Arterial graft spasm may cause critical cardiac ischemia during and after CABG. The reported incidence of arterial graft spasm with compromised cardiac pump function and hemodynamic stability was between 0.5% and 1.3%3, 19, 20. Currently, the commonly accepted perioperative intervention to prevent arterial graft spasm is to locally and/or systemically apply vasodilators with coronary selectivity. Diltiazem and nitroglycerin became frequently chosen agents based on the results of RCTs conducted mostly in patients who received LITA grafts, with a very limited number of studies targeting arterial grafts of other sources, including RA grafts. However, the usage of RA grafts is usually the main reason for perioperative antispasmodic intervention because of the known high tendency of spasm of RA grafts. There were limited, nonrandomized control data of intraoperative direct flow checks indicating that continuous iv infusion of diltiazem and nitroglycerine increased blood flow in the LITA and RA grafts. However, there has been no definitive anatomical evidence supporting that perioperative continuous iv application of diltiazem had a direct vasodilatory effect on coronary grafts after the sternum was closed. Diltiazem became the preferred antispasmodic agent because, compared to nitroglycerine, it had more favorable perioperative outcome profiles, including lower incidences of new onset A-fib and cardiac ischemia7, 9, 21, 22. Noticeably, data from these RCTs also suggest that patients on diltiazem may need prolonged hemodynamic support from inotropic and/or vasoactive support, indicating that the usage of diltiazem may have potential negative perioperative and long-term outcome impacts22.
Due to the limitation of the small sample sizes, there were no available data on short- and long-term mortalities reported from these RCTs. In fact, despite decades of perioperative diltiazem application for preventing graft spasm in CABG, there are scarcely available observational data of long-term outcomes after hospital discharge. In our institute, diltiazem has been routinely applied in patients who underwent on-pump CABG, especially those who received RA grafts. As part of the clinical quality improvement initiative, we conducted this retrospective study to validate the practice and explore the perioperative and long-term outcome effects of perioperative diltiazem in our patient population. To summarize the findings of this propensity matched cohort study, there were no significant differences in perioperative outcomes if diltiazem was applied. There was no significant difference in 30-day and long-term all-cause mortality. Patients who received preventive perioperative diltiazem had a significantly higher requirement for hemodynamic support from inotropic and/or vasoactive agents 24 hours postoperatively. In addition, data from the subgroup analyses revealed that diltiazem may be associated with reduced long-term survival in patients who received LITA with additional arterial grafts, which were mostly RA grafts. Based on these findings, we could not confirm that perioperative diltiazem had significant perioperative and long-term outcome benefits in our studied patient population.
Although due to the limitation of a single-center retrospective study, it is premature to conclude that diltiazem has no or negative benefits in patients who underwent on-pump CABG, we think the data from this study do have important clinical implications.
The data of our study validated those from previously published studies showing that the vasodilatory and negative inotropic effects of diltiazem had significant perioperative hemodynamic consequences, which may negatively affect the perioperative outcomes due to reduced coronary perfusion pressures as well as perfusion pressure for other end organs. Studies have shown that the length and dosage of the application of perioperative inotropic and/or vasoactive agents were predictive of negative postoperative outcomes, including mortalities, in patients who underwent cardiac surgeries23. In our study, the calculated NNHs for several perioperative outcomes indicated that the potential side effects of continuous iv infusion of diltiazem may have to be taken into consideration for starting the intervention. We suspect that the perioperative hemodynamic instability associated with diltiazem may cause unfavorable effects on perioperative and long-term outcomes. One speculation for the negative long-term outcome in the subgroup of patients who received two or more arterial grafts is that the decreased coronary pressure from the systemic application of diltiazem might negate the antispasmodic effect. It may be reasonable to consider the combination of a preventive perioperative intra-aortic balloon pump (IABP) with perioperative diltiazem, rather than diltiazem alone, for better protection of cardiac ischemia caused by arterial graft spasm, although a well-designed randomized clinical trial would be necessary to test this hypothesis.
As mentioned above, the preventive application of diltiazem is based on the data from RCTs focused on LITA grafts; however, in practice, patients receiving RA grafts are more likely to be treated with perioperative diltiazem, assuming that the effect of diltiazem on all types of arterial grafts is the same. The dosage of diltiazem, 0.05~0.1mg/kg, is also based on the same studies. This could be an important confounding issue because studies have reported that different types of arterial grafts may, in fact, have different responses to diltiazem and other vasodilators. The majority of past studies have shown that LITA was more responsive to local and/or systemic applications of diltiazem with more graft dilation and blood flow7, 9, 21, 24, 25, and diltiazem had more perioperative outcome advantages than nitroglycerin in patients who received LITA grafts as the only arterial graft14, 26–31. When RA or other arterial grafts are involved, however, diltiazem may not be the best choice. An earlier RCT by Guadino et al. suggested that long-term postoperative CCB was not associated with better RA graft patency and may not provide outcome benefits for patients who had RA grafts29, 32, although their recent study with questionable methodology argued against their previous conclusion: the post hoc analysis of data pooled from six RCTs comparing RA and SVG showed that chronic postoperative CCB therapy may improve RA graft patency and reduce the incidence of major cardiovascular events33. Numbers of in vitro and in vivo studies of RA sections or conduits indicated that nitroglycerin was more effective than diltiazem in preventing the contraction of RA grafts30, 34; compared to other CCBs, diltiazem was less effective in preventing graft contraction caused by endothelin-1 and norepinephrine, which affected RA more than LITA28. Chanda et al. proposed that the combination of nitroglycerin and CCB may be more effective than a single agent for preventing RA graft spasm31. In addition, data from recent studies investigating various categories of vasodilators support that the antispasmodic effects may depend on the types of vessels and mechanisms of graft spasm35–39. Taken together, evidence suggests that instead of applying diltiazem to every patient, tailoring the antispasmodic interventions to the types and conditions of arterial grafts, as well the clinical condition of each individual patient, may be more effective. To better understand the effects of diltiazem on RA grafts, we think a large-scale, multicenter retrospective study and a well-designed, properly powered RCT investigating the preventive effects and outcome impacts of diltiazem may be warranted.
As a part of the quality improvement and cost-reducing study, we did compare the lengths of ICU admission and hospitalization as well as the likely discharge locations of patients who had or did not have perioperative diltiazem. Data suggested that the lengths of care were similar between cohorts; the patients who received diltiazem were more likely to be discharged to home instead of cardiac rehabilitation facilities, suggesting diltiazem cohort may have improved social and economic outcomes, however, we cannot draw a conclusion unless it can be proved by a well-conducted clinical trial.
Our study does have important limitations. First, like other retrospective clinical studies, selection bias cannot be eliminated. Considering the limited sample volume, we were not able to include every covariate in the PSM; therefore, it is possible that certain patient baseline and perioperative characteristics were unequal between matched cohorts, and some of the unmatched covariates could be potential confounding factors for the studied outcomes. We noticed that the DILT cohort had a significantly higher percentage of patients who had a history of COPD, longer cardiopulmonary bypass time, and higher tendency to receive two or more arterial grafts. Although unconfirmed, it was also possible that there was a tendency of more frequently applying perioperative iv infusion of diltiazem in patients whose graft condition was not reassuring judged by the visualization and the Doppler flow check. Second, while previous RCTs enrolled patients undergoing elective CABG only, the current study included patients undergoing both elective and urgent/emergent procedures. Patients who received RA or other arterial grafts in addition to LITA grafts and those who required insertion of IABP prior to planned CABG were included in our study because the severity of the coronary pathologies rendered these patients more vulnerable to graft spasm, and diltiazem therapy could be potentially more beneficial; however, those patients were mostly excluded from early RCTs. This could be an explanation why the favorable perioperative outcome effects observed were not reproduced. Thirdly, the study may be underpowered. Based on the observed data of this study, the post hoc estimated sample size for detecting differences in perioperative all-cause mortality was 1100 in each cohort; however, after PSM, the number of patients enrolled in each cohort was 502; therefore, the study may be underpowered for the investigation of certain perioperative outcomes. Finally, in the current study, the chosen starting rate of infusion for diltiazem was 5 mg/hr, which fell within the range of 0.05~0.1 mg/kg, the dosage used in earlier RCTs. However, the variation of the serum diltiazem concentrations due to the difference of body weights as well as that in the management of the infusion by ICU staff may affect the outcomes.
In conclusion, data from the current retrospective propensity matched cohort study did not validate the short- and long-term outcome benefits of perioperative diltiazem revealed by previous clinical studies. The preventive application of arterial graft spasm may have to be individualized, tailored to the types and conditions of the grafts as well as the patient’s clinical conditions. We propose that a large-scale multicenter retrospective outcome study and further clinical trials of diltiazem and/or other coronary selective vasodilators on RA grafts, in combination with treatment maintaining adequate coronary perfusion, may be warranted.