Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States. LDL-C (low-density lipoprotein cholesterol) is a key driver and modifiable risk factor of ASCVD, particularly in high-risk patients, including those with genetic lipid disorders.¹ PCSK9i (proprotein convertase subtilisin/kexin type 9) inhibitors represented a major advancement in LDL-C management following Food and Drug Administration approval in 2015 to further lower elevated LDL-C in ASCVD and familial hypercholesterolemia. The label was expanded after 2017 to reduce events in patients with ASCVD and lower elevated LDL-C in patients with primary hypercholesterolemia.²

A previous analysis of eligible patients with PCSK9i prescriptions from 2015 to 2017 in the Family Heart Database showed a high percentage of patients with rejected (61%) and abandoned (15%) prescription status, which was associated with higher cardiovascular event rates relative to patients with paid PCSK9i prescription status.³ Between 2017 and early 2019, 4 developments were expected to increase PCSK9i utilization: (1) clinical practice guidelines recommending PCSK9i to reach LDL-C thresholds¹; (2) PCSK9i label expansion; (3) positive results from 2 major cardiovascular outcomes trials demonstrating PCSK9i benefit,¹ and (4) 60% reduction in PCSK9i prices.⁴

To evaluate the impact of these changes, the Family Heart Foundation characterized PCSK9i uptake and durable PCSK9i coverage status.

The Family Heart Database, comprised of US health care claims data sourced from Symphony Health (ICON plc Company, Blue Bell, PA) representing more than half of the US census was used to conduct a retrospective cohort study of adults prescribed a PCSK9i between July 2015 and December 2021. Patients’ coverage for new prescriptions was classified as paid (covered by insurer; retrieved by individual), rejected (rejected by the insurer); or abandoned (covered by insurer; not retrieved).

PCSK9i initial and durable coverage was evaluated across 2 time periods (2015–2018 and 2019–2021). Initial coverage status was calculated as use during the first 90 days. Durable, paid coverage was defined as patients having received ≥168 days of paid PCSK9i medication within any 12-month period. The ≥168-day period denotes adequate therapy to potentially affect ASCVD events.³ Initial coverage of other branded guideline-recommended cardiometabolic medications with demonstrated cardiovascular outcomes trial benefits (apixaban, sacubitril/valsartan, dapagliflozin, empagliflozin, and liraglutide) served as a frame of reference. The same methodology for determining coverage status was used for PCSK9i and cardiometabolic medications. See Myers et al for additional details of the data set and methodology.³ The data used in this study are available from the corresponding author upon reasonable request.

Patients included in the study were identified from retrospective anonymized claims data; thus, neither informed consent nor institutional review board approval was required.

In the Family Heart Database, 238 704 patients were newly prescribed a PCSK9i from 2015 to 2018, which increased to 470 018 patients from 2019 to 2021 (Table). The demographics between the 2 time periods were similar: ≈50% female, 60% White, 7% Black, 5% Hispanic, and 28% to 29% unknown ethnicity. Income was unknown for two-thirds of individuals.

Table. Prescription Status of Patients From the Family Heart Database

NA indicates not applicable; and PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors.

* Discontinuation of therapy without rejected or abandoned status; reasons for discontinuation are unknown but may include individuals no longer included in the database, prescription discontinuation by physician, and death, among others.

The number of patients with paid prescriptions in the first 90 days rose by 2.7-fold from 85 215 (2015–2018) to 234 703 (2019–2021). Despite the increase, paid prescription rates for initial PCSK9i coverage (35.70%–49.93%) were substantially lower than that for other guideline-recommended cardiometabolic therapies (ranging from 68.49% to 84.45%).

The percentage of rejected PCSK9i prescriptions declined to 30.95% from 2019 to 2021 but remained higher than that for other cardiometabolic therapies. The proportion of PCSK9i abandonment remained similar and slightly higher than that for cardiometabolic drugs.

Results from this real-world analysis suggest continuing barriers for PCSK9i use. Compared with a previous analysis of the Family Heart Database,³ PCSK9i utilization was markedly higher. New PCSK9i prescriptions increased 2.7-fold in the time periods assessed, which may reflect the incorporation of PCSK9i into guideline treatment algorithms as well as the expanded indication to reduce ASCVD risk. However, the rate of paid initial PCSK9i prescriptions (49.93%) lagged that of other branded cardiometabolic therapies, which ranged from 68.49% (liraglutide) to 84.45% (apixaban).

The retrieval rate of paid PCSK9i prescriptions was considerably lower than that for other cardiometabolic drugs. In October 2018, manufacturers reduced PCSK9i cost by 60%, making them similarly priced to guideline-indicated cardiometabolic drugs. Therefore, list pricing cannot fully explain the disparity in PCSK9i utilization versus that of branded cardiometabolic therapies. Despite the price reduction, some patients may continue to face high copays, which can increase abandonment rates.

The proportion of rejected prescriptions remains high for PCSK9i (30.95%) versus branded cardiometabolic therapies (3.53%–14.61%). Prior authorization requirements and provider intervention, 2 mechanisms to limit medication accessibility, have been shown to be much higher for PCSK9i than for guideline-indicated cardiometabolic drugs (97% versus 44% and 100% versus 50% to 54%, respectively).⁵

Study limitations include potential misclassification or other biases in administrative claims data.

Label expansion, price reduction, and guideline recommendations have increased PCSK9i approval and utilization rates, which remain relatively low. This real-world evidence demonstrates persistent barriers to guideline-recommended LDL-C management, perpetuating the societal burden of ASCVD.

The Family Heart Foundation independently funded this study. As a 501c3 public charity research and advocacy organization, the Family Heart Foundation receives contributions and sponsorships from individuals, foundations, and pharmaceutical companies.

Nonstandard Abbreviations and Acronyms

ASCVD	atherosclerotic cardiovascular disease
LDL-C	low-density lipoprotein cholesterol
PCSK9i	proprotein convertase subtilisin/kexin type 9 inhibitors

atherosclerotic cardiovascular disease

low-density lipoprotein cholesterol

proprotein convertase subtilisin/kexin type 9 inhibitors

Disclosures D.E. MacDougall, C.D. Ahmed, Dr McGowan, and K.A. Wilemon are employees of the Family Heart Foundation; Dr Baum is an unpaid advisor and board director to the Family Heart Foundation.

For Sources of Funding and Disclosures, see page 201.

中文翻译：

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2015 年至 2021 年美国大型理赔数据库中患者获取和使用处方 PCSK9 抑制剂的趋势

动脉粥样硬化性心血管疾病（ASCVD）仍然是美国的首要死因。LDL-C（低密度脂蛋白胆固醇）是 ASCVD 的关键驱动因素和可改变的危险因素，特别是对于高危患者，包括患有遗传性脂质疾病的患者。¹ PCSK9i（前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型）抑制剂代表了继 2015 年美国食品和药物管理局批准用于进一步降低 ASCVD 和家族性高胆固醇血症中升高的 LDL-C 后 LDL-C 管理方面的重大进步。该标签在 2017 年之后得到扩展，以减少 ASCVD 患者的事件并降低原发性高胆固醇血症患者升高的 LDL-C。²

之前对家庭心脏数据库中 2015 年至 2017 年持有 PCSK9i 处方的合格患者进行的分析显示，拒绝 (61%) 和放弃 (15%) 处方状态的患者比例很高，这与相对于患者较高的心血管事件发生率相关具有付费 PCSK9i 处方状态。³ 2017 年至 2019 年初，预计有 4 项进展将提高 PCSK9i 的利用率：(1) 临床实践指南建议 PCSK9i 达到 LDL-C 阈值¹；(2)PCSK9i标签扩展；(3) 2 项主要心血管结局试验的积极结果证明 PCSK9i 的益处，¹和 (4) PCSK9i 价格降低 60%。⁴

为了评估这些变化的影响，家庭心脏基金会描述了 PCSK9i 的吸收率和持久的 PCSK9i 覆盖状态。

家庭心脏数据库由来自 Symphony Health（ICON plc Company，Blue Bell，PA）的美国医疗保健索赔数据组成，代表美国人口普查的一半以上，用于对 2015 年 7 月期间服用 PCSK9i 的成年人进行回顾性队列研究2021 年 12 月。患者对新处方的承保分为付费（由保险公司承保；由个人检索）、拒绝（被保险公司拒绝）；或被遗弃（由保险公司承保；未取回）。

PCSK9i 的初始覆盖率和持久覆盖率在 2 个时间段（2015-2018 年和 2019-2021 年）进行了评估。初始承保状态按前 90 天内的使用情况计算。持久付费承保范围定义为在任何 12 个月期间接受付费 PCSK9i 药物治疗时间≥168 天的患者。≥168 天的期限表示足够的治疗可能会影响 ASCVD 事件。³初步报道的其他品牌指南推荐的心脏代谢药物（阿哌沙班、沙库巴曲/缬沙坦、达格列净、恩格列净和利拉鲁肽）已证明具有心血管结局试验益处，可作为参考框架。PCSK9i 和心脏代谢药物使用相同的方法来确定覆盖状态。有关数据集和方法的更多详细信息，请参阅 Myers 等人。³本研究中使用的数据可根据合理要求从通讯作者处获得。

纳入研究的患者是根据回顾性匿名索赔数据确定的；因此，既不需要知情同意，也不需要机构审查委员会批准。

在家庭心脏数据库中，2015 年至 2018 年有 238 704 名患者新开出 PCSK9i，2019 年至 2021 年增加至 470 018 名患者（表）。这两个时期的人口统计数据相似：约 50% 为女性，60% 为白人，7% 为黑人，5% 为西班牙裔，28% 至 29% 为未知种族。三分之二的人的收入未知。

桌子。家庭心脏数据库中患者的处方状态

NA表示不适用；和 PCSK9i，前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型抑制剂。

* 在没有拒绝或放弃状态的情况下停止治疗；中止的原因尚不清楚，但可能包括不再包含在数据库中的个人、医生中止处方以及死亡等。

前 90 天内付费处方的患者数量从 85 215 名（2015-2018 年）增加到 234 703 名（2019-2021 年），增加了 2.7 倍。尽管有所增加，但初始 PCSK9i 承保的付费处方率 (35.70%–49.93%) 远低于指南推荐的其他心脏代谢疗法的付费处方率（范围从 68.49% 到 84.45%）。

从 2019 年到 2021 年，PCSK9i 处方被拒绝的比例下降至 30.95%，但仍高于其他心脏代谢疗法。PCSK9i 的放弃比例保持相似，略高于心脏代谢药物。

实际分析结果表明 PCSK9i 的使用仍然存在障碍。与之前对家庭心脏数据库的分析相比，³ PCSK9i 的利用率明显更高。新的 PCSK9i 处方在评估的时间段内增加了 2.7 倍，这可能反映出 PCSK9i 纳入指南治疗算法以及扩大适应症以降低 ASCVD 风险。然而，首次 PCSK9i 处方付费率 (49.93%) 落后于其他品牌心脏代谢疗法，范围从 68.49%（利拉鲁肽）到 84.45%（阿哌沙班）。

PCSK9i付费处方的检索率明显低于其他心脏代谢药物。2018 年 10 月，制造商将 PCSK9i 成本降低了 60%，使其价格与指南指示的心脏代谢药物相似。因此，定价不能完全解释 PCSK9i 的使用与品牌心脏代谢疗法的差异。尽管价格下降，一些患者可能仍面临高额共付额，这可能会增加放弃率。

与品牌心脏代谢疗法 (3.53%–14.61%) 相比，PCSK9i (30.95%) 被拒绝处方的比例仍然很高。事先授权要求和提供者干预是限制药物可及性的两种机制，PCSK9i 已被证明比指南指示的心脏代谢药物高得多（分别为 97% 与 44% 和 100% 与 50% 至 54%）。⁵

研究局限性包括行政索赔数据中潜在的错误分类或其他偏差。

标签扩展、价格降低和指南建议提高了 PCSK9i 的批准率和使用率，但目前 PCSK9i 的批准率和使用率仍然相对较低。这一现实世界的证据表明，指南建议的 LDL-C 管理始终存在障碍，使 ASCVD 的社会负担长期存在。

家庭心脏基金会独立资助了这项研究。作为 501c3 公共慈善研究和倡导组织，家庭心脏基金会接受个人、基金会和制药公司的捐款和赞助。

非标准缩写词和首字母缩略词

化学气相沉积法	动脉粥样硬化性心血管疾病
低密度脂蛋白胆固醇	低密度脂蛋白胆固醇
PCSK9i	前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型抑制剂

动脉粥样硬化性心血管疾病

低密度脂蛋白胆固醇

前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型抑制剂

DE MacDougall、CD Ahmed、McGowan 博士和 KA Wilemon 是家庭心脏基金会的员工；鲍姆博士是家庭心脏基金会的无薪顾问和董事会董事。

有关资金来源和披露信息，请参阅第 201 页。