Jewish General Hospital and McGill University, Montreal, Quebec, Canada.
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Arthritis Rheumatol. 2021 Sep;73(9):1749-1757. doi: 10.1002/art.41710. Epub 2021 Jul 27.
The treatment of gout with allopurinol is effective at reducing urate levels and the frequency of flares. Several observational studies have shown important reductions in mortality with allopurinol use, with wide variations in results. We undertook this review to assess the extent of bias in these studies, particularly time-related biases such as immortal time bias.
We searched the literature to identify all observational studies describing the effect of allopurinol use versus nonuse on all-cause mortality.
We identified 12 observational studies, of which 3 were affected by immortal time bias and 3 by immeasurable time bias, while the remaining 6 studies avoided these time-related biases. Reductions in all-cause mortality with allopurinol use were observed among the studies with immortal time bias, with a pooled hazard ratio (HR) of death associated with allopurinol of 0.71 (95% confidence interval [95% CI] 0.50-1.01), as well as in those with immeasurable time bias (pooled HR 0.62 [95% CI 0.56-0.67]). The 6 studies that avoided these biases demonstrated a null effect of allopurinol on mortality (pooled HR 0.99 [95% CI 0.87-1.11]), though the lack of an analysis based on treatment adherence may have attenuated the effect.
Observational studies are important to provide real-world data on medication effects. The observational studies showing significantly decreased mortality with allopurinol treatment cannot be used as evidence, however, mainly due to time-related biases that tend to greatly exaggerate the potential benefit of treatments. The ALL-HEART randomized trial, which is currently underway and evaluates the effect of adding allopurinol to usual care (compared to no added treatment), will provide reliable evidence on mortality.
别嘌醇治疗痛风可有效降低尿酸水平和痛风发作频率。几项观察性研究表明，别嘌醇的使用与死亡率的显著降低有关，但结果差异很大。我们进行了这项综述，以评估这些研究中的偏倚程度，特别是与时间相关的偏倚，如不朽时间偏倚。
我们检索了文献，以确定所有描述别嘌醇使用与不使用对全因死亡率影响的观察性研究。
我们确定了 12 项观察性研究，其中 3 项受到不朽时间偏倚的影响，3 项受到不可测量时间偏倚的影响，而其余 6 项研究避免了这些与时间相关的偏倚。在有不朽时间偏倚的研究中，使用别嘌醇可降低全因死亡率，其死亡相关的总体危险比（HR）为 0.71（95%置信区间[95%CI]为 0.50-1.01），在有不可测量时间偏倚的研究中，死亡相关的总体 HR 为 0.62（95%CI 为 0.56-0.67）。这 6 项避免了这些偏倚的研究表明，别嘌醇对死亡率无影响（死亡相关的总体 HR 为 0.99[95%CI 为 0.87-1.11]），尽管缺乏基于治疗依从性的分析可能会削弱这一效果。
观察性研究对于提供药物治疗效果的真实世界数据非常重要。然而，观察性研究表明，别嘌醇治疗可显著降低死亡率，不能作为证据，主要是因为与时间相关的偏倚往往极大地夸大了治疗的潜在益处。目前正在进行的 ALL-HEART 随机试验评估了在常规治疗（与无附加治疗相比）中添加别嘌醇的效果，将提供死亡率的可靠证据。
