From the Wolfson Centre for the Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, Wolfson Building-John Radcliffe Hospital, University of Oxford, United Kingdom.
Neurology. 2023 Aug 8;101(6):e645-e652. doi: 10.1212/WNL.0000000000207479. Epub 2023 Jun 15.
Patients with multimorbidity are underrepresented in clinical trials. Inclusion in stroke trials is often limited by exclusion based on premorbid disability, concerns about worse poststroke outcomes in acute treatment trials, and a possibly increased proportion of hemorrhagic vs ischemic stroke in prevention trials. Multimorbidity is associated with an increased mortality after stroke, but it is unclear whether this is driven by an increased stroke severity or is confounded by particular stroke subtypes or premorbid disability. We aimed to determine the independent association of multimorbidity with stroke severity taking account of these main potential confounders.
In a population-based incidence study (Oxford Vascular Study; 2002-2017), prestroke multimorbidity (Charlson Comorbidity Index [CCI]; unweighted/weighted) in all first-in-study strokes was related to postacute severity (≈24 hours; NIH Stroke Scale [NIHSS]), stroke subtype (hemorrhagic vs ischemic; Trial of Org 10172 in Acute Stroke Treatment [TOAST]), and premorbid disability (modified Rankin scale [mRS] score ≥2) using age-adjusted/sex-adjusted logistic and linear regression models and to 90-day mortality using Cox proportional hazard models.
Among 2,492 patients (mean/SD age = 74.5/13.9 years; 1,216/48.8% male; 2,160/86.7% ischemic strokes; mean/SD NIHSS = 5.7/7.1), 1,402 (56.2%) had at least 1 CCI comorbidity, and 700 (28.1%) had multimorbidity. Although multimorbidity was strongly related to premorbid mRS ≥2 (adjusted odds ratio [aOR] per CCI comorbidity 1.42, 1.31-1.54, < 0.001), and comorbidity burden was crudely associated with an increased severity of ischemic stroke (OR per comorbidity 1.12, 1.01-1.23 for NIHSS 5-9, = 0.027; 1.15, 1.06-1.26 for NIHSS ≥10; = 0.001), no association with severity remained after stratification by TOAST subtype (aOR 1.02, 0.90-1.14, = 0.78 for NIHSS 5-9 vs 0-4; 0.99, 0.91-1.07, = 0.75 for NIHSS ≥10 vs 0-4), or within any individual subtype. The proportion of intracerebral hemorrhage vs ischemic stroke was lower in patients with multimorbidity (aOR per comorbidity 0.80, 0.70-0.92, < 0.001), and multimorbidity was only weakly associated with 90-day mortality after adjustment for age, sex, severity, and premorbid disability (adjusted hazard ratio per comorbidity 1.09, 1.04-1.14, < 0.001). Results were unchanged using the weighted CCI.
Multimorbidity is common in patients with stroke and is strongly related to premorbid disability but is not independently associated with an increased ischemic stroke severity. Greater inclusion of patients with multimorbidity is unlikely therefore to undermine the effectiveness of interventions in clinical trials but would increase external validity.
患有多种合并症的患者在临床试验中代表性不足。在中风试验中，纳入常常受到限制，主要基于发病前残疾、对急性治疗试验中卒中后结局恶化的担忧，以及预防试验中出血性与缺血性卒中比例可能增加。多种合并症与卒中后死亡率增加相关，但尚不清楚这是由卒中严重程度增加驱动，还是由特定的卒中亚型或发病前残疾混杂所致。我们旨在确定多种合并症与卒中严重程度的独立关联，同时考虑这些主要潜在混杂因素。
在一项基于人群的发病研究（牛津血管研究；2002-2017 年）中，所有首发卒中患者（N = 2492）的发病前多种合并症（Charlson 合并症指数 [CCI]；未加权/加权）与发病后急性期严重程度（约 24 小时；NIH 卒中量表 [NIHSS]）、卒中亚型（出血性 vs 缺血性；急性卒中治疗组织 10172 试验 [TOAST]）和发病前残疾（改良 Rankin 量表 [mRS]评分≥2）相关，使用年龄校正/性别校正的逻辑回归和线性回归模型进行评估，并使用 Cox 比例风险模型评估 90 天死亡率。
在 2492 例患者中（平均/标准差年龄=74.5/13.9 岁；1216/48.8%为男性；2160/86.7%为缺血性卒中；平均/NIHSS 标准差=5.7/7.1），1402 例（56.2%）至少存在 1 项 CCI 合并症，700 例（28.1%）存在多种合并症。尽管多种合并症与发病前 mRS≥2 密切相关（每增加 1 项 CCI 合并症的校正优势比 [aOR] 为 1.42，1.31-1.54，<0.001），并且合并症负担与缺血性卒中严重程度的增加大致相关（NIHSS 为 5-9 时，每增加 1 项合并症的 OR 为 1.12，1.01-1.23，P=0.027；NIHSS≥10 时，OR 为 1.15，1.06-1.26，P=0.001），但在按照 TOAST 亚型分层后，与严重程度无关联（NIHSS 为 5-9 与 0-4 时，aOR 为 1.02，0.90-1.14，P=0.78；NIHSS≥10 与 0-4 时，aOR 为 0.99，0.91-1.07，P=0.75），或在任何单一亚型中，均无关联。发病时存在多种合并症的患者中，颅内出血与缺血性卒中的比例较低（每增加 1 项合并症的 aOR 为 0.80，0.70-0.92，<0.001），且在调整年龄、性别、严重程度和发病前残疾后，多种合并症与 90 天死亡率仅呈弱相关（每增加 1 项合并症的调整危险比为 1.09，1.04-1.14，<0.001）。使用加权 CCI 后，结果不变。
患有多种合并症的患者在卒中患者中很常见，且与发病前残疾密切相关，但与缺血性卒中严重程度增加无关。因此，增加多种合并症患者的纳入不太可能削弱临床试验中干预措施的有效性，但会增加外部有效性。
