Yet uncertainty remains as to whether a restrictive transfusion strategy is optimal in certain patient populations, such as those at high cardiac risk after major noncardiac surgery. This is the focus of the Transfusion Trigger After Operations in High Cardiac Risk Patients (TOP) trial.6<\/a><\/sup> Patients with cardiac comorbidity face competing risks in the postoperative setting, whereby anemia may exacerbate the mismatch in myocardial oxygen supply and demand, whereas transfusion may worsen outcomes through volume overload, changes in viscosity, and immunomodulation.7<\/a><\/sup>-9<\/a><\/sup><\/a><\/p>\n\n\n\n In this edition of JAMA<\/em>, Kougias and colleagues6<\/a><\/sup> report findings from the TOP trial in which 1428 patients with high baseline cardiac risk (history of ischemic heart disease, myocardial infarction [MI], peripheral arterial disease, stroke, or transient ischemic attack) who had undergone a major vascular or general surgery operation. Patients from across 16 Veterans Affairs (VA) medical centers were randomized either to a liberal (hemoglobin <10 g\/dL) or to a restrictive (hemoglobin <7 g\/dL) postoperative RBC transfusion strategy. The primary composite outcome\u201490-day composite of all-cause mortality, MI, stroke, coronary revascularization, or acute kidney failure\u2014occurred in 9.1% of the liberal transfusion group compared with 10.1% of the restrictive group (relative risk [RR], 0.90; 95% CI, 0.65-1.24). The authors concluded that a liberal strategy did not significantly reduce major ischemic events or death relative to a restrictive approach. Although not statistically significant, the point estimates for all elements of the primary composite outcome consistently favored the liberal strategy.<\/a><\/p>\n\n\n\n Several features strengthen inference from the study\u2019s findings. First, the trial enrolled patients with complex comorbidities (eg, 72% had peripheral artery disease, 59% had coronary artery disease), thus reflecting typical surgical populations, and 91% had undergone vascular surgery, which is associated with high rates of postoperative anemia and cardiovascular complications. Second, there was distinct separation between treatment groups, with mean hemoglobin levels differing by approximately 2 g\/dL by day 5; there was also a larger distribution in the number of transfused units of blood than in many previous studies of similar design, thus, improving the ability to detect a clinically meaningful effect of a given transfusion strategy if indeed present. Third, protocol adherence was generally high, with major protocol violations occurring in 8.7% of patients who were randomized to the liberal strategy and 3.8% of those who were randomized to the restrictive strategy; all randomized patients were analyzed according to their assigned group regardless of protocol adherence, preserving the intention-to-treat principle.<\/a><\/p>\n\n\n\n Two limitations temper broad extrapolation of findings from the TOP trial. First, the event rate was lower than anticipated, reducing power for the primary outcome, with the authors estimating that more than 36\u202f000 participants would be needed to exclude small effects with 90% power\u2014an impractical undertaking. Second, enrollment in the VA system yielded a cohort that was almost entirely male (97.8%), thus limiting generalizability both to females as well as to certain noncardiac surgical domains (eg, major oncological resections).<\/a><\/p>\n\n\n\n The secondary outcome of increased cardiac complications in the restrictive group (9.9% vs 5.9%; RR, 0.59; 99% CI, 0.36-0.98) is intriguing. This outcome, which encompassed both new arrhythmias requiring treatment (4.3% vs 2.6%) and new or worsening heart failure (5.8% vs 4.0%), favored a liberal transfusion strategy. When MI was included with the other cardiac complications in a post hoc analysis, the difference remained substantial (8.2% liberal vs 12.5% restrictive; RR, 0.66; 99% CI, 0.43-1.01), but did not reach statistical significance.<\/a><\/p>\n\n\n\n Intuitively, minimizing transfusions should mitigate the risk of transfusion-associated volume overload, particularly in patients with underlying cardiac disease. Therefore, the higher rate of heart failure in the restrictive group\u2014despite receiving substantially less blood\u2014was unexpected. This finding suggests a complex pathophysiology, highlighting that prolonged anemia itself may exacerbate myocardial ischemia, which in turn can impair contractility and precipitate heart failure.10<\/a><\/sup> Additional factors, including the severity and duration of anemia, the rates and volume of concomitant intravenous fluid administration, and diuretic management also need to be considered, but they were not systematically assessed in the trial.<\/a><\/p>\n\n\n\n A restrictive transfusion strategy (hemoglobin <7 g\/dL) is recommended for most stable patients without active cardiac symptoms.11<\/a> <\/sup>Nevertheless, the findings from the TOP trial, in which the primary outcome did not reach statistical significance, yet most point estimates favored a liberal transfusion strategy, merit consideration in clinical decision-making. In this regard, the TOP trial joins a growing number of studies comparing restrictive and liberal transfusion practice in cardiac populations, whereby primary outcomes may not meet the threshold for statistical significance, yet heterogeneity in the primary outcomes coupled with conflicting findings in regard to the reported point estimates and secondary outcomes, complicate clinical recommendations (Table<\/a>).12<\/a><\/sup>-17<\/a><\/sup> This is reflected in the guidelines from the Association for the Advancement of Blood and Biotherapies, which endorse restrictive transfusion thresholds broadly yet acknowledge the residual uncertainty in patients with preexisting or acute ischemic cardiac disease (eg, 8 g\/dL for orthopedic surgery or preexisting cardiovascular disease, 7.5 g\/dL in cardiac surgery).11<\/a><\/sup><\/a><\/p>\n\n\n\n Table. Key Studies Assessing Restrictive vs Liberal Red Blood Cell Transfusion Strategies for Patients With Preexisting or Acute Cardiac Complications<\/p>\n\n\n\n![\"\"\/](\"https:\/\/cdn.jamanetwork.com\/ama\/content_public\/journal\/jama\/0\/jed250084t1_1762286233.50409.png?Expires=1765748177&Signature=TW3Dh-Pg2Z26khmX4npZCyOAwSx1EMeDYpxjjKRZnFDv0-uHz4C9SjHrUsrEXBzG2PybD3kurEqnKN0mM95LqQ4hogGITWST3BaUymJsg0HMugX8QIpahvWjqQh3eAB6~wE6fuW0SoGfzO14K88JxQn67nMsmVY7tmkJKjKEggnjBAwtGnrbaz2JJpZ6PgPV~itY4rFCOomjdESzNmSr3LeN~dvl-NAIVQdop4~GHmbYwTfyvs67Z-YPp3Onmghe0wBIEvP8O7HcnW30dtjRFdrTi9IRNmKiTNpXjvLxGGg1pgZ0oD-~wqXcWkkqd~ic1nPWZwebjSV3RvfYMrTDKw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA\")
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