Percutaneous Coronary Intervention with Procedural Unfractionated Heparin without Activated Clotting Time Guidance: A Unique Opportunity to Assess Thrombotic and Bleeding Events

Background Rates of major bleeding and intraprocedural thrombotic events (IPTE) in the setting of percutaneous coronary intervention (PCI) using weight-adjusted unfractionated heparin (UFH) without activated clotting time (ACT) monitoring are not known. Methods We reviewed 2,748 consecutive patients who underwent coronary angiography at our tertiary care university hospital between January 2017 and December 2020. All patients who underwent PCI with weight-adjusted UFH without ACT guidance were considered for further analysis. Major bleeding complications occurring within 48 hours of PCI were collected from patients' medical records. IPTE were collected independently by two interventional cardiologists after review of coronary angiograms. Results There were 718 patients included in the analysis (65.4 ± 12.2 years old; 81.3% male). In total, 45 patients (7.8%) experienced a major bleed or IPTE. The most common IPTE were slow/no reflow (1.5%) and coronary artery dissection with decreased flow (1.1%). Other IPTE occurred in <1% of cases. Major bleeding occurred in 11 patients (1.5%), of whom 8 required blood transfusion and 3 required vascular intervention. Bleeding complications were more common with femoral compared with radial access (6.6% vs. 0.2%, P < 0.001). Conclusion Weight-adjusted UFH use during PCI without ACT monitoring was related to low rates of major bleeding or IPTE.


Introduction
Unfractionated heparin (UFH) remains the most commonly used anticoagulant during percutaneous coronary interventions (PCIs) [1,2].UFH contains glycosaminoglycans which bind to antithrombin III, catalysing the inhibition of several coagulation factors, especially factors IIa and Xa [3].However, UFH has an unpredictable therapeutic response because of marked variability in bioavailability, in part due to variable binding to plasma proteins and endothelial cells [4].For this reason, the activated clotting time (ACT) test is used to monitor its therapeutic efect [5].Current guidelines recommend target ACT values within 200 to 250 seconds with planned use of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors and 250 to 300 seconds (HemoTec device) or 300 to 350 seconds (Hemochron device) in the absence of GP IIb/ IIIa inhibitors [2].
Recently, the fnancial crisis in Lebanon generated signifcant medical equipment shortages, such that routine ACT testing became unavailable.Terefore, many PCI procedures were performed with unmonitored UFH at the American University of Beirut Medical Center.Tis provided a unique opportunity to assess thrombotic and bleeding events associated with this approach.

Study Design and Population.
Tis is a single-center retrospective observational study conducted to assess intraprocedural thrombotic events (IPTE) and major bleeding complications during PCI performed with unmonitored UFH.We reviewed consecutive patients who underwent PCI with UFH for any indication between January 2017 and December 2020.All patients who received an alternative anticoagulant or whose UFH dosage was guided by ACT were excluded.Coronary angiography was performed according to validated standards.Te choice of guiding catheter, guidewire, balloon, and stent size was decided by the interventional cardiologist.As per hospital protocol, patients undergoing PCI with UFH received the guideline-recommended weight-adjusted boluses of 70-100 U/kg or 50-70 U/kg with planned use GP IIb/IIIa inhibitor.Tere is no unifed protocol for additional UFH boluses during prolonged PCI procedures at our institution.Patients diagnosed with out-of-hospitalST-segment elevation myocardial infarction (STEMI) were given a loading dose of 4000 units of UFH in the Emergency Department, followed by completion of the dose at the time of primary PCI (within 90-120 minutes) for a total of 70-100 U/kg.Hemostasis was achieved with a compression bracelet in case of radial access and manual compression in case of femoral access.

Statistical Analysis.
Data management and analyses were carried out using SPSS Version 22.0 (IBM Corp, Armonk, New York).Descriptive statistics were performed by calculating the counts and percentages for categorical variables and mean and standard deviation for continuous variables.Categorical variables were compared using Pearson's chi-square test.A P value of 0.05 was used for signifcance.

Data Collection.
Coronary angiograms, procedural reports, and medical records were reviewed retrospectively for prespecifed clinical and procedural variables.Trombotic and bleeding complications were validated independently by two interventional cardiologists.Study patients were assigned a unique identifcation number to ensure privacy of study data.Te study was approved by the research ethics committee at our institution.

Study Population and Procedural
Characteristics.Out of 2,748 consecutively screened patients, 718 patients who underwent PCI without ACT monitoring were included in our study.Most patients were male (81.3%), and mean age was 65.4 years.Cardiovascular risk factors included hypertension (67.7%), dyslipidemia (53.6%), diabetes (42.8%), and active smoking (45.3%).Over a third of patients (36.2%) had a history of PCI, and 9.9% had a history of coronary artery bypass grafting (Table 1).Most procedures were done radially (78.3%), and the most common presentation was stable coronary artery disease (55.7%) (Table 2).Te majority of patients (82.3%) received an ad hoc loading dose of an oral P2Y12 inhibitor at the time of PCI, and the most commonly prescribed agent was clopidogrel (69.5%).In total, 465 (64.8%)PCI procedures involved the left anterior descending artery, and none involved coronary bypass grafts.Te number of implanted stents ranged from 0 to 7 (mean: 1.64; standard deviation: 0.9), with 0 representing unsuccessful PCI or conventional balloon angioplasty.Among the 87 patients presenting with STEMI, 33 received tirofban at the discretion of the interventional cardiologist.
Four patients did not survive to hospital discharge.One patient died during primary PCI of the left main coronary artery and had already sustained several cardiac arrests in the Emergency Department.Te other three causes of death were listed as follows: (1) multiorgan failure, (2) severe anoxic brain injury after out-of-hospital cardiac arrest, and (3) mixed cardiogenic and septic shock.

Discussion
In this study, PCI performed with UFH was related to low rate of thrombotic and bleeding complications when no ACT guidance was used.To our knowledge, this is the frst study to report the acute procedural outcomes of patients undergoing PCI with unmonitored UFH.

4.1.
Evidence for ACT Testing.ACT testing at the time of PCI has been proposed to minimize the risk of periprocedural ischemic or bleeding events.However, despite its widespread use and guideline endorsement, results of various studies about this topic seem conficting.In a meta-analysis of 6 randomized trials (N � 5,216 patients), ACT between 350 and 375 seconds provided the lowest composite ischemic event rate [6].More recently, a Mayo Clinic study totalling 12,055 patients found no independent association between ACT values and in-hospital or 1-year ischemic or bleeding events [7].Furthermore, in patients undergoing PCI with planned GPIs, no correlation was found between ACT and 2 International Journal of Clinical Practice ischemic events in both the TAO [8] and FUTURA/OASIS-8 [9] trials.Te occurrence of periprocedural bleeding and thrombotic events is likely multifactorial and difcult to predict.Tis is refected in the 2018 European Society of Cardiology guidelines on myocardial revascularization in which no specifc recommendation is made about the role of ACT testing in current PCI practice [10].

Radial vs. Femoral Access Site.
In our analysis, radial access was associated with fewer bleeding complications compared with femoral access (0.2% vs. 6.6%,P < 0.001), which refects prior data [11,12].In a meta-analysis of 9 randomized controlled trials totalling 10,760 patients with acute coronary syndrome, radial access was associated with decreased mortality (odds ratio (OR): 0.71; 95% confdence  International Journal of Clinical Practice interval (CI): 0.56-0.90;P � 0.004), major bleeding (OR: 0.55; 95% CI: 0.41-0.73;P < 0.001), and vascular access complications (OR: 0.32; 95% CI: 0.20-0.52;P < 0.001) at 30 days [13].Furthermore, the ACT threshold predicting bleeding was higher for the radial (290 s) than the femoral approach (240 s) in the TAO trial [8].Put together, these results can help adjust clinical decision making regarding the use of ACT testing and intensity of anticoagulation according to PCI access site, especially when resources are limited.

Comparison to Larger Databases.
Although no direct comparison can be drawn, ischemic and bleeding event rates in our study are comparable to those reported in larger databases.In a contemporary ACS population of over 8,600 patients, rates of no/slow refow (1.5%), dissection with decreased fow (1.2%), stent thrombosis (0.7%), and new procedural thrombus (0.2%) were almost numerically identical to those reported in our study (1.5%, 1.1%, 0.7%, and 0.3%, respectively) [14].We observed a low rate of major bleeding of 1.5% in our study population.Tese rates are lower compared to larger studies [15], likely to due to varying defnitions of major bleeding, transfusion thresholds, and follow-up durations.

Limitations.
Our study was a single-center retrospective study with a modest sample size.Given that ACT testing remained available for select patients during the study period, UFH's therapeutic efect may have been monitored in complex cases based upon operator preference.Tis could explain the paucity of patients with bypass graft (0%) or left main (2.2%) PCI in our analysis; our results may thus not be applicable to higher risk populations.Furthermore, we did not compare outcomes with patients who received ACT monitoring.Clinical outcomes were not collected; however, none of the 4 reported mortalities were directly attributable to major bleeding or IPTE.Since GP IIb/IIIa inhibitors were used in less than 5% of cases in our study, caution should be exercised when extrapolating our fndings to situations involving frequent GP IIb/IIIa inhibitor use.In addition, it is important to note that our hospital protocol, which excludes STEMI cases, necessitates the withholding of baseline anticoagulation for all patients.However, the retrospective nature of our study resulted in a lack of systematically available detailed information regarding baseline anticoagulant intake, including warfarin or DOACs; however, given the small percentage of STEMI patients in our cohort (12%), the impact of baseline anticoagulation on overall results is expected to be minimal.Finally, the restrictive transfusion protocol requiring a hemoglobin of 7.0 g/dL or less at our institution may have reduced the rate of reported major bleeding events.

. Conclusion
In this single-center study, weight-adjusted UFH use during PCI without ACT monitoring was related to low rates of major bleeding or IPTE.

Disclosure
Tis paper's abstract was presented in the Journal of the Society for Cardiovascular Angiography & Interventions [16].International Journal of Clinical Practice