Appropriate Use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors for Atherosclerotic Cardiovascular Disease: Comparison of Recommendations from Different Guidelines or Consensus Around the World

Abstract

Increased low-density lipoprotein cholesterol (LDL-C) is the most crucial risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the mainstay therapy, but many patients need to add non-statin treatment to reach the recommended LDL-C goal. Although proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are the most effective agents in LDL-C reduction, they are much more expensive than other lipid-lowering agents. In January 2020, the Taiwan National Health Insurance (NHI) program started to reimburse PCSK9 inhibitors for select ASCVD patients with certain conditions. Major guidelines or consensus worldwide also provide specific recommendations about how to appropriately use these agents. This review summarizes the Taiwan NHI regulations of using PCSK9 inhibitors and compared them with other guidelines or consensus around the world.

INTRODUCTION

Atherosclerotic cardiovascular disease (ASCVD) is a very common cardiac disease, which is the second leading cause of death in Taiwan.¹ An abundance of scientific evidence from genetic studies, epidemiologic cohort studies, and randomized intervention trials has indicated that increased low-density lipoprotein cholesterol (LDL-C) plays a pivotal role in the development and progression of ASCVD.² Statins are the mainstay treatment for increased LDL-C, and enormous clinical benefits of intensive LDL-C lowering with high-intensity statins have been demonstrated in meta-analyses of clinical trials.^3,4 However, statin therapy alone is not sufficient to control LDL-C under certain circumstances. In patients with ASCVD who have very high levels of LDL-C, very high risk of recurrent ischemic events or are unable to take high-intensity statins due to side effects, non-statin therapies, including ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have been demonstrated to be effective in LDL-C reduction and beneficial in cardiovascular risk reduction.⁵ The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines on the management of blood cholesterol suggest adding ezetimibe or PCSK9 inhibitors for patients with ASCVD at very high risk who are on maximally tolerated statin therapy and have an LDL-C level of 70 mg/dL or higher.⁶ The 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias recommend an LDL-C goal of < 55 mg/dL in patients with ASCVD at very high risk, and combination treatment with PCSK9 inhibitors is recommended in patients not achieving their goals on a maximum tolerated dose of statins with ezetimibe.⁷

PCSK9 inhibitors are much more effective in LDL-C reduction than ezetimibe. As an add-on therapy after statins, ezetimibe can only provide another 19-23% LDL-C reduction, while PCSK9 inhibitors can provide up to 54-59% LDL-C reduction.^8-10 The drug inhibits PCSK9 function by preventing PCSK9 binding to LDL receptors, decreasing LDL receptor degradation, increasing the reuse of LDL receptors, and enhancing uptake of circulating LDL-C into cells.¹¹ Two outcome clinical trials, the FOURIER and ODYSSEY OUTCOMES studies, have demonstrated the clinical benefits of adding PCSK9 inhibitors to statin therapy in patients with stable ASCVD or acute coronary syndrome (ACS).^9,10 Despite the demonstrated efficacy, high cost prevents the widespread use of PCSK9 inhibitors in patients with ASCVD. Cost-effectiveness is a significant problem of the drug at its current price,^12-14 and so how to "appropriately" use the drug has become a controversial issue worldwide. Recently, the Taiwan National Health Insurance (NHI) program started to reimburse for the use of PCSK9 inhibitors in patients with ASCVD.¹⁵ The purpose of this review was to highlight the similarities and differences about recommendations for the use of PCSK9 inhibitors in ASCVD between the Taiwan NHI regulations and four other guidelines or consensus from different regions around the world: (1) the 2019 ESC/EAS guidelines for the management of dyslipidemia (2019 ESC/EAS guidelines),⁷ (2) the 2018 AHA/ACC guidelines on the management of blood cholesterol (2018 AHA/ACC guideline),⁶ (3) the 2018 Japan Atherosclerosis Society (JAS) statement for appropriate clinical use of PCSK9 inhibitors (2018 JAS statement),¹⁶ and (4) the 2017 National Lipid Association (NLA) update on the use of PCSK9 inhibitors in adults (2017 NLA update).¹⁷ In the Taiwan lipid guidelines for high-risk patients, PCSK9 inhibitors are recommended for patients with familial hypercholesterolemia (FH), ASCVD not achieving the LDL-C goal despite maximally tolerated statins ± ezetimibe, or statin intolerance.^18,19 In the current review, we only focused on patients with ASCVD. Recommendations of PCSK9 inhibitors for other high-risk groups are not covered in this review due to the limitation of space.

ASCVD PATIENTS

The subgroups of patients with ASCVD for whom PCSK9 inhibitors are recommended are slightly different among guidelines or consensus. The Taiwan NHI regulations include three major ASCVD groups in whom PCSK9 inhibitors can be considered within one year of the events: (1) myocardial infarction (MI), (2) coronary artery disease (CAD), peripheral artery disease (PAD) or other arterial diseases that received revascularization, and (3) atherosclerosis-related ischemic stroke.¹⁵ In the 2019 ESC/EAS guidelines, PCSK9 inhibitors are recommended for secondary prevention in patients at very high risk not achieving their LDL-C goal on a maximum tolerated dose of a statin and ezetimibe. All patients with documented ASCVD, based on either clinical or imaging diagnosis, are considered to be at very high risk. Clinical ASCVD includes previous ACS (MI or unstable angina), coronary revascularization, stroke/transient ischemic attack and PAD. Imaging-diagnosed ASCVD includes significant plaque on conventional coronary angiography or computed tomography (CT) angiography (multivessel coronary disease with two major coronary arteries > 50% stenosis) or on carotid ultrasound.⁷ In the 2018 AHA/ACC guidelines, PCSK9 inhibitors are suggested for ASCVD patients at very high risk, defined as those with a history of multiple major ASCVD events or one major ASCVD event with multiple high-risk conditions (Table 1).⁶ The major ASCVD events include recent ACS within 12 months, history of MI, ischemic stroke or symptomatic PAD. The 2018 JAS statement suggests that PCSK9 inhibitors can be considered if the LDL-C target is not achieved in patients with CAD. In this statement, patients with CAD are divided into two groups with different LDL-C targets: (1) < 70 mg/dL for CAD with ACS and/or diabetes mellitus (DM) with other high-risk conditions; and (2) < 100 mg/dL for other CAD without group 1 conditions.¹⁶ The high-risk conditions other than DM are: non-cardiogenic ischemic stroke, PAD, chronic kidney disease (CKD), metabolic syndrome, multiple major risk factors, and smoking. Patients with atherothrombotic cerebral infarction and PAD but without CAD are not considered for PCSK9 inhibitor therapy in the 2018 JAS statement.¹⁶ The 2017 NLA update recommends that PCSK9 inhibitors should be considered for: (1) stable ASCVD, particularly in those with additional ASCVD risk factors, and (2) progressive ASCVD with recurrent ASCVD events. The experts of the 2017 NLA panel cited the FOURIER study, and mentioned the inclusion criteria of the FOURIER study for ASCVD including previous MI, nonhemorrhagic stroke, or symptomatic PAD.¹⁷ Overall, the suggestions from the 2019 ESC/EAS guidelines and 2018 AHA/ACC guidelines limit the use of PCSK9 inhibitors to very high-risk patients with ASCVD. The 2018 JAS statement recommends PCSK9 inhibitors only for CAD patients. Comparisons of the recommendations from different guidelines and consensus are summarized in Table 2.

Table 1. Very high risk ASCVD in 2018 AHA/ACC guideline includes a history of multiple major ASCVD events or one major ASCVD event and multiple high risk conditions.

Major ASCVD events

Recent ACS (within the past 12 months)

History of MI (other than recent ACS event listed above)

History of ischemic stroke

Symptomatic peripheral arterial disease (history of claudication with ABI < 0.85, or previous revascularization or amputation)

High-risk conditions

Age ≥ 65 years

Heterozygous familial hypercholesterolemia

History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD events

Diabetes mellitus

Hypertension

CKD (eGFR 15-59 mL/min/1.73 m2)

Current smoking

Persistently elevated LDL-C (LDL-C ≥ 100 mg/dL despite maximally tolerated statin therapy and ezetimibe)

History of congestive heart failure

ABI, ankle-brachial index; ACC, American College of Cardiology; ACS, acute coronary syndrome; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction.

Adapted from reference 6.

Table 2. Taiwan NHI regulation and other guideline or consensus for appropriate use of PCSK9 inhibitor.

	ASCVD population	Drugs before PCSK9 inhibitor	LDL-C target/threshold
2020 Taiwan NHI regulation	Major ASCVD event within 1 year, including: (1) MI or (2) CAD, PAD or other arterial disease that received revascularization or (3) atherosclerosis-related ischemic stroke	Ezetimibe necessary	Threshold approach for all LDL-C > 135 mg/dL
2019 ESC/EAS guideline	(1) Documented ASCVD, either clinical or imaging*	Ezetimibe optional by clinical judgement	Target approach
	(2) Recurrent vascular events with 2 years while under maximally tolerated statin		LDL-C < 55 mg/dL in group (1)
			LDL-C < 40 mg/dL in group (2)
2018 AHA/ACC guideline	(1) Multiple major ASCVD events or (2) One major ASCVD event + multiple high risk conditions#	Ezetimibe necessary	Threshold approach for all LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL
2018 JAS statement	(1) CAD with (a) ACS and/or (b) DM + high risk condition†	Ezetimibe necessary	Target approach
	(2) CAD without conditions in group (1)		LDL-C < 70 mg/dL in group (1)
			LDL-C < 100 mg/dL in group (2)
2017 NAL update	(1) Stable ASCVD including previous MI, nonhemorrhagic stroke, or symptomatic PAD with additional ASCVD risk factors	Ezetimibe optional by clinical judgement	Threshold approach for all LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL
	(2) Progressive ASCVD with recurrent ASCVD events

* Clinical ASCVD: previous ACS (MI or unstable angina), coronary revascularization, stroke/transient ischemic attack and PAD; ASCVD on imaging: significant plaque on coronary angiography or CT angiography or carotid ultrasound.

^# See Table 1.

^† High-risk condition: non-cardiogenic ischemic stroke, PAD, CKD, metabolic syndrome, multiple major risk factors, and smoking.

ACC, American College of Cardiology; ACS, acute coronary syndrome; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CT, computed tomography; DM, diabetes mellitus; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; FH, familial hypercholesterolemia; JAS, Japan Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NHI, National Health Insurance; NLA, National Lipid Association; PAD, peripheral artery disease; PCSK9, proprotein convertase subtilisin/kexin type 9.

DRUGS BEFORE PCSK9 INHIBITORS

Basically, all guidelines suggest high-intensity statins or maximally tolerated statins as the first-line treatment for ASCVD if there are no statin contraindications or intolerance. The Taiwan NHI regulations suggest that patients should be treated with high-intensity statins (rosuvastatin 20 mg/day or atorvastatin ≥ 40 mg/day) or maximally tolerated statins for more than 3 months, and that if the LDL-C target is not achieved ezetimibe 10 mg/day should be added for another 3 months before starting PCSK9 inhibitors. The 2019 ESC/EAS guidelines recommend ezetimibe if the LDL-C goal is not achieved after 4-6 weeks with maximally tolerated statins.⁷ Then, PCSK9 inhibitors are considered if the LDL-C goal is not achieved after another 4-6 weeks with maximally tolerated statins and ezetimibe. However, the guidelines also suggest that adding PCSK9 inhibitors directly after statins is feasible, particularly in the secondary prevention of ASCVD with very high risk.^9,10 The duration of statins and/or ezetimibe required before PCSK9 inhibitors is much longer in the 2020 Taiwan NHI regulations than that in the 2019 ESC/EAS guidelines. Sufficient time is needed to titrate statins and observe their efficacy, however the effectiveness of LDL-C reduction is usually obvious within a few weeks after initiating the drug. The 2018 AHA/ACC guidelines suggest a strategy of ezetimibe before PCSK9 inhibitors. The guidelines consider ezetimibe has proven safety and tolerability, and two simulation studies favored the strategy of adding ezetimibe before PCSK9 inhibitors.^20,21 The 2018 JAS statement also suggests adding on ezetimibe before PCSK9 inhibitors. However, the 2017 NLA update does not make ezetimibe mandatory before initiating PCSK9 inhibitors. It leaves the decision to the physicians’ clinical judgment and suggests that PCSK9 inhibitors can be added directly as second-line therapy after statins.

LDL-C TARGET/THRESHOLD

Regarding LDL-C level, there are two approaches when considering adding PCSK9 inhibitors in these guidelines. The first is the LDL-C target approach, which is that PCSK9 inhibitors should be considered when the recommended LDL-C target is not achieved after high-intensity or maximally tolerated statin therapy with or without ezetimibe. The second uses the LDL-C threshold approach, in which initiation of PCSK9 inhibitors is based on a starting LDL-C level after maximal LDL-C lowering therapy. The concept of the threshold approach is from a cost-effectiveness perspective. Since PCSK9 inhibitors are more expensive than other pharmacological therapies, they should be considered only in those who would likely obtain the most benefits, but not for everyone who has not achieved their goal. Previous clinical trials have demonstrated that PCSK9 inhibitors can reduce LDL-C by approximately ≥ 50%;^9,10 therefore, the threshold to start PCSK9 inhibitors is set at about two times the recommended LDL-C target in some guidelines or consensus.

Current Taiwan lipid guidelines suggest an LDL-C target of < 70 mg/dL for patients with ACS or CAD.^18,19 The Taiwan NHI regulations use a threshold approach and suggest starting PCSK9 inhibitors when LDL-C > 135 mg/dL after high-intensity or maximally tolerated statin therapy with ezetimibe.¹⁵ The 2019 ESC/EAS guidelines use a targeted approach. For patients with documented ASCVD, the LDL-C target is < 55 mg/dL, whereas in those with ASCVD and recurrent vascular events within 2 years, LDL-C < 40 mg/dL should be considered.⁷ Patients with ASCVD not achieving the goals after high-intensity or maximum tolerated statin and ezetimibe therapy, PCSK9 inhibitors are recommended. The 2018 AHA/ACC guidelines provide a treatment threshold throughout the whole guidelines without mentioning any targets.⁶ Two treatment thresholds of PCSK9 inhibitors for very high-risk ASCVD are recommended in the 2018 AHA/ACC guidelines: LDL-C ≥ 70 mg/dL or a non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dL after maximally tolerated LDL-C lowering therapy. The 2018 JAS statement uses the targeted approach and suggests different targets for different CAD patients.¹⁶ For those with ACS and/or DM with other high-risk conditions, the LDL-C target is < 70 mg/dL, and for other CAD patients, the LDL-C target is < 100 mg/dL. PCSK9 inhibitors can be considered if the LDL-C target is not achieved after maximally tolerated statins with ezetimibe. The recommendations from the 2017 NLA update are quite similar to those of the 2018 ACC/AHA guidelines and use two thresholds, LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL, for both stable and progressive ASCVD when considering PCSK9 inhibitor therapy. The LDL-C treatment threshold before PCSK9 inhibitors is much higher in the Taiwan NHI regulations than in the 2018 AHA/ACC guidelines and 2017 NLA update.

CONCLUSIONS

Current evidence has demonstrated that intensive LDL-C lowering therapy is crucial in reducing the risk of ASCVD. Currently, statins are still the first-line and cornerstone therapy. High-intensity statin or maximum tolerated statins are recommended in most guidelines or consensus for ASCVD, because they can more easily help patients to reach the LDL-C target. PCSK9 inhibitors should be used "appropriately" as a second- or third-line therapy and only for high-risk patients. Based on studies of the drug’s cost-effectiveness, some guidelines or consensus use an LDL-C threshold approach. Although the "appropriateness" of PCSK9 inhibitor use is still under debate, to reduce recurrent ASCVD events in high-risk patients, earlier initiation of PCSK9 inhibitors should be considered if the LDL-C goal is not achieved with statins and/or ezetimibe. There is no doubt that PCSK9 inhibitors will become more cost-effective, and the use of PCSK9 inhibitors can then be extended to a wider range of patients that need the drug to achieve the recommended LDL-C target.

CONFLICTS OF INTEREST

All authors declare no conflicts of interest.