按照新版胆固醇指南 他汀使用者将增1300万

《新英格兰医学杂志》上发表的一项研究显示，假如严格遵循新版基于风险的美国心脏病学会-美国心脏协会(ACC-AHA)胆固醇管理指南，符合他汀类药物治疗适应证的成年患者将增加近1300万人。

主要作者、杜克大学杜克临床研究所的Michael J. Pencina博士指出，在增加的这1300万患者中，大多数为没有心血管疾病的老年人。


Eric Peterson博士

研究人员使用了3,773名参加2005~2010年全国健康与营养调查(NHANES)、年龄40~75岁的成年人的空腹血脂数据，以估算按照新指南应当接受他汀类药物治疗的患者数量，并与按照2007年国家胆固醇教育计划ATP Ⅲ指南应当接受他汀类药物治疗的患者数量进行比较。

将这一结果外推到年龄40~75岁的美国成人（1.154亿人），研究者发现按照新版指南，会新增1440万需接受他汀类药物治疗的成人，而在按照原有指南应接受他汀类药物治疗的成人中，大约160万人根据新版指南将不再符合治疗适应证，即适宜接受他汀类药物治疗的成人总数将由4320万人（38%）增至5600万人（49%）（N. Engl. J. Med. 2014 March 19 [doi: 10.1056/NEJMoa1315665]）。

在净增加的1280万适宜接受他汀类药物治疗的成人中，1040万人并无心血管疾病，840万人的年龄介于60~75岁；在年龄60~75岁且没有心血管疾病的成人中，适宜接受他汀类药物治疗的比例将分别从30%增加到87%（男性）和从21%增加到54%（女性）。

“按照ACC-AHA新版指南新增加的符合他汀类药物治疗适应证的成年人的中位年龄为63.4岁，其中61.7%为男性。这些成人的LDL胆固醇中位水平为105.2 mg/dl。根据新版指南，所有亚组中符合他汀类药物治疗适应证的成人数量均会增加。”

增长最明显的将是10年心血管疾病风险提示需要接受一级预防的人群（根据新版指南为1510万人，而根据ATP Ⅲ指南为690万人）。

“此外，240万名患有心血管疾病但LDL胆固醇水平低于100 mg/dl的成人，根据ATP III指南不宜接受他汀类药物治疗，而根据ACC-AHA新版指南则适宜治疗。最后，由于LDL胆固醇治疗阈值从100 mg/dl降至70 mg/dl，适宜接受他汀类药物治疗的糖尿病患者数量将从450万人增加到670万人。”

根据ATP Ⅲ指南，已确诊心血管疾病或糖尿病且LDL胆固醇水平≥100 mg/dl的患者适宜接受他汀类药物治疗。该指南还建议，综合考虑LDL胆固醇水平和10年冠心病风险以判断是否采用他汀类药物进行一级预防。

ACC-AHA新版指南与ATP Ⅲ指南存在本质区别，前者扩大了治疗适应证，建议所有心血管疾病成年患者无论LDL胆固醇水平如何均应接受治疗；并建议所有LDL胆固醇水平≥70 mg/dl且患有糖尿病或10年心血管疾病风险≥7.5%（基于新的汇总队列公式计算）的所有人接受他汀类药物治疗。


Donald Lloyd-Jones博士

“与中青年人群（40~59岁）相比，新版指南的建议对老年人群（60~75岁）的影响更大。尽管无心血管疾病的中青年人中有多达30%将符合他汀类药物一级预防适应证，但这一比例在老年人中更是高达77%。这一差异可能在一定程度上与新的汇总队列公式将卒中纳入到预防目标中有关。”由于心血管疾病的患病率随着年龄增加而显著上升，老年人中适宜接受他汀类药物治疗者的比例更高可能是合理的。“还需要进一步研究以确定中青年人是否也需要更积极的预防策略。”

尽管受到多种因素的限制，例如将来自3,773名NHANES受试者的数据外推至1.154亿美国成人，以及不能准确地量化分析新旧指南对目前正在接受降脂治疗的患者的影响（因为不清楚为何开始治疗），但上述结果仍然提示，对新版指南的应用需要个体化。

该研究的主要作者、杜克大学的Eric D. Peterson博士指出，新版指南“将风险视为治疗患者的主要原因”。然而，尚无足够证据表明这种方法是否适用于老年人。“我不想说根据新版指南将会过度治疗这些患者，但我们确实需要更多的数据。”相反，新版指南可能导致血脂水平高的年轻患者治疗不足。

Peterson博士指出：“这是一种可怕的现象。一名10年心血管疾病风险相对较低而血脂水平高的年轻人，按照旧版指南不需要接受治疗，尽管他/她实际上很可能最终会发生心血管疾病。这是一项很好的研究，它告诉我们应当治疗这类患者，即使指南并不推荐这样做。假如我们严格遵循指南，我们就将会对年轻患者治疗不足。”

重要的是，新版指南并不是“法律”。“显然，我们现在需要对患者进行某种程度的个体化治疗。”

ACC-AHA指南联合主席、西北大学Feinberg医学院预防医学系主任Donald M. Lloyd-Jones博士表示：“我同意Pencina博士、Peterson博士及其同事开展的细致分析。这些研究结果与我们在指南中报告的对NHANES数据的分析结果一致。”

值得注意的是，基于ATP Ⅲ指南和ACC-AHA指南的估计值之间的差异，主要是源于后者采用了更低的治疗阈值，其支持证据来自新近开展的一级预防随机临床试验。

“作者们已经意识到，他们报告的是对他汀类药物治疗潜在适用人群扩大的最大估计值，因为指南提出的建议是临床医生和患者应将风险计算公式作为风险讨论的出发点，而并非直接授权开具他汀类药物处方。”

此外，上述结果“反驳了数月前媒体上的大量危言耸听之词，即新版指南将使7千万~1亿美国人接受他汀类药物治疗”。

“每3名美国人中就有1人将死于可预防的或可延缓的心血管事件，超过一半会在去世前发生主要血管事件，推荐半数美国成人考虑他汀类药物治疗的循证指南似乎是正确的。此外，我们目前建议约7千万美国人接受降压治疗，这样看来，建议5千万人考虑接受他汀类药物治疗似乎也是正确的。”

这项研究获得了美国杜克临床研究所和M. Jean de Granpre and Louis and Sylvia Vogel津贴的资助。Pencina博士报告称接受了由麦克吉尔大学医学部和雅培生命公司提供的研究经费（与本项研究无关）。Peterson博士报告称接受了礼来公司的资助，以及杨森公司和勃林格殷格翰公司的津贴支持和/或个人经费。其余作者报告称无相关利益冲突。

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By: SHARON WORCESTER, Cardiology News Digital Network

Strict adherence to the new risk-based American College of Cardiology–American Heart Association guidelines for managing cholesterol would increase the number of adults eligible for statin therapy by nearly 13 million, a study suggests.

Most of the increase would be among older adults without cardiovascular disease, Michael J. Pencina, Ph.D., of the Duke Clinical Research Institute of Duke University, Durham, N.C., and his colleagues reported online March 19 in the New England Journal of Medicine.

The investigators used fasting data from 3,773 adults aged 40-75 years who participated in the National Health and Nutrition Examination Survey (NHANES) of 2005-2010 to estimate the number of individuals for whom statin therapy would be recommended under the new guidelines, published in November 2013, compared with the previously recommended 2007 guidelines from the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program.

After extrapolating the results to the estimated population of U.S. adults aged 40-75 years (115.4 million adults), they determined that 14.4 million adults would be newly eligible for statin therapy based on the new guidelines, and that 1.6 million previously eligible adults would become ineligible under the new guidelines, for a net increase in the number of adults receiving or eligible for statin therapy from 43.2 million (38%) to 56.0 million (49%), the investigators said (N. Engl. J. Med. 2014 March 19 [doi: 10.1056/NEJMoa1315665]).

Of the 12.8 million additional eligible adults, 10.4 million would be individuals without existing cardiovascular disease, and 8.4 million of those would be aged 60-75 years; among the 60- to 75-year-olds without cardiovascular disease, the percentage eligible would increase from 30% to 87% for men, and from 21% to 54% for women.

"The median age of adults who would be newly eligible for statin therapy under the new ACC-AHA guidelines would be 63.4 years, and 61.7% would be men. The median LDL cholesterol level for these adults is 105.2 mg per deciliter," the investigators wrote, adding that the new guidelines increase the estimated number of adults who would be eligible across all categories.

The largest increase would occur among adults who have an indication for primary prevention on the basis of their 10-year risk of cardiovascular disease (15.1 million by the new guidelines vs. 6.9 million by ATP III), they said.

"Furthermore, 2.4 million adults with prevalent cardiovascular disease and LDL cholesterol levels of less than 100 mg per deciliter who would not be eligible for statin therapy according to the ATP III guidelines would be eligible under the new ACC-AHA guidelines. Finally, the number of adults with diabetes who are eligible for statin therapy would increase from 4.5 million to 6.7 million as a result of the lowering of the threshold for LDL cholesterol treatment from 100 to 70 mg per deciliter," the investigators wrote.

According to the ATP III guidelines, patients with established cardiovascular disease or diabetes and LDL cholesterol levels of 100 mg/dL or higher were eligible for statin therapy. Those guidelines also recommended statins for primary prevention in patients on the basis of a combined assessment of LDL cholesterol and a 10-year risk of coronary heart disease.

The new ACC-AHA guidelines differ substantially from the ATP III guidelines in that they expand the treatment recommendation to all adults with known cardiovascular disease, regardless of LDL cholesterol level, and for primary prevention they recommend statin therapy for all those with an LDL cholesterol level of 70 mg/dL or higher and who also have diabetes or a 10-year risk of cardiovascular disease of 7.5% or greater based on new pooled-cohort equations.

"These new treatment recommendations have a larger effect in the older age group (60 to 75 years) than in the younger age group (40 to 59 years). Although up to 30% of adults in the younger age group without cardiovascular disease would be eligible for statin therapy for primary prevention, more than 77% of those in the older age group would be eligible. This difference might be partially explained by the addition of stroke to coronary heart disease as a target for prevention in the new pooled-cohort equations," they wrote. Because the prevalence of cardiovascular disease rises markedly with age, the large proportion of older adults who would be eligible for statin therapy may be justifiable, they added.

"Further research is required to determine whether more aggressive preventive strategies are needed for younger adults," they said.

Though limited by a number of factors, such as the extrapolation of data from 3,773 NHANES participants to 115.4 million U.S. adults, and by an inability to accurately quantify the effects of the new and old guidelines on patients currently receiving lipid-lowering therapy (since it was unclear why therapy was initiated), the findings nonetheless suggest a need for personalization with respect to applying the new guidelines.

The new guidelines "treat risk as the predominant reason for treating patients," according to one of the study’s lead authors, Dr. Eric D. Peterson of Duke University.

However, there is a paucity of data on the whether this approach works for older adults, Dr. Peterson said in an interview.

"I’m not willing to say we will be overtreating these patients [based on the new guidelines], but we need more data; this is a pretty big leap," he said.

Conversely, the new guidelines could lead to undertreatment of younger patients with high lipid levels, he added.

"This is kind of frightening," Dr. Peterson said, explaining that a younger patient who appears to have a relatively low 10-year risk of developing cardiovascular disease, but who has high lipid levels, would not be recommended for intervention – even though such a patient has a high likelihood of eventually developing cardiovascular disease.

"There is good research saying we should treat these patients, but these guidelines don’t recommend that. If we strictly follow the guidelines, we will undertreat younger patients," he said.

It is important to remember that the new guidelines are not "the letter of law," but rather are guides.

"Some degree of personalization for the patient in front of us is definitely needed right now," he said.

Dr. Donald M. Lloyd-Jones, cochair of the ACC-AHA guidelines, said he "agrees with the careful analysis" by Dr. Pencina, Dr. Peterson, and their colleagues.

"These findings are consistent with the analyses we reported in the guideline documents using NHANES data," said Dr. Lloyd-Jones, senior associate dean and professor and chair of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago.

Of note, the majority of the difference between the estimates based on the ATP III guidelines and the ACC-AHA guidelines is due to the lower threshold for consideration of treatment, which was derived directly from the evidence base from newer primary-prevention randomized clinical trials, he said.

"The authors recognized that the reported estimate is the maximum estimate of the increase in the number of people potentially eligible for statin therapy, because the guideline recommendation is for the clinician and patient to use the risk equations as the starting point for a risk discussion, not to mandate a statin prescription," he said.

Additionally, the results "refute the alarmist claims that we saw from a number of commentators in the media a few months ago that 70-100 million Americans would be put on statin therapy as a result of the new guidelines," Dr. Lloyd-Jones said.

"With one in three Americans dying of a preventable or postponable cardiovascular event, and more than half experiencing a major vascular event before they die, evidence-based guidelines that recommend that statins be considered for about half of American adults seem about right. Furthermore, we currently recommend that about 70 million Americans be treated for hypertension, so recommending that about 50 million should be considered for statins also seems about right," he said.

This study was funded by the Duke Clinical Research Institute and by grants from M. Jean de Granpre and Louis and Sylvia Vogel. Dr. Pencina reported receiving research fees (unrelated to this study) from McGill University Health Center and AbbVie. Dr. Peterson reported receiving grants from Eli Lilly and grant support and/or personal fees from Janssen and Boehringer Ingelheim. The remaining authors reported having nothing to disclose.