Cardiovascular Outcomes and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: Current Data and Future Prospects

Figures & data

Table 1 Prospective Phase 3 Cardiovascular Outcomes Trials

	FOURIER^Citation61	ODYSSEY OUTCOMES^Citation62	ORION-4 (NCT03705234)
IMP	Evolocumab	Alirocumab	Inclisiran
Patients, n	27,564 (prior ASCVD: MI, non-hemorrhagic stroke, PAD, and ≥1 major/2 minor additional risk factors)	18,924 (ACS in previous 1–12 months)	15,000 planned (elevated LDL-C and ASCVD)
Trial design	r, db, pc	r, db, pc	r, db, pc
Trial status	Completed	Completed	Ongoing
Dosing regimen	140 mg Q2W or 420 mg Q4W	75^a/150 mg Q2W	300 mg SC injection at 3 months, then every 6 months
Inclusion criteria	LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL on background high-intensity statin following at least atorvastatin 20 mg/day or its equivalent, with/without ezetimibe	LDL-C ≥70 mg/dL, non-HDL-C ≥100 mg/dL, or apoB ≥80 mg; on background atorvastatin 40–80 or rosuvastatin 20–40 mg/day, or maximum tolerated dose, age ≥40 years	Age ≥55 years; history of MI/IS/PAD
High-intensity statins	69% (atorvastatin ≥40 mg, rosuvastatin ≥20 mg, or simvastatin 80 mg)	89% (evidence-based statin dose)
Median follow-up	2.2 years	2.8 (44% with ≥3 years)	5 years
Endpoints	Primary: CV death, MI, stroke, revascularization, or hospitalization for UA Secondary: CV death, MI/stroke	Primary: CHD death, MI, IS, or hospitalization for UA Secondary: CHD (any or major) or CV event; composite of death from any cause/nonfatal MI/stroke; death from CHD, CV, or any cause	Primary: Time to first occurrence of CHD death/MI/fatal or non-fatal IS/urgent coronary revascularization

Note: ^a7.7% blindly switched to placebo at median 8.3 months after 2 consecutive LDL-C measurements of <15 mg/dL on the 75 mg dose.

Abbreviations: apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; db, double-blind; CHD, coronary heart disease; CV, cardiovascular; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; IMP, investigational medicinal product; IS, ischemic stroke; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; non-HDL-C, non-high-density lipoprotein cholesterol; ODYSSEY OUTCOMES, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; PAD, peripheral artery disease; pc, placebo-controlled; PCSK9, proprotein convertase subtilisin/kexin type 9; Q2W, every 2 weeks; Q4W, every 4 weeks; r, randomized; SPIRE, Studies of PCSK9 Inhibition and the Reduction of Vascular Events; SC, subcutaneous; UA, unstable angina.

Figure 1 FOURIER.⁶³ (A) primary and secondary endpoints and (B) secondary analyses in high-risk subgroups. ^aCV death, MI/stroke, hospitalization for UA or coronary revascularization; ARR and RRR are indicated when reported in the reference, and NNT values were calculated as 1/ARR. ^bCV death, MI/stroke. ^cDue to the hierarchical nature of the statistical testing, the P values for ‘Other secondary endpoints’ are considered exploratory. ^dIncidence RR reported from negative binomial regression model as RR (95% CI)⁶⁸ e2.5-year Kaplan–Meier rate⁶⁹ fNumber of patients (3-year Kaplan–Meier rate).⁷⁰

Abbreviations: ARR, absolute risk reduction; CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; HR, hazard ratio; MI, myocardial infarction; NNT, number needed to treat; PAD, peripheral arterial disease; RR, rate ratio; RRR, relative risk reduction; UA, unstable angina.

Figure 2 ODYSSEY OUTCOMES (A) primary and key secondary endpoints,⁶² and (B) secondary analyses in high-risk subgroups.^73,77-79 aCHD death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina; ARR and RRR are indicated when reported in the reference, and NNT values were calculated as 1/ARR. ^bMonovascular disease (coronary); 2 beds (coronary and peripheral artery or cerebrovascular); 3 vascular beds (coronary, peripheral artery, cerebrovascular).

Abbreviations: ARR, absolute risk reduction; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; NNT, number needed to treat; RRR, relative risk reduction; UA, unstable angina.

Figure 3 FOURIER⁶³ safety summary and antidrug antibody incidence. ^aNot reported.

Abbreviations: DM, diabetes mellitus; SAE, serious adverse event.

Figure 4 ODYSSEY OUTCOMES⁶² safety summary and antidrug antibody incidence. ^aNot reported.

Abbreviations: DM, diabetes mellitus; SAE, serious adverse event.

Figure 5 ASCVD risk categories from (A) the 2018 ACC/AHA cholesterol guidelines,⁴ (B) the 2019 ESC/EAS dyslipidemia guidelines,⁶ and (C) the 2017 AACE/ACE guidelines.⁵ aUnequivocally documented ASCVD on imaging includes findings known to be predictive of clinical events, such as significant plaque on coronary angiography or CT scan defined by multivessel coronary disease with 2 major epicardial arteries having >50% stenosis.

Abbreviations: AACE, American Association of Clinical Endocrinologists; ABI, ankle-brachial index; ACC, American College of Cardiology; ACE, American College of Endocrinology; ACS, acute coronary syndrome; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CABG, coronary artery bypass graft; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; SCORE, Systematic Coronary Risk Estimation; TC, total cholesterol; TIA, transient ischemic attack.

Figure 6 Cardiovascular outcomes trials of PCSK9 inhibitors^62,63 and benefit in high-risk subgroups.^69,70,77,78

Abbreviations: ACS, acute coronary syndrome; ARR, absolute risk reduction; ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus, LDL-C, low-density lipoprotein cholesterol; PAD, peripheral arterial disease; PVD, polyvascular disease; RRR, relative risk reduction.

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