Highlights
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PRACTICAL HERO: RCT in patients undergoing diagnostic cardiac catheterization.
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Evaluates heparin vs placebo for preventing radial artery occlusion.
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Compares high-dose vs low-dose unfractionated heparin strategies.
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Assesses net outcome: radial artery occlusion and bleeding.
ABSTRACT
Rationale
Radial artery occlusion (RAO) and bleeding are the principal complications of transradial cardiac catheterization. Although unfractionated heparin (UFH) reduces RAO, it may increase bleeding risk; thus, the optimal balance between efficacy and safety remains uncertain.
Primary hypothesis
Among patients undergoing transradial coronary angiography, UFH (high-dose 50 U/kg or low-dose 25 U/kg) compared with placebo reduces RAO, assessed by Doppler ultrasound prior to discharge.
Design
Multicenter, randomized, controlled trial comparing high-dose UFH, low-dose UFH, and placebo. Patients undergo standardized radial hemostasis (30-minute compression followed by stepwise 20-minute release). Net clinical benefit defined as composite of RAO and hematoma ≥5 cm.
Clinical trial registration
URL: www.clinicaltrials.gov ; Unique identifier: NCT04374799.
Background
The transradial approach (TRA) is preferred for diagnostic coronary angiography because it is associated with lower risk of vascular complications than the transfemoral approach. ,,,
However, the principal limitation of TRA is radial artery occlusion (RAO). Reported RAO rates vary widely and depend largely on the method of assessment; studies using routine Doppler ultrasound consistently report higher incidences. ,,,,, RAO is usually asymptomatic due to dual perfusion of the hand via the radial and ulnar arteries. However, RAO may limit the use of the radial artery for subsequent procedures, including repeat coronary angiography or as a conduit for coronary artery bypass grafting. Additionally, a small proportion of patients may experience prolonged forearm pain. The risk of RAO is influenced by several procedural factors, including shorter radial compression times after removal of the radial hemostatic device (RHD) and the use of patent hemostasis techniques, which are facilitated by specific RHD designs. ,,,
The most commonly employed strategy to reduce RAO is the administration of unfractionated heparin (UFH). However, UFH may increase the risk of access-site bleeding or hematoma, particularly when the RHD is removed early. UFH administration is also associated with nonaccess-site bleeding, which may lead to serious complications. Approximately 10% of patients undergoing percutaneous coronary interventions (PCI), in whom variable doses of UFH are used, experience nonaccess-site bleeding, such as gastrointestinal, retroperitoneal or intracranial hemorrhage, which is associated with a substantial increase in mortality. In the large CathPCI registry, 12.1% of deaths were related to post PCI bleeding events.
Despite these risks, UFH is routinely administered during transradial coronary angiography primarily to reduce RAO, including in patients with a history of gastrointestinal or intracranial bleeding or in those receiving oral anticoagulation. In contrast, routine UFH use during femoral-access catheterization has largely been abandoned, reflecting advances in catheter design and the use of smaller sheath sizes.
In the PRACTICAL-2 trial, we evaluated the incidence of RAO in the absence of UFH administration. A total of 450 patients were randomized to 10, 20, or 30 minute RHD application times. The overall RAO incidence was 8%, with no significant differences among groups. Notably, one-third of RAO cases resolved spontaneously at 1 month, and access-site bleeding events were infrequent and minor.
The aim of the present study is to evaluate the incidence of RAO, access-site bleeding, and nonaccess-site bleeding among patients randomized to UFH vs placebo.
Methods
Trial design and management
The PRACTICAL-HERO trial is a multicenter, prospective, 3-arm, randomized controlled trial comparing 2 doses of UFH with placebo in patients undergoing diagnostic transradial cardiac catheterization. The trial is designed to evaluate the safety and efficacy of UFH and was approved by Clinical Trials Ontario and each participating site’s Research Ethics Board. The study is registered at www.clinicaltrials.gov ; identifier NCT04374799.
The coordinating center is the Interventional Cardiology Research group at London Health Sciences Centre Research Institute, responsible for trial organization, randomization, and coordination across sites. Participating sites included London Health Sciences Centre and Hamilton Health Sciences . The trial is funded by a grant from the Academic Medical Organization of Southwestern Ontario (#INN20-011), and the coordinating center and steering committee retain full responsibility for the trial design, data analysis, manuscript preparation, and decisions regarding publication.
Study population, inclusion, and exclusion criteria
Inclusion criteria: Patients undergoing elective diagnostic cardiac catheterization via the TRA using a 5F, 5F Slender, or 6F slender Glidesheath; demonstrated patency of the ulno-palmar circulation as defined by Barbeau et al. (Barbeau A-C ).
Exclusion criteria: Patients with abnormal ulno-palmar circulation (Barbeau D pattern). Patients who had prior radial artery thrombosis, prior surgery close to the access site, who are undergoing emergent cardiac catheterization, or who require anticoagulation during the procedure.
Patients receiving anticoagulants could be included in the study provided the anticoagulant is held until it is no longer therapeutic, in accordance with standard clinical practice. As antiplatelet agents are not routinely discontinued prior to cardiac catheterization, they are continued.
All patients provide written informed consent prior to enrollment.
Study procedures
After sheath insertion, diagnostic cardiac catheterization is performed using standard techniques and equipment at the operator’s discretion, including left ventricular angiography and coronary graft injections if required. Patients are excluded if ad hoc PCI is performed or if UFH is required for invasive hemodynamic assessment (eg, fractional flow reserve measurement) ( Figure ).
CONSORT flow diagram of patient participation.
There are no restrictions on operator participation in order to reflect real-world practice. Both interventional cardiologists and trainees working in the cardiac catheterization laboratory are included. At the end of the procedure, the radial sheath is removed and a radial hemostatic device (RHD) applied for 30-minutes based on our previous data.
Use of introducer sheaths and hemostatic devices is permitted according to local practice.
Randomization and hemostatic device release
Patients are randomized 1:1:1 to:
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Low-dose UFH (25 IU/kg; maximum 3,000 IU).
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High-dose UFH (50 IU/kg; maximum 5,000 IU).
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Placebo (0.9% NaCl bolus).
The study drug is administered intravenously after sheath insertion and before removal, with exact timing at the operator’s discretion. The degree of anticoagulation, as measured by ACT or similar tests, is not routinely assessed, as diagnostic procedures are brief and no standard ACT target has been established. Randomization is performed prior to sheath insertion using REDCap, stratified by center and sheath size, with permuted block sizes. Physicians, patients, and outcome assessors are blinded to allocation.
The RHD is applied for 30 minutes, followed by a gradual 20-minute release using a controlled technique. Access-site bleeding or hematoma during device loosening or removal is recorded. If bleeding occurs, the device is retightened for 10 minutes and released again over 20 minutes.
This is an investigator-initiated trial; manufacturers and distributors of the RHDs or introducer sheaths have no role in study design, conduct, data collection, or analysis.
Study endpoints
The trial initially included coprimary endpoints of RAO and hematoma to reflect the competing risks of TRA. Superiority was initially assumed for the placebo arm in terms of hematoma, and a noninferiority framework was chosen for RAO. Following a blinded interim analysis (Oct 2025) , very low hematoma rates were observed, prompting us to focus on RAO as the primary endpoint (assumed superiority with UFH). This change was carefully implemented to preserve the overall statistical integrity of the trial. The composite of RAO and hematoma was incorporated into net clinical outcome.
The primary outcome is RAO, assessed by color Doppler ultrasound 1 hour post-RHD removal. Secondary endpoint: Access-site hematoma ≥5 cm. (grade 2 or higher according to the early discharge after transradial stenting of coronary arteries scale). The net clinical outcome is defined as a combination of RAO and hematoma.
Other secondary endpoints include: any access site bleeding or hematoma (according to the early discharge after transradial stenting of coronary arteries scale), nonaccess site bleeding (BARC 2, defined as any overt actionable sign of hemorrhage requiring medical evaluation, diagnostic testing, hospitalization or treatment), other vascular access site complications, actual duration of RHD, time to discharge from post procedure care area.
Sample size calculation
The sample size calculation is based on our previously observed RAO rate of 8% in the placebo group, assuming a 2:1 allocation (UFH:placebo), a relative risk reduction (RRR) of 50%, 5% type 1 error, and 2-sided superiority testing. With 80% power, we require 404 patients in the placebo group, and 808 patients in the UFH groups combined, for a total of 1,212 patients. With a 90% power, we require 541 patients in the placebo arm and 1,082 patients in UFH, for a total of 1,623 participants.
Following a blinded interim analysis, the observed RAO rate was 3.8%, which required recalculation of the sample size. Assuming a 50%-60% RRR, the number of participants required with 80% power is estimated to range between 1,164 and 1,959, as summarized in the table below ( Table ):
Table
Sample size and power calculation
| UFH reduction | Assumed RAO placebo | Assumed RAO UFH | n-placebo | n-UFH | Total n |
|---|---|---|---|---|---|
| 30% | 4.75% | 3.33% | 2,396 | 4,792 | 7,188 |
| 50% | 5.7% | 2.85% | 653 | 1,306 | 1,959 |
| 60% | 6.33% | 2.53% | 388 | 776 | 1,164 |
| 70% | 7.13% | 2.14% | 241 | 482 | 723 |
| 100% | 11.4% | 0% | 61 | 122 | 183 |
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