Activated Clotting Time and Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From the PROGRESS-CTO Registry

Background. The optimal range of activated clotting time (ACT) in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study.

Methods. We examined the association between ACT and in-hospital ischemic and bleeding outcomes in patients who underwent CTO PCI in the Prospective Global Registry for the Study of CTO Intervention.

Results. ACT values were available for 4377 patients who underwent CTO PCI between 2012 and 2023 at 29 centers. The mean ACT distribution was less than 250 seconds (19%), 250 to 349 seconds (50%), and greater than or equal to 350 seconds (31%). The incidence of ischemic events, bleeding events, and net adverse cardiovascular events (NACE) was 0.8%, 3.0%, and 3.8%, respectively. In multiple logistic regression analysis, increasing nadir ACT was associated with decreasing ischemic events (adjusted odds ratio [aOR] per 50-second increments: 0.69 [95% confidence interval (CI), 0.50-0.94; P=.017]; and increasing peak ACT was associated with increasing bleeding events (aOR per 50-second increments: 1.17 [95% CI ,1.01-1.36; P=.032]). A U-shaped association was seen between mean ACT and NACE, where restricted cubic spline analysis demonstrated that patients with a low (<200 seconds) or high (>400 seconds) ACT had increasing NACE risk compared with an ACT of 200 to 400 seconds (aOR 2.06, 95% CI 1.18-3.62; P=.012).

Conclusions. Among patients who underwent CTO PCI, mean ACT had a U-shaped relationship with NACE, where patients with a low (<200 seconds) ACT (driven by ischemic events) or high (>400 seconds) ACT (driven by bleeding) had higher NACE compared with an ACT of 200 to 400 seconds.

Unfractionated heparin (UFH) is the most used anticoagulant in percutaneous coronary intervention (PCI).¹ Activated clotting time (ACT) is used to evaluate the level of anticoagulation in UFH-treated patients during PCI and guides intraprocedural UFH dosing. While some studies show no association between ACT values and PCI outcomes,² others found that higher ACTs are associated with lower risk of ischemic events³ at the price of a greater risk of major bleeding.⁴ Consequently, the exact dosing of UFH based on ACT values is considered uncertain by current guidelines.⁵ While it is generally acknowledged that ACT targets should be higher in chronic total occlusion (CTO) PCI,^6,7 the optimal ACT range in such setting has received very limited study. Therefore, we evaluated the association between ACT and in-hospital clinical outcomes in a large international multicenter CTO PCI registry.

We used the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO, NCT02061436) for this study. PROGRESS-CTO includes patient-level data for CTO PCI procedures performed at experienced CTO PCI centers in the United States, Canada, Greece, Turkey, Egypt, Russia, and Lebanon.⁸Study data were collected and managed using REDCap electronic data capture tools (Vanderbilt) hosted at the Minneapolis Heart Institute Foundation.^9,10The PROGRESS-CTO collects the lowest (nadir) and highest (peak) ACT values (measured in seconds) during CTO PCI. The study was approved by the institutional review board of each participating site.

Definitions. CTOs were defined, according to the definition of CTO Academic Research Consortium, as absence of antegrade flow through the lesion with a presumed or documented duration of greater than or equal to 3 months.¹¹

Technical success was defined as the successful recanalization of the CTO vessel with less than 30% residual stenosis and final Thrombolysis in Myocardial Infarction (TIMI) 3 flow. Calcification was assessed by angiography as mild (spots), moderate (involving ≤50% of the reference lesion diameter), or severe (involving ≥50% of the reference lesion diameter).  

Nadir and peak ACT were defined as the minimum and maximum ACT value recorded during CTO PCI, respectively. Mean ACT was defined as the sum of the nadir ACT and peak ACT divided by 2.

The Multicenter CTO Registry of Japan (J-CTO) score was calculated as described by Morino et al¹² and the PROGRESS-CTO score as described by Christopoulos et al.¹³

Acute myocardial infarction (MI) was defined using the Third Universal Definition of MI.¹⁴

In-hospital ischemic events were defined as the composite of acute MI, re-PCI, dissection/thrombosis of donor artery, and acute closure of the CTO target vessel after recanalization.

Bleeding events were defined as the composite of vascular access site complications (small hematoma [<5 cm], large hematoma [≥5 cm], arteriovenous fistula, and pseudoaneurysm), retroperitoneal hematoma, gastrointestinal bleeding, genitourinary bleeding, and cardiac tamponade requiring pericardiocentesis.

In-hospital major adverse cardiovascular events (MACE) were defined as the composite of in-hospital all-cause mortality, MI, stroke, urgent repeat revascularization (re-PCI or surgery), and pericardiocentesis.

Net adverse cardiovascular events (NACE) were defined as the composite of bleeding events and MACE.

Procedures in which retrograde crossing was attempted were classified as retrograde cases.

Patients in whom left ventricular assist devices were used (n=129) were excluded from this analysis, since large-bore access is directly associated with bleeding.¹⁵

Statistical analysis. Continuous variables were presented as mean ± SD or median (interquartile range) and compared using the independent t-test, Mann-Whitney U-test, or analysis of variance (ANOVA), as appropriate. Categorical variables were presented as absolute numbers and percentages and compared using chi-square or Fisher’s exact test, as appropriate.

Multivariable logistic regression for ischemic events, bleeding, and NACE was performed separately to adjust for potential confounders using variables with P<.10 on univariable analysis and clinical plausibility. Restricted cubic spline analysis was performed as described by Marteen Buis¹⁶ and Frank Harrell¹⁷ to model the relationship between mean ACT and clinical outcomes. For NACE, the knots were set at 250, 300, and 350 seconds; for ischemic events, the knots were set at 150 and 200 seconds; and for bleeding events the knots were set at 300, 350, and 400 seconds. The analysis was adjusted for age, sex, calcification, stump, and crossing strategy (and access site for bleeding events and NACE). Statistical analyses were performed using Stata v17.0 (StataCorp) and R v4.1.3 (R Foundation for Statistical Computing) in RStudio environment, version 2022.07.02 (RStudio, PBC).

Clinical and angiographic characteristics. ACT values were available for 4377 patients who underwent CTO PCI at 29 centers. The mean ACT distribution was less than 250 seconds (19%), 250 to 349 seconds (50%), and greater than or equal to 350 seconds (31%). The mean age was 64 ± 11 years, 21% were women, and comorbidity burden was high, including diabetes mellitus (44%), prior coronary artery bypass graft surgery (CABG) (28%), and prior PCI (62%).

Anatomic complexity of the CTO lesions was also high (mean J-CTO score 2.5 ± 1.2). Technical success was 88%. The incidences of in-hospital complications were as follows: ischemic events 0.8% (n=34), bleeding 3.0% (n=133), MACE 1.5% (n=66), and NACE 3.8% (n=166).

With regards to ischemic events, acute MI was diagnosed in 15 patients (0.3%), re-PCI was performed in 3 (0.1%), thrombosis of the donor artery was found in 17 (0.4%), and acute closure of the CTO target vessel was seen in 4 (0.1%).

The incidence of each of the bleeding endpoint components was as follows: small hematoma in 108 patients (2.5%), large hematoma in 7 (0.2%), pseudoaneurysm in 1 (0.1%), retroperitoneal hematoma in 6 (0.1%), gastrointestinal bleeding in 2 (0.1%), genitourinary bleeding in 1 (0.1%), and tamponade requiring pericardiocentesis in 36 (0.8%). No cases of arteriovenous fistula were observed.

Rates of the individual components of the MACE endpoint were as follows: all-cause death in 11 patients (0.3%), acute MI in 15 (0.3%), stroke in 9 (0.2%), re-PCI in 3 (0.1%), emergency CABG in 5 (0.1%), and tamponade requiring pericardiocentesis in 36 (0.8%).

As shown in Table 1, patients with mean ACT of 250 to 349 seconds were younger and more likely to have diabetes mellitus, prior MI, and prior CABG. They were also more likely to have proximal cap ambiguity, blunt/no stump, and moderate-severe calcification.

As indicated in Table 2, patients who had a nadir ACT of less than 200 seconds were more likely to be female and have hypertension, prior MI, prior PCI, and prior CABG compared with patients who had a higher nadir ACT. They were also more likely to have angiographically unfavorable characteristics demonstrated by a higher J-CTO score and PROGRESS-CTO score, including moderate/severe proximal tortuosity and moderate-severe calcification compared with other groups.

As shown in Table 3, patients who had a peak ACT of greater than or equal to 400 seconds were more likely to have hypertension and dyslipidemia, and less likely to have diabetes, prior MI, and prior PCI compared with patients who had a lower highest ACT. They were also more likely to have proximal cap ambiguity and higher J-CTO scores.

In retrograde cases (n=1277, 30%), peak ACT (368 [330-406] vs 342 [296-390] seconds, P<.001) and mean ACT (310 [282-341] vs 304 [269-340] seconds, P<.001) were higher compared with antegrade-only cases (n=2988, 60%). However, in retrograde cases, nadir ACT was lower (255 [225-285] vs 261 [230-297] seconds, P<.001).

In retrograde cases, 18 out of 20 (90%) ischemic events occurred where nadir ACT was less than 300 seconds (P=.462) (Appendix). In retrograde cases where nadir ACT was greater than 300 seconds, mean ACT was 375 seconds.

Procedural and in-hospital outcomes. Technical success was lower in patients with a nadir ACT of less than 200 seconds. Ischemic events and MACE were higher in patients with a nadir ACT less than 200 seconds, while bleeding events and NACE were similar compared with patients with an ACT greater than or equal to 200 seconds (Table 2, Figure 1A).

Technical success was lower in patients with a peak ACT greater than or equal to 400 seconds. Bleeding events and NACE were higher in patients with a peak ACT greater than or equal to 400 seconds, while ischemic events and MACE were similar compared with patients with an ACT less than 400 seconds. (Table 3, Figure 1B).

After adjusting for potential confounders, increasing nadir ACT was associated with decreasing ischemic events: adjusted odds ratio (aOR) per 50-second increase 0.69 (95% confidence interval [95% CI], 0.50-0.94; P=.017) (Figure 2A). Increasing peak ACT was associated with increasing bleeding: aOR per 50-second increase 1.17 (95% CI, 1.01-1.36; P=.032) (Figure 2B).

We observed a U-shaped association between mean ACT and NACE, with the aOR of NACE being lowest at an ACT of approximately 300 seconds (Figure 3). After adjusting for age, sex, stump morphology, calcification, crossing strategy, and access site, a mean ACT of less than 200 or greater than 400 seconds was associated with higher NACE risk compared with a mean ACT of 200 to 400 seconds: aOR 2.06 (95% CI, 1.18-3.62; P=.012).

To the best of our knowledge, this is the first study investigating the association between ACT and ischemic and bleeding outcomes in patients undergoing CTO PCI. Our main findings are the following: (1) increasing nadir ACT was associated with decreasing ischemic events; (2) increasing peak ACT was associated with increasing bleeding events; (3) mean ACT and NACE had a U-shaped association with lowest NACE risk observed at an ACT of approximately 300 seconds, while an ACT less than 200 or greater than 400 seconds was associated with higher NACE risk, compared with an ACT of 200 to 400 seconds; and (4) in retrograde cases, only 10% of ischemic events occurred where nadir ACT was greater than 300 seconds; in these cases, the corresponding mean ACT was greater than 375 seconds.

CTO PCI requires dual access (frequently involving at least 1 femoral sheath), which increases the risk of vascular complications and bleeding.^18-20 Moreover, longer procedural times requiring higher total doses of heparin and higher ACT values,^6,7 coupled with increased risk of coronary perforation,²¹ also increase the risk of bleeding. In addition, retrograde crossing, instrumentation of areas not part of the CTO lesion, and longer procedural time could increase ischemic events. As such, optimal ACT management is particularly relevant in CTO PCI.

Guidelines and consensus documents. The ACC/AHA/SCAI guidelines for coronary artery revascularization⁵ recommends an ACT of 250 to 300 seconds on HemoTec (HemoTec GmbH), and 300 to 350 seconds on Hemochron (Werfen) devices. In CTO PCI or in acute coronary syndromes, a suggestion is made to consider a higher ACT target. However, these recommendations are based on studies from the 1990s and 2000s, and whether they apply to the current practice with potent dual antiplatelet therapy, as well as modern stent technology and vascular access, is unclear.⁵

Expert reviews and consensus documents recommend maintaining an ACT of greater than or equal to 300 to 350 seconds in order to reduce the risk of donor vessel thrombosis (closer to 350 seconds if the retrograde approach is performed), and that ACT should be checked at least every 30 minutes during the procedure.^6,7 

ACT in CTO PCI studies. Only 1 study has so far analyzed the role of ACT in CTO PCI. In an analysis of the Latin American (LATAM) CTO registry, patients who had coronary artery perforation were more likely to have higher mean ACT values (353 vs 331 seconds, P<.01), and increasing peak ACT was independently associated with coronary artery perforation.²² However, no specific ACT threshold analysis was conducted to inform clinical practice and the study only focused on coronary perforation.

ACT in all-comers undergoing PCI. Similar to our findings, an analysis of 2026 patients with non-ST-segment elevation acute coronary syndrome undergoing PCI from the Fondaparinux With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA/OASIS-8) trial found that patients with an ACT less than or equal to 300 seconds had increased rates of death, MI, and target vessel revascularization.²³ However, no association was seen between ACT and bleeding outcomes.²³ In contrast, increasing peak ACT was associated with increasing bleeding in our study (Figure 2B).

In a cohort of 12 055 patients who underwent PCI between 2001 and 2012, ACT was not associated with in-hospital death or bleeding after adjusting for potential confounders.² A recent study with 14 637 patients undergoing transradial or transfemoral PCI with UFH monotherapy concluded that, after adjusting for potential confounders, ACT greater than 290 seconds was associated with major bleeding with transfemoral access but not with transradial access.⁴

In an analysis of the 1234 patients with acute coronary syndrome from the Early Discharge after Transradial Stenting of CoronarY Arteries (EASY) trial, an ACT greater than 330 seconds was associated with a 47% reduction in 30-day MI: aOR 0.53 (95% CI, 0.29-0.93; P=.024).²⁴

Summary of current evidence and contribution of the present study. While several studies found increased ischemic events at lower ACT values and increased bleeding at higher ACT values in all-comers undergoing PCI,^3,4,25 the association between ACT and clinical outcomes is not clear.^{2-4,23,24,26-28} Systematic reviews and meta-analyses of ACT and clinical outcomes also had disparate results.^3,27,28 Such findings are likely related to differences in patient comorbidities, PCI indications (acute coronary syndrome vs stable angina), access site (radial vs femoral), antiplatelet regimen, ACT cut-off, and outcome definitions.

Our study provides significant additional information to this matter, as we identified ACT between 200 and 400 seconds as a safe range that reduces the risk of both ischemic and bleeding events. An ACT of approximately 300 seconds appeared to be associated with the lowest risk of NACE (Figure 3). Moreover, we observed clinically small differences in ACT values between antegrade-only vs retrograde cases (on average between 6-26 seconds). This suggests that operators do not seem to adopt different approaches to ACT management depending on the crossing strategy utilized. While the peak and mean ACT values were higher in retrograde cases, the nadir ACT value was lower in retrograde cases. This can be explained by the fact that procedures where the retrograde approach is utilized are longer and thus more susceptible to wider variability in ACT values. Indeed, the procedures with the highest (≥400 seconds) peak ACT and lowest (<200 seconds) nadir ACT were the longest, as shown in Tables 2 and 3.

In addition, in retrograde cases, 90% of ischemic events occurred in cases where the nadir ACT was less than 300 seconds. In retrograde cases where the nadir ACT was greater than 300 seconds, the mean ACT was 375 seconds. These findings may imply that, in retrograde cases, as suggested by the current guidelines, pursuing a higher ACT (350-375 seconds) target may be beneficial.

Limitations. Our study has limitations. First, the PROGRESS-CTO registry is observational. Second, clinical events were not adjudicated by an independent committee. Third, core laboratory analysis was not performed. Fourth, PROGRESS-CTO operators are highly experienced in CTO PCI, which could limit the external validity of our findings. Fifth, the brand/model of ACT measuring device was not collected. Finally, only the peak and nadir ACT values were recorded. Therefore, more nuanced analyses (eg, using all ACT values obtained during the case) could not be performed.

We found that increasing nadir ACT was associated with decreasing in-hospital ischemic events, especially at lower (<200 seconds) ACT levels. Bleeding increased with increasing peak ACT, with a steeper increase at higher (>400 seconds) ACT levels. We found a U-shaped relationship between mean ACT and NACE, with a mean ACT of approximately 300 seconds corresponding to the lowest NACE risk. NACE risk increased with lower (<200 seconds) and higher (>400 seconds) mean ACT, driven by increased ischemic events at lower ACT values and increased bleeding events at higher ACT values. Our findings may also suggest that retrograde cases could benefit from higher ACT values (350-375 seconds).

From the ¹Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, Minneapolis, Minnesota, USA;  ²Department of Cardiology, Biruni University, Istanbul, Turkey; ³Division of Cardiology, Henry Ford Hospital, Detroit, Michigan, USA; ⁴Department of Cardiology, The Christ Hospital, Cincinnati, Ohio, USA; ⁵Department of Cardiology, Ondokuz Mayis University, Samsun, Turkey; ⁶University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA; ⁷Department of Cardiology, Selcuk University, Konya, Turkey; ⁸North Oaks Healthcare System, Hammond, Louisiana, USA; ⁹Department of Cardiology, London Health Sciences Center, Western University, London, Ontario, Canada; ¹⁰Department of Cardiology, Wellspan York Hospital, York, Pennsylvania, USA; ¹¹Memorial Bahçelievler Hospital, Istanbul, Turkey; ¹²Department of Cardiology, Texas Health Presbyterian Hospital, Dallas, Texas, USA; ¹³Department of Cardiology, Kettering Health Medical Group, Dayton, Ohio, USA; ¹⁴UC Health Medical Center of the Rockies, Loveland, Colorado, USA; ¹⁵Ascension Saint Thomas Heart Hospital, Nashville, Tennessee, USA; ¹⁶Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA.

Acknowledgments: The authors are grateful for the philanthropic support of our generous anonymous donors, and the philanthropic support of Drs. Mary Ann and Donald A Sens; Mrs. Diane and Dr. Cline Hickok; Mrs. Wilma and Mr. Dale Johnson; Mrs. Charlotte and Mr. Jerry Golinvaux Family Fund; the Roehl Family Foundation; the Joseph Durda Foundation. The generous gifts of these donors to the Minneapolis Heart Institute Foundation's Science Center for Coronary Artery Disease (CCAD) helped support this research project.

Disclosures: Dr. Alaswad is consultant and speaker for Boston Scientific, Abbott Cardiovascular, Teleflex, and CSI Dr. Poommipanit is a consultant for Medtronic, Asahi Intecc, Inc., Abbott Vascular, and Boston Scientific. Dr. Abi Rafeh is a proctor for and receives speaker honoraria from Boston Scientific and Shockwave Medical. Dr. Davies receives speaking honoraria from Abiomed, Asahi Intec, Boston Scientific, Medtronic, Siemens Healthineers, Shockwave, and Teleflex, and serves on advisory boards for Abiomed, Boston Sci, Medtronic, and Rampart. Dr. Kearney receives consulting fees from Abiomed, Abbott Vascular, Boston Scientific, Medtronic, Teleflex, Philips, and Cardiovascular Systems, Inc. Dr. Sandoval previously served on the Advisory Boards for Roche Diagnostics and Abbott Diagnostics without personal compensation. Dr. Burke is a shareholder for Egg Medical and MHI Ventures. Dr. Brilakis receives consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor, Circulation), Amgen, Asahi Intecc, Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), ControlRad, CSI, Elsevier, GE Healthcare, IMDS, InfraRedx, Medicure, Medtronic, Opsens, Siemens, and Teleflex; research support from Boston Scientific and GE Healthcare; is the owner of Hippocrates LLC; and is a shareholder of MHI Ventures, Cleerly Health, and Stallion Medical. Dr. Azzalini receives consulting fees from Teleflex, Abiomed, GE Healthcare, Abbott Vascular, Reflow Medical, and Cardiovascular Systems, Inc.; serves on the advisory board of Abiomed and GE Healthcare; and owns equity in Reflow Medical. The remaining authors report no financial relationships or conflicts of interest regarding the content herein.

Address for correspondence: Lorenzo Azzalini, MD, PhD, MSc, Division of Cardiology, Department of Medicine, University of Washington Medical Center, 1959 NE Pacific St, Box 356422, Seattle, WA 98195, USA. Email: azzalini@uw.edu