Anesthesia needs large international clinical trials.

Throughout the majority of the last century, anesthesiology research primarily focused on physio-logic phenomena within the time window of the intraoperative and immediate postoperative period [1]. During the last two decades, the spectrum of interest has broadened to include intermediate and long-term effects of anesthesia-related interventions [1].

Examples of this evolution include large clinical trials evaluating the impact of cardiovascular drugs on 30-day major cardiovascular outcomes [2,3,4] and the impact of anesthesia techniques on cancer recurrence in the years after surgery [5,6,7].

Major cardiovascular complication occurred in 1.4% (95% CI 1.0-1.8%) of patients older than 50 years hospitalized for elective non-cardiac surgery at 30 days [2]. Conservative estimates [8] sug-gest that at least half of the 200 million adults undergoing non-cardiac surgery are in an at-risk age group [9].

This suggests that worldwide 1-1.8 million adults suffer a major perioperative vascular complication annually. There is concern, however, that this data substantially underestimate the current incidence. In a recent large international randomized controlled study conducted in 190 hospital in 23 countries, 6.9% of patients over 45 years, with or at risk of cardiovascular disease, hospitalized for non-cardiac surgery (both elective and urgent) suffered a cardiovascular event within 30 days [10].

This implies that the current worldwide incidence of adults suffering a major perioperative vascular complication in the first 30 days after surgery is probably in the range of 3-5.4 million annually.

The research tools to tackle the enormous global burden of perioperative cardiovascular complica-tions by rigorous research are different from the ones we have primarily used for intraoperative anesthesiology research. The change in the spectrum of the research question requires a change in research methods and research culture. Given the well known errors associated with the extrapo-lation of physiologic variables to clinical effects [11], there is a need to move from physiology to endpoints suitable to answer the new questions we are asking, i.e. patient-important outcomes [12].

Perioperative myocardial infarction, stroke,death, and other perioperative patient-important outco-mes share two common traits. In unselected adult perioperative populations these events will occur in less than 10% of patients and they are mediated through multiple pathways. These two points have substantial implications for the required sample size to ensure a reliable study result.

The appropriate change in focus from a dichotomous surrogate outcome that occurs in 20% of the control patients to a patient-important outcome developing in 5% of the patients will increase the planned sample size (chi-squared, alpha 0.05, power 80%, estimated relative risk reduction 50%), from 450 to round 2,000 patients. This however, is only half of the truth.

The calculation assumed a relative risk reduction of 50%. This assumption becomes unwarranted by the substitution of a surrogate endpoint, ideally related to the beneficial effect of the intervention by a direct mechanism, to a patient-important outcome mediated by multiple pathways [13].

The multiple pathways leading to the outcome make it implausible that any single intervention, which targets no more than a few mechanisms, will have a large effect. The intervention will achieve a moderate effect in the range of 10-30% [13]. Therefore, optimistically assuming a 25% relative risk reduction, the sample size required to assess a patient-important outcome occurring in 5% of the controls, will be round 9,000 patients.

The conduct of trials enrolling several thousand perioperative patients is beyond a realistic expec-tation of any single institution or even most nations. This calls for the development of international perioperative research collaborations. Tackling the large global burden of perioperative cardiova-scular events after non-cardiac surgery requires large global trials. These trials are starting to happen and the perioperative culture is starting to embrace large international trials.