A recent systematic review published in Critical Care Medicine has re-evaluated the association between angiotensin II therapy and thromboembolic events in critically ill patients. The analysis, led by Caragata et al., suggests a lack of robust evidence supporting a consistent link between angiotensin II and an increased risk of venous or arterial thromboembolism, contrasting with earlier concerns raised by the FDA. This finding prompts a closer look at the complexities of thromboembolism reporting and the clinical context in which angiotensin II is administered.
The FDA had previously issued a warning about the potential for thromboembolic events with angiotensin II, based on data from the Angiotensin II for the Treatment of High Output Shock (ATHOS-3) trial. However, the systematic review aggregates data from seven studies, including both randomized controlled trials and nonrandomized studies, and finds that the frequency of thromboembolic events was generally similar or numerically lower in the angiotensin II group compared to controls. Specifically, the review reported venous thromboembolic events in 8.8% of angiotensin II patients versus 9.4% in the control group, and arterial thromboembolic events in 11.3% versus 12.7%, respectively.
Methodological Considerations
The authors of the review emphasize the importance of considering potential biases introduced by aggregating data from different study designs. Nonrandomized studies, in particular, may present outcome data without adequate adjustments for confounding factors. Moreover, the diagnostic processes for identifying thromboembolic events vary significantly across studies, with a lack of standardized definitions and reliable prediction models. This variability in diagnostic criteria and reporting methodology contributes to discrepancies in thromboembolism event data.
Clinical Heterogeneity
Clinical heterogeneity among the included studies further complicates the assessment of thromboembolic risks. Factors such as patient population (e.g., vasodilatory shock, postcardiac surgery vasoplegia, COVID-19), background vasopressor use, comparator treatments, and timeframe for thromboembolic event assessment varied considerably. These factors can influence thromboembolic event rates independently of angiotensin II administration.
Concomitant Treatments
Concomitant treatments, such as conventional vasopressors and anticoagulation therapy, can also modify the association between angiotensin II and thromboembolic events. For example, high doses of norepinephrine and vasopressin have been linked to an increased risk of ischemic events. Conversely, angiotensin II may reduce the need for high doses of conventional vasopressors, potentially mitigating their associated risks. The use of anticoagulation therapy, which is common in critically ill patients, can also affect thromboembolic event rates.
Future Directions
The authors propose several directions for future research to better understand the relationship between angiotensin II and thromboembolic events. These include:
- Developing a consensus definition and diagnostic criteria for thromboembolic events.
- Accounting for heterogeneity in patient populations, background vasopressor use, and observation timeframes.
- Considering the impact of co-interventions, such as comparator vasopressors and anticoagulation therapy.
- Evaluating the efficacy and safety of early angiotensin II initiation.
Recent evidence suggests potential survival benefits from early angiotensin II administration, prompting a re-evaluation of thromboembolic risks in this context. Future prospective studies that address the current reporting and diagnostic challenges will help guide optimal angiotensin II therapy and minimize potential complications.
