When elephants fight, it is the grass that suffers.

—African proverb

The foundational strategy for preventing cardiovascular disease (CVD) and recurrent cardiovascular events consists of lowering levels of low-density lipoprotein cholesterol (LDL-C), controlling blood pressure, and preventing and treating diabetes mellitus, combined with smoking avoidance and cessation, a healthy diet, and regular exercise. Despite decades of global progress in implementing risk factor reduction, progress has plateaued, and a recent uptick in risk has been observed in many areas characterized by lower income and lower levels of education.¹ In the United States, a significant increase in cardiometabolic disease resulting from the erosion of gains in modifying common risk factors has combined with opioid overdose and rising suicide rates to drive a downward trajectory in average life expectancy for 4 years in a row.²

I approach this topic with significant conflicts of interest. As a former Commissioner of the US Food and Drug Administration, I have regulated LDL-C–lowering drugs. I have also conducted clinical trials, advised pharmaceutical companies, practiced cardiovascular medicine, and served as an institutional official for a large academic medical center and its health system, and I currently work for a company with an interest in the prevention and treatment of CVD. Therefore, my views and comments on the issue should be considered in light of these interactions, prior expressed beliefs, and financial conflicts.

Although dietary and behavioral approaches to lowering LDL-C should be attempted, the results are modest and, for a majority of patients over longer intervals, only partly sustainable despite behavioral intervention. The use of statins, a class of drug that prevents the production of cholesterol by the liver, substantially reduces LDL-C and cardiovascular events, including death, stroke, myocardial infarction, and other sequelae of vascular disease. However, during the first decade that statins were broadly available, substantial cynicism directed toward the drugs fueled uncertainty that ultimately limited their use in clinical practice. Analyses show reduced use of statins and associated increases in cardiovascular events and death in countries when negative reports about statins appeared in popular media.³ Statins eventually achieved blockbuster status after multiple blinded randomized trials conducted in large populations confirmed a substantial benefit in terms of lowering rates of cardiovascular events, particularly in people who had already had such an event. Unfortunately, however, despite the use of statins coupled with good-faith efforts at diet modification, many continue to be at risk of cardiovascular events because of elevated levels of LDL-C.

Even individuals with what were previously considered normal levels of LDL-C but also a high residual risk of recurrent CVD have been shown to benefit from further lipid lowering. The IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) demonstrated that the cholesterol absorption inhibitor ezetimibe can provide additional, albeit modest, reduction of cardiovascular events when added to high-intensity statin therapy.⁴ Although the use of ezetimibe in primary prevention has never been evaluated, its effect in secondary prevention is entirely consistent with predictions based on the effect of statins: a small reduction in LDL-C resulting in a small reduction in cardiovascular events. Now that multiple generic versions of ezetimibe are available, its price has dropped substantially and is now commensurate with its modest value in reducing events.

Most recently, a scientific tour de force resulted in the development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Over a short period, a human genetic polymorphism associated with lower low-density lipoprotein levels and lower cardiovascular event rates in epidemiological studies was translated into functional models at multiple preclinical levels, enabling target identification and the development of therapeutic molecules. The companies that won the race to develop PCSK9 inhibitors moved through development rapidly and were granted approval to market their drugs in limited populations on the basis of the demonstration of dramatic reductions in LDL-C levels without any accompanying serious toxicity. Before marketing approval, large clinical outcomes trials were initiated to evaluate the impact of these drugs on major cardiovascular events and to identify possible toxicities. These trials, now reporting their results after several drugs in the class attained marketing approval, demonstrate a reduction in cardiovascular events consistent with predictions based on trials of statins and ezetimibe.⁵

Although the 2017 FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) of the PCSK9 drug evolocumab found a reduction in cardiovascular events within the expected range for reduction in LDL-C, no significant decline in mortality was observed.⁶ The reasons for this finding have been debated; however, the trial lacked the statistical power to consider mortality as an isolated end point and was stopped early because of the definitive reduction in clinically important nonfatal events observed by the data monitoring committee.

In comparison, the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) with the PCSK9 drug alirocumab had a longer period of follow-up and showed remarkably similar results, except that the trial also showed a reduction in mortality.⁷ A third PCSK9 antibody, bococizumab, failed in phase 3 because of attenuation of effect over time resulting from antibody formation.

The combined data from 2 groundbreaking trials constitute a rich resource for calculating the impact of PCSK9 inhibitors as a function of underlying risk. Those same data also allow us to calculate the overall cost reduction in clinical care produced by reducing cardiovascular events independently and, when combined with pricing information, to calculate a value equation. Although the initial data that led to marketing approval for PCSK9s included only modeled estimates of effects on events, current extensive outcomes data provide an excellent basis for calculating the value of PCSK9 treatment, defined as cost per unit of benefit, including survival, prevention of nonfatal events, and reduction in costs associated with these nonfatal events.

Because lowering LDL-C does not eliminate all cardiovascular events and because total risk can be lowered by a combination of lifestyle changes and generic medications, there is ample reason to recommend these measures before considering PCSK9 inhibitors. Nevertheless, a significant number of Americans with LDL-C levels above the desired range will have major cardiovascular events that could have been prevented by appropriate use of PCSK9 inhibitors in conjunction with other effective therapies. This is now reflected in the latest version of the American College of Cardiology/American Heart Association cholesterol guidelines, which recommend adding ezetimibe to statin therapy and, if LDL-C levels remain high, then adding PCSK9 inhibitors for high-risk adults with atherosclerotic CVD.

Despite this consistent set of facts, the uptake of PCSK9 inhibitors has been slow and uneven. Large numbers of people both in the United States and worldwide continue to have elevated LDL-C, putting them at risk of recurrent cardiovascular events. Although the majority of these people have not adhered to all other effective interventions, millions of people in the United States doubtless would qualify for PCSK9 inhibitors even after these measures are instituted. Only a tiny fraction, however, are currently being treated with PCSK9 drugs.

What does this tell us about the US clinical ecosystem and the use of medicines within that system? It tells us that, at least to some extent, the systemic dysfunction mirrors a problem plaguing American healthcare in general: In a fragmented system where all the sectors are profitable, each sector has little motivation to change on its own. The proverb that provides the epigraph for this article is a metaphor for what happens when large and powerful interests contend against each other to the ultimate detriment of patients, who have little power in the overall ecosystem. Here, I examine the key factors that led to this dynamic in the context of the PCSK9 story.

The US pricing model for patented medicines during their period of exclusivity is broadly agreed to be opaque and not configured to optimize clinical outcomes for patients. In that light, the initial prices charged by pharmaceutical companies for PCSK9 inhibitors seemed unreasonable, particularly given the absence of proven reduction in cardiovascular events when they first came to market. These high prices unleashed a torrent of criticism and articles that made various claims about cost-effectiveness. European and US technology evaluators panned the pricing, concluding that it yielded cost-effectiveness estimates outside of the desirable range.^8–10

Although various explanations have been offered, it remains unclear exactly how these initial pricing decisions are made in the first place. Fundamentally, when a new molecule has an effect on death or major clinical outcomes relevant to a patient, what is a fair price? When mortality benefit is not established empirically but serious events such as stroke and myocardial infarction are prevented, what is a fair price that rewards development of an important drug without resulting in broad denial of access to the new treatment? It appears that the dominant scheme for pricing in the United States is based on an estimate of what the market will bear, a good strategy for consumer products but one that raises questions about the ethics of differential access to therapies that save lives or prevent devastating deterioration in functional status.

Professional medical organizations responded to the advent of PCSK9 drugs with a mixture of excitement and serious skepticism. The proof of concept in the trials of PCSK9 antibodies demonstrated that lowering LDL-C levels by this mechanism was beneficial and that the reductions seen were consistent with a reproducible calculation generated from statin and ezetimibe trials.^5,11 These findings bolstered the confidence of leaders who were invigorated by the “low-density lipoprotein hypothesis.” However, the growing number of academic critics of the pharmaceutical industry weighed in heavily, asserting that the price was too high and that patient survival was not improved initially, giving cover to those in the professional community who were reluctant to change practice or to absorb cost increases.

Health systems almost universally took the position that prices for PCSK9 drugs were too high. Voluble criticism of PCSK9 clinical trials and their results provided justification for administrators and practice leaders who devised or tolerated systems that made it difficult to prescribe a PCSK9 inhibitor.¹² Despite ubiquitous electronic health records and associated data warehouses and data lakes that facilitate the identification of patients fitting a profile that would predict benefit, almost no health systems sought to proactively identify suitable patients, nor did mainstream medicine demand a proactive program for the same.

Simply put, the vast majority of Americans now receive health care from systems with digital data repositories that should enable rapid identification of people who would benefit from a proven therapy. Such systems could equally well prevent the use of expensive therapies in patients when there is no evidence that doing so would benefit them. A naïve person might think that health systems have an obligation to use their digital infrastructure to improve outcomes for the leading cause of death in a systematic fashion, but this did not happen. Although PCSK9 inhibitors may be less important than statins, blood pressure, smoking cessation, and control of diabetes mellitus in terms of the capacity of health systems to use the power of information to improve outcomes, there is nonetheless an opportunity to put rational schemes into action for high-price drugs.

As PCSK9 drugs entered the market, pharmaceutical benefits managers negotiated with health systems and developed complex, opaque use management programs. Interestingly, the role of pharmaceutical benefits managers is so convoluted that experts disagree on whether their net effect is to reduce cost or to increase it. The reason is a byzantine system in which charges escalate and prices are reduced through a system of rebates,¹³ leading to suspicion that pharmaceutical benefits managers keep prices high on purpose because their profit is partially generated by the difference between the list and negotiated prices. In the case of PCSK9 drugs, cumbersome prior authorization programs, which obliged physicians to make more than half a dozen phone calls, were clearly designed to exhaust the doctor’s capacity to battle the system, whereas high copays had the effect of discouraging patients.¹² As a result, <1 in 3 patients prescribed a PCSK9 ever received the therapy.¹²

With the exception of the FH (Familial Hypercholesterolemia) Foundation, patient advocacy groups initially stayed out of the fray. This is in stark contrast to advocacy for cancer and rare diseases, for which new drugs generate tremendous excitement and create reputational risk for those who deny payment or restrict access for relevant patients. The American Heart Association and the American College of Cardiology were muted in their endorsement of the science underpinning PCSK9s and the proven benefits of the drugs and were not aggressive in their advocacy.

Over time, however, patient groups representing families with familial hypercholesterolemia have stepped up their efforts through public “outing” of denial of access with significant success.¹⁴ A recent publication, partially driven by efforts from the FH Foundation, demonstrated that the confluence of factors discussed above resulted in denial of access to deserving patients, which in turn was associated with a significant increase in cardiovascular events in patients with known atherosclerotic CVD who failed to gain access to PCSK9 therapy compared with those who did.¹⁵ Furthermore, minority patients and those with less education and wealth were more likely to be denied access or to give up when confronted with the maze of prior authorization.

Simple calculations imply that hundreds of thousands of Americans have an indication for a PCSK9 inhibitor. Given the degree of risk reduction seen in the clinical trials and the underlying event rates among people with a previous cardiovascular event, many deaths, nonfatal myocardial infarctions, or nonfatal strokes could have been prevented with wider access to these drugs. However, because cardiovascular events emanate from multiple risk factors and other effective treatments remain underused, there is no smoking gun that has generated a public outcry. Indeed, the balanced dysfunction of our national health system has enabled each sector to blame the others, and although some progress is being made, the problem has not been addressed adequately. This not only affects patients today but also has further reinforced a decline in investment in new cardiovascular therapies. If investors see that even proven therapies are not used, investments will flow to other therapeutic areas that offer a greater return on investment. Although we should redouble our efforts to support the use of low-cost medical and behavioral interventions, there is no doubt that many people will continue to have LDL-C levels that confer increased risk despite more aggressive secondary prevention efforts.

Nevertheless, the elegant science of identifying a target through the use of human genetic epidemiology, refining a therapeutic class of molecules, and conducting complex and definitive human trials stands in stark contrast to the arcane, irrational pricing and implementation of PCSK9 inhibitor therapy. It is difficult to find any sector within the system that did its job of acting on the basis of these data well. In an ideal system, trial results would produce an evaluation of the benefit and risk that would enable an accurate calculation of the value of the treatment, which in turn would enable the therapy to be priced according to the measurement of clinical outcome improvement and associated costs. The relevant trial population would be matched with electronic health record data to identify candidates for treatment in clinical practices and health systems—in this case, patients with a prior cardiovascular event and elevated LDL-C even after lifestyle modification efforts and use of a statin plus ezetimibe or patients with a documented statin intolerance. These candidates would be evaluated, taking into account the full clinical context, and if all other factors checked out, they would be offered the opportunity to add a PCSK9 inhibitor without a financially toxic copayment.

These drugs are not amenable to a value-based pricing approach based on a therapeutic response in the individual patient because the vast majority of people will have a reduction in LDL-C without toxicity. Instead, the value of the treatment in a population could be modeled to provide an expected clinical outcome profile of the relevant population that could be compared with actual results.

As I was writing this perspective, the price of 1 PCSK9 antibody was dropped, and the other followed suit.¹⁶ New clinical practice guidelines¹⁷ have recommended PCSK9 inhibitors as a Class IIa recommendation despite data from 2 large randomized clinical outcomes trials showing benefit. Furthermore, a new class of PCSK9 drugs using antisense technology had positive results in initial clinical trials, potentially offering the same benefit for a much lower cost.¹⁸ But for the present, when a patient dies suddenly or arrives at the hospital with a stroke or myocardial infarction and has an LDL-C measurement of >100 mg/dL, people will not talk about the absence of adequate LDL-C–lowering therapy as a medical error by the doctor, an administrative error of the health system or insurance company, a profit-taking error of the pharmaceutical company for setting the price too high, or a failure of advocacy. The blame is balanced, but the result is the same: a tragedy that could have been prevented had the “elephants” figured out how to work together on behalf of the people they should be serving.

Dr Califf sits on the corporate board for Cytokinetics and is board chair for the People-Centered Research Foundation. He receives personal fees for consulting from Merck, Amgen, Biogen, Genentech, Eli Lilly, and Boehringer Ingelheim. He is also employed as an advisor by Verily Life Sciences (Alphabet).

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

https://www.ahajournals.org/journal/circ

大象战斗时，是草在受苦。

—非洲谚语

预防心血管疾病（CVD）和复发性心血管事件的基本策略包括降低低密度脂蛋白胆固醇（LDL-C）的水平，控制血压，预防和治疗糖尿病，以及避免和戒烟，健康饮食，并定期运动。尽管全球在降低风险因素的实施方面取得了数十年的进展，但进展已停滞不前，而且在许多以收入较低和教育水平较低为特征的地区，近期风险呈上升趋势。^1个在美国，由于改变常见危险因素的收益受到侵蚀而导致心脏代谢疾病的显着增加，再加上阿片类药物的过量服用和自杀率上升，导致平均预期寿命连续4年下降。^2个

我在解决这个主题时存在重大利益冲突。作为美国食品和药物管理局的前任专员，我监管降低LDL-C的药物。我还进行了临床试验，为制药公司提供咨询服务，实践了心血管医学，并担任大型学术医学中心及其卫生系统的机构官员，目前我在一家对CVD的预防和治疗感兴趣的公司工作。因此，应根据这些相互作用，事先表达的信念和财务冲突来考虑我​​对这个问题的看法和评论。

尽管应尝试通过饮食和行为方式降低LDL-C，但结果适中，而且对大多数患者而言，间隔较长，尽管采取了行为干预措施，但仍只能部分维持可持续性。他汀类药物是一种防止肝脏产生胆固醇的药物，它可以大大降低LDL-C和心血管事件，包括死亡，中风，心肌梗塞和其他血管疾病后遗症。但是，在他汀类药物广泛使用的第一个十年中，针对药物的实质性犬儒主义加剧了不确定性，最终限制了它们在临床实践中的使用。分析显示，当大众媒体上出现有关他汀类药物的负面报道时，在国家中，他汀类药物的使用减少，心血管事件和死亡的相关增加。³在大量人群中进行的多次盲法随机试验证实他汀类药物在降低心血管事件发生率方面具有重大益处后，他汀类药物最终获得了重磅炸弹状态，特别是对于已经发生此类事件的人。然而，不幸的是，尽管使用他汀类药物并在饮食调整中进行了真诚的努力，但由于LDL-C水平升高，许多人仍处于发生心血管事件的风险中。

甚至具有先前被认为LDL-C水平正常但复发性CVD的高残留风险的个体也可从脂质进一步降低中受益。IMPROVE-IT试验（改善的结果减少：Vytorin功效国际试验）表明，将胆固醇吸收抑制剂依泽替米贝添加到高强度他汀类药物疗法中后，可以减少心血管事件，尽管程度适中。⁴尽管尚未评估依泽替米贝在一级预防中的使用，但其在二级预防中的作用与基于他汀类药物作用的预测完全一致：LDL-C的少量降低导致心血管事件的少量降低。现在，有多种通用版本的依泽替米贝可用，其价格已大幅下降，并且与减少事件的适度价值相称。

最近，科学探索力导致了前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）抑制剂的开发。在短期内，流行病学研究中与较低的低密度脂蛋白水平和较低的心血管事件发生率相关的人类遗传多态性被转换为多个临床前水平的功能模型，从而能够进行靶标鉴定和治疗分子的开发。在开发PCSK9抑制剂的竞赛中获胜的公司迅速发展，并因证明LDL-C水平显着降低而没有任何严重的毒性，而被批准在有限的人群中销售其药物。在获得市场批准之前，开展了大规模的临床结果试验，以评估这些药物对重大心血管事件的影响并确定可能的毒性。这些试验现在在该类别的几种药物获得市场认可后报告了其结果，证明了心血管事件的减少与基于他汀类药物和依泽替米贝试验的预测一致。⁵

尽管PCSK9药物evolocumab的2017年FOURIER试验（在具有较高风险的受试者中进行PCSK9抑制的进一步心血管结果研究）发现心血管事件的减少在LDL-C降低的预期范围内，但并未观察到死亡率显着下降。⁶对此发现的原因进行了辩论；但是，该试验缺乏将死亡率视为孤立终点的统计能力，并且由于数据监测委员会观察到的具有临床意义的重要非致命事件的确定减少，因此该试验被提前终止。

相比之下，使用PCSK9药物alirocumab的ODYSSEY OUTOUTES试验（急性冠脉综合征在急性冠脉综合征治疗后的评估）的随访时间更长，并且显示出非常相似的结果，不同之处在于该试验还显示出死亡。⁷第三种PCSK9抗体bococizumab在阶段3中失败，因为抗体形成导致的作用随时间推移而减弱。

来自2项开创性试验的合并数据构成了丰富的资源，可用于根据潜在风险来计算PCSK9抑制剂的影响。这些相同的数据还使我们能够通过独立地减少心血管事件来计算临床护理的总体成本降低，并在与价格信息结合使用时计算出价值方程。尽管导致PCSK9上市许可的初始数据仅包括对事件影响的模型估计，但当前广泛的结果数据为计算PCSK9治疗的价值（定义为每单位收益的成本，包括生存，预防非致命性疾病）提供了极好的基础。事件，并降低与这些非致命事件相关的成本。

由于降低LDL-C并不能消除所有心血管事件，并且由于生活方式的改变和非专利药物的组合可以降低总风险，因此在考虑使用PCSK9抑制剂之前，有充分的理由推荐这些措施。尽管如此，仍有大量LDL-C水平高于所需范围的美国人发生重大心血管事件，可以通过适当使用PCSK9抑制剂和其他有效疗法来预防。现在，这反映在美国心脏病学会/美国心脏协会胆固醇指南的最新版本中，该指南建议在他汀类药物治疗中添加依泽替米贝，如果LDL-C水平仍然很高，则为患有动脉粥样硬化性CVD的高危成年人添加PCSK9抑制剂。

尽管有这些一致的事实，但PCSK9抑制剂的吸收缓慢且不均衡。在美国和世界范围内，大量人群的LDL-C升高，使他们处于复发性心血管事件的风险中。尽管这些人中的大多数还没有遵守所有其他有效的干预措施，但是即使在采取了这些措施之后，美国仍有数百万人无疑将有资格使用PCSK9抑制剂。但是，目前只有一小部分正在使用PCSK9药物进行治疗。

这告诉我们关于美国临床生态系统以及该系统中药物使用情况的哪些信息？它告诉我们，至少在某种程度上，系统性功能障碍反映了困扰美国医疗机构的普遍问题：在一个分散的系统中，所有部门都盈利，每个部门几乎没有动力自行改变。为这篇文章提供题词的谚语是一个隐喻，说明了当强大而强大的利益相互竞争，最终损害了整个生态系统中几乎没有力量的患者时会发生什么。在这里，我研究了在PCSK9故事中导致这种动态的关键因素。

The US pricing model for patented medicines during their period of exclusivity is broadly agreed to be opaque and not configured to optimize clinical outcomes for patients. In that light, the initial prices charged by pharmaceutical companies for PCSK9 inhibitors seemed unreasonable, particularly given the absence of proven reduction in cardiovascular events when they first came to market. These high prices unleashed a torrent of criticism and articles that made various claims about cost-effectiveness. European and US technology evaluators panned the pricing, concluding that it yielded cost-effectiveness estimates outside of the desirable range.^8–10

尽管提供了各种解释，但是仍然不清楚究竟是如何首先做出这些初始定价决定的。从根本上讲，当一种新分子对患者的死亡或重大临床结局产生影响时，合理的价格是多少？如果没有凭经验确定死亡率，但是可以防止发生中风和心肌梗塞等严重事件，那么在不导致广泛拒绝使用新疗法的情况下，奖励重要药物开发的合理价格是多少？看来，美国的主要定价方案是基于对市场承受能力的一种估计，这是一种良好的消费产品战略，但提出了关于以不同方式获得挽救生命或防止毁灭性恶化的疗法的伦理学的问题。处于功能状态。

专业医疗组织对PCSK9药物的出现感到兴奋和严重怀疑。PCSK9抗体试验中的概念验证表明，通过这种机制降低LDL-C水平是有益的，并且观察到的降低与他汀和依泽替米贝试验产生的可重复计算相一致。^5,11这些发现增强了因“低密度脂蛋白假说”而振奋的领导者的信心。但是，越来越多的制药行业学术评论家对此表示沉重的印象，他们声称价格太高，患者的生存率并没有得到最初的改善，从而为那些不愿改变执业方式或吸收费用的专业人士提供了保障。增加。

卫生系统几乎普遍认为PCSK9药物的价格过高。对PCSK9临床试验及其结果的大量批评为设计或容忍难以开具PCSK9抑制剂处方的系统的管理员和实践领导者提供了理由。¹²尽管无处不在的电子健康记录以及相关的数据仓库和数据湖可帮助识别符合预测益处的资料的患者，但几乎没有卫生系统试图主动识别合适的患者，主流医学也没有为此要求积极的计划。

简而言之，现在绝大多数美国人都从带有数字数据存储库的系统中获得医疗保健，该系统应该能够快速识别将受益于行之有效的治疗方法的人们。当没有证据表明这样做可以使患者受益时，此类系统同样可以很好地防止患者使用昂贵的疗法。幼稚的人可能会认为卫生系统有义务使用其数字基础设施以系统的方式改善主要死亡原因的结果，但这并没有发生。尽管就健康系统利用信息力量改善结果的能力而言，PCSK9抑制剂的作用可能不如他汀类药物，血压，戒烟和控制糖尿病重要，

随着PCSK9药物进入市场，药品福利管理者与卫生系统进行了协商，并制定了复杂的，不透明的使用管理程序。有趣的是，药品收益管理者的角色是如此复杂，以至于专家们对于净收益是降低成本还是增加成本持不同意见。原因是拜占庭式的系统，在该系统中，通过回扣系统，费用不断提高，价格降低了，[ ^13]导致人们怀疑药品福利经理人故意将价格保持在较高水平，因为他们的利润部分是由于清单价格与议定价格之间的差异而产生的。对于PCSK9药物，显然繁琐的事前授权程序（使医生不得不打六打以上的电话）显然是在耗尽医生应对系统的能力，而高额共付费用却使患者望而却步。¹²结果，在接受PCSK9处方的患者中，不到3分之1接受过该疗法。¹²

除了FH（家族性高胆固醇血症）基金会以外，患者倡导团体起初没有参与竞争。这与癌症和罕见病的倡导形成鲜明对比，新药引起了极大的兴奋，并给拒绝付款或限制相关患者就诊的人带来了名誉风险。美国心脏协会和美国心脏病学院对支持PCSK9s的科学以及该药的已证实的益处的认可默默无闻，并且在宣传方面并不积极。

但是，随着时间的流逝，代表家族性高胆固醇血症家庭的患者群体通过公开“拒绝”拒绝治疗取得了巨大的成功，加大了他们的努力。¹⁴最近的出版物，部分由FH基金会的努力推动，表明上述因素的融合导致拒绝获得应得的患者，这反过来与已知动脉粥样硬化CVD患者的心血管事件显着增加有关，与那些人相比，没有获得PCSK9治疗的机会。¹⁵此外，少数族裔患者以及教育程度和财富较少的患者在面临事先授权的迷宫时，更容易被拒绝访问或放弃。

简单的计算就意味着成千上万的美国人有PCSK9抑制剂的适应症。考虑到在临床试验中发现的降低风险的程度以及先前有心血管事件的人群的潜在事件发生率，可以通过更广泛地使用这些药物来预防许多死亡，非致命性心肌梗塞或非致命性中风。但是，由于心血管事件是由多种危险因素引起的，而其他有效的治疗方法仍未得到充分利用，因此没有引起公众强烈抗议的吸烟枪。确实，我们国家卫生系统的平衡失调已经使每个部门都可以责备其他部门，尽管正在取得一些进展，但尚未充分解决该问题。这不仅影响当今的患者，而且进一步加剧了对新的心血管疗法的投资下降。如果投资者发现甚至没有使用经过验证的疗法，投资将流向其他可带来更大投资回报的治疗领域。尽管我们应该加倍努力以支持使用低成本的医学和行为干预措施，但是毫无疑问，尽管人们采取了更加积极的二级预防措施，许多人仍将继续拥有低密度脂蛋白胆固醇水平，这会增加患病风险。

然而，通过使用人类遗传流行病学来确定目标，完善分子的治疗类别以及进行复杂而确定的人体试验的优雅科学与PCSK9抑制剂的神秘，不合理的定价和实施形成了鲜明的对比。很难在系统中找到任何能够根据这些数据很好地完成工作的部门。在理想的系统中，试验结果将对收益和风险进行评估，从而能够准确计算出治疗的价值，从而使治疗能够根据临床结果改善和相关费用的定价进行定价。相关的试验人群将与电子健康记录数据相匹配，以识别在临床实践和卫生系统中治疗的候选人-在这种情况下，即使经过改变生活方式和使用他汀类药物后，先前有心血管事件和LDL-C升高的患者依泽替米贝或他汀类药物不耐受的患者。将对这些候选药物进行评估，并考虑到整个临床情况，如果所有其他因素都被检查出，他们将有机会添加PCSK9抑制剂而无需承担有毒的共付额。

这些药物不适合基于基于个体患者治疗反应的基于价值的定价方法，因为绝大多数人的LDL-C降低而无毒性。取而代之的是，可以对人群中治疗的价值进行建模，以提供相关人群的预期临床结果概况，并将其与实际结果进行比较。

当我写这个观点时，一种PCSK9抗体的价格下降了，而另一种也效仿了。¹⁶新的临床实践指南¹⁷推荐PCSK9抑制剂作为IIa类推荐药物，尽管来自2项大型随机临床结果试验的数据显示获益。此外，使用反义技术的新型PCSK9药物在初步临床试验中取得了积极成果，可能以更低的成本提供相同的益处。^18岁但是就目前而言，当患者突然死亡或中风或心肌梗塞而到达医院且LDL-C值> 100 mg / dL时，人们不会谈论缺乏适当的降低LDL-C的疗法如医生的医疗错误，卫生系统或保险公司的行政错误，制药公司因价格过高而牟利的错误或提倡失败。责任是平衡的，但结果是一样的：如果“大象”想出了如何代表他们所服务的人民​​一起工作，那么本来可以避免的悲剧。

Califf博士是细胞动力学的公司董事会成员，也是“以人为本”研究基金会的董事会主席。他从默克公司，安进公司，Biogen公司，Genentech公司，礼来公司和勃林格殷格翰公司获得咨询服务的个人费用。他还被Verily Life Sciences（Alphabet）聘为顾问。

本文表达的观点不一定是编辑者或美国心脏协会的观点。

https://www.ahajournals.org/journal/circ