PCSK 9 Inhibition as Secondary Prevention in Renal Transplant Patients With Cardiovascular Disease.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Any major cardiovascular events
研究概览
简要总结
From this randomized controlled study, we aim to:
A.Do do cardiovascular risk stratification of renal transplant recipients who are followed up in Hamed Al-Essa organ transplant center of Kuwait.
B. To compare the effectiveness of a PCSK9 inhibitor plus maximum tolerated statin therapy vs. maximum tolerated statin therapy alone in the reduction of major cardiovascular events among renal transplant recipients with cardiovascular disease.
C. To compare the effectiveness of a PCSK9 inhibitor plus maximum tolerated statin therapy vs. maximum tolerated statin therapy alone in terms of LDL-C-lowering, muscle symptoms, and quality of life.
D. To compare patient adherence to the different treatment protocols.
详细描述
Background:
Low-density lipoprotein (LDL) cholesterol is a well-established and modifiable risk factor for cardiovascular disease. Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) have emerged as a new class of drugs that effectively lower LDL cholesterol levels.1 Approximately 735,000 Americans have a myocardial infarction each year (2), and about 800,000 have a stroke. (3) Many patients remain at increased cardiovascular risk despite maximum tolerated statin therapy and could benefit from further LDL-C reduction. Most patients are treated with HMG-CoA reductase inhibitors, commonly known as statins. Millions of patients are eligible for cholesterol-lowering medication, according to current guidelines.4 High-intensity statin therapy reduces LDL-C and cardiovascular events more than moderate intensity statin therapy. 5 However, the response to statins is variable, and in some patients it is not tolerable (between 7 percent and 29 percent of patients taking statins report having muscle symptoms) 6, which represent a principal reason for nonadherence. Moreover, high-intensity statin therapy may have less benefit in low-risk primary prevention patients with a modest increase in the incidence of diabetes in such cases 5, 7. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are currently indicated for some patients at high risk, including those with familial hypercholesterolemia or pre-existing cardiovascular disease. PCSK9 inhibitors are a new class of medications that have been found to be very effective in reducing LDL-C, either as monotherapy or when added to background statin therapy. Normally, PCSK9 binds to low-density lipoprotein cholesterol (LDL-C) receptors, reducing the activity of the LDL-C receptors. PCSK9 inhibitors prevent PCSK9 from binding to the LDL receptor, thereby increasing the activity of the receptors and enhancing removal of LDL-C from circulation. 8 Current guidelines recommend that patients whose 10-year risk of major cardiovascular events is 10 percent or greater take statins. 9 Two PCSK9 inhibitors are currently available and approved by FDA for use in the United States: evolocumab and alirocumab. These drugs are monoclonal antibodies (mAbs) administered by Proposed Clinical Trial Protocol on Use of PCSK9 Inhibitors for Primary Prevention of Cardiovascular Disease 3 subcutaneous injection bi-weekly or monthly and are currently approved for patients with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Two recent reports on the effects of evolocumab and alirocumab have raised expectations that these drugs will dramatically reduce cardiovascular events.10,11 the rate of major cardiovascular events was lower with alirocumab than with placebo (1.7 percent versus 3.3 percent; hazard ratio 0.52; 95 percent confidence interval 0.31 to 0.90; P=0.02). 11 Notably, the annual cost for a single patient in the United States for PCSK9 inhibitors is approximately $14,000.9 The prevalence of cardiovascular diseases (CVD) has increased in kidney transplant recipients. CVD remains a leading cause of mortality among recipients with functioning grafts. The pathophysiology of CVD recipients is a complex interplay between preexisting risk factors, metabolic sequelae of immunosuppressive agents, infection, and rejection.17
Aim of the study:
A. Cardiovascular risk stratification of renal transplant recipients who are followed up in Hamed Al-Essa organ transplant center of Kuwait.
B. To compare the effectiveness of a PCSK9 inhibitor plus maximum tolerated statin therapy vs. maximum tolerated statin therapy alone in the reduction of major cardiovascular events among renal transplant recipients with cardiovascular disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent,
- •Male or female Kuwaiti older than 30 and younger than ≤ 80 years of age at the signing of informed consent
- •History of clinically evident cardiovascular disease(diagnosis of myocardial infarction; non-hemorrhagic stroke or symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with the ankle-brachial index (ABI) < 0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease,
- •At least 1 major risk factor or at least 2 minor risk factors below: Major Risk Factors (1 Required): o diabetes (type 1 or type 2) o age ≥ 65 years at randomization (and ≤ 85 years at the time of informed consent) o MI or non-hemorrhagic stroke within 6 months of screening o additional diagnosis of myocardial infarction or non-hemorrhagic stroke excluding qualifying MI or non-hemorrhagic stroke o current daily cigarette smoking o history of symptomatic PAD (as mentioned before) if eligible by MI or stroke history; Minor Risk Factors (2 Required): o history of non-MI related coronary revascularization o residual coronary artery disease with ≥ 40% stenosis in ≥ 2 large vessels o Most recent HDL-C <1.0 mmol/L for men and <1.3 mmol/L for women by the central laboratory before randomization o Most recent CRP > 2.0 mg/L by the central laboratory before randomization o Most recent LDL-C ≥ 3.4 mmol/L or non-HDL-C ≥ 4.1 mmol/L by the central laboratory before randomization o metabolic syndrome.
排除标准
- •Exclusion Criteria:
- •Recent MI or stroke
- •NYHA class III or IV, or last known left ventricular ejection fraction < 30%
- •Known hemorrhagic stroke at any time
- •Uncontrolled or recurrent ventricular tachycardia
- •Planned or expected cardiac surgery or revascularization within 3 months after randomization
- •Uncontrolled hypertension (sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg),
- •Prior use of PCSK9 inhibition treatment other than evolocumab or use of evolocumab < 12 weeks prior to final lipid screening
- •Untreated or inadequately treated hyperthyroidism or hypothyroidism (thyroid-stimulating hormone (TSH) < lower limit of normal or > 1.5 times the upper limit of normal and free thyroxine (T4) levels that are outside normal range at the final screening. ,
- •Severe renal graft dysfunction(estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 at final screening,
- •Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as determined by central laboratory analysis at the final screening.
- •Personal or family history of hereditary muscular disorders.
- •Malignancy or HIV patients,
- •Known major active infection or major hematologic, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator,
- •Female subject who has either (1) not used-acceptable method(s) of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment with IP and for an additional 15 weeks after the end of treatment with IP unless the subject is sterilized or postmenopausal;
- •Known sensitivity to any of the active substances or their excipients to be administered during dosing.
研究组 & 干预措施
Group 1
Evolocumab group, patients who are receiving this therapy for 12 months.
干预措施: Evolocumab (Drug)
Group 2
The Statin group includes patients who are maintained on statin therapy.
干预措施: Evolocumab (Drug)
结局指标
主要结局
Any major cardiovascular events
时间窗: 24 months
cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization
次要结局
未报告次要终点
研究者
Osama Gheith
Consultant nephrologist
Hamid Al-Essa Organ Transplant Center