Lessons learned from recent cardiovascular clinical trials: Part I
Lessons learned from recent cardiovascular clinical trials: Part I
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DOI：
10.1161/01.cir.0000023219.51483.66
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发表时间：
2002-08-06
期刊：
影响因子：
37.8
通讯作者：
Califf, RM
中科院分区：
文献类型：
--
作者：
DeMets, DL;Califf, RM
HIV阳性患者。复合材料的有效性取决于其各个组成部分的有效性。不幸的是，在大多数情况下，潜在的代孕者没有得到充分的验证。有效的代理结果必须满足至少两个统计和逻辑标准。6首先，代孕药的变化必须能够预测相关的临床结果。第二个也是更关键的要求是，潜在的代孕者必须完全(或几乎如此)捕捉到干预对临床结果的影响(图1a)。第二个要求可能很难完全理解。在考虑替代治疗结果时，研究人员可能会为治疗想出一个简单的因果关系路径。如果这是真正的生物过程，那么测量替代品就可以测量所有的治疗效果，因此就足够了。然而，如图1b所示，许多(如果不是大多数)治疗方法有几种影响途径。这种治疗可能会改变两种途径的临床结果，尽管替代者只测量其中一种；例如，药物可能有多个结合位点。或者，治疗可能会影响与替代者正在测量的路径无关的路径上的临床结果。在这些情况下，仅测量建议的代孕物并不能反映治疗的最终临床影响。此外，拟议代孕背后的概念可能是正确的，但衡量概念可能存在缺陷。然而，拟议的代孕是这一概念的具体衡量标准，如果该衡量标准有缺陷，建议的代孕可能无效。在过去，这些标准，特别是第二个标准，并不容易达到，7，8和心血管试验中提出的替代结果衡量标准一直非常令人失望。在心律失常抑制试验(CAST)中，可能最戏剧性的替代结局失败是证明的。9这项试验测试了一类抗心律失常药物中的3种药物是否可以防止因室性早搏而有猝死风险的患者。室性心律失常被反复发现是猝死和完全心血管死亡的危险因素。结果，一类抑制心律失常的药物被开发出来，这些药物被监管机构批准用于这一适应症。心血管学界认为，由于室性心律失常预示着猝死，而且这些药物可以抑制室性心律失常，这些药物将减少猝死和总的心血管死亡。CAST在有记录的心律失常患者中测试了恩卡胺、氟卡胺和莫里西嗪。患者首先必须经历一段确定他们是否有可抑制的心律失常的前随机化“磨合期”。如果是这样的话，他们随后被随机分配到三种药物中的一种或匹配的安慰剂中。主要结果是猝死，次要结果是任何原因造成的死亡。结果令人惊讶。9，10在CAST的早期，2个ARM(恩卡胺和氟卡胺)被终止，因为积极治疗的患者的猝死和全因死亡率都有非常显著的增加。第三只手臂后来因死亡率增加而停止。10在另一个例子中，改善的心功能(由心输出量估计)被命名为慢性心力衰竭患者的替代指标。几种肌力药物被开发出来，可以改善各种心功能指标，如心输出量，这些药物后来在一系列试验中进行了测试。11-14尽管有证据表明这些药物会在短期内改善心输出量，但许多人在…
HIV-positive patients. The validity of a composite depends on the validity of its individual components. Unfortunately, potential surrogates have been inadequately validated in most cases. A valid surrogate outcome must fulfill at least 2 statistical and logical criteria. 6 First, changes in the surrogate must be predictive of the relevant clinical outcome. The second, and more critical requirement, is that a potential surrogate must fully (or nearly so) capture the effect of the intervention on the clinical outcome (Figure 1a). This second requirement can be difficult to fully appreciate. In considering surrogate outcomes, investigators might think of a simple cause-and-effect pathway for the treatment. If this were the true biological process, then measuring the surrogate would measure all of the treatment effect and would thus be adequate. Many, if not most, treatments have several effect pathways, however, as depicted in Figure 1b. The treatment may alter the clinical outcome in 2 pathways, although the surrogate measures only 1 of them; drugs, for example, may have multiple binding sites. Alternatively, a treatment may affect the clinical outcome on a pathway that is not related to the pathway the surrogate is measuring. In these cases, measuring only the proposed surrogate does not reflect the ultimate clinical impact of the therapy. In addition, the concept behind the proposed surrogate may be correct, but the measure of the concept may be flawed. However, the proposed surrogate is a specific measure of the concept and if the measure is flawed, the proposed surrogate may be invalid. In the past, these criteria, especially the second, have not been easily met, 7, 8 and proposed surrogate outcome measures in cardiovascular trials have been extremely disappointing. Perhaps the most dramatic failure of a proposed surrogate outcome was demonstrated in the Cardiac Arrhythmia Suppression Trial (CAST). 9 This trial tested whether 3 drugs in a class of antiarrhythmic drugs prevented sudden deaths in patients at risk because of premature ventricular contractions. Ventricular arrhythmias have been repeatedly found to be a risk factor for sudden death and total cardiovascular death. As a result, a class of drugs was developed that suppressed arrhythmias, and these drugs were approved for this indication by regulatory agencies. The cardiovascular community believed that because ventricular arrhythmias were predictive of sudden death and because these drugs could suppress ventricular arrhythmias, the drugs would reduce sudden death and total cardiovascular death.CAST tested encainide, flecainide, and moricizine in patients with documented arrhythmias. Patients first had to go through a prerandomization “run-in” period that determined whether they had suppressible arrhythmias. If so, they were then randomly assigned, either to one of the three drugs or to a matching placebo. The primary outcome was sudden death, and the secondary outcome was death from any cause. The results were surprising. 9, 10 Very early in CAST, 2 arms (encainide and flecainide) were terminated because of a highly significant increase in both sudden death and all-cause mortality for patients on active treatment. The third arm was later stopped because of an increase in mortality. 10 In another example, improved cardiac function (as estimated by cardiac output) was named as a surrogate in patients with chronic heart failure. Several inotropic drugs were developed that improved various heart function measures, such as cardiac output, and these were later tested in a series of trials. 11–14 Despite the demonstration that these drugs would improve cardiac output in the short term, many …