Chronic total occlusions (CTO) of the coronary arteries are usually treated with drug-eluting stents (DES) after successful recanalization. Permanent metallic scaffolds carry recognized long-term limitations, including late malapposition, very late stent thrombosis, impairment of positive vascular remodeling, and edge restenosis after geographic miss. Drug-coated balloons (DCB) deliver an antiproliferative agent to the vessel wall without leaving a permanent implant, and may be particularly attractive in long, fibrocalcific recanalized CTO segments. NoTrace-CTO is a prospective, single-center, investigator-initiated, single-arm pilot study evaluating an exclusive DCB-only strategy, with no stent implantation, after successful CTO recanalization. Thirty-eight patients are planned, to yield thirty evaluable patients with paired angiographic follow-up. The primary endpoint is in-balloon late lumen loss at nine months, measured by quantitative coronary angiography (QCA) and tested against a pre-specified performance goal of 0.50 mm derived from a pooled contemporary second-generation DES benchmark. The proportion of lesions completing the DCB-only strategy without bailout stenting is reported descriptively alongside it. Serial intravascular ultrasound (IVUS) performed at baseline, immediately after DCB delivery and at nine months is the mechanistic centerpiece of the study, assessing vascular remodeling directly. Secondary assessments include quantitative flow ratio (QFR), Seattle Angina Questionnaire (SAQ) scores, binary restenosis, reocclusion, target lesion and target vessel revascularization, major adverse cardiovascular events (MACE), bleeding classified by the Bleeding Academic Research Consortium (BARC) criteria, and acute kidney injury defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The study is not powered for comparative clinical superiority or non-inferiority against DES; its findings are hypothesis-generating and intended to inform the design of an adequately powered multicenter trial.
Design: Prospective, single-center, investigator-initiated, single-arm pilot study conducted at the Heart Institute (InCor), Hospital das Clinicas, University of Sao Paulo Medical School. Consecutive eligible patients are enrolled by convenience sampling from the institutional chronic total occlusion (CTO) recanalization waiting list, following routine care pathways without modification of clinical prioritization or therapeutic decision-making. Index procedure: Recanalization follows standard interventional practice under the hybrid CTO algorithm, including antegrade wire escalation, antegrade dissection and re-entry, and retrograde approaches. Baseline lesion complexity is graded with the Multicenter CTO Registry of Japan (J-CTO) and Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO) scores. Lesion preparation uses sequential semi-compliant and non-compliant balloon predilatation sized approximately 1:1 to the intravascular ultrasound (IVUS) measured reference lumen diameter; cutting or scoring balloons are used at operator discretion where fibrocalcific tissue prevents adequate luminal gain. Drug-coated balloon (DCB) delivery proceeds only after angiographic and IVUS confirmation of adequate lesion preparation, defined as absence of flow-limiting or otherwise significant dissection, and satisfactory conditions for drug delivery. Device and technique: The AGENT paclitaxel-coated percutaneous transluminal coronary angioplasty (PTCA) balloon catheter (2 micrograms/mm2 dose density) is sized 1:1 to the IVUS-measured reference vessel diameter, with length selected to cover the full treated segment. Each inflation is maintained for a minimum of 120 seconds at nominal pressure, a pre-specified protocol requirement exceeding the instructions-for-use reference inflation time, adopted to prolong balloon-wall contact in recanalized fibrocalcific segments. Where more than one balloon is required, each inflation independently meets the minimum duration, with at least 2 mm of overlap documented by IVUS. No permanent metallic scaffold is implanted as part of the strategy. Imaging: Intravascular ultrasound is acquired with a rotational 60 MHz high-definition system by automated motorized pullback at 0.5 mm/s, extending at least 5 mm beyond each device edge, before and immediately after DCB angioplasty and again at nine months. Serial pullbacks are co-registered using fixed anatomical landmarks. Quantitative coronary angiography (QCA) is performed offline using validated edge-detection software with guiding-catheter calibration and matched angiographic projections between time-points. Analyses are performed by independent readers at the InCor core laboratory blinded to clinical data and time-point; inter- and intra-observer reproducibility are assessed by intraclass correlation coefficient and Bland-Altman limits of agreement, and approximately 10% of paired IVUS studies undergo external over-read by an independent reader unaffiliated with InCor. Bailout: If a flow-limiting dissection (Thrombolysis in Myocardial Infarction \[TIMI\] flow below 3) occurs after DCB dilation and cannot be optimized with repeat inflation, stent implantation is performed. Such cases are classified as technical failure of the DCB-only strategy, count as failures in the DCB-only strategy success proportion, and are retained in the intention-to-treat sensitivity analysis with a pre-specified penalized late lumen loss value rather than being treated as missing. Antithrombotic therapy: Dual antiplatelet therapy (DAPT) for 6 months is standard, abbreviated to 3 months in patients at high bleeding risk based on clinical judgment and validated scores. Follow-up: Elective angiographic and IVUS reassessment of the target vessel is performed at nine months. Patients declining invasive reassessment may accept coronary computed tomography angiography as a fallback; these patients contribute exploratory descriptive data but not paired QCA or IVUS data to the primary endpoint. Cumulative contrast volume and radiation exposure across both procedures are prospectively tracked. Analysis populations: The per-protocol population, comprising enrolled and successfully recanalized lesions that complete the DCB-only strategy without bailout stenting, is the primary analysis population for late lumen loss. The intention-to-treat population is analyzed as a pre-specified, mandatory co-reported sensitivity analysis in which bailout-stented lesions are assigned a penalized late lumen loss value set a priori at 0.50 mm, with rank-based worst-rank imputation additionally reported. DCB-only strategy success is calculated on the full intention-to-treat denominator. Statistical approach: Sample size was determined under a one-sample performance-goal framework. The benchmark, derived from a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) aligned pooled analysis of six contemporary second-generation drug-eluting stent (DES) CTO cohorts under independent core-laboratory QCA using a random-effects model with Hartung-Knapp-Sidik-Jonkman adjustment, is a mean in-stent late lumen loss of 0.20 mm with a pooled within-study standard deviation of approximately 0.50 mm. Under a one-sample t-test with one-sided alpha of 0.025 and 90% power, 30 evaluable patients with paired angiographic follow-up are required; allowing approximately 20% attrition, target enrollment is 38. The primary objective is met if the upper bound of the one-sided 97.5% confidence interval for mean in-balloon late lumen loss lies below 0.50 mm. The full type I error is allocated to this single primary endpoint; all other endpoints are supportive or exploratory.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
38
Paclitaxel-coated balloon at a dose density of 2 micrograms/mm2, sized 1:1 to the intravascular ultrasound (IVUS) measured reference vessel diameter and of sufficient length to cover the full treated segment. Each inflation is maintained for a minimum of 120 seconds at nominal pressure. Where more than one balloon is required for full longitudinal coverage, each inflation independently meets the minimum duration with at least 2 mm of documented overlap.
Intravascular ultrasound with automated motorized pullback at 0.5 mm/s is performed before and immediately after drug-coated balloon angioplasty and repeated at nine months, together with elective diagnostic coronary angiography of the target vessel, to quantify late lumen loss and serial vascular remodeling. Patients declining invasive reassessment may be offered coronary computed tomography angiography as a non-invasive fallback.
InCor - Instituto do Coracao - University of Sao Paulo Heart Institute
São Paulo, São Paulo, Brazil
In-balloon late lumen loss at nine months
Difference between the minimal luminal diameter measured by quantitative coronary angiography immediately after the index procedure and the minimal luminal diameter at nine-month follow-up angiography. This is the sole endpoint against which the pre-specified performance goal of 0.50 mm is formally tested, using the upper bound of the one-sided 97.5% confidence interval, in the per-protocol population.
Time frame: 9 months
DCB-only strategy success
Proportion of enrolled, successfully recanalized lesions treated exclusively with a drug-coated balloon without bailout stent implantation, defined consistent with Drug-Coated Balloon Academic Research Consortium recommendations and calculated on the full intention-to-treat denominator. Reported descriptively with an exact Clopper-Pearson 95% confidence interval; not hypothesis-tested against a performance goal.
Time frame: Periprocedural
In-segment late lumen loss at nine months
Late lumen loss measured across the analysis segment including the 5 mm proximal and distal margins adjacent to the treated segment, reported as a supportive quantitative coronary angiography measure.
Time frame: 9 months
Change in quantitative flow ratio
Quantitative flow ratio (QFR) derived by the frame-count contrast-flow method from at least two angiographic projections separated by 25 degrees or more, with intracoronary nitrate administered before each acquisition, compared between the post-procedural baseline and nine-month follow-up. Exploratory and hypothesis-generating. Unit of Measure: ratio
Time frame: Periprocedural and 9 months
In-balloon binary angiographic restenosis at 9 months
Percent diameter stenosis of 50% or greater within the in-balloon analysis segment at follow-up angiography, defined consistent with Drug-Coated Balloon Academic Research Consortium (DCB-ARC) recommendations and reported as a proportion of lesions with a 95% confidence interval. Unit of Measure: percentage of lesions
Time frame: 9 months
In-segment binary angiographic restenosis at 9 months
Percent diameter stenosis of 50% or greater within the in-segment analysis segment, which includes the 5 mm proximal and distal margins adjacent to the treated segment, at follow-up angiography, defined consistent with Drug-Coated Balloon Academic Research Consortium (DCB-ARC) recommendations and reported as a proportion of lesions with a 95% confidence interval. Unit of Measure: percentage of lesions
Time frame: 9 months
Target lesion reocclusion
Complete occlusion of the target lesion, defined as 100% diameter stenosis with TIMI 0 antegrade flow at follow-up angiography, reported as a proportion with 95% confidence interval.
Time frame: 9 months
Clinically driven target lesion revascularization
Any clinically driven repeat revascularization of the target lesion, percutaneous or surgical, reported as a proportion with 95% confidence interval.
Time frame: 9 months
Clinically driven target vessel revascularization
Any clinically driven repeat revascularization of the target vessel outside the target lesion, reported as a proportion with 95% confidence interval.
Time frame: 9 months
Change in minimal lumen area by intravascular ultrasound
Minimal lumen area within the treated segment measured by IVUS at matched anatomical cross-sections, compared between the immediate post-procedure acquisition and nine-month follow-up.
Time frame: Periprocedural and 9 months
Change in external elastic membrane cross-sectional area by intravascular ultrasound
External elastic membrane cross-sectional area measured by intravascular ultrasound (IVUS) at matched anatomical cross-sections within the treated segment, compared between the immediate post-procedure acquisition and nine-month follow-up. Together with the vascular remodeling index this forms the mechanistic centerpiece of the study, testing whether an exclusive drug-coated balloon strategy preserves the vessel's capacity for positive remodeling. Unit of Measure: square millimeters (mm\^2)
Time frame: Periprocedural and 9 months
Vascular remodeling index by intravascular ultrasound
Ratio of the external elastic membrane cross-sectional area at nine-month follow-up to the external elastic membrane cross-sectional area immediately after the index procedure, measured by intravascular ultrasound (IVUS) at matched anatomical cross-sections. Values above 1.0 indicate positive remodeling and values below 1.0 indicate negative remodeling. Unit of Measure: ratio
Time frame: Periprocedural and 9 months.
Change in plaque burden by intravascular ultrasound
Plaque plus media cross-sectional area divided by external elastic membrane cross-sectional area, measured by intravascular ultrasound (IVUS) at matched anatomical cross-sections within the treated segment, compared between the immediate post-procedure acquisition and nine-month follow-up. Reported as the absolute change in percentage points. Unit of Measure: percentage of external elastic membrane area
Time frame: Periprocedural and 9 months
Change in percent atheroma volume by intravascular ultrasound
Volumetric percent atheroma volume across the treated segment, calculated as the sum of plaque plus media areas divided by the sum of external elastic membrane areas across all analyzed cross-sections, measured by intravascular ultrasound (IVUS) and compared between the immediate post-procedure acquisition and nine-month follow-up. Reported as the absolute change in percentage points. Unit of Measure: percentage of total vessel volume
Time frame: Periprocedural and 9 months
Change in Seattle Angina Questionnaire Physical Limitation domain score
Change from baseline in the Physical Limitation domain of the Seattle Angina Questionnaire (SAQ), which measures the degree to which angina restricts physical activities. The Seattle Angina Questionnaire is a 19-item disease-specific instrument for coronary artery disease. Each domain is scored from 0 to 100, where 0 is the worst possible and 100 the best possible status; higher scores indicate a better outcome. Change from baseline is reported, so positive values indicate improvement.
Time frame: Baseline, 1 month, and 9 months
Change in Seattle Angina Questionnaire Angina Stability domain score
Change from baseline in the Angina Stability domain of the Seattle Angina Questionnaire (SAQ), which measures the change in angina frequency relative to four weeks earlier. The Seattle Angina Questionnaire is a 19-item disease-specific instrument for coronary artery disease. Each domain is scored from 0 to 100, where 0 is the worst possible and 100 the best possible status; higher scores indicate a better outcome. Change from baseline is reported, so positive values indicate improvement.
Time frame: Baseline, 1 month, and 9 months
Change in Seattle Angina Questionnaire Angina Frequency domain score
Change from baseline in the Angina Frequency domain of the Seattle Angina Questionnaire (SAQ), which measures how often angina and nitroglycerin use occur. The Seattle Angina Questionnaire is a 19-item disease-specific instrument for coronary artery disease. Each domain is scored from 0 to 100, where 0 is the worst possible and 100 the best possible status; higher scores indicate a better outcome. Change from baseline is reported, so positive values indicate improvement.
Time frame: Baseline, 1 month, and 9 months
Change in Seattle Angina Questionnaire Treatment Satisfaction domain score
Change from baseline in the Treatment Satisfaction domain of the Seattle Angina Questionnaire (SAQ), which measures satisfaction with the explanation and management of angina. The Seattle Angina Questionnaire is a 19-item disease-specific instrument for coronary artery disease. Each domain is scored from 0 to 100, where 0 is the worst possible and 100 the best possible status; higher scores indicate a better outcome. Change from baseline is reported, so positive values indicate improvement.
Time frame: Baseline, 1 month, and 9 months
Change in Seattle Angina Questionnaire Angina-Related Quality of Life domain score
Change from baseline in the Angina-Related Quality of Life domain of the Seattle Angina Questionnaire (SAQ), which measures the perceived impact of angina on enjoyment of life. The Seattle Angina Questionnaire is a 19-item disease-specific instrument for coronary artery disease. Each domain is scored from 0 to 100, where 0 is the worst possible and 100 the best possible status; higher scores indicate a better outcome. Change from baseline is reported, so positive values indicate improvement.
Time frame: Baseline, 1 month, and 9 months
Number of participants with major adverse cardiovascular events
Number of participants experiencing the composite of all-cause death, myocardial infarction, or stroke. Death is classified as cardiovascular or non-cardiovascular where possible; myocardial infarction is defined by the Fourth Universal Definition and includes procedural type 4a and spontaneous events; stroke includes ischemic and hemorrhagic events. The reported value is the number of participants with at least one component event; individual components are reported as separate categories within this measure.
Time frame: Up to 9 months
Number of participants with bleeding events by Bleeding Academic Research Consortium type
Number of participants experiencing a bleeding event classified according to Bleeding Academic Research Consortium (BARC) criteria. The reported value is the number of participants with any BARC type 1 through 5 bleeding event; events are reported as separate categories for major bleeding (BARC type 3 or 5), clinically relevant non-major bleeding (BARC type 2), and minor bleeding (BARC type 1).
Time frame: Up to 9 months
Number of participants with acute kidney injury
Number of participants developing acute kidney injury as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, assessed after the index procedure and after the nine-month follow-up angiography. Cumulative contrast volume across both procedures is recorded.
Time frame: Periprocedural
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.