Influence of Activated Protein C Resistance on Short-Term Hospital Outcomes Following Admission for Acute Ischemic Stroke in the United States
Authors: Ajitha Salini , Adla Jala Saisree Reddy , Chennapragada Suma Sri , Dandwani Mehndi , Savani Saloni , Singh Vaishnavi , Pramudita Arcita Hanjani , Aggarwal Shruti , Aisha Fnu , Sombans Shaheen , Pekyi-Boateng Prince Kwabla , Goyal Shriya , Thevuthasan Sindhu , Ramphul Yogeshwaree , Sakthivel Hemamalini , Ramphul Kamleshun , Sharma Shivani 
Published: December 2023

Introduction: Activated protein C (APC) plays a crucial role in breaking down factor Va and VIIIa, preventing excessive blood clotting. APC resistance occurs when protein C is unable to degrade these factors, leading to a higher risk of thrombosis. This condition can be either hereditary or acquired, with the most common cause being the factor V Leiden mutation. While previous studies have indicated that APC resistance increases the likelihood of acute ischemic stroke (AIS), their specific outcomes have not been extensively studied. Our research aims to bridge this gap via a national study.

Methods: We used hospital records via the National Inpatient Sample (NIS) for our study. It consists of de-identified in-patient data, released on an annual basis by HCUP, AHRQ, and collaborating hospitals. Patients admitted with a primary diagnosis of AIS were recruited. We excluded all hospitalizations of ages &lt;18 years. The impact of APCR status on outcomes and in-hospital complications such as acute kidney injury (AKI), myocardial infarction (MI), thrombolysis, mechanical thrombectomy (MT), vasopressor use, seizures, unfavorable discharge (discharge to another center such as short-term hospital, skilled nursing facility, intermediate care facility, and another type of facility) was studied using multivariable regression analysis, while adjusting for the impact of several potential patient and hospital characteristics.

Results: Our selection criteria identified 2631890 admissions for AIS between 2016-2020, including 5910 (0.2%) patients also reporting a diagnosis of APCR (Table 1). In addition, APCR patients were younger (mean age 60.1 vs. 70.1 years, p&lt;0.01) with a lower mean Charlson Comorbidity Index (CCI) score (3.50 vs. 3.87, p&lt;0.01), and showed higher odds of a history of prior stroke (19.3% vs. 15.4%, aOR 1.482, 95% CI 1.387-1.584, p&lt;0.01). While both groups were primarily covered by Medicare (65.0% in non-APCR group and 47.3% in APCR patients), a higher proportion of patients with APCR were also covered by private insurance (33.0% vs 19%, p&lt;0.01). The APCR group also showed a higher prevalence of Whites (85.9% vs. 68.2%, p&lt;0.01). Most cases in both cohorts were treated in Urban teaching centers.

While higher prevalences of smoking(43.2% vs. 39.8%, p&lt;0.01), obesity (20.3% vs. 14.5%, p&lt;0.01), and drug abuse (4.4% vs. 2.8%, p&lt;0.01) were seen in APCR patients, they also expressed fewer cases of cirrhosis (0.3% vs. 0.7%, p&lt;0.01), diabetes (30.6% vs 39.2%, p&lt;0.01), hypertension (51.9% vs 58.2%, p&lt;0.01), chronic kidney disease (13.7% vs 18.3%, p&lt;0.01), atrial fibrillation (18.8% vs 24.9%, p&lt;0.01), and lipid disorder (53.8% vs 60.3%, p&lt;0.01).

After careful adjustments of confounders, APCR patients showed a higher use of mechanical thrombectomy (aOR 1.523, 95% CI 1.374-1.689, p&lt;0.01) and vasopressor use (aOR 1.877, 95% CI 1.435-2.455, p&lt;0.01) and also reported higher odds of seizures (aOR 1.413, 95% CI 1.265-1.578, p&lt;0.01) and unfavorable discharge (aOR 1.065, 95% CI 1.006-1.128, p=0.03). However, lower odds of acute kidney injury (aOR 0.87, 95% CI 0.794-0.952, p&lt;0.01) and death(aOR 0.708, 95% CI 0.597-0.838, p&lt;0.01) were noted. No differences in events of MI (aOR 1.161, 95% CI 0.994-1.358, p=0.06) and thrombolysis (aOR 0.94, 95% CI 0.863-1.024, p=0.159) use were seen between the two groups.

Conclusion: The study reported higher short-term outcomes, including increased use of mechanical thrombectomy and vasopressors and higher odds of seizures and unfavorable discharge in APCR patients with acute stroke. However, no similar increased odds of in-patient death, acute kidney injury, thrombolysis, and myocardial infarction were noted. While the impact of APCR on stroke recurrence has been highly debated in prior studies, our analysis provides a novel update showing an increased risk of subsequent stroke in patients with a history of stroke. Encouraging more extensive studies in a clinical setting, with larger groups of people and more extended observation periods, can provide a clearer understanding of the situation and thus improve their long-term outcomes.