LDL Cholesterol TARGETs in OLDer Patients (Age≥75 Years) With ASCVD (TARGET OLD)

NCT ID: NCT05765370

Last Updated: 2023-04-10

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 4200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-24
• Study Completion Date: 2026-12-24

Brief Summary

To determine whether treating to an LDL-C target of 25 to <70 mg/dL is superior to an LDL-C target of 70 to <100 mg/dL with respect to major cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) in patients aged ≥75 years with atherosclerotic cardiovascular disease (ASCVD).

To determine whether treating to an LDL-C target of 25 to <70 mg/dL is non-inferior to an LDL-C target of 70 to <100 mg/dL with respect to major safety events (hemorrhagic stroke, new-onset diabetes, muscle-related events, neurocognitive adverse events, new or recurrent cancer, cataract, or hepatic disorder [Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) >3× ULN, or total bilirubin >2× ULN]) in patients aged ≥75 years with ASCVD.

Detailed Description

The benefits of LDL cholesterol-lowering treatment for the prevention of atherosclerotic cardiovascular disease (ASCVD) are well established. LDL-C lowering is associated with a significant reduction in major adverse cardiovascular events in a linear fashion, apparently without any plateau at low LDL-C levels. On the other hand, the degree to which LDL-C levels can be safely lowered remains unclear. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus or possibly hemorrhagic stroke) and long-term data are needed to address safety concerns.

It should be noted that the benefits and risks from LDL cholesterol lowering in older patients (age ≥75 years) remains debated because most randomized trials have explicitly excluded or enrolled few older adults. In clinical practice, the appropriate treatment target for LDL-C in patients ≥75 years of age with ASCVD remains uncertain. Current US and European cholesterol guidelines have no specific recommendations regarding the LDL-C treatment goal for older patients and noted that the level of evidence in older patients is low. Currently, there is no direct evidence from randomized clinical trials (RCTs) for the most appropriate treatment targets for LDL-C among patients ≥75 years of age with ASCVD in worldwide.

The TARGET OLD trial is a multicenter, open-label, parallel-group, event-driven, randomized, controlled trial with blinded end-point evaluation. Consecutive patients aged ≥75 years with ASCVD who meet the inclusion criteria and none of the exclusion criteria outlined above will be randomized in a 1:1 fashion to LDL-C target of 25 to <70 mg/dL or LDL-C target of 70 to <100 mg/dL. The proposed study will examine the comparative efficacy and safety of treating to an LDL-C target of 25 to <70 mg/dL compared with an LDL-C target of 70 to <100 mg/dL among patients aged 75 years or older with ASCVD. Our primary hypothesis is that, among such patients, targeting an LDL-C of 25 to less than 70 mg/dL is superior to a target of 70 to less than 100 mg/dL on reducing the risk of major adverse cardiovascular events (primary efficacy end point), while is non-inferior towards the composite of major safety outcomes (key secondary safety end point).

Prescription of lipid-lowering agents (drug and dosage up to the investigator according to the assigned target LDL-C level. Statin monotherapy or in combination with ezetimibe, PCSK9 inhibitor or other drugs were adjusted on the basis of the study-group assignment. Patients will follow-up at 1, 2, 4, 6, 12 months, and then every 6 months throughout 36 months with an evaluation of patients' lipid profiles, any cardiovascular events, safety and adverse events, muscle-related symptoms, quality of life (EQ-5D), and patient-reported cognition function (ECog scale). The trial will continue until 726 adjudicated primary endpoint events have occurred. We estimated that 4,200 patients would be needed to provide the necessary number of confirmed endpoints to test the study hypothesis. All analyses will be according to the intention-to-treat (ITT) principle.

Conditions

Atherosclerotic Cardiovascular Disease; Older Patients; LDL Cholesterol

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

LDL-C Lower-Target Group (25mg/dL≤ LDL-C<70mg/dL)

Participants randomized into the LDL-C lower-target arm will have a goal of 25mg/dL≤ LDL-C<70mg/dL.

Prescription of lipid-lowering agents (drug and dosage) were initiated or adjusted on the basis of the investigator according to the assigned target LDL-C level.

Group Type: EXPERIMENTAL

Achieving a Target LDL-C level of 25mg/dL≤ LDL-C<70mg/dL

Intervention Type: PROCEDURE

Investigators initiated or adjusted lipid-lowering agents (drug and dosage) to achieve the target of 25mg/dL≤ LDL-C<70mg/dL. The protocol encouraged, but did not mandate, the initiation of moderate-intensity statin therapy for secondary prevention with the evaluation of the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences. Statin monotherapy or in combination with ezetimibe, PCSK9 inhibitor or other drugs were adjusted on the basis of LDL-C levels.

At each follow-up visit, the investigators should verify whether the target LDL-C has been obtained. If the target level of LDL cholesterol was achieved, it is reasonable to continue to monitor adherence to lifestyle modifications, medication, and ongoing LDL-C response to therapy. If the target level of LDL cholesterol was not achieved, adjustment of the type and dose regimen of statin, or the additional of a nonstatin agent should be considered.

LDL-C Higher-Target Group (70mg/dL≤ LDL-C<100mg/dL)

Participants randomized into the LDL-C lower-target arm will have a goal of 70mg/dL≤ LDL-C<100mg/dL.

Prescription of lipid-lowering agents (drug and dosage) were initiated or adjusted on the basis of the investigator according to the assigned target LDL-C level.

Group Type: ACTIVE_COMPARATOR

Achieving a Target LDL-C level of 70mg/dL≤ LDL-C<100mg/dL

Intervention Type: PROCEDURE

Investigators initiated or adjusted lipid-lowering agents (drug and dosage) to achieve the target of 70mg/dL≤ LDL-C<100mg/dL. The protocol encouraged, but did not mandate, the initiation of moderate-intensity statin therapy for secondary prevention with the evaluation of the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences. Statin monotherapy or in combination with ezetimibe, PCSK9 inhibitor or other drugs were adjusted on the basis of LDL-C levels.

At each follow-up visit, the investigators should verify whether the target LDL-C has been obtained. If the target level of LDL cholesterol was achieved, it is reasonable to continue to monitor adherence to lifestyle modifications, medication, and ongoing LDL-C response to therapy. If the target level of LDL cholesterol was not achieved, adjustment of the type and dose regimen of statin, or the additional of a nonstatin agent should be considered.

Interventions

Achieving a Target LDL-C level of 25mg/dL≤ LDL-C<70mg/dL

Investigators initiated or adjusted lipid-lowering agents (drug and dosage) to achieve the target of 25mg/dL≤ LDL-C<70mg/dL. The protocol encouraged, but did not mandate, the initiation of moderate-intensity statin therapy for secondary prevention with the evaluation of the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences. Statin monotherapy or in combination with ezetimibe, PCSK9 inhibitor or other drugs were adjusted on the basis of LDL-C levels.

At each follow-up visit, the investigators should verify whether the target LDL-C has been obtained. If the target level of LDL cholesterol was achieved, it is reasonable to continue to monitor adherence to lifestyle modifications, medication, and ongoing LDL-C response to therapy. If the target level of LDL cholesterol was not achieved, adjustment of the type and dose regimen of statin, or the additional of a nonstatin agent should be considered.

Intervention Type: PROCEDURE

Achieving a Target LDL-C level of 70mg/dL≤ LDL-C<100mg/dL

Investigators initiated or adjusted lipid-lowering agents (drug and dosage) to achieve the target of 70mg/dL≤ LDL-C<100mg/dL. The protocol encouraged, but did not mandate, the initiation of moderate-intensity statin therapy for secondary prevention with the evaluation of the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences. Statin monotherapy or in combination with ezetimibe, PCSK9 inhibitor or other drugs were adjusted on the basis of LDL-C levels.

At each follow-up visit, the investigators should verify whether the target LDL-C has been obtained. If the target level of LDL cholesterol was achieved, it is reasonable to continue to monitor adherence to lifestyle modifications, medication, and ongoing LDL-C response to therapy. If the target level of LDL cholesterol was not achieved, adjustment of the type and dose regimen of statin, or the additional of a nonstatin agent should be considered.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

1. Men or women ≥75 years of age

2. Diagnosis of clinical atherosclerotic cardiovascular disease (ASCVD) with one or more of the following:

1. Diagnosis of coronary heart disease (one or more of the following criteria must be satisfied):

• Hospitalization for acute coronary syndrome
• Treatment or hospitalization for stable angina pectoris with documented ischemia on invasive or noninvasive testing
• History of myocardial infarction
• History of coronary revascularization procedure (eg, percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG])
• Invasive diagnostic coronary angiography indicating >50% stenosis in at least one major epicardial coronary artery or CT-imaging (eg, CCTA/MDCT) evidence of coronary atherosclerosis (>50% stenosis in at least two major epicardial coronary artery)

2. Diagnosis of atherosclerotic cerebrovascular or carotid disease (one or more of the following criteria must be satisfied):

• History of ischemic stroke or transient ischemic attack (TIA) confirmed by symptoms with a documented ischemic lesion on CT or MRI in the cerebral regions corresponding to the symptoms;
• Documented intracranial atherosclerotic stenosis on the basis of conventional cerebral angiography, magnetic resonance angiography, CT angiography, transcranial doppler ultrasound, and high-resolution MRI;
• Symptomatic carotid artery disease with ≥50% carotid arterial stenosis;
• Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per angiography or duplex ultrasound;
• History of carotid revascularization (catheter-based or surgical).

3. Diagnosis of atherosclerotic peripheral artery disease (one or more of the following criteria must be satisfied):

• History of aorto-iliac or peripheral arterial intervention (catheter-based or surgical).
• Prior non-traumatic amputation of a lower extremity due to peripheral artery disease
• History of intermittent claudication and one or more of the following:

1. An ankle/arm blood pressure (BP) ratio < 0.90, or

2. Significant peripheral artery stenosis (≥50%) documented by angiography, or by duplex ultrasound

3. Baseline LDL-C level should be satisfied:

• Patients were required to have a baseline LDL-C level ≥100mg/dL (2.6mmol/L) if they were taking a regimen of lipid-lowering therapy <4 weeks or they had not previously received lipid-lowering therapy.
• Patients were required to have a baseline LDL-C level ≥70mg/dL (1.8mmol/L) if they were on stable treatment with lipid-lowering therapy ≥4 weeks

4. Signed written informed consent.

Exclusion Criteria

1. Subject was clinically unstable:

1. Hypotension, defined as sustained systolic blood pressure of <90 mmHg due to cardiac failure with associated symptoms;

2. Unstable or severe pulmonary edema/decompensated congestive heart failure;

3. Acute mitral regurgitation or acute ventricular septal defect;

4. Cardiogenic shock and/or need for mechanical/pharmacologic hemodynamic support

5. Ongoing Non-STEMI with biomarkers (cardiac troponin) still rising

6. Recent STEMI (≤7 days prior to randomization)

7. Recurrent symptoms of cardiac ischemia

2. Moderate to severe heart failure (New York Heart Association [NYHA] Functional Classification III or IV) or last known left ventricular ejection farction (LVEF) <40%.

3. Severe renal dysfunction, defined as creatinine clearance <30 mL/min or estimated glomerular filtration (eGFR) rate less than 30 ml/min/1.73 m2, or requirement for peritoneal dialysis or hemodialysis for renal insufficiency.

4. History of hemorrhagic stroke or unknown classified stroke.

5. Uncontrolled or recurrent ventricular tachycardia (such as ventricular fibrillation, recurrent and highly symptomatic ventricular tachycardia, complete heart block, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications).

6. Uncontrolled hypertension (greater than 180 mm Hg systolic and/or greater than 110 mm Hg diastolic at randomization visit).

7. History or clinical evidence of active liver disease or hepatic dysfunction, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN), or total bilirubin > 2 × ULN.

8. Unexplained elevated creatine kinase (CK) concentration >5 × ULN or elevation due to known muscle disease.

9. Planned or expected cardiac surgery, PCI or carotid stenting, or planned major noncardiac surgery during the study period. If angiography or revascularization is planned, patients may be screened and enrolled after all such planned procedures are completed.

10. Active Malignancy (except nonmelanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) including those patients requiring surgery, chemotherapy, and/or radiation in the past 3 years.

11. Drug or alcohol abuse, and inability/unwillingness to abstain from drug abuse and excessive alcohol consumption during the study.

12. Severe, concomitant noncardiovascular disease that is expected to reduce life expectancy to <3 years

13. Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies), or receiving other investigational agent(s)

14. Subject has received drugs via a systemic route that have known major interactions with background statin therapy (eg, itraconazole, ketoconazole, and other antifungal azoles, erythromycin, clarithromycin, or cyclosporine nefazodone) within 1 month prior to randomization or is likely to require such treatment during the study period.

15. Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal)

16. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and investigator's knowledge.

17. Any uncontrolled or serious disease, or any medical or surgical condition (such as known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction, or a chronic disease or infection [eg, HIV]), that may either interfere with participation in the clinical study and is not currently stable and appropriately managed in the judgment of the investigator, and/or put the subject at significant risk (according to investigator's judgment) if he/she participates in the clinical study.

18. Mental/psychological impairment/neurocognitive disorder, or any other reason to expect patient difficulty in complying with the requirements of the study or understanding the goal and potential risks of participating in the study

• Minimum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

China National Center for Cardiovascular Diseases

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kefei Dou, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing

Hao-Yu Wang, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing

Locations

Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College

Beijing, Beijing Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Kefei Dou, MD, PhD

Role: CONTACT

drdoukefei@126.com

+86-10-13801032912

Hao-Yu Wang, MD, PhD

Role: CONTACT

wanghaoyu@fuwai.com

+86-10-15810671272

Facility Contacts

Kefei Dou, MD

Role: primary

drdoukefei@126.com

+86-13801032912

Hao-Yu Wang, MD

Role: backup

wanghaoyu@fuwai.com

+86-15810671272

Other Identifiers

2022-1879

Identifier Type: -

Identifier Source: org_study_id