We performed a non-randomized study in administrative data to examine the effectiveness of bivalirudin in routine care. Our multivariate-adjusted results suggested that bivalirudin use in routine care has a short-term protective effect against several negative outcomes, including haemorrhage requiring transfusion, death, and possibly repeat PCI, when compared to heparin plus GPI. Findings from our instrumental variable analysis, which attempted to take both measured and unmeasured confounders into account, support the conclusions of the REPLACE-2 randomized trial3
with respect to non-inferiority of bivalirudin vs. heparin plus GPI for these negative outcomes. The protection against blood transfusions described in several trials3,7–9
was similarly observed in our study. We also observed a statistically significant protective effect against in-hospital death that was observed in only one of the trials.8
Despite the possibility of residual confounding or an inappropriate IV, we believe that our findings suggest that bivalirudin is as effective and safe in routine care as it was shown to be in trials, and may have additional previously unrecognized benefits.
Like REPLACE-2, but unlike HORIZONS-AMI and ACUITY, our patients were a mix of those undergoing primary and elective PCIs. HORIZONS-AMI considered STEMI patients only, whereas ACUITY looked at the broader category of acute coronary syndrome (ACS) patients. The design of our study also differed from that of the trials. Most importantly, the trials continued to follow patients after their discharge; we considered only endpoints that occurred in-hospital. Given that, our follow-up time was shorter than that of the trials, and we therefore expected that event rates in our routine care population would differ from those in trials. With respect to blood transfusions, we observed an event rate in the heparin group comparable with that of REPLACE-2; the relative risk from our fully adjusted analysis (HR = 0.67; 0.61–0.73) was similar to that observed in the heparin group of REPLACE-2 (OR = 0.67; 0.45–1.01). Compared with patients enrolled in HORIZONS-AMI, our patients were somewhat older and had higher prevalence of several risk factors, but we saw lower event rates in the comparison group of our study than that of HORIZONS-AMI, likely because of HORIZONS’ MI population. That said, the relative risk estimate for blood transfusion in HORIZONS (OR = 0.58; 0.38–0.87) was qualitatively similar to our result of HR = 0.67. Relative risks are generally closer to the null in populations with higher baseline risks.41
Mortality was substantially higher in our study of routine care (2.1% in the heparin group) than in REPLACE-2 (0.4%), likely because our routine care population was at higher baseline risk for death than the trial's subjects. Relative risk of death was HR = 0.51 (0.44–0.60) vs. OR = 0.58 (0.23–1.48) in REPLACE-2, and was significant in our study. HORIZONS-AMI reported a frequency of death of 3.1% in their comparison group, higher than that we observed. Their reported relative risk of death, OR = 0.66 (0.44–1.00), was numerically but not qualitatively different from our findings.
We approached the Premier database with an eye towards possible residual confounding due to limited information on clinical details recorded in the administrative data. If, for example, sicker patients were more likely to receive bivalirudin during PCI because it was perceived equally effective but safer than its alternatives, this would result in a bias towards less protective effect of bivalirudin. The overall similarity of the crude and adjusted results suggested that either there may have been little unmeasured confounding in our analysis, or the measured covariates did not account for a substantial portion of the unmeasured confounding that existed. We therefore employed IVA, which is a method that, under the strong assumptions noted in Appendix 1, can provide consistent effect estimates even in the presence of unmeasured confounders. The Durbin–Wu–Hausman test confirmed that the treatment was correlated with other variables in the model (P
< 0.0001), and suggests that the treatment was confounded and that IV estimation was required.42
There is an extensive literature on the correlation between hospital facility and quality of care; which hospital patients choose to go to may well have a bearing on their outcomes.30
This correlation may introduce a violation of the assumption that the instrument should not be related to outcome,24
as hospital preference for bivalirudin may be related to quality of care. The literature suggested several important factors that may contribute to this relationship, including hospital size, teaching or non-teaching status, and frequency of performing the procedure in question.30–32
Though we controlled for each of these factors in our IVA, we cannot rule out the possibility that residual confounding may persist. Further, as an inexpensive and widely available drug, heparin use may have been under-reported in the administrative data, especially in those patients who received GPI but had no recorded heparin use. In a study of bivalirudin vs. heparin plus GPI, unrecorded use of heparin in the bivalirudin group could introduce bias that would not necessarily move point estimates towards the null.
In one of our subgroup analyses, we attempted to isolate those patients undergoing early emergency PCI in order to broadly approximate a primary PCI population. Because of potential misclassification, we do not assert that this was wholly a primary PCI population. Misclassification may come from several sources: (i) both elective and primary PCIs will generally happen soon after admission; (ii) some hospitals may, by protocol, examine elective PCI patients in the emergency room before admission, and (iii) the 414.01 diagnosis code may capture many patients with unstable angina, who may in turn be more likely to be scheduled for elective PCI. To address these concerns, we performed a sensitivity analysis in which we excluded the patients with 414.01 diagnoses, and separately ER admission based on professional charges in the ER rather than recorded admission source. These sensitivity analyses led to no meaningful differences in the observed results.
We examined bivalirudin in the context of routine care of PCI patients treated across the USA. Our non-randomized study showed that bivalirudin is protective compared to heparin plus GPI with regard to the risk of blood transfusions, and may even exceed trial estimates for protection against death. Because of conventional analyses’ potential for bias as a result of residual confounding, IVA-based methods, with their known limitations, may help in studying the safety and effectiveness of medications outside the constrained setting of clinical trials.