Background
Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion therapy for ST-elevation myocardial infarction (STEMI) [
1]. Despite the restoration of epicardial flow after PPCI, impaired myocardial perfusion, known as the no-reflow phenomenon (NR), remains observed in a significant proportion of patients [
2]. The NR after PPCI for the treatment of STEMI contributes to infarct size expansion, reduced ventricular function, and increased mortality [
3‐
5]. Several potential mechanisms have been hypothesized to cause NR, including embolization of atherothrombotic material, vasoconstriction, activation of the inflammatory cascade, neutrophil plugging, platelet aggregation, toxic free-radical generation, and myocardial edema [
2,
6]. A basic understanding of the process has contributed to several pharmacological drugs proposed to improve myocardial reperfusion after PPCI, such as adenosine, diltiazem, nicorandil, nitroprusside, urapidil, and verapamil [
2,
6]. A number of meta-analyses have been conducted to assess whether intracoronary adenosine, diltiazem, nitroprusside, nicorandil, and verapamil can reduce NR and improve clinical outcomes after PPCI. However, these meta-analyses were limited in size and yielded inconclusive results [
7]. After the most recent meta-analyses were published [
8‐
12], new randomized controlled trials (RCTs) on this subject have been published, and these additional data may help reduce the amount of uncertainty surrounding the treatment effects. Anisodamine, unlike the aforementioned vasodilators, is a muscarinic cholinergic antagonist [
13]. Basic and clinical studies have shown that anisodamine can increase blood pressure and coronary perfusion pressure and improve microcirculation, making it a potentially useful drug for preventing NR [
14‐
16]. However, the value of anisodamine in improving myocardial reperfusion after PPCI has not been studied in any previous meta-analysis.
Traditional pairwise meta-analyses are limited for simultaneously synthesizing all evidence because head-to-head comparisons between treatments are often unavailable [
17]. Bayesian network meta-analysis combines direct and indirect comparisons and forms hierarchies for the efficacy of various treatments [
18]. Thus, this technique better informs clinicians regarding the optimal use of candidate agents in clinical practice. In this study, we performed standard pairwise and Bayesian network meta-analyses to comprehensively evaluate available intracoronary agents as adjuncts to PPCI, to estimate the relative efficacy and safety of the various agents, and to provide a hierarchy of treatments for the outcomes of interest.
Discussion
Through the present meta-analysis comprising 41 RCTs involving 4069 patients, we found that the addition of anisodamine to standard PPCI for STEMI was associated with improved post-procedural coronary flow, more occurrences of STR, and improvement of LVEF. The cardioprotective effect of anisodamine conferred a MACE-free survival benefit. Among the 7 treatment strategies, anisodamine was superior to the other treatments in efficacy outcomes (TFG < 3, STR, LVEF, and MACEs). Severe or life-threatening AEs were not observed in patients treated with anisodamine. Nitroprusside was also regarded as effective for improving coronary flow and clinical outcomes. Additionally, the intracoronary administration of adenosine, nicorandil, and verapamil exerted some cardioprotection in patients with STEMI undergoing PPCI.
The present network meta-analysis included all available RCTs involving intracoronary agents (adenosine, anisodamine, diltiazem, nicorandil, nitroprusside, urapidil, and verapamil) as adjuncts to PPCI. This study took into account the most recent studies and had the largest sample size to date among meta-analyses assessing the effect of intracoronary agents on NR in patients with STEMI undergoing PPCI. Demonstration of the improvement in indicators of myocardial reperfusion is a key step to the investigation of improved clinical outcomes for intracoronary agents as adjuncts to PPCI [
7]. Our network meta-analysis, by evaluating surrogate outcomes (TFG, STR, and LVEF) and the composite clinical endpoint (MACEs), provided a comprehensive insight into the use of 7 intracoronary agents during PPCI. However, most included RCTs were designed to assess angiographic or electrocardiographic outcomes, thus partly leading to a limited number of participants. Although angiographic and electrocardiographic indicators of myocardial reperfusion are well-known prognostic factors [
4,
5], the improvement in surrogate markers does not always correspond to improved clinical outcomes. For example, aspiration thrombectomy was considered a simple way to remove the thrombus before stent deployment, thereby improving coronary reperfusion. However, recent trials have demonstrated a lack of benefit of thrombus aspiration on clinical outcomes and suggested possible harm from an increased risk of stroke [
67,
68]. Therefore, our finding should be viewed as hypothesis generating, given the limitations of the current available evidence.
Anisodamine, a muscarinic cholinergic antagonist, has been reported with multiple pharmacological effects in basic and clinical studies [
13‐
16,
69,
70]. First, anisodamine inhibits the acetylcholine receptor and modulates the balance between sympathetic and vagus nerve activity during myocardial ischemia/reperfusion [
13]. Numerous studies have shown that anisodamine can increase blood pressure and heart rate, and further increase the coronary perfusion pressure [
16,
69]. The action of anisodamine is especially appealing, because it can help improve coronary microcirculation and has practical importance. Clinicians often have concerns about hypotension and bradycardia, although they are short-lived after the intracoronary administration of vasodilators. Anisodamine may be a promising drug to address these safety concerns. Second, anisodamine has a similar role to a calcium channel blocker. Anisodamine can prevent intracellular calcium overload, reduce lipid superoxidation, inhibit oxygen free radical formation, and relieve microvascular spasms [
70]. Finally, anisodamine decreases post-ischemia/reperfusion myocardial swelling, which can reduce capillary compression from surrounding edematous myocytes [
14,
15]. This is the first meta-analysis of RCTs of anisodamine to demonstrate a significant benefit of adjuvant anisodamine over standard care in patients with STEMI undergoing PPCI. Our results showed that anisodamine could significantly improve myocardial reperfusion (reflected by TFG and STR) and cardiac function (reflected by LVEF). Importantly, these effects were translated into improvement of composite clinical outcome (MACEs). Moreover, the analyses of rank probabilities revealed that of 7 treatment strategies, anisodamine consistently ranked the highest in improving TFG, promoting post-procedure STR, ameliorating LVEF, and decreasing the risk of MACEs, which made it the most efficacious drugs according to our results. Therefore, anisodamine may be regarded as an effective, well-tolerated, and possibly cost-effective regimen (currently about a dollar per 10 mg) for prevention of NR. However, it should be noted that this evidence was based on relatively small head-to-head RCTs. Large, high-quality RCTs are needed to fully evaluate the role of anisodamine as an adjunct to reperfusion in patients with STEMI.
Nitroprusside is a direct donor of nitric oxide, which is a potent vasodilator of the resistance arteriolar circulation and has anti-platelet and anti-inflammatory effects [
71]. Zhao et al. analyzed 7 studies involving 781 patients who were treated with nitroprusside [
12]. They assessed TFG < 3, STR, and MACEs, and their results were consistent with our findings. However, this previous meta-analysis included a retrospective study, which may have introduced bias. Our results included all RCTs to date with 4 additional summarized trials [
49,
56,
57,
64]. Moreover, our meta-analysis expands previous evidence by demonstrating that the intracoronary administration of nitroprusside significantly increased LVEF after PPCI compared to standard care. We also found that nitroprusside was inferior to anisodamine for improving STR.
Adenosine is an endogenous nucleoside that modulates numerous physiological processes, such as antagonizing platelets and neutrophils, reducing calcium overload and oxygen free radicals, and inducing vasodilation [
7]. Two recent meta-analyses have evaluated the role of adenosine in patients with STEMI undergoing PPCI [
8,
9]. Our findings are consistent with the results of these 2 previous meta-analyses, which showed that adenosine use was associated with fewer occurrences of TFG < 3 and more occurrences of STR. However, we failed to observe the significant improvement of LVEF and benefit of the MACE endpoint for adenosine. The reason for these conflicting results may be that we included new trials [
44,
49]. In the well-conducted REFLO-STEMI trial, Nazir et al. concluded that adenosine did not reduce the infarct size or NR [
49]. Furthermore, they found that there were significantly worse outcomes for the adenosine group than for the control, mainly due to an excess of heart failure events. Although the findings were hypothesis generating and difficult to explain, the new data challenge the role of adenosine in PPCI and should be re-evaluated in a meta-analysis. Our updated meta-analysis showed that adenosine had no benefits in terms of LVEF and MACE endpoints, but adenosine use increased the reperfusion indices without having a harmful effect on cardiovascular outcomes other than AEs. On the basis of our results, it is still necessary to perform larger well-powered studies to definitively assess the role of adenosine in this clinical scenario.
Diltiazem and verapamil, two non-dihydropyridine calcium channel blockers, have been shown to produce endothelium-independent vasodilation and reduce calcium overload within intracellular compartments [
72]. Wang et al. pooled 8 RCTs with 494 participants and found that verapamil or diltiazem was associated with a significantly improved TFG and reduced incidence of MACEs [
10]. In this meta-analysis, however, verapamil and diltiazem were classified as the same group and the three included trials evaluated the effect of oral diltiazem, which might affect the results. In the current study, we separately analyzed the role of intracoronary verapamil or diltiazem. Our results based on RCTs suggest that diltiazem adjunctive therapy did not improve any outcomes studied in patients with STEMI. Although verapamil had a beneficial effect on coronary flow after PPCI, it was not associated with consistent advantages on other outcomes (STR, LVEF, and MACEs).
Nicorandil is a hybrid of nitrates and an adenosine triphosphate-sensitive potassium channel opener [
73]. The mechanisms for the beneficial actions of nicorandil have been postulated, including dilation of resistance arteries, reduction of reactive oxygen species production in mitochondria, and attenuation of polymorphonuclear leukocytes activation during ischemia/reperfusion [
73]. Recent meta-analysis has indicated that nicorandil was associated with improvement of coronary flow and LVEF in patients with STEMI undergoing PPCI [
11]. However, the results could have been confounded by the intracoronary and intravenous administrations of nicorandil. Results of our meta-analysis showed that intracoronary nicorandil therapy leads to improvement in TFG and STR after PPCI. Unfortunately, this did not translate into significant improvement in cardiac function and clinical outcomes.
As a selective adrenoceptor blocker, urapidil may help attenuate the vasoconstrictive tendency of the coronary circulation observed after PPCI [
74]. Only 2 RCTs compared urapidil with a control, and urapidil improved ventricular function in both studies. In our network meta-analysis, urapidil did not show any benefits in TFG, STR, and MACEs. For LVEF, the result of our pairwise meta-analysis showed significant improvement, whereas the result of the network meta-analysis indicated a favorable trend when intracoronary urapidil was used during PPCI. However, the relatively small sample size (49 patients) can make it difficult to interpret the data. The results for urapidil should be interpreted with caution.
It is clinically relevant to further investigate the effect of confounding factors such as age, the time to reperfusion, and duration of follow-up on the intervention effect. Ageing has been shown to be associated with reduced efficacy of cardioprotective therapies [
75]. The total ischemic time was the major determinant of myocardial damage in patients with STEMI [
6]. The present study evaluated MACEs at follow-up ranged from in-hospital to 12 months. Compared to studies with a longer follow-up period, those with shorter follow-up period may be inadequate for determining the differences in MACEs. Network meta-regression can be used to estimate interactions of treatment with study-level characteristics when treatment effects are heterogeneous [
23]. Our meta-regression analyses suggested that the results of network meta-analysis were not confounded by age, the time to reperfusion, and duration of follow-up. However, more studies are needed to confirm these results of meta-regression analyses. Additionally, large, well-designed RCTs have shown that complete revascularization was associated with a reduction of MACEs compared with treatment of the culprit lesion only in patients with STEMI and multivessel disease [
76]. This reduction was mainly driven by fewer repeat revascularizations, because all-cause mortality and non-fatal reinfarction did not differ between groups. In the present meta-analysis, the median proportion of patients with multivessel disease across 14 included studies was 52%. However, few of included studies provided data about the proportion of patients undergoing complete revascularization. Therefore, we did not perform meta-regression analysis to adjust the results of network meta-analysis for complete revascularization. We suggest that future research should investigate the impact of complete revascularization on the intervention effect. Epinephrine has beta-2 receptor agonist properties leading to the potent coronary vasodilator effect and beta-1 agonist properties mediating chronotropic and inotropic effects on the heart. Pilot studies have shown that the intracoronary administration of epinephrine reversed refractory NR in patients with STEMI [
77]. We did not evaluate the safety and efficacy of epinephrine in the present study due to a lack of relevant RCTs. Additional data from RCTs are warranted to assess the effect of epinephrine on NR during PPCI.
A main strength of the present meta-analysis is that it provides the most comprehensive analysis to date of the likelihood of a range of adjunctive pharmacotherapies to prevent or reduce NR. Our results are based on mixed comparisons of multiple treatments and report treatment rankings for 7 types of intracoronary drugs. The findings from our meta-analysis can offer positive evidence regarding the use of anisodamine as an adjunct to PPCI, and pave the way for further RCTs to confirm this beneficial role of anisodamine in patients with STEMI.
Our study has several limitations. First, the present meta-analysis is based on the data of existing publications, and we could not fully assess the potential influences of comorbidities and cardiovascular medications. Second, we did not include other measures of myocardial perfusion, such as the corrected TIMI frame count, myocardial blush grade, and TIMI myocardial perfusion grade. These indices are not commonly used in clinical practice and were unavailable in most of the included studies. TFG and STR, classical indicators of reperfusion, are closely related to short-term and long-term clinical outcomes of patients with STEMI [
4,
5]. Third, drug protocols varied across the eligible studies. It was difficult for us to ascertain the optimal drug protocols. Fourth, the sample size in each study was relatively small, and the CI for certain outcomes was wide because of low event rates or the absence of events. Finally, the quality of trials included in our analysis was not high.