Clotting Time During Percutaneous 
Coronary Intervention and Outcomes: The Randomized OPTIMAL-
ACT Trial 
 
The objective of this proposal is to identify the optimal range of the activated clotting time 
(ACT) during percutaneous coronary intervention (PCI) that is associated with the lowest rates 
of adverse clinical events.  The optimal ACT target during PCI has not previously been 
investigated in a prospective clinical trial, leaving uncertainty regarding the level of 
anticoagulation intensity during coronary revascularization procedures.  The primary research 
hypothesis is that in the modern cardiac catheterization laboratory, where PCI procedural 
duration is relatively short and rates of intracoronary stenting and dual antiplatelet therapy use is 
high, lower ACT targets, as compared with higher ACT targets, will be associated with lower 
rates of bleeding while having similar rates of ischemic events. 
 
 
Principal Investigator: 
 
S. Michael Gharacholou, MD, MSc 
 
Co-Investigators: 
 
Peter M. Pollak, MD 
Gary E. Lane, MD 
Dilip P. Pillai, MD 
Colleen S. Thomas, MS 
Elizabeth R. Lesser, MS 
Amy Swenson, RCIS 
Cynthia Lynady,RCIS, RCES 
Brad Karon, MD, PhD 
Paula Santrach, MD 
Leslie Donato, PhD 
Mandeep Singh, MD 


Rationale:  For the past three decades, unfractionated heparin (UFH) has remained the 
mainstay of anticoagulation during invasive cardiac procedures(1-3) and has been the only 
available anticoagulant in interventional cardiology for many years (4). Advantages to UFH are 
related to availability, familiarity, low cost, point-of-care (POC) testing using the activated 
clotting time (ACT), and reversibility with protamine sulfate.  Use of peri-procedural 
anticoagulation with UFH during percutaneous coronary intervention (PCI) is recommended to 
reduce thrombus formation on interventional devices and thrombotic complications during 
PCI(4-6).POC testing allows targeting ACT values to recommended ranges, gives fairly 
reproducible results, and ACT values increase linearly with UFH supplementation and decrease 
without additional UFH over time(7).  However, despite guideline suggested use of ACT 
monitoring in UFH-treated patients undergoing PCI, there are limited and often conflicting data 
regarding the association of ACT target values and outcomes(6,8-10).  Importantly, data for the 
relationship between ACT and outcomes are sparse in contemporary PCI practice that now 
includes the use of lower profile equipment, high rates of intracoronary stenting, transradial 
procedures, and dual antiplatelet therapy(10).  Early small studies found low rates of ischemic 
complications with low and fixed dose heparin(11,12), while pooled data from clinical trial 
participants suggested lower ischemic event rates with higher ACT targets of 350 to 375 
seconds, though at a cost of higher rates of bleeding(8).  Other studies analyzing low risk 
patients from clinical trials have not observed an association between ACT levels and ischemic 
endpoints(9,10). Despite widespread use of ACT monitoring during PCI, uncertainty remains 
regarding the association between ACT cutoffs and outcomes in contemporary practice, largely 
related to lack of randomized trials evaluating the optimum ACT target and its relation with 
events.  Practice guidelines conclude that despite the use of recommended ACT levels, often 
based on empiricism and ranges used in clinical trials of PCI, the utility of ACT in clinical 
practice remains uncertain (4). 
 
The pOint-of-care PracTice to IMProve use of AnticoaguLation (OPTIMAL)-ACT trial is a 
prospective, randomized, investigator-initiated, trial to determine the optimal ACT target value in 
patients undergoing PCI.  This will be the first prospective outcomes trial powered to identify the 
optimal ACT target range for reducing the rate of in-hospital bleeding (Bleeding Academic 
Research Consortium and EASY grading defined (Appendix I)).  Different bleeding definitions 
will be used to account for shift in access site practice from femoral to radial, both here at Mayo 
Clinic Florida, and in the United States.  In addition, the EASY grading scale is unique to 
transradial catheterization and complications related to bleeding may be more frequent among 
women (13).  Rates of net adverse cardiovascular events (NACE) (defined as all-cause 
mortality, myocardial infarction (MI), stroke, or bleeding) would be identified as a primary safety 
endpoint in the trial.  We aim to test the hypothesis that lower ACT target values, as compared 
to higher ACT target values, are associated with lower risk of bleeding without compromising 
efficacy as assessed by the primary safety endpoint.  This finding would have significant 
implications for improving the safety of PCI by reducing bleeding complications.  
 
A. Significance:  The significance of the study proposal can be highlighted by 1) the recognition 
of the burden of coronary artery disease (CAD), 2) the widespread adoption and performance of 
PCI, and 3) the limited data regarding appropriate anticoagulation intensity during PCI. CAD 
causes 1 out of 6 deaths in the United States.  Annually, over 600,000 patients suffer a coronary 
event, defined as a first hospitalized myocardial infarction or CAD-related death (14). 
Improvements in adherence to guideline-recommended therapies for patients with ischemic 
heart disease, including use of coronary revascularization procedures, have impacted the 
decline in deaths related to cardiovascular disease over the past several years.  PCI is 
performed commonly in the United States with an estimated 490,000 procedures in 2010 alone 
(15). In patients with acute coronary syndromes, early revascularization with PCI has been 


demonstrated to improve outcomes.  As the technical success rates of PCI have continued to 
remain very high, there has been a renewed interest in delivering PCI safely and reducing 
complications.  This evolution in contemporary PCI includes use of lower profile devices, smaller 
caliber intravascular sheaths, shorter procedural durations, and greater adoption of transradial 
catheterization.  In addition, strategies to mitigate bleeding have garnered greater attention 
given the association of bleeding with adverse short and long-term outcomes.  A fundamental 
aspect of current PCI practice involves the use of anticoagulants during the procedure to reduce 
the risk of thrombus formation on interventional devices (i.e., guiding catheters, wires) and 
reduce the risk of abrupt vessel closure.  The intensity of anticoagulation to reduce thrombotic 
risk is, however, on balance with increased bleeding risk, which have led to recommendations 
on appropriate ACT targets during PCI (4). Despite these recommended ACT targets, bleeding 
events are observed in 1 out of 10 patients at currently recommended ACT target ranges (8).  In 
addition, due to the limited evidence base, guidelines have also acknowledged that “the utility of 
measured ACT levels in current practice should be considered uncertain”(4).  Despite the 
influential role of an ACT value on an operator’s decision to intensify or reduce the level of 
anticoagulation in the patient, and thus directly impact the ischemic vs. bleeding risk-calculus, 
optimizing the dose of UFH during PCI has clinical equipoise.  The current gaps in knowledge, 
therefore, underscores the need for a rigorous study of anticoagulation intensity during PCI to 
improve patient safety and advance scientific understanding of ACT monitoring.  This has 
significant public health implications and tremendous potential to impact the current practice of 
PCI.  In alignment with Mayo Clinic’s commitment to improving the safety of patient care, the 
knowledge gap with regard to intensity of heparinization during PCI remains an important and 
unanswered question in interventional cardiology. 
 
B. Specific Aims:  Anticoagulation is routinely administered prior to performing PCI in 
interventional cardiology practice and intensity of anticoagulation is monitored using POC 
testing for the ACT.  However, current target values were derived from older, case-control 
studies (6,16), and supported by post-hoc retrospective analysis from trials of antithrombotic 
therapies (9,10).  In the modern era of high rates of dual antiplatelet therapy use, low profile 
devices, greater attention to access site management, and shorter procedural duration, the 
optimal ACT target for PCI remains unknown.  The overall objective of this proposal is to identify 
the optimal range of the activated clotting time (ACT) during percutaneous coronary intervention 
(PCI) that is associated with the lowest rates of adverse clinical events.  The optimal ACT target 
during PCI has not previously been investigated in a prospective clinical trial, leaving uncertainty 
regarding the level of anticoagulation intensity during coronary revascularization procedures.  
We hypothesize that in the modern cardiac catheterization laboratory, where PCI procedural 
duration is relatively short and rates of intracoronary stenting and dual antiplatelet therapy use is 
high, lower ACT targets, as compared with higher ACT targets, will be associated with lower 
rates of bleeding while having similar rates of ischemic events. The specific aims of this study 
are as follows: 
B.1.1 Aim 1 (Primary):  The primary aim of this study of patients undergoing PCI is to compare 
the risk of bleeding in patients randomized to a low ACT target to those randomized to either a 
medium or high ACT target. We hypothesize that the risk of bleeding will be lower in those with 
a low ACT target compared to those with a medium ACT target as well as those with a high 
ACT target.  See Figure 1 for ACT target ranges. 
B.1.2 Aim 2 (Primary): We aim to estimate the incidence of both our primary study outcome 
(bleeding) and our primary safety endpoint (NACE) separately for those with a low, medium, 
and high ACT target. 
B.1.3 Aim 3 (Primary): We aim to establish whether there is evidence of non-inferiority of a low 
ACT target compared to a high ACT target with respect to the proportion of patients undergoing 


PCI with respect to NACE.  We hypothesize that the rate of NACE is the same as or lower than 
that for patients with a high ACT target. 
B.1.4 Aim 4 (Secondary): We aim to study the impact of sex, access-site (i.e., radial vs femoral), 
and concomitant use of glycoprotein (GP) IIb/IIIa inhibitors on the association of ACT target with 
bleeding.  It has been shown that female sex is associated with higher ACT targets during PCI 
(17), and work from our group has shown an important observed interaction with myocardial 
infarction risk in women, but not men, with ACT targets >350 seconds(18).  This observation of 
a potential differential sex-specific interaction has not previously been reported and requires 
validation in a prospective study.  In addition, it has previously been shown that women appear 
to be at higher risk for developing forearm bleeding complications after transradial 
catheterization. The use of transradial PCI has steadily increased in the United States, though 
adoption of this technique remains lower than that observed in Canada and Europe.  However, 
recent internal PCI data from the cardiac catheterization laboratory at Mayo Clinic Rochester 
has shown increasing utilization of the radial artery for PCI, now over 50%.  At Mayo Clinic 
Florida, the percentage of radial access is over 70% and is considered the default access site 
for catheterization.  It remains unknown whether ACT targets can be similarly interpreted for 
radial PCI, as these original targets were derived from studies in primarily transfemoral access 
cohorts with larger vascular access sheaths.  Finally, the additional use of GP IIb/IIIa inhibitors 
in UFH-treated patients has been associated with higher rates of major and minor bleeding (9), 
thus lower ACT target values (i.e., 200-250 sec) are recommended in patients concomitantly 
treated with these agents.  In the Mayo Clinic experience, there was no apparent interaction by 
GP IIb/IIIa inhibitor status when testing the association of ACT values to outcomes, however, 
baseline characteristics of groups receiving or not receiving these agents differed and residual 
confounding may have been present (18).  The OPTIMAL-ACT trial will incorporate a pre-
specified analysis with specific ACT targets in patients receiving GP IIb/IIIa inhibitors to better 
understand ACT targets and outcomes. 
B.1.5 Aim 5 (Exploratory):  We will explore the association of ACT targets with individual 
components of NACE and stent thrombosis for purposes of hypothesis generation. 
 
C. Innovation/Experience:  There are two innovative and unique aspects of this proposal.  1. 
This study will define the optimal ACT target during PCI.  2. Mayo Clinic (S. Michael 
Gharacholou, senior author) has published the largest non-randomized (observational) study on 
the relation of ACT and outcomes in the peer-reviewed literature(18).  Our observations that 
ACT values were associated with unadjusted events, but were not independently associated 
with outcome after multivariable adjustment, offers credible background evidence for performing 
a prospective trial (18)  2.  This study will incorporate an evidence-based algorithm for UFH 
supplementation and ACT sampling frequency to provide critical standardization to the process 
of intra-procedural anticoagulation.  In addition, the study will be novel in formally defining the 
use of the ACT target as the value prior to first coronary device activation, which is 
recommended as it is a single, unique value, and unbiased as compared to peak ACT or closing 
ACT values which are greatly influenced by sampling frequency.  ACT prior to device activation 
has been used as the primary predictor variable in retrospective analyses from previous 
antiplatelet trials (19-21), however, the extant literature is not consistent with use of pre-device 
ACT values.  
 
D. Approach:  Patients >18 years of age referred for coronary angiography with intent to 
perform revascularization, if clinically indicated, will be prospectively identified and eligible for 
participation.  .  Patients who undergo adjunctive intracoronary imaging or physiologic 
assessment of lesion severity that requires administration of UFH and ACT sampling prior to 
coronary vessel wiring may also be randomized. The following inclusion criteria for OPTIMAL-
ACT are as follows: 


Inclusion Criteria: 
 
• 
Age>18 
• 
Ability of subject to give appropriate consent 
• 
Referred for coronary angiography with possible coronary revascularization or 
adjunctive invasive diagnostic testing (IVUS/OCT, FFR, or iFR) 
 
Specific exclusions would include patients receiving low-molecular weight heparin at treatment 
doses with last dose within 6 hours of coronary angiography (patients on low-molecular weight 
heparin (LMWH) for venous thromboembolism prophylaxis would be eligible), upstream 
treatment with GP IIb/IIIa inhibitors within the previous 72 hours, use of warfarin or a novel oral 
anticoagulant at the time of the procedure, patients being bridged with LMWH in the peri-
procedural setting, PCI performed within the proceeding 30 days, need for rotational 
atherectomy, and planned use of bivalirudin as the procedural anticoagulant.  If the operator 
was uncertain as to whether bivalirudin would be used, the patient would be eligible for 
screening and randomization.  In the event that bivalirudin was selected to support the PCI 
procedure, the patient would be excluded from the OPTIMAL-ACT trial and recommendations 
would be for dosing bivalirudin per the manufacturer’s instructions with ACT monitoring as used 
in the REPLACE-2 trial (22), which included ACT value 5 minutes after initial bolus and if <225 
sec, an additional bolus of 0.3 mg/kg if needed. The following exclusion criteria for OPTIMAL-
ACT are as follows: 
Exclusion Criteria: 
 
• Receipt of LMWH at treatment dose (not DVT prophylaxis dose) within 6 hours of 
coronary angiography 
• Prior GP IIb/IIIa use within the previous 72 hours 
• Use of warfarin (vitamin K antagonist) or direct oral anticoagulant 
• Patients on LMWH bridging strategy 
• PCI within prior 30 days 
• Planned use of bivalirudin as the procedural anticoagulant 
• Rotational atherectomy 
• Excimer laser coronary angioplasty 
• Chronic total occlusions 
• Patients with active bleeding disorders or bleeding diathesis 
• Patients with ST-segment elevation myocardial infarction 
• Patient with clinical evidence of cardiogenic shock (defined as SBP<90 mmHg for ≥30 
min OR support to maintain SBP ≥90 mmHg AND evidence of end-organ 
hypoperfusion (urine output <30 mL/h or cool extremities) 
• Chronic kidney disease stage 4/5 (GFR 30 mL/min) 
 
Patients would be randomized to one of three ACT target groups (Figure 1). Patients will 
undergo randomization (1:1:1) to either low ACT target, medium ACT target, or high ACT target 
using a software automatic program (insert information on SDMS). ACT target ranges would be 
modified based on intended or provisional use of GP IIb/IIIa inhibitors.  Target ranges for the 
OPTIMAL-ACT trial were based on both review of practice guideline recommendations, 
including the uncertainty expressed in the guidelines regarding ACT values and outcomes (4), 
and consensus agreement by study interventional cardiologists regarding clinical equipoise in 
the target ranges studied. . PCI would be performed per routine clinical practice and selection of 
adjunctive oral antiplatelet therapies would be at the discretion of the operator and in 
accordance with clinical practice guidelines (4).  Patients would be observed post PCI for 


bleeding (primary endpoint), defined as BARC 1, 2,3 or 5 and EASY I-V (Appendix) and for 
NACE (i.e., ischemic events or bleeding as the primary safety endpoint).  Follow-up would 
extend for 30-days post PCI for occurrence of the primary endpoint and primary safety endpoint. 
A dedicated telephone script will be used to contact the patient 30 days post-procedure. If the 
patient experienced a possible endpoint event and was treated at an outside facility, medical 
records will be obtained for review of whether the endpoint was met.   
 
OPTIMAL-ACT TRIAL
Randomization
High ACT Target
(325-375 sec if no 
planned GP IIb/IIIa; 
200-250 sec if GP 
IIb/IIIa
Medium ACT Target
(275-325 sec if no 
planned GP IIb/IIIa; 
200-250 sec if GP 
IIb/IIIa)
Low ACT Target
(225-275 sec if no 
planned GP IIb/IIIa; 
200-250 sec if GP 
IIb/IIIa)
PCI performed per usual strategy with protocol-defined sampling frequency for ACT 
monitoring and heparin supplementation
In-hospital bleeding (EASY and BARC bleeding scale)—primary efficacy endpoint
30-day Net Adverse Clinical Event (NACE)—primary safety endpoint
Figure 1
 
 
The ACT target algorithm closely mirrors practice guidelines for UFH supplementation and ACT 
monitoring (Figure 2)(4).  The algorithm provides rigorous standardization to the process of ACT 
sampling and UFH supplementation to reduce the risk for bias in the study.  Although there will 
be multiple ACT values for each PCI procedure, the use of the ACT value prior to device 
activation will be the “target” for the purposes of the trial. In the event that an ACT prior to 
device activation was not obtained, the ACT value closest to the time of initial device activation 
will be used and the procedure time between the ACT sample and device activation will be 
recorded. 
 


OPTIMAL-ACT TRIAL
(post diagnostic cath; PCI intended)
High ACT Target
Medium ACT Target
Low ACT Target
No prior anticoagulant and no planned GP IIb/IIIa Inhibitor (70 U/Kg IV/IA bolus UFH)
No prior anticoagulant and planned GP IIb/IIIa inhibitor (50 U/Kg IV/IA bolus UFH)
If prior anticoagulant given, obtain baseline ACT and follow UFH supplementation algorithm below
3 minute post bolus ACT check
Coronary wire insertion begins when ACT is in target range based on randomization
If ACT above target <50 sec, repeat ACT in 3 min
If ACT above target 51-100 sec, repeat ACT in 5 min
If ACT above target 101-200 sec, repeat ACT in 10 min
If ACT value is at target range, repeat ACT in 5 min
If ACT below target >50 sec, give 1000 U UFH bolus IV/IA, repeat ACT in 3 min
If ACT below target 51-100 sec, give 2000 U bolus IV/IA, repeat ACT in 3 min
If ACT below target 101-200 sec, give 3000 U bolus IV/IA, repeat ACT in 3 min
Figure 2
 
 
The Hemochron Signature Elite (Hemochron® Jr.) whole blood microcoagulation system 
(International Technidyne Corporation, Edison, NJ) for ACT is the POC test performed in the 
cardiac catheterization laboratory at Mayo Clinic Florida.  The ACT demonstrates linear 
correlation to the anticoagulation effects of heparin to 2.5 units/,L of blood. The device is 
intended for clinical use during in vitro diagnostic testing of whole blood for POC monitoring of 
anticoagulation intensity in UFH-treated patients undergoing medical procedures. The test result 
is automatically converted to a reference Celite® ACT value and both displayed and 
electronically recorded on the device. No other ACT assay system will be used for the 
OPTIMAL-ACT trial. Although some patients receive non-UFH anticoagulants, ACT is most 
commonly used to monitor patients receiving UFH and undergoing cardiac catheterization.  The 
Mayo Clinic Department of Laboratory Medicine and Pathology oversees POC testing in the 
cardiac catheterization laboratories at Mayo Clinic Florida.  For the OPTIMAL-ACT trial, 
collaborators from the Mayo Clinic Department of Laboratory Medicine and Pathology will be co-
investigators to provide technical expertise regarding POC testing using ACT.  Quality controls 
are outlined in an institutional Standard Operating Procedure document.  
 
E. Preliminary Work:  Data for the relationship between ACT and outcomes are sparse in 
contemporary PCI practice and guideline recommended targets for ACT during PCI were based 
on small studies in angioplasty alone settings (23) or proof-of-concept studies that did not report 
clinical outcomes (24).  Table 1 summarizes the existing literature comprising the largest studies 
with regard to ACT target values and outcomes.  These studies have primarily been derived 
from “lower-risk” populations in trials and are entirely post-hoc analyses, the exception being the 
registry based design of the Mayo Clinic experience by Rajpurohit et al (S.M. Gharacholou, 


senior author), representing the largest study on this topic to date (18).  However, the study is 
primarily limited in terms of drawing firm conclusions by its retrospective design. 
 
Table 1. Summary of studies investigating association of ACT and outcomes 
Study 
Year 
Study Design 
Patients 
(n) 
Rates of 
adjunctive 
therapies 
ACT associated with 
ischemic/thrombotic 
events? 
ACT associated with 
bleeding? 
 
Comments 
Bittl et al6 
1998 
Post hoc analysis 
of clinical trial 
comparing 
heparin with 
bivalirudin 
4,098 
Balloon 
angioplasty 
only study, no 
thienopyridine, 
no GP IIb/IIIa 
inhibition 
Higher risk of abrupt 
vessel closure in heparin-
treated patients at lower 
initial ACT  
 
No risk difference 
observed in bivalirudin 
treated patients 
 
Bleeding requiring 
transfusion was not 
associated with initial 
ACT result, but was 
associated with peak ACT 
for both heparin and 
bivalirudin groups 
ACT was only repeated 
if procedure>45 
minutes or if patient 
developed 
intraprocedural 
ischemic complication 
(i.e, abrupt vessel 
closure) 
 
Multivariable 
adjustment not 
performed 
Chew et 
al8 
2001 
Meta analysis of 
pooled data from 
6 trials of GP 
IIb/IIIa inhibitors 
5,216 
Majority of 
patients were  
angioplasty 
alone (<8% 
stenting), no 
thienopyridine 
 
Reduction in composite 
ischemic events with 
increasing ACT, with 
optimal ACT range of 350 
sec-375 sec 
 
In subgroup of GP IIb/IIIa 
treated patients, there 
was no association 
between ACT and 
composite ischemic 
events across the ACT 
range of 275 sec to 375 
sec 
Peak ACT associated 
with bleeding, including 
higher rates of bleeding in 
patients additionally 
treated with GP IIb/IIIa 
inhibitors 
 
Optimal ACT range did 
not vary when 
analyzed by procedural 
duration 
 
Multivariable 
adjustment not 
performed 
Tolleson 
et al9 
2003 
Post hoc analysis 
of clnical trial 
comparing 
heparin with 
eptifibatide 
2,064 
High rates of 
dual 
antiplatelet 
therapy (97%) 
and coronary 
stenting (97%) 
 
No association between 
ACT at time of device 
activation and ischemic 
events (p=0.43). No 
increased risk of ischemic 
complications at low ACT 
values (as low as 200 
sec). 
 
 
No association between 
ACT and major bleeding 
(p=0.9). Higher ACT 
values associated with 
bleeding among GP 
IIb/IIIa treated patients 
The lowest rate of 
ischemic events were 
seen in the lowest ACT 
tertile, with similar 
observation among GP 
IIb/IIIa treated patients 
 
Lower-doses of weight-
adjusted heparin used 
 
Lower profile vascular 
devices 
Brener et 
al10 
2004 
Meta-analysis of 
pooled data from 
4 trials 
 
9,974 
Clopidogrel 
(81%), GP 
IIb/IIIa 
inhibitors 
(89%), and 
coronary 
stents (93%) 
No association between 
peak ACT and composite 
ischemic events 
(p=0.40))  
Higher peak ACTs were 
associated with bleeding 
(p=0.01) 
 
No interaction between 
ACT and ischemic or 
bleeding outcomes in 
cohorts of patients 
presenting with 
unstable angina or 
diabetes 
ACT data missing in 
16% of patients 
Rajpurohit
et al18 
2016 
Mayo Clinic PCI 
Registry/DataMart 
12,055 
High rates of 
clopidogrel 
(98%) and 
coronary 
stenting (93%) 
No association between 
ACT at time of device 
activation and ischemic or 
thrombotic events 
No association between 
ACT at time of device 
activation and clinically 
overt bleeding 
Largest study on topic 
to date 
 
Increasing ACT 
associated with MI risk 
in women at 1 year 
 
 
F. Statistical Considerations:   
F1. Randomization and blinding: Patients will be randomized (1:1:1) to one of the three ACT 
target groups (low, medium, or high) using a dynamic minimization algorithm so as to optimize 
the likelihood that balance between the low, medium, and high ACT target groups will be 


achieved with respect to sex (male or female) and glomerular filtration rate (30 to 59 
ml/min/1.73m2 or ≥60 ml/min/1.73m2). The algorithm will be will be implemented in RAVE 
RTSM, a secure web-based interface, and accessed by the study coordinator or other 
appointed study personnel.  Randomization will be conducted after the diagnostic portion of the 
procedure on only patients who will require ACT monitoring.  Since eligible patients will require 
ACT monitoring during PCI, we will not conduct the study in a strictly blinded fashion. However, 
study participants will not be informed of their randomization assignment. 
 
F2. Data collection and handling: Electronic case report forms along with a corresponding 
secure REDCap database will be created for data collection (29).  Data to be collected will 
include baseline demographics, comorbidities, procedural variables, in-hospital events, NACE 
component, and adverse events. 
 
F3: Definition of study outcomes:  Study endpoints are summarized in Appendix II. 
F3.1 Primary study endpoint: Our primary study endpoint is bleeding and is defined as either 
a Bleeding Academic Research Consortium (BARC) hemorrhage grade of 1, 2, 3, or 5 or an 
EASY hematoma scale grade of I-V from the time of PCI to the time the patient is discharged 
from the hospital.   
F3.2 Primary safety endpoint: Our primary safety endpoint is a composite of net adverse 
clinical events (NACE) and stent thrombosis, as defined by the Academic Research 
Consortium, from the time of PCI to the time the patient is discharged from the hospital.   
F3.2.1 NACE is the composite of all-cause mortality, myocardial infarction (MI), stroke, target 
lesion revascularization, and major bleeding within 30 days after PCI.   
F3.2.2 MI will be defined as any two of the following 3 criteria: 1) chest pain for at least 20 
minutes; 2) elevation of cardiac biomarkers, preferably troponin, above the laboratory upper limit 
of normal; and 3) new pathological Q wave on electrocardiogram.   
F3.3.3 Stroke will have occurred if post-PCI neurological symptom is confirmed as a stroke by a 
consultant neurologist at Mayo Clinic with documentation on appropriate neuroimaging (CT or 
MRI).  
F3.3.4 Major bleeding will be defined as BARC grade 3 or 5 or EASY grade ≥III. 
F3.3.5 Target vessel revascularization will be defined as clinically driven revascularization, 
either by percutaneous or surgical means.   
F3.3.6 Intra-procedural events would include both bleeding and thrombotic complications. Intra-
procedural thrombus will be defined as a visible filling defect noted by the primary operator on 
the guiding catheter or intracoronary wire or device on selective angiogram.   
F3.4 The study definition of non-inferiority will be defined based on the 95% confidence interval 
for the difference in proportions of patients with NACE in the low and high ACT target groups, Δ 
= pL-pH, with a lower limit of ΔL and an upper limit of ΔU  .  Low ACT target will be considered to 
be non-inferior to high ACT target if one of the following holds, depending on the estimate pH : 
• ΔU  < 0.12 if pH ≥0.12 
• ΔU  < pH if 0.04<pH<0.12 
• ΔU  < 0.04 if pH ≤0.04 
Note that italicized version are the theoretical proportions and the estimates are not 
italicized. 
F.4. Sample size determination: Recognizing the limitations of previously performed studies 
regarding ACT and risk of bleeding, including variability in definitions of bleeding, we estimate 
that the highest ACT target group will experience the in-hospital primary outcome at a rate of 
25%, while the lowest ACT target will experience the in-hospital primary outcome at a rate of 
5%.   A sample size of of 504 patients was determined to ensure more than 80% power at the 


two-sided overall 5% significance level with Bonferroni adjustment for multiple testing (p value 
≤0.025 considered as statistically significant) to detect an absolute difference in in-hospital 
bleeding (Aim 1) between the low ACT target and the medium ACT target (ie. 5% vs. 15%) in 
addition to a 20% absolute difference between the low ACT target and the high ACT target (ie. 
5% vs. 25%).  The power was estimated on the the basis of 5000 simulations.  Patients meeting 
eligibility criteria for the study and who consent for participation but that do not undergo 
randomization due to either not receiving intracoronary diagnostic imaging (IVUS/OCT) or 
physiologic testing (iFR/FFR) or PCI will be entered into the ACT registry and observed for 
clinical events, including 30-day outcomes.  The reason these patients are not categorized as 
screen failures is because the final criterion for eligibility is receipt of PCI, a criterion that is not 
known until the coronary angiogram is performed which is after patients have signed informed 
consent.  Because patients receive moderate sedation during their procedure as part of 
standard of care, ethical and scientific prudence dictates that informed consent be obtained 
prior to procedural start.  True screen failures, therefore, are those subjects not meeting study 
inclusion or exclusion criteria.  .  Based on current lab practice patterns at our institution, it is 
anticipated that approximately 20% of patients who enroll in the study will not require ACT 
monitoring after the diagnostic portion of the procedure, therefore we intend to consent up to 
780 patients.   In 2016, there were 240 PCI procedures and 220 adjunctive coronary 
imaging/physiology procedures (Fractional Flow Reserve = 158, Intravascular Ultrasound = 59, 
Optical Coherence Tomography = 12) establishing the feasibility of performing the study and 
meeting patient accrual targets over an 18 - 24 month period.   
 
We also considered the implications of this samples size with the other primary aims.  For 
purposes of estimating the incidence of our study endpoint and safety endpoint (Aim 2), a 
sample size of 504 with equal allocation to each of the three study arms would produce a two-
sided 95% confidence interval with a width of 0.15 or less using the Wilson score method.  This 
sample size would also ensure more than 80% power to show evidence of non-inferiority for our 
primary safety endpoint (NACE, Aim 3) in patients with a low ACT target compared to those with 
a high ACT target according to the above criteria (section F3.4) when the low and high ACT 
targets are the same with respect to NACE assuming the probability of NACE with a high ACT 
target is 12% or more. A review of the published literature had a median estimated rate of 12% 
for NACE (range 4% to 20% (Table 2).  
 
Table 2.  
 
Study 
Hematoma 
Rate (%) 
Major 
bleeding 
Rate (%) 
NACE 
Rate (%) 
Mean 
ACT 
range 
(sec) 
Comments 
Petroglou et 
al (25) 
18 
3 
NR 
147 
Mostly diagnostic 
procedures, all radial 
cases, 5F sheaths, no 
high risk patients 
Jolly SS (26) 
3 
3 
4 
NR 
Acute coronary 
syndrome patients, 
strict bleeding 
definitions 
Bertrand OF 
(27) 
5 
1 
20 
315 
All radial cases 
 
  


 
F5. Statistical analysis plans:  
F5.1 Patient population for analysis: The primary analysis will include all randomized patients.  
Since patients will be randomized after the diagnostic portion of the procedure and the primary 
study outcome will be collected during their initial hospitalization after PCI, we anticipate 
negligible loss to follow-up and negligible imbalance between study arms. Analysis of the study 
aims will be conducted using an intent-to-treat approach, which means it will be an analysis 
including all randomized patients according to the group they were randomized regardless of 
whether or not the assigned ACT target was achieved. 
F5.2 Primary analysis plan: Aim 1: The risk of in-hospital bleeding in the medium ACT target 
group and the high ACT target group will be compared to the risk of in-hospital bleeding in the 
low ACT target group using pair-wise chi-square tests (or Fisher’s exact test).  Relative risks 
and 95% confidence intervals will be reported.  For these two tests of the primary study 
outcome, a two-sided p-value ≤ 0.025 will be considered statistically significant using the 
Bonferroni adjustment for multiple testing.  This means that the overall two-sided level of 
significance for the trial will be 0.05.  Aim 2: We will estimate the proportion of patients with each 
outcome (bleeding, NACE) along with 95% confidence intervals for the proportions using the 
Wilson score method separately for the three groups.  Aim 3: We will create a 95% confidence 
interval for the difference in proportions of patients with NACE in the low and high ACT target 
groups using the Newcombe score method.  This will be used to assess whether there is 
evidence of non-inferiority of low ACT target compared to high ACT target according to the 
definition in section F3.4. 
 
F5.3 Secondary analysis plan: We will evaluate if associations between ACT target group (low, 
medium, high) and in-hospital bleeding are independent of sex, access site, and concomitant 
use of glycoprotein (GP) IIb/IIIa inhibitors (Aim 2) using a Cochran-Mantel-Haenszel test.  For 
these pre-planned tests, a two-sided p-value≤0.0167 will be considered statistically significant 
using a Bonferroni adjustment for multiple testing.   Descriptive summaries and relative risks will 
be reported as in the primary analysis, except stratified by each of the patient or procedure 
characteristics. 
 
Baseline patient and procedure characteristics of the three groups will be reported as number 
and percentage for categorical variables and median and interquartile range for continuous 
variables. To evaluate the possibility of imbalance, we will make comparisons between the three 
randomized groups using a Kruskal-Wallis test for ordered or numeric variables and a chi-
square test (or Fisher’s exact test) for categorical variables.  For those baseline characteristics 
with imbalance between groups, we will summarize the number and percentage as well as 
relative risk and 95% confidence intervals as was done with the pre-planned analyses of sex, 
access site, and concomitant use of glycoprotein (GP) IIb/IIIa inhibitors with stratification by the 
baseline characteristic.  In addition, we will use a multivariable logistic regression model with in-
hospital bleeding as our outcome measure and fixed effects for group (reference group = low 
ACT target), sex, access site, concomitant use of glycoprotein (GP) IIb/IIIa inhibitors, and any 
other baseline characteristics with evidence of potential imbalance between groups (p-
value≤0.20) allowing no more than one variable for every 10 patients who experience in-hospital 
bleeding. 
 
F5.4 Exploratory analysis plan: We will explore the association of ACT target with individual 
components of bleeding and NACE using a Cochran-Armitage trend test and report the number 
and percent of patients with each component separately for each group. Adjustment for multiple 
testing will be conducted using the Holm step-down method. 
 


F5.5 Interim analysis plan:  A blinded review of the study’s overall incidence of the primary study 
outcome and the primary safety endpoint will be planned after 50% of patients have completed 
the study.  If this review suggests that assumed incidence used to plan the study is much higher 
than the actual event rate then we may reestimate the sample size to ensure the study is 
adequately powered.  Since the analysis will be conducted blind to group assignment this will 
not introduce statistical bias and adjustment to the study’s significance level is not required...


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Appendix I 
 
Bleeding Academic Research Consortium (BARC) Standard Bleeding Definition(26) 
BARC 0 
No bleeding 
BARC 1 
Non-actionable bleeding 
BARC 2 
Actionable bleeding, even if on imaging alone, that meets one of the following:1) 
requires non-surgical (medical) intervention by healthcare personnel; 2) leads to 
hospitalization or escalation in level of care; 3) prompts evaluation. 
BARC 3a 
Overt bleeding AND hemoglobin drop 3 to 5 g/dL OR blood transfusion 
BARC 3b 
Overt bleeding AND hemoglobin drop ≥5 OR cardiac tamponade, bleeding 
requiring surgical intervention for control, need for intravenous vasopressor 
BARC 3c 
Intracranial/intraspinal hemorrhage or intraocular hemorrhage with any visual 
impairment 
BARC 4 
CABG-related bleeding 
BARC 5 
Probable or definite fatal bleeding 
 
EASY Hematoma Classification Scale 
 


Appendix II 
Optimal Target of Activated Clotting Time During Percutaneous Coronary 
Intervention and Outcomes: The OPTIMAL-ACT Trial 
Study Endpoint Definitions: 
Bleeding 
-EASY hematoma classification after Transradial/Ulnar PCI 
Type 1: less than 5cm in diameter from puncture site 
Type 2: 5-10 cm in diameter from puncture site 
Type 3: >10 cm in diameter but below the elbow limited to the forearm 
Type 4:>10 cm in diameter and extends above the elbow 
Type 5: any bleeding location with compartment syndrome (ischemic threat to the limb)  
-BARC 2, 3, or 5 bleeding using BARC defined bleeding scale 
BARC 0 
No bleeding 
BARC 1 
Non-actionable bleeding 
BARC 2 
Actionable bleeding, even if on imaging alone, that meets one of the following:1) 
requires non-surgical (medical) intervention by healthcare personnel; 2) leads to 
hospitalization or escalation in level of care; 3) prompts evaluation. 
BARC 3a 
Overt bleeding AND hemoglobin drop 3 to 5 g/dL OR blood transfusion 
BARC 3b 
Overt bleeding AND hemoglobin drop ≥5 OR cardiac tamponade, bleeding 
requiring surgical intervention for control, need for intravenous vasopressor 
BARC 3c 
Intracranial/intraspinal hemorrhage or intraocular hemorrhage with any visual 
impairment 
BARC 4 
CABG-related bleeding 
BARC 5 
Probable or definite fatal bleeding 
 
Net Adverse Clinical Events (composite of all-cause mortality, myocardial infarction, stroke, 
target lesion revascularization, or bleeding) 
Stent thrombosis (ST) 1,2:  
Definite (ST): ACS with angiography or autopsy evidence of stent thrombosis. 
Probable (ST): Unexplained death within 30 days of index procedure or acute myocardial 
infarction involving the target-vessel territory without angiographic confirmation. 


Myocardial infarction: presence of 2 of the following: ischemic symptoms; elevation of cardiac 
troponin >99th percentile of lab upper reference range with typical rise and fall; ECG changes 
compatible with infarction. For cardiac troponin elevated prior to PCI due to myocardial 
infarction, the subsequent troponin would need to be increased by 20% or more than the 
previous value to be considered an endpoint event3. 
Stroke: Focal loss of neurological function caused by an ischemic or hemorrhagic insult, with 
residual symptoms lasting at least 24 hours, and confirmed on neuroimaging (CT or MRI) with 
final impression deemed as stroke by a consulting neurologist 
Target lesion revascularization: repeated PCI of the stented segment  
Intra-procedural thrombus: visible filling defect noted by the operator on the guiding catheter 
or intracoronary wire or device during selective angiography with or without adjunctive 
confirmation on alternative coronary imaging modality (IVUS/OCT) 
 


 
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