Predictors of premature termination of cardiac surgery trials: insights from the Clinicaltrial.gov database.

OBJECTIVES: Clinical trials that are terminated prematurely may generate incomplete and potentially biased data and the reasons for premature trials termination are poorly understood. Our objective was to describe the incidence of premature trial termination and identify factors associated with it. METHODS: We performed a systematic search on ClinicalTrials.gov to identify all cardiac surgery trials from 1991 to 2023. Trials that were terminated prematurely were identified. Factors independently associated with premature termination were identified using multivariable logistic regression analysis. RESULTS: A total of 746 clinical trials were included; of them 577 were completed and 169 (22.6%) were terminated prematurely. Most of the trials originated from North America [294 (39.4%)], Europe [264 (35.4%)] or Asia [141 (18.9%)]. Fourteen of the trials terminated prematurely (8.3%) were phase 1, 75 (44.4%) phase 2, 49 (29.0%) phase 3 and 31 (18.3%) phase 4. Fifty (29.6%) trials were terminated because of slow recruitment, 20 (11.8%) because of sponsor decision and 12 (7.1%) because of lack of funding. Left ventricular assist device trials [odds ratio (OR) 3.65, 95% confidence interval (CI) (1.65-8.00) P = 0.001], valve surgery trials [OR 4.30, 95% CI (2.33-8.00) P < 0.001], aortic surgery trials [OR 2.86 95% CI (1.22-6.43) P = 0.012], phase 2 [OR 3.02, 95% CI (1.31-7.93) P = 0.015] and phase 4 trials [OR 3.62, 95% CI (1.43-10.23) P = 0.010] were at higher risk of premature termination while trials performed in Asia [OR 0.18, 95% CI (0.07-0.39) P ≤ 0.001] and Europe [OR 0.49, 95% CI (0.30-0.80) P = 0.004] were less likely to be terminated prematurely. CONCLUSIONS: Slow recruitment is the most common reason for premature termination of cardiac surgery trials. Trials on left ventricular assist device, valve surgery, aortic surgery, phase 2 trials and phase 4 trials are more likely to be terminated, while trials conducted in Asia and Europe are less likely to be terminated prematurely.

Supplemental fibrinogen restores thrombus formation in cardiopulmonary bypass-induced platelet dysfunction ex vivo.

BACKGROUND: Major cardiac surgery related blood loss is associated with increased postoperative morbidity and mortality. Platelet dysfunction is believed to contribute to post-cardiopulmonary bypass (CPB)-induced microvascular bleeding. We hypothesised that moderately hypothermic CPB induces platelet dysfunction and that supplemental fibrinogen can restore in vitro thrombus formation. METHODS: Blood from 18 patients, undergoing first-time elective isolated aortic valve surgery was drawn before CPB, 30 min after initiation of CPB, and after CPB and protamine administration, respectively. Platelet aggregation was quantified by optical aggregometry, platelet activation by flow-cytometric detection of platelet surface expression of P-selectin, annexin V, and activated glycoprotein IIb/IIIa, thrombus formation under flow and effect of supplemental fibrinogen (4 mg ml-1) on in vitro thrombogenesis. RESULTS: Post-CPB adenosine-diphosphate and TRAP-6-induced aggregation decreased by 40% and 10% of pre-CPB levels, respectively (P<0.0001). Although CPB did not change glycoprotein IIb/IIIa receptor expression, it increased the percentage of unstimulated P-selectin (1.2% vs 7%, P<0.01) positive cells and annexin V mean fluorescence intensity (15.5 vs 17.2, P<0.05), but decreased percentage of stimulated P-selectin (52% vs 26%, P<0.01) positive cells and annexin V mean fluorescence intensity (508 vs 325, P<0.05). Thrombus area decreased from 6820 before CPB to 5230 after CPB (P<0.05, arbitrary units [a.u.]). Supplemental fibrinogen increased thrombus formation to 20 324 and 11 367 a.u. before CPB and after CPB, respectively (P<0.001), thereby restoring post-CPB thrombus area to levels comparable with or higher than pre-CPB baseline. CONCLUSIONS: Single valve surgery using moderately hypothermic CPB induces partial platelet dysfunction. Thrombus formation was restored in an experimental study design by ex vivo supplementation of fibrinogen.