原创 毛毛弟 一起学科研 2022-05-02 17:00
Frequent moderate to vigorous physical activity is an important strategy in prevention of cardiovascular-specific and all-cause mortality, and is graded as “strong” evidence unlikely to be changed with new evidence by Health and Human Services. Exercise appears to be strongly associated with decreases in mortality risk at up to 5 times the minimum-recommended weekly exercise dose (HR: 0.58), although evidence from the Copenhagen City Heart Study suggests that extreme exercise routines beyond this threshold may attenuate these benefits, and a more recent review evaluated risks and benefits of extreme exercise. Thus, the relationship between exercise and mortality risk is nonlinear: more exercise appears to correspond to even greater reductions in mortality risk in cohort meta-analyses, within reason. This effect, as demonstrated in these prior studies, is comparable in magnitude across modality of exercise (ie, biking vs walking), race, sex, age, and weight. The association is also robust among participants living in countries differing in socioeconomic class, an important indicator that exercise does not benefit only the wealthy.
经常进行中等强度的体力活动是预防心血管疾病特异性和全因死亡率的重要策略，被卫生与公众服务部评为“强”证据，不太可能因新证据而改变。尽管哥本哈根市心脏研究的证据表明，超过这个阈值的极端运动方式可能会削弱这些益处，但运动似乎与死亡风险的降低密切相关，而最近的一项综述评估了极端运动的风险和益处。因此，运动和死亡风险之间的关系是非线性的：在队列Meta分析中，在合理的范围内，更多的运动似乎对应着更大的死亡风险的降低。正如这些先前的研究所证明的那样，这种效应在不同的运动方式（即骑自行车与步行）、种族、性别、年龄和体重之间的程度是相当的。这种关联在生活在不同社会经济阶层的国家的参与者中也是稳健的，这是一个重要的指标，表明运动并不只对富人有利。
Because there is such strong evidence for the relationship of exercise with cardiovascular disease and mortality, estimation of the effect of exercise is primarily abstracted from cohort studies, rather than randomized controlled trials. As such, numerous selection biases are challenging to mitigate in generating reliable point estimates. Important confounders include other health behaviors associated with both exercise and mortality, such as chronic disease burden, dietary intake, medication adherence, and abstinence from maladaptive behaviors like tobacco and alcohol abuse. Further, these studies frequently rely on single or mean survey responses to quantify physical activity; participants who are followed longitudinally may change their activity levels without being accurately recategorized for analysis. Multivariable analysis with propensity score matching is frequently used to mitigate bias from known confounders in these studies, but little can be done to mitigate misclassification of exercise activity levels over time if there are no or few repeated surveys.
由于有如此强有力的证据表明运动与心血管疾病和死亡率的关系，对运动效果的估计主要来自队列研究，而不是随机对照试验。因此，在产生可靠的点估计时，许多选择偏倚是难以缓解的。重要的混杂因素包括与运动和死亡率相关的其他健康行为，如慢性病负担、饮食摄入、药物依从性以及戒除烟草和酒精滥用等不良行为。此外，这些研究经常依靠单一的或平均的调查反应来量化体力活动；长期跟踪的参与者可能会改变他们的活动水平，而不被准确地重新分类分析。在这些研究中，经常使用倾向性评分匹配的多变量分析来减轻已知混杂因素的偏倚，但如果没有或很少有重复调查，就无法减轻运动量水平随时间变化的错误分类。
Meta-analysis, or the synthesis of evidence gathered from multiple studies of the same relationship, is a powerful method for maximizing the reliability of available evidence in an unbiased manner. Investigators typically rely on either pooled (individual patient) data or aggregate (studylevel) data to combine evidence across studies and generate effect estimates with greater precision. Typically, the studies are weighted for metaanalysis based on their variance; studies with more patients and more precise CIs contribute more heavily to the meta-analysis estimates. Investigators may even perform network meta-analysis, which synthesizes direct evidence from within studies with indirect evidence between studies. Thus, metaanalysis and network meta-analysis are used to generate the evidentiary foundation for cardiovascular guidelines on topics ranging from drug-related adverse events to intervention efficacy. The inherent danger of these methods is that differences between studies—heterogeneity—may still bias the estimated association. Therefore, it is critical to maintain strict inclusion criteria and to perform numerous sensitivity analyses to demonstrate that the main results are robust.
Meta分析，或对从同一关系的多项研究中收集到的证据进行综合，是以无偏倚的方式最大限度地提高现有证据的可靠性的有力方法。研究者通常依靠汇集的（单个病人）数据或汇总的（研究水平）数据来综合各研究的证据，并产生具有更大精度的效应估计。通常情况下，研究是根据其方差加权进行Meta分析的；具有更多患者和更精确CI的研究对Meta分析的估计值贡献更大。研究者甚至可以进行网络Meta分析，将研究内部的直接证据与研究之间的间接证据进行综合。因此，Meta分析和网络Meta分析被用来产生心血管指南的证据基础，主题包括与药物相关的不良事件和干预疗效。这些方法的内在危险是，研究之间的差异--异质性--仍可能使估计的关联出现偏倚。因此，保持严格的纳入标准并进行大量的敏感性分析以证明主要结果是稳健的，这一点至关重要。
In this issue of the Journal of the American College of Cardiology, Gonzalez-Jaramillo et al synthesized evidence from cohort studies to estimate the effect of changes in exercise behavior on cardiovascular disease incidence and mortality in participants with established coronary heart disease. Although they did not have access to individual patient data, they used the published HRs and CIs from the included studies to estimate the effect, compared with remaining sedentary over time, of the following: 1) increasing physical activity over time; 2) decreasing physical activity over time; and 3) maintaining high physical activity levels over time on mortality. They searched for all cohort studies that contained at least 2 measures for physical activity over time and estimated the effect on cardiovascular and/or all-cause mortality. Although their search criteria allowed for both retrospective and prospective cohort designs, results yielded exclusively prospective cohort studies. Mixing retrospective and prospective study designs is potentially dangerous, as this is only reliable when there is strong certainty that the measured exposures are not different across study designs. The authors used random effects weighting, which is appropriate where the assumption is that the exposures across the study are not identical.
在本期的《美国心脏病学院杂志》中，Gonzalez-Jaramillo等人综合了队列研究的证据，以估计运动行为的改变对已患冠心病的参与者的心血管疾病发病率和死亡率的影响。尽管他们没有获得单个病人的数据，但他们使用所包括的研究中公布的HRs和CIs来估计与长期保持静坐相比，以下方面的影响：1）随着时间的推移增加体力活动；2）随着时间的推移减少体力活动；以及3）随着时间的推移保持高体力活动水平对死亡率的影响。他们搜索了所有的队列研究，这些研究包含了至少2个随时间变化的体力活动的措施，并估计了对心血管和/或全因死亡率的影响。尽管他们的检索标准允许回顾性和前瞻性的队列设计，但结果只得到了前瞻性的队列研究。混合回顾性和前瞻性研究设计有潜在的危险性，因为只有在非常确定测量的暴露在不同的研究设计中没有差异时，这才是可靠的。作者使用了随机效应加权，在假设整个研究的暴露不完全相同的情况下，这种方法是合适的。
After screening >12,000 published papers, the authors identified 42 cohort studies that assessed physical activity and mortality over time. Of those, only 9 included multiple measures for physical activity and all-cause mortality, and were ultimately included in the meta-analysis. Of these, 6 included cardiovascular-specific mortality, 4 were in patients who had acute CHD, and 5 were in cohorts with chronic CHD.
在筛选了超过12,000篇已发表的论文后，作者确定了42项评估体力活动和死亡率的队列研究。在这些研究中，只有9项包括了对体力活动和全因死亡率的多种测量，并最终被纳入了Meta分析。在这些研究中，有6项包括了心血管特异性死亡率，4项是在患有急性CHD的病人中，5项是在患有慢性CHD的队列中。
Findings for all-cause mortality were statistically and clinically significant: maintaining an active lifestyle was associated with a 50% reduction in all-cause mortality, participants who increased physical activity over time had a 45% reduction, and patients who decreased physical activity over time had a 20% reduction compared with those who remained sedentary. These trends were largely consistent in both the acute and chronic CHD subcohorts. The main findings were robust in sensitivity analyses, but there was substantial heterogeneity bias risk in each category: it is likely that the cohorts and exposures meaningfully differed across studies. Although this means that the reported effect may be biased, stratification by source population (studies with participants from the general population vs studies with participants from a CHD-exclusive population) drastically decreased the calculated heterogeneity bias risk scores across all categories. Findings were similar for cardiovascular disease–specific mortality: in the 6 studies (n =9,422) that reported cardiovascular mortality, there was a 51% reduction in risk for those that stayed active over time, a 37% reduction in risk for those that became more active over time, and a nonsignificant 9% reduction in risk for those that decreased physical activity over time.
对全因死亡率的研究结果具有统计学和临床学意义：保持积极的生活方式与全因死亡率减少50%有关，随着时间推移增加体力活动的参与者减少45%，而随着时间推移减少体力活动的患者与保持久坐的人相比减少20%。这些趋势在急性和慢性CHD亚群中基本一致。主要研究结果在敏感性分析中是稳健的，但在每个类别中都有大量的异质性偏倚风险：在不同的研究中，队列和暴露可能有意义的不同。虽然这意味着报告的效果可能有偏倚，但按来源人群进行分层（由普通人群参与的研究与由CHD专属人群参与的研究）大大降低了所有类别的异质性偏倚风险计算得分。对心血管疾病特异性死亡率的研究结果类似：在报告心血管死亡率的6项研究中（n =9,422），随着时间的推移保持活动的人的风险降低了51%，随着时间的推移变得更加活跃的人的风险降低了37%，随着时间的推移减少体力活动的人的风险降低了9%，但这并不显著。
The authors are to be commended for the development of this important meta-analysis. They performed numerous sensitivity analyses and subanalyses that should give the reader greater confidence in the findings as a whole. The authors also point out the limitation that unmeasured confounders that may have appeared in the follow-up periods, such as peripheral arterial disease and heart failure, may affect the association of decreased physical activity over time and mortality, and that these factors should be examined in future studies.
作者对这一重要的Meta分析的发展是值得赞扬的。他们进行了大量的敏感性分析和亚组分析，应该使读者对整个研究结果更有信心。作者还指出了一个局限性，即在随访期间可能出现的未测量的混杂因素，如外周动脉疾病和心力衰竭，可能会影响随着时间推移身体活动减少与死亡率的关联，这些因素应在未来的研究中加以研究。
What then is the impact of the study for the practicing clinician? First, it is important to recognize that there will not be any long-term randomized trials that have groups assigned to maintaining, increasing, reducing, or stopping physical activity. Thus, this meta-analysis provides the highest level of evidence generated on the long-term benefits of physical activity and survival in CHD patients. The message therefore is clear and straightforward: physical activity is extremely important for long-term outcomes in the patient with CHD! Increasing physical activity after an event is highly beneficial, and conversely, if an individual becomes inactive, much of the benefit is lost, which is supportive of the phrase “use it or lose it.” Physical activity, which ideally according to guidelines should include aerobic exercise and resistance training, should be considered a foundational therapy for patients with CHD. Cardiac rehabilitation programs have proven benefits in patients with CHD and should be used routinely. Unfortunately, they are very underutilized, and thus it is imperative that all health care providers include a history of physical activity and exercise at every visit for patients with CHD and include recommendations in the treatment plan and after-visit summary to address this critical issue.
那么，这项研究对实践中的临床医生有什么影响？首先，重要的是要认识到，不会有任何长期的随机试验，将小组分配到维持、增加、减少或停止体力活动。因此，这项Meta分析提供了关于体力活动和CHD患者生存的长期益处的最高水平的证据。因此，信息是清晰而直接的：体力活动对CHD患者的长期疗效极为重要! 在事件发生后增加体力活动是非常有益的，反之，如果一个人变得不活跃，大部分的好处就会丧失，这也是对“不使用就失去”这句话的支持。体力活动，根据指南，理想情况下应该包括有氧运动和阻力训练，应该被认为是CHD患者的基础治疗。心脏康复项目已被证明对CHD患者有好处，应常规使用。不幸的是，它们的利用率很低，因此，所有医疗服务提供者必须在CHD患者的每次就诊中包括体育活动和运动史，并在治疗计划和就诊后总结中包括建议，以解决这一关键问题。
