Comparison of the Incidence of Major Cardiovascular Events Between the Combination of Percutaneous Intervention and Optimal Drug Therapy and the Optimal Drug Therapy Alone in Patients With Chronic Coronary Syndrome

Background:

In patients with chronic coronary syndrome (CCS), the role of percutaneous coronary intervention (PCI) beyond symptom relief - particularly in preventing future major cardiovascular events - remains an area of active debate. Landmark trials such as COURAGE and ISCHEMIA raised questions about the incremental benefit of PCI over optimal medical therapy (OMT) alone; however, both trials allowed crossover from the medical arm to PCI, and included periprocedural myocardial infarction (MI) in their primary endpoints, which may have diluted the observed treatment effects. Moreover, since those trials were conducted, both PCI techniques and pharmacological therapies have advanced substantially. Imaging-guided PCI using intravascular ultrasound (IVUS) or optical coherence tomography (OCT) has been shown to reduce adverse cardiac events, and lipid-lowering strategies have been further strengthened by the addition of ezetimibe and PCSK9 inhibitors. Against this background, a rigorous re-evaluation of PCI's role in CCS, using contemporary devices and a more conservative definition of clinically driven revascularization, is warranted.

Study Design:

The PIVOT trial is a multicenter, prospective, open-label, randomized controlled trial conducted at multiple sites in South Korea. Eligible patients with CCS who have a functionally or anatomically significant coronary stenosis confirmed by coronary angiography are randomized 1:1 to either (1) PCI plus optimal medical therapy or (2) optimal medical therapy alone. Randomization is stratified by participating center and sex using a web-based system managed independently by the Medical Research Collaborating Center (MRCC).

Main RCT - Intervention:

In the PCI arm, the target lesion(s) are treated with drug-eluting stent(s) according to each site's standard practice. Imaging-guided PCI with IVUS or OCT is strongly recommended and is mandatory for complex PCI cases. The BioFreedom ULTRA stent (polymer-free, Biolimus A9-coated) is used preferentially; other approved drug-eluting stents may be used when clinically indicated. Following PCI, dual antiplatelet therapy is maintained for 6 months per guideline recommendation, with adjustments permissible based on individual bleeding and ischemic risk. Both arms receive guideline-directed optimal medical therapy, including intensive lipid-lowering treatment (LDL-C target <55 mg/dL), antiplatelet agents, and anti-anginal medications as indicated. Lifestyle interventions (smoking cessation, weight management, dietary modification, and physical activity) are also recommended.

Primary Endpoint (Main RCT):

Patient-oriented composite outcome (POCO): a composite of cardiovascular death, non-fatal myocardial infarction, or clinically driven revascularization at 2 years after completion of enrollment. Periprocedural MI is excluded from the primary endpoint. The trial is powered for superiority (one-sided α = 0.025, power = 90%), assuming a 2-year POCO rate of 12.0% in the OMT arm and 8.5% in the PCI arm. A total of 2,301 participants are required.

Follow-up:

Participants are followed at 6 months, 1, 2, 3, 4, and 5 years after enrollment (±90 days). Clinical outcomes, vital signs, laboratory tests, concomitant medications, and angina-related quality of life (Seattle Angina Questionnaire-7, SAQ-7) are assessed at every visit. Long-term follow-up up to 5 years after the last enrolled patient is planned to evaluate durability of treatment effects.

Nested RCT - Design and Rationale:

An embedded, independently randomized substudy (Nested RCT) is conducted within the PIVOT trial. Among participants in the main trial for whom beta-blocker therapy is deemed clinically appropriate - based on pre-specified criteria including heart rate control needs, history of prior MI, concurrent hypertension, tachyarrhythmia, or intolerance to calcium channel blockers - an additional 1:1 randomization is performed to compare carvedilol sustained-release (SR) versus immediate-release (IR) formulations. This substudy addresses the evidence gap regarding whether the two formulations are clinically equivalent in terms of angina symptom control in CCS patients, as head-to-head randomized data are currently lacking despite both being widely prescribed.

Nested RCT - Intervention:

Participants assigned to the SR arm receive carvedilol SR (Dilatrend SR; starting dose 32 mg once daily, up-titrated to 64 mg or 128 mg as tolerated). Participants assigned to the IR arm receive carvedilol IR (Dilatrend; starting dose 12.5 mg twice daily, up-titrated to 25 mg twice daily or 50 mg twice daily as tolerated). Both formulations are titrated to the maximal tolerated dose with a resting heart rate target of 55-60 bpm. Medication adherence is assessed by pill count at 6 and 12 months.

Primary Endpoint (Nested RCT):

Change in SAQ-7 Summary score from baseline to 12 months. Non-inferiority of carvedilol SR versus IR is concluded if the lower bound of the 95% confidence interval for the between-group difference exceeds -5 points, analyzed by ANCOVA adjusting for baseline SAQ-7 score. A total of 220 participants are required (one-sided α = 0.025, power = 80%, non-inferiority margin Δ = 5 points).

Statistical Analysis:

For the main RCT, the primary endpoint is analyzed using the Kaplan-Meier method with a stratified log-rank test in the intention-to-treat (ITT) population. Secondary time-to-event endpoints are analyzed using the cumulative incidence function with a Fine and Gray model, treating death as a competing risk. The Nested RCT primary endpoint is analyzed by ANCOVA in both the ITT and per-protocol (PP) populations.

Inclusion criteria

• Patients aged 40 years or older
• Patients suspected of having chronic coronary syndrome who have undergone coronary angiography and confirmed stenotic lesions
• Patients with lesions suitable for stent insertion who have 50% or more visually estimated stenosis in major coronary arteries with a diameter of 2.5 mm or greater observed on coronary angiography, and who satisfy one or more of the following conditions:

• Patients with stenosis of 70% or more confirmed via Quantitative coronary angiography (50% or more for the left main coronary artery)
• Minimum lumen area (MLA) ≤ 4 mm² or plaque burden >70% on intravascular ultrasound (IVUS)
• MLA <3.5 mm² or area stenosis (AS) >65% on Optical Coherence Tomography (OCT)
• The corresponding stenosis on localizing stress imaging using SPECT or PET When there is a significant focal ischemic deficit in the coronary artery region of the lesion and the total perfusion deficit (TPD) is ≥10%
• Pressure wire-based fractional flow reserve (FFR) ≤0.80
• Patients who can verbally confirm their understanding of invasive physiological or imaging evaluations and the benefits, harms, and alternative treatments of coronary angioplasty using drug-eluting stents, and for whom the patient or their legal representative can submit a written consent form.

Additional Criteria for nested RCT Studies

• When heart rate control is deemed therapeutically important due to an accompanying increase in heart rate at rest or during symptomatic episodes.
• When the use of beta-blockers is deemed clinically advantageous due to a history of myocardial infarction.
• When beta-blockers can help control blood pressure and symptoms in cases of concomitant hypertension.
• When there is a clinical situation requiring associated tachyarrhythmia or heart rate control.
• When beta-blockers are deemed more appropriate due to a history of contraindications, intolerance, or side effects of calcium channel blockers.

Exclusion criteria

• Patients with Left Ventricular Ejection Fraction (LVEF) less than 35%
• Patients with cardiogenic shock
• Patients with pulmonary edema or heart failure unresponsive to standard treatment
• Patients with unstable angina whose symptoms persist despite maximal drug therapy
• Patients with a history of ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), or unstable angina within the last 6 months
• Patients with active bleeding
• Patients with major bleeding of the gastrointestinal or urinary system within the last 3 months
• Patients with coagulation disorders prone to bleeding (including heparin-induced thrombocytopenia)
• Patients with hypersensitivity to or contraindications to the following drugs: Heparin, Aspirin, Clopidogrel, Prasugrel, Contrast media (Patients sensitive to contrast media are not excluded if the condition can be effectively prevented through pretreatment with steroids or diphenhydramine (e.g., flare-ups).
• Patients for whom percutaneous coronary intervention (PCI) is contraindicated
• Patients who have already undergone coronary artery bypass grafting (CABG)
• Patients with in-stent restenosis in the target lesion
• Patients with chronic total occlusion (CTO) in major coronary arteries
• Patients with lesions having an FFR of less than 0.64
• Patients with coronary arteries that are anatomically unsuitable for both PCI and CABG
• Patients with non-ischemic dilated cardiomyopathy or hypertrophic cardiomyopathy
• Patients with severe valvular disease or those judged by the investigator to be likely to require valve surgery or percutaneous valve replacement during the study period
• Patients with non-cardiac diseases, etc., with a life expectancy of less than one year or expected to have low treatment adherence (at the investigator's judgment)
• Pregnant or breastfeeding patients
• Other patients deemed by the investigator to be unsuitable for participation in the clinical trial

Additional Criteria for nested RCT Studies

• Significant bradycardia at rest, second-degree or higher atrioventricular block, or significant conduction disturbance
• Bronchial asthma or clinically significant bronchospasmodic disease
• Symptomatic hypotension
• Variant angina as a main presentation
• Other cases where the supervising investigator deems the use of beta-blockers medically inappropriate