From the Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Epidemiology. 2020 Nov;31(6):860-871. doi: 10.1097/EDE.0000000000001256.
We examined whether the apparent association between renal cell carcinoma (RCC) and use of dihydropyridine calcium channel blockers (CCBs) was explained by confounding by indication since hypertension, the main indication for CCBs, is a risk factor for RCC.
Using Danish health registries, we conducted a nested case-control study including 7315 RCC cases during 2000-2015. We matched each case with up to 20 controls on age and sex using risk-set sampling. We estimated odds ratios (ORs) for long-term CCB use associated with RCC using conditional logistic regression. We addressed confounding by indication by (1) adjusting for hypertension severity indicators; (2) evaluating dose-response patterns; (3) examining whether other first-line anti-hypertensives were associated with RCC; and (4) using an active comparator new user design by nesting the study in new users of CCBs or angiotensin-converting enzyme inhibitors (ACEIs).
The adjusted OR for RCC associated with long-term CCB use compared to non-use was 1.76 (1.63-1.90). After we additionally adjusted for hypertension severity indicators, the OR remained elevated (OR 1.37; confidence interval [CI] 1.25, 1.49) with evidence of a dose-response pattern. Other anti-hypertensives were also associated with RCC, for example, ACEIs (OR 1.27; 95% CI = 1.16, 1.39) and thiazides (OR 1.22; 95% CI = 1.12, 1.34). In the active comparator new user design, the OR was 1.21 (95% CI = 0.95, 1.53) for use of CCBs compared with ACEIs.
In this population, confounding by indication appeared to explain at least part of the association between RCC and dihydropyridine CCBs.
我们研究了肾细胞癌（RCC）与二氢吡啶钙通道阻滞剂（CCB）使用之间的明显关联是否可以通过指示性混杂来解释，因为高血压是 CCB 的主要适应症，也是 RCC 的一个危险因素。
使用丹麦健康登记处，我们进行了一项嵌套病例对照研究，纳入了 2000 年至 2015 年间的 7315 例 RCC 病例。我们使用风险集抽样按年龄和性别与每个病例匹配最多 20 名对照。我们使用条件逻辑回归估计与 RCC 相关的长期 CCB 使用的比值比（OR）。我们通过以下方式解决指示性混杂问题：（1）调整高血压严重程度指标；（2）评估剂量-反应模式；（3）检查其他一线抗高血压药物是否与 RCC 相关；（4）通过将研究嵌套在 CCB 或血管紧张素转换酶抑制剂（ACEI）的新使用者中，使用活性比较器新使用者设计。
与非使用者相比，长期 CCB 使用与 RCC 相关的调整后 OR 为 1.76（1.63-1.90）。在我们进一步调整了高血压严重程度指标后，该 OR 仍然升高（OR 1.37；95%CI 1.25, 1.49），并且存在剂量-反应模式的证据。其他抗高血压药物也与 RCC 相关，例如 ACEI（OR 1.27；95%CI = 1.16, 1.39）和噻嗪类（OR 1.22；95%CI = 1.12, 1.34）。在活性比较器新使用者设计中，与 ACEI 相比，CCB 的使用 OR 为 1.21（95%CI = 0.95, 1.53）。
在该人群中，指示性混杂似乎至少部分解释了 RCC 与二氢吡啶 CCB 之间的关联。
