Ranolazine in Chronic Total Occlusion Percutaneous Coronary Intervention

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Ranolazine is an antianginal medication given to patients with chronic angina and persistent symptoms despite medical therapy. We examined 11 491 chronic total occlusion (CTO) percutaneous coronary interventions (PCI) that were performed at 41 US and non-US centers between 2012 and 2023 in the PROGRESS-CTO Registry. Patients on ranolazine at baseline had more comorbidities, more complex lesions, lower procedural and technical success (based on univariable but not multivariable analysis), and higher incidence of major adverse cardiac events (MACE) (on both univariable and multivariable analysis).

Ranolazine is an antianginal medication given to patients with chronic angina and persistent symptoms despite medical therapy.^1,2 We analyzed a large, multicenter chronic total occlusion (CTO) percutaneous coronary intervention (PCI) registry to determine the baseline clinical and angiographic characteristics and procedural outcomes of patients undergoing CTO PCI who were using ranolazine at baseline.

Based on the methodology previously described,³ we analyzed 11 491 CTO PCIs (11 487 patients) that were performed at 41 US and non-US centers between 2012 and 2023, and recorded in the PROGRESS-CTO Registry. Univariable logistic regression was performed to identify variables that might be associated with the outcomes; variables with a P-value of less than .10 and that were considered clinically/angiographically significant were included in the multivariable analysis, in addition to clinically relevant variables chosen a priori and deemed to influence the outcomes of interest. All statistical analyses were conducted using R Statistical Software, version 4.2.2 (R Foundation for Statistical Computing). A P-value of less than 0.05 was considered statistically significant.

During the study period, 1720 (15%) patients undergoing CTO PCI were using ranolazine at baseline. These patients had a higher prevalence of diabetes (49.0% vs 42.1%; P < .001), hypertension (91.9% vs 87.6%; P < .001), dyslipidemia (93.6% vs 83.4%; P < .001), family history of coronary artery disease (38.4% vs 29.9%; P < .001), prior history of PCI (74.8% vs 59.4%; P < .001), coronary artery bypass graft surgery (CABG) (54.2% vs 23.5%; P < .001), cerebrovascular disease (12.2% vs 9.6%; P < .001), and peripheral arterial disease (16.7% vs 13.4%; P < .001). They were more likely to have stable angina at presentation (72.0% vs 65.4%; P < .001) and receive concomitant treatment with beta blockers (88.3% vs 81.6%; P < .001), long-acting nitrates (61.8% vs 33.0%; P < .001), and calcium channel blockers (35.6% vs 23.1%; P < .001).

The right coronary artery was more likely to be the target CTO vessel in ranolazine-treated patients (56.0% vs 51.8%; P < .001). These patients had higher Japanese-CTO (2.85 ± 1.19 vs 2.31 ± 1.27; P < .001) and PROGRESS-CTO (1.45 ± 1.03 vs 1.21 ± 1.00; P < .001) scores, longer lesion length (35.10 vs 30.16 mm; P < .001), and higher prevalence of proximal cap ambiguity (45.5% vs 33.4%; P < .001), blunt/no stump (64.0% vs 51.4%; P < .001), moderate to severe calcification (57.8% vs 42.8%; P < .001), proximal tortuosity (34.9% vs 27.9%, P < .001), and in-stent CTO (24.9% vs 14.8%; P < .001).

The first crossing strategy was less likely to be antegrade in these patients (77.4% vs 86.3%; P < .001), and they were more likely to undergo the retrograde approach during the procedure (41.0% vs 28.2%; P < .001). Their procedure (139 vs 108 min; P < .001) and fluoroscopy (53 vs 40 min; P < .001) times were longer, and air kerma radiation dose was higher (2.32 vs 2.16 Gy; P = .006), while contrast volume was lower (200 [135, 280] vs 200 [145, 290] ml; P = .002).

Technical (83.7% vs 87.8%; P < .001) and procedural (81.4% vs 86.6%; P < .001) success were lower in patients using ranolazine, while the incidence of major adverse cardiovascular events (MACE) was higher (3.2% vs 1.8%; P < .001). In-hospital mortality (0.8% vs 0.4%; P = .051), acute myocardial infarction (0.9% vs 0.4%; P = .006), repeat PCI (0.5% vs 0.1%; P = .006), stroke (0.4% vs 0.1%; P = .008), and perforation (5.8% vs 4.6%; P = .030) were also higher. Ranolazine was associated with higher MACE in both univariable (OR 1.98; 95% CI, 1.44-2.68; P < .001) and multivariable (OR 2.21; 95% CI, 1.44-3.30; P < .001) analysis (Figure), while it was not associated with technical success in multivariable analysis (OR 1.00; 95% CI, 0.82-1.22; P > .9).

The major findings of our study are that patients on ranolazine undergoing CTO PCI have more comorbidities, more complex lesions, lower procedural and technical success (on univariable but not multivariable analysis), and higher MACE (on both univariable and multivariable analysis) rates. Use of ranolazine in our study (15%) is similar to the OPEN-CTO Registry (15.1%); in the OPEN-CTO, ranolazine patients were more likely to have new or residual angina at 6-month follow-up.⁴ Ranolazine is usually used for refractory chronic angina.⁵ The underlying reasons for the association between use of ranolazine and higher MACE are not clear, but it is possible that persistent and severe symptoms may increase the likelihood of more aggressive attempts to recanalize the CTO in order to achieve symptomatic relief.

One reason that operators may persist with CTO crossing attempts is severe symptoms. However, even in highly symptomatic patients, operators must know when to stop a CTO-PCI attempt. Ranolazine use at baseline was associated with longer procedure duration. Rempakos et al reported 1.6% MACE for CTO-PCI cases crossed within 30 minutes vs 4.2% for cases that required at least 30 minutes for guidewire crossing.³ Adopting a “first do no harm” approach is essential; in some cases, it may be preferable to accept failure than to implement overly aggressive CTO treatment strategies even in highly symptomatic patients, such as those receiving ranolazine.

Limitations. The limitations of this study include the observational design and the absence of core laboratory assessment of the study angiograms and limited external validity of the results due to the inclusion of highly experienced CTO-PCI centers in the registry.

Patients using ranolazine at baseline had higher comorbidity burden, more complex lesions, lower technical success, and higher in-hospital MACE.

From the ¹Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, Minnesota, USA; ²Texas Health Presbyterian Hospital, Dallas, Texas, USA; ³Baylor Scott & White Heart and Vascular Hospital, Dallas, Texas, USA; ⁴University Hospitals, Case Western Reserve University, Cleveland, Ohio, USA; ⁵Henry Ford Cardiovascular Division, Detroit, Michigan, USA; ⁶WellSpan York Hospital, York, Pennsylvania, USA; ⁷Massachusetts General Hospital, Boston, Massachusetts, USA; ⁸Medical Center of the Rockies, Loveland, CO, USA; ⁹Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA; ¹⁰Selcuk University, Konya, Turkey; ¹¹Kettering Medical Center, Dayton, Ohio, USA; ¹²Tristar Hospitals, Tennessee, USA; ¹³Biruni University Medical School, Istanbul, Turkey; ¹⁴Cleveland Clinic, Cleveland, Ohio, USA; ¹⁵Meshalkin Novosibirsk Research Institute, Novosibirsk, Russia; ¹⁶St. Vincent Hospital, Indianapolis, Indiana, USA; ¹⁷St. Boniface General Hospital, Winnipeg, Manitoba, Canada.

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; Ms. Marilyn and Mr. William Ryerse; Mr. Greg and Mrs. Rhoda Olsen. 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. Choi serves on the Medtronic advisory board. Dr. Poommipanit is a consultant for Asahi Intecc. and Abbott Vascular. Dr. Alaswad is a consultant and speaker for Boston Scientific, Abbott Cardiovascular, Teleflex, and Cardiovascular Systems Inc. Dr. Basir is consultant for Abbott Vascular, Abiomed, Cardiovascular Systems, Inc (CSI), Chiesi, and Zoll. Dr. Davies receives speaker honoraria from Abiomed, Asahi Intec, Boston Scientific, Medtronic, Teleflex, and Shockwave Medical, and serves on advisory boards for Abiomed, Avinger, Boston Scientific, Medtronic, and Rampart. Dr. Jaffer has done sponsored research for Canon, Siemens, Shockwave, Teleflex, Mercator, and Boston Scientific; has been a consultant for Boston Scientific, Siemens, Magenta Medical, IMDS, Asahi Intecc, Biotronik, Philips, and Intravascular Imaging Inc.; has equity interest in Intravascular Imaging Inc., and DurVena; and holds the right to receive royalties through Massachusetts General Hospital licensing arrangements with Terumo, Canon, and Spectrawave. Dr. Azzalini received consulting fees from Teleflex, Abiomed, GE Healthcare, Asahi Intecc, Philips, Abbott Vascular, Reflow Medical, and Cardiovascular Systems, Inc.  Dr. Khatri has received personal honoraria for proctoring and speaking from Abbott Vascular, Medtronic, Terumo, Shockwave, and Boston Scientific. Dr. Burke receives consulting and speaker honoraria from Abbott Vascular and Boston Scientific. Dr. Sandoval is on the advisory board for Abbott Diagnostics, GE, and Zoll; is on the advisory board and is a speaker for Roche Diagnostics and Philips; is an associate editor for JACC Advances; and holds Patent 20210401347 for machine learning models for ECG-based troponin level detection. Dr. Brilakis receives consulting/speaker honoraria from Abbott Vascular, the American Heart Association (associate editor, Circulation), Amgen, Asahi Intecc, Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), CSI, Elsevier, GE Healthcare, IMDS, Medicure, Medtronic, Siemens, Teleflex, and Terumo; receives research support from Boston Scientific and GE Healthcare; is the owner of Hippocrates LLC; and is a shareholder in MHI Ventures, Cleerly Health, and Stallion Medical. The remaining authors report no financial relationships or conflicts of interest regarding the content herein.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Minneapolis Heart Institute, 920 E 28th Street #300, Minneapolis, MN 55407, USA. Email: esbrilakis@gmail.com; X: @CCAD_MHIF, @m1chaella_alex, @esbrilakis