In this study, we conducted a systematic meta-analysis of all existing, enrolled and randomized studies comparing milrinone treatment to placebo/standard care in patients who underwent CABG surgery. The results showed that compared with placebo treatment, milrinone treatment did not contribute to mortality. Although milrinone failed to reduce mortality, the risk of postoperative complications, such as MI, myocardial ischemia, and arrhythmia, was significantly decreased when patients underwent CABG surgery.
Approximately 110 million people are affected by CAD, which resulted in 8.9 million deaths in 2015. [52] CAD is considered the most common cause of death globally because of its high mortality risk (15.9 %). [53] From 1980 to 2010, the number of cases and the risk of death from CAD for a given age both declined, especially in developed countries. [54, 55] Some well-determined risk factors, including high blood pressure, smoking, diabetes, obesity, family history, and excessive alcohol, were controlled. Approximately half of the cases result from genetics among all these factors[56-58]. Obesity and smoking are associated approximately 20 % and 36 % of cases, respectively[59]. The typical pathophysiological characteristic of CAD is limited blood flow to the heart, which may result in ischemia and long-term oxygen deficiencies in heart muscle, leading to cell death and, ultimately, causing myocardial infarction (MI). In addition, transient ischemia resulting from coronary artery stenosis may lead to ventricular arrhythmia, devolve into a dangerous heart rhythm, and lead to death, which is known as ventricular fibrillation[60]. Although a Cochrane review in 2015 suggested that combining preventive strategies such as persisting appropriate physical exercise, maintaining a healthy diet, treating hypertension, reducing cholesterol and quitting smoking could effectively prevent the risk of CAD[61-65]. there was insufficient evidence to prove an impact on mortality or actual cardiovascular events[66]. Until now, the most effective treatment options for moderate to severe CAD have been medications (such as statins, nitroglycerin, calcium channel blockers, and/or beta-blockers and aspirin)[67-69] and surgery (such as CABG surgery)[70-72]. CABG surgery is performed to treat coronary artery disease (CAD) by using a grafted vein to establish vascular access between the root of the ascending aorta and the distal end of the lesion site so that blood can bypass the coronary artery lesion site and reach the ischemic myocardium, thus improving coronary perfusion and increasing myocardial oxygen supply, which is also called myocardial revascularization[73, 74]. Numerous studies have demonstrated that CABG surgery is associated with low mortality (in both the short term and the long term) as well as cognitive and renal function benefits[75, 76]. In the past decade, percutaneous coronary intervention (PCI) has been increased to treat unprotected left main coronary artery disease. PCI can be selectively performed in patients who are candidates for revascularization but who are ineligible for CABG. Compared with CABG, PCI with stenting has a similar mortality but higher rates of myocardial infarction and repeat revascularisation in patients with left main coronary artery disease. So current guidelines recommend CABG as the treatment of choice for patients with asymptomatic ischemia, stable angina, or unstable angina/non-ST elevation myocardial infarction who have left main coronary artery disease[77, 78]. However, multiple complications (including MI, myocardial ischemia, arrhythmia, stroke, and kidney failure) are common postoperative syndromes after CABG[7, 17, 19, 20, 79]. Surgery, combined with medication pre- and/or postoperatively, such as inotropic agents, which can increase myocardial contractility that results, in most cases, in increasing intracellular cAMP levels, can effectively avoid or ameliorate these unwanted outcomes[80-82]. Increased cAMP subsequently stimulates adenylate cyclase and inhibits PDE III simultaneously[83]. Despite (or because of) their effectiveness, inotropic agents face various substantial limitations, such as acute myocardial β-adrenergic receptor desensitization, limiting the function for post-bypass cardiac failure[84]; additional observational data suggest that inotropic agents contribute to worse clinical outcomes due to the high incidence of renal dysfunction and death ratio[85-88].
PDE III inhibitors such as milrinone provide an alternative option to inotropic support [84] because they have not only positive inotropic effects but also vasodilatory effects[83, 89]. The preemptive use of milrinone has been beneficial for renal tubular injury[85]. Unlike dobutamine, milrinone does not increase heart rate or myocardial oxygen consumption[90], and some studies have reported that milrinone can significantly reduce the risk of postoperative myocardial ischemia and infarction in patients undergoing CABG surgery[44]. However, one of the current controversies or unknown questions in terms of milrinone application is whether the drug is associated with mortality. A recent meta-analysis by Zangrillo A et al. [34] showed that compared with control agents, milrinone had a tendency to increase mortality and the incidence of arrhythmia in patients who underwent cardiac surgery [13/249 (5.2 %) in milrinone vs. 6/269 (2.2 %) in the control arm, OR = 2.67 (1.05–6.79), p for effect = 0.04, p for heterogeneity = 0.23, I2 = 25 %). However, in their study, 13 trials were included that involved different control agents (3 with levosimendan, 2 with nesiritide, 7 with placebo, and 1 with nothing). These factors may have induced a bias risk. For instance, a subanalysis with placebo or nothing as a control demonstrated no difference in the risk of mortality [4/165 (2.4 %) with milrinone vs. 3/164 (1.8 %) in the control arm, OR = 1.27 (0.28–5.84), p for effect = 0.76, p for heterogeneity = 0.45, I2 = 0 %, 329 patients and 8 studies included]. In addition, an updated meta-analysis [34] showed that neither the overall nor the subgroup (adult patients) mortality in the milrinone-treated group was significantly different from that in the control group (mortality, 2.2 % vs. 2.1 %, p = 0.70 overall, 3 % vs. 2.4 %, p = 0.70 in adult patients). However, the sensitivity analysis with a low risk of bias showed a trend, but not statistical significance, toward an increase in mortality with milrinone [8/153 (5.2 %) in the milrinone arm vs. 2/152 (1.3 %) in the control arm, RR = 2.71 (0.82–9), p for effect = 0.10]. Furthermore, the most recent studies published in 2015[91] and 2016[92] demonstrated that there were no differences in mortality in patients administered milrinone compared to the control groups. All these reasons may induce a bias risk.
To avoid these interference factors, we enrolled 16 trials with a randomized total of 698 patients undergoing CABG surgery (346 treated with placebo or standard care and 352 treated with milrinone); the results showed that there was no difference in mortality between the group receiving milrinone and the placebo/standard care group. Nevertheless, the subanalysis demonstrated that the occurrence of myocardial infarction, myocardial ischemia, and arrhythmia decreased significantly with milrinone treatment compared to the placebo or standard care group. However, the occurrence of stroke and renal failure, need for IABP, and duration of inotropic support (h) and mechanical ventilation (h) between these two groups showed no differences. Milrinone was introduced as an agent that causes reduced left and right heart-filling pressures due to its greater reduction in vascular resistance, and it has been used in the treatment of low cardiac output syndrome following cardiac surgery. In the meta-analysis of patients with myocardial infarction suffering from CABG surgery, milrinone was used at any dose and administration time. Mortality after milrinone treatment was not improved despite reductions in important cardiovascular (CV) endpoints. Although the results and conclusions were associated with those of other studies, there may be several reasons for the presented results. First, the association between bias risk and estimates of intervention effects was ignored. Second, the number of included patients was still far too small to draw any firm conclusions. Third, the indications for CABG surgery are relatively extensive. We did not classify the causes of CABG surgery in detail. Therefore, in future studies, additional trial details need to be considered.
Although the evidence in the present study demonstrated that milrinone failed to show an advantage in mortality in adult CABG patients, it significantly reduced the occurrence of MI, myocardial ischemia, and arrhythmia compared to the placebo. All these findings may be helpful for the clinical application of milrinone and may provide therapeutic strategies for CABG surgery. Furthermore, along with clinical milrinone application, sufficient data from randomized clinical trials need to be collected, and the potential benefits or adverse effects should be analyzed and reevaluated.
Limitations
Our study has several limitations. First, the authors acknowledge that only 4 of the 16 studies included in this meta-analysis were of high quality. Second, in the enrolled RCTs, the doses of milrinone were between 30 and 75 μg/kg (as an intravenous bolus) and between 0.5 and 0.75 μg/kg/min (as continuous infusion). This fact suggests that the current reference lacks generalizability of milrinone at doses beyond the range of 0.3 - 0.75 μg/kg/min. Third, our study on the incidence of myocardial ischemia, stroke, and renal failure was performed using a small number of studies and patients. Therefore, the current results are not conclusive due to the possibility of induced error. Finally, only one trial was evaluated with a 1-year follow-up, so deficits in the short follow-up could have potentially impacted our mortality analyses.