Original research
645
Effect of intracoronary anisodamine and diltiazem administration during primary percutaneous coronary intervention in acute myocardial infarction Yuhong Penga, Xianghua Fua, Wei Lia, Wei Genga, Kun Xinga, Leisheng Rub, Jiaan Sunb and Yuying Zhaob Objective The aim of this study was to examine the role of intracoronary anisodamine and diltiazem administration performed before stenting on the immediate angiographic and clinical outcome in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods STEMI patients during primary PCI were randomized to two bolus injections of intracoronary anisodamine (1 mg/5 ml) and diltiazem (2 mg/5 ml) (COM group, n = 54) or saline (5 ml) and diltiazem (2 mg/5 ml) (diltiazem group, n = 54) before stenting. The primary endpoint was the incidence of no/slow reflow [thrombolysis in myocardial infarction (TIMI) flow grade ≤ 2] immediately after stenting. TIMI myocardial perfusion grade and corrected TIMI frame count were assessed. The secondary endpoints were major adverse cardiac events including death, nonfatal myocardial infarction, and target vessel revascularization. Results The percent of TIMI flow grade 3 was found to be higher in the COM group than in the diltiazem group (92.6 vs. 75.9%, P = 0.032). The percent of TIMI myocardial perfusion grade 3 was 46.3% in the diltiazem group and improved in the COM group (68.5%, P = 0.032). Corrected TIMI frame count was significantly lower in the COM group
Introduction The no-reflow performance is a predictive factor of continuous myocardial ischemia, ventricular remodeling, and cardiac dysfunction during primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) [1]. A higher incidence was identified in men, older patients, those with diabetes mellitus, those with a prolonged interval from symptom onset to admission, those with cardiogenic shock, and patients with longer lesions, bifurcation lesions, proximal left anterior descending coronary artery lesions, pre-PCI thrombus score of at least 4, collateral circulation 0–1, and impaired preprocedure thrombolysis in myocardial infarction (TIMI) flow [2]. Intracoronary infusion of diltiazem can reverse no reflow during primary PCI for STEMI [3]. After the application of intracoronary 5 mg diltiazem, heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP), and corrected TIMI frame counts (cTFC) were found to be 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
than in the diltiazem group (P < 0.0001). The COM group showed low incidences of bradyarrhythmia and rapid arrhythmia (7.4 vs. 24.1% and 3.7 vs. 18.5%, respectively, P = 0.032, P = 0.029). In addition, there were no significant differences in the secondary outcome measures. Conclusion Intracoronary anisodamine and diltiazem administration before stenting improved the angiographic results and prevented reperfusion arrhythmia in patients with STEMI undergoing PCI. Coron Artery Dis 25:645–652 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:645–652 Keywords: anisodamine, arrhythmias, cardiac, diltiazem, myocardial infarction, myocardial reperfusion injury, no-reflow phenomenon, percutaneous coronary intervention a
Department of Cardiology, Second Hospital of Hebei Medical University and Department of Cardiology, Bethune International Peace Hospital, Hebei, People’s Republic of China b
Correspondence to Xianghua Fu, MD, PhD, Department of Cardiology, Second Hospital of Hebei Medical University, 215 Heping West Road; Shijiazhuang, Hebei 050000, People’s Republic of China Tel: + 86 138 331 31680; fax: + 86 0311 8361 5346; e-mail: [email protected] Received 18 May 2014 Revised 2 August 2014 Accepted 4 August 2014
significantly lower than predrug values [4]. Calcium channel blockers work by several mechanisms including endothelium-mediated vasodilatation, reduction of myocardial oxygen demand by negative inotropic and chronotropic effects, and may reduce oxygen free radical damage during reperfusion [5]. It is important to note that although no reflow partly results from microvascular spasm, capillary destruction and microemboli to small arteries are likely to be major factors. However, diltiazem is mainly limited by side effects (bradycardia/hypotension) and shrunk by vasomotion effects. Therefore, we need drugs with broader pharmacological effects to prevent no reflow. Anisodamine is a nonspecific cholinergic antagonist. Many basic and clinical studies have proved that anisodamine can exert a significant effect on relieving microvascular spasm, and improving and dredging the coronary microcirculation. Intracoronary administration of anisodamine is effective in reversing no reflow following PCI DOI: 10.1097/MCA.0000000000000167
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
646
Coronary Artery Disease 2014, Vol 25 No 8
in STEMI patients; it is especially suitable for patients with bradycardia or hypotension [6]. Benefit beyond vasodilation makes it a potentially useful drug for the treatment of no reflow. Therefore, we hypothesize that intracoronary administration of these two vasodilate drugs might result in synergistic effects in STEMI patients. The aim of our study was to examine the role of intracoronary anisodamine and diltiazem administration during primary angioplasty on the immediate angiographic results and clinical course.
Methods Study design and population
This study is a prospective, randomized, control study. Patients presenting with STEMI were selected among 150 patients consecutively referred to the catheterization laboratory of our institution for emergency primary coronary angioplasty between January 2012 and January 2014. The study was approved by the local medical ethics committee and was carried out in accordance with the Helsinki II declaration. All patients provided written informed consent. The femoral and radial artery accesses were obtained, and heparin was administered at a dose of 100 IU/kg to maintain an activated clotting time greater than 250 s. Selection of a bare-metal or a drug-eluting stent was made according to the clinical and angiographic characteristics and considering financial limitations. The inclusion criteria were as follows: (1) Symptoms suggesting acute myocardial ischemia lasting 30 min. (2) Ischemic chest pain associated with ST-segment elevation of 0.1 mV in two or more leads on the ECG. (3) Patients with STEMI with symptom onset within the previous 12 h or symptom onset within the previous 12–24 h who had clinical and/or ECG evidence of ongoing ischemia. (4) Culprit coronary artery abnormalities: initial TIMI grade of 2 or less. The exclusion criteria were bradycardia (heart rate ≤ 60 bpm) or hypotension (SBP ≤ 90 mmHg or DBP ≤ 60 mmHg); atrioventricular block; previous myocardial infarction resulting in left ventricular dysfunction (previous of left ventricular ejection fraction ≤ 0.50); history of any malignancy within the past 5 years; cardiogenic shock; nonmelanoma skin cancer or cervical cancer in situ; history of thrombocytosis (platelets ≥ 500 000/mm3); history of thrombocytopenia; history of stroke or transient ischemic attack within the past 6 months; chronic liver disease that might interfere with survival; chronic renal insufficiency as defined by a creatinine level of at least 2 mg/dl; and inability to provide informed consent.
Randomization and treatment
After the performance of an initial coronary angiography, patients who fulfilled the eligibility criteria were randomly allocated in a ratio of 1 : 1 to two groups: COM group (n = 54, received anisodamine, 1 mg/5 ml and diltiazem, 2 mg/5 ml; first anisodamine, then diltiazem) and diltiazem group (n = 54, received saline 5 ml and diltiazem, 2 mg/5 ml). Randomization concealment was carried out by the sealed envelope technique. Administration was by an injection through the guiding catheter: the injection was administered immediately after we crossed the lesion of the infarct-related artery with the guidewire, or after the balloon passed the lesion, or after the balloon inflation before stenting (TIMI > 0 before the intracoronary injection). Electrocardiogram analysis
A 12-lead ECG was assessed at baseline and 90 min after primary PCI. The existing ST-segment deviation in the single ECG had a maximum deviation of 90 min on judging myocardial reperfusion after primary angioplasty [7]. A decrease in the single lead with a maximum deviation of ST-segment elevation was categorized as complete (>70%), partial (70–30%), or no improvement (< 30%) in ST-segment resolution, and was used as an indirect measure of myocardial reperfusion. Angiographic analysis
Coronary angiograms were reviewed by two experienced interventional cardiologists who were blinded to the therapy that the patients received. PCI was considered successful when the residual stenosis was 10%, in the absence of dissection, thrombosis, or distal vessel embolization. During PCI, TIMI, cTFC, and TIMI myocardial perfusion grade (TMPG) were assessed at an angiographic core laboratory as defined previously [8,9]. Two-dimensional echocardiography and laboratory data
We performed an echocardiography to assess the severity of left ventricular remodeling. At baseline, within a week after PCI, 2D echocardiography was used to assess conventional parameters such as left ventricular end systolic volume, left ventricular end diastolic volume, and left ventricular ejection fraction. At the 6-month follow-up, 2D echocardiography was performed again. Blood samples were obtained at 4, 8, 12, 16, and 24 h in all patients after the intervention for creatine kinase-MB, and after 12 h for cardiac troponin I. The levels above the cut-off points were considered markers of myonecrosis. Biochemical indicators including high-sensitivity C-reactive protein and N-terminal prohormone brain natriuretic peptide were detected before PCI and 1 week after PCI. Clinical follow-up
Side effects that were specifically documented were bradycardia (including symptomatic bradycardia,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Intracoronary anisodamine and diltiazem Peng et al. 647
atrioventricular block) and tachyarrhythmia (including ventricular fibrillation, ventricular tachycardia, accelerated idioventricular rhythm, and frequent ventricular premature beats), hypotension, flushing, thirst, blurred vision, and retention of urine. The primary endpoint was the incidence of no/slow reflow (TIMI flow grade ≤ 2) after stenting; TMPG and cTFC were also observed. The secondary endpoints were major adverse cardiovascular events (MACEs) including death, nonfatal myocardial infarction, and target vessel revascularization. All patients were followed for 6 months. Follow-up data after primary PCI were collected from hospital records, written questionnaires, and telephone interviews.
Sample size
On the basis of a clinical audit in our hospital and a literature review, we estimated that the incidence of no/ slow reflow (TIMI ≤ 2) during primary PCI would be 35% in the diltiazem group and 10% in the COM group. A minimum of 108 patients (n = 54 per group) would provide 90% power to reject the null hypothesis with a type 1 error of 0.05.
Statistical analysis
Categorical variables were presented as frequency values and proportions and were compared using the χ2-test or the Fisher exact test. Continuous normally distributed variables were presented as mean values and SDs and were compared using the two-tailed Student’s t-test. For skewed distributed variables, median values with interquartile range were calculated and the variables were compared using the Mann–Whitney U-test. Kaplan–Meier plots were generated to determine the clinical follow-up data differences over time among different groups. For all analyses, a P-value less than 0.05, two-tailed, was considered statistically significant. Statistical analysis was carried out using the Statistical Package for IBM SPSS Statistics 16.0 (IBM Corporation, Chicago, Illinois, USA) and MedCalc statistical software 12.3.0 (MedCalc Software bvba, Brussels, Belgium). Data were presented as mean ± SD, n/N (%), or interquartile range.
Results Patient characteristics
After the initial angiography, 108 patients, 78 men and 30 women, who fulfilled the inclusion criteria and followed up in the end were randomized to the COM group and the diltiazem group (Fig. 1). There was no statistically significant difference in the clinical characteristics, laboratory examination results, and drug treatment between the two groups before the operation (Table 1).
Myocardial reperfusion as assessed by angiography and electrocardiography
Before PCI, the angiographic characteristics of the two groups were similar. After coronary reperfusion, TIMI flow grade 3 occurred in 50 patients in the COM group and 41 patients in whom anisodamine was not administered (92.6 vs. 75.9%; P = 0.032) (Fig. 2). TMPG 3 was found to be higher in 37 patients in the anisodamine and the diltiazem administration group and 25 patients in the diltiazem group (68.5 vs. 46.3%; P = 0.032) (Fig. 2) immediately after PCI. An intracoronary injection with combination resulted in greater cTFC than injection with diltiazem after PCI (Fig. 3). Table 2 shows the angiographic procedure and outcomes. Resolution of single-lead ST-segment elevation (>70%) was more frequently observed in the COM group than in the diltiazem group. However, a Q-wave myocardial infarction developed in 46 patients in the COM group and in 48 patients in the diltiazem group (85.2 vs. 88.9%, P = 0.775). Patients in the diltiazem group were more likely to use a temporary pacemaker. The highsensitivity C-reactive protein level in patients of the COM group was higher than that of the control group. There was no significant difference in left ventricular ejection fractions in those in whom drugs were or were not administered within 1 week after PCI (Table 2). From the baseline to 1 week after PCI, there was a significant increase in the levels of N-terminal prohormone brain natriuretic peptide and high-sensitivity C-reactive protein level in the entire patient population (P < 0.0001). However, no difference was observed between the two groups in the levels of N-terminal prohormone brain natriuretic peptide between baseline and 1 week. Side effects
Side effects were reported during the PCI procedure. Symptomatic bradycardia, and II and III degree atrioventricular blocks were observed in four patients in the COM group and in 13 patients in the diltiazem group (7.4 vs. 24.1%; P = 0.032). In the COM group, two patients (3.7%) developed accelerated idioventricular rhythm and tachyarrhythmia, whereas the frequency of rapid reperfusion arrhythmias was higher in 10 patients (18.5%) administered diltiazem (P = 0.029). However, the incidence of adverse effects unassociated with the heart did not differ between the two groups (Table 3). All side effects disappeared within 2–3 h and no clinical sequela was observed. Follow-up
Left ventricular ejection fraction at 6 months after PCI was 59.2 ± 12.3% in patients randomized to intracoronary anisodamine and diltiazem versus 51.2 ± 13.4% in the group with only diltiazem (P = 0.002). Only one patient (1.9%) randomized to the COM group died compared
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
648
Coronary Artery Disease 2014, Vol 25 No 8
Fig. 1
Assessed for eligibility (n=150)
Initial angiogram
Excluded (n=19); not meeting inclusion criteria (n=16); declined to participate (n=3); other reasons (n=2)
Randomized (n=110)
Diltiazem group
COM group
Wire passage (n=55) Ballon angioplasty (n=55)
Wire passage (n=55) Ballon angioplasty (n=55)
Intracoronary anisodamine (1 mg/5 ml) and diltiazem (2 mg/5 ml)
Intracoronary saline (5 ml) and diltiazem (2 mg/5 ml)
Follow-up (n=110) Lost to follow-up (n=1) Discontinued intervention (n=0)
Lost to follow-up (n=1) Discontinued intervention (n=0) Analysis (n=108)
Flow diagram: randomization, treatment, and angiographic recordings during primary, percutaneous coronary intervention.
with two patients (3.7%) randomized to the diltiazem group (P = 1.000). Reinfarction occurred in one patient (1.9%) in every group (P = 1.000). Target vessel revascularization was performed in two patients (3.7%) randomized to the COM group and in seven patients (13.0%) randomized to the diltiazem group (P = 0.161). Fig. 4 shows the Kaplan–Meier curve of MACEs free survival rate. There was no difference in MACEs in the two groups at 6 months (log-rank χ2 = 2.853, P =0.091).
Discussion In the present study, we have evaluated the combined administration of anisodamine and diltiazem during primary PCI in STEMI patients. The major findings of our study are as follows: (a) the percent of TIMI flow grade 3 and TMPG 3 was found to be higher after intracoronary anisodamine and diltiazem infusion. cTFC was significantly lower in the COM group than in the diltiazem group; (b) during the PCI procedure, reperfusion
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Intracoronary anisodamine and diltiazem Peng et al. 649
Table 1 Baseline clinical characteristics of patients randomized to an intracoronary combined administration of anisodamine and diltiazem or only diltiazem
Age (years) Male [n(%)] Risk factors Hypertension [n (%)] Smoking [n (%)] Diabetes mellitus [n (%)] Dyslipidemia [n (%)] BMI (kg/m2) Family history of coronary artery disease [n (%)] Killip grade [n (%)] I II III Pain-to balloon time (h) Door-to-balloon time(min) Infarct-related vessel [n(%)] Left artery descendent Left circumflex artery Right coronary artery Thrombus grade [n (%)] 0/1 2 3 4 TIMI flow pre-PCI [n(%)] 0 or 1 2 Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) N-terminal prohormone brain natriuretic peptide (pg/ml) High-sensitivity C-reactive protein (mg/l) Creatinine clearance (ml/min)
COM group (n = 54)
Diltiazem group (n = 54)
P
63.1 ± 4.3 40 (74.1)
63.2 ± 10.1 45 (83.3)
0.947 0.347
23 (42.6) 31 (57.4) 32 (59.3) 16 (29.6) 28.1 ± 2.6 12 (22.2)
21 (38.9) 36 (66.7) 25 (46.3) 22 (40.7) 27.3 ± 2.9 18 (33.3)
0.845 0.428 0.248 0.386 0.134 0.283 0.413
40 (74.1) 11 (20.4) 3 (5.6) 8.5 ± 1.7 69 (IQR 48–84)
45 (83.3) 8 (14.8) 1 (1.9) 8.9 ± 1.8 61 (IQR 50–79)
26(48.1) 5 (9.3) 23 (42.6)
23 (42.6) 8 (14.8) 23 (42.6)
4 (7.4) 10 (18.5) 12 (22.2) 28 (51.9)
9 (16.7) 13 (24.1) 9 (16.7) 23 (42.6)
38 (70.4) 6 (11.1) 126.5 ± 23.4 77.9 ± 11.3 72.9 ± 10.8 222 (IQR 128–255) 27.6 ± 5.8 89.2 ± 28.6
32 (59.3) 15 (27.8) 128.9 ± 24.7 78.1 ± 11.6 70.1 ± 17.6 212 (IQR 123–555) 28.3 ± 5.1 87.4 ± 24.5
0.238 0.238 0.645
0.357
0.086
0.605 0.928 0.321 0.627 0.507 0.726
Data are expressed as mean ± SD, median [25–75% interquartile range (IQR)], or as number (%). Creatinine clearance less than 70 ml/min is defined as renal damage. PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.
arrhythmia rates were significantly lower for the patients in the COM group. No reflow following primary PCI, despite the presence of a patent epicardial vessel, is a serious complication resulting in increased mortality. There is considerable evidence suggesting that no reflow is mainly because of dysfunctional microcirculation and the presence of vasospasm at the level of the resistance arterioles. Some researchers suggested that distal end occlusion resulting from microthrombus, lipoids, or plaque fragments may be relevant. Among these, microvascular spasm is one of the main causes [10]. Upfront strategies to reduce the incidence of no reflow could be considered for high-risk patients to improve outcomes. Clinical and basic studies have shown that calcium antagonists could attenuate microvascular spasm [11,12]. As a vasodilator, diltiazem has been shown to improve myocardial microcirculation by dilating the coronary arteriole [11]. Intravenous diltiazem treatment improved cardiac function and microvascular thrombotic injury in a rat model of coronary thrombotic microembolism [12]. Intracoronary infusion of diltiazem or verapamil can reverse no reflow more effectively than nitroglycerin during primary PCI for acute myocardial infarction [4].
The efficacy of diltiazem and verapamil is similar, and diltiazem seems to be safer [3]. However, these favorable results should be interpreted with caution because they are limited by a small sample size, potential selection bias, or a nonrandomized trial design. Although intracoronary verapamil and diltiazem have been utilized during PCI to maximize coronary blood flow, both have dose-limiting chronotropic, dromotropic, and negative inotropic effects on the heart. Intensive lowering of blood pressure in most STEMI is associated with an increase in the risk of low cardiac output. Reduced heart rate or blood pressure has limited the use of diltiazem. Our previous studies showed that the SBP, DBP, and mean pressures of intracoronary artery after intracoronary administration of anisodamine increased from 115 to 123, 75 to 84, and 88 to 95 mmHg, respectively, along with an increase in heart rate from 68 to 84 beats/min [6]. Thus, we hypothesized that intracoronary administration of anisodamine before administration of diltiazem might exert synergistic effects on myocardial reperfusion while offsetting these side effects. Anisodamine is a naturally occurring atropine derivative that has been isolated, synthesized, and characterized by scientists in China. Anisodamine alleviates inflammatory
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
650
Coronary Artery Disease 2014, Vol 25 No 8
Fig. 2
Fig. 3
(a)
P =0.03
100 90 70
75.90%
60 50 40
92.60%
TIMI3 TIMI≤2
30 20 24.10%
10 0
Diltiazem group
(b) 90
Patients (%)
70
46.30% 68.50%
60 40 30
53.70% 31.50%
10 0
10
TMPG3 TMPG≤2
50
20
5 Time after PCI (min)
Myocardial reperfusion as assessed by cTFC in patients randomized to intracoronary two drugs and intracoronary diltiazem, 30 (interquartile range, 27–32) versus 44 (interquartile range, 40–48) immediately after PCI (P < 0.0001), 24 (interquartile range, 21–27) versus 30 (interquartile range, 27–32) after 5 min (P < 0.0001), 16 (interquartile range, 14–20) versus 24 (interquartile range, 21–28) after 10 min (P < 0.0001). cTFC, corrected TIMI frame count; PCI, percutaneous coronary intervention.
P =0.03
80
Group COM group Diltiazem group
0
7.40% COM group
100
cTFC
Patients (%)
80
50 45 40 35 30 25 20 15 10 5 0
COM group
Diltiazem group
Myocardial reperfusion as assessed by angiography in patients randomized to intracoronary anisodamine and diltiazem and intracoronary placebo. The percentages of patients according to (a) thrombolysis in myocardial infarction (TIMI), (b) TIMI myocardial perfusion grade (TMPG) are shown.
damage and exerts protective effects in an animal model of infusion phlebitis [13]. Many studies have shown that it improves microcirculation by relieving vasospasms, reducing microthrombosis, inhibiting inflammation, and protecting the vascular endothelium [14–16]. Yin et al. [17] assumed that the cellular protective effect of anisodamine is partially attributable to its inhibition of the endoplasm reticulum stress response in cardiomyocytes; this activity may also be associated with its improvement of microcirculation blood current. Several mechanisms have been proposed to explain its beneficial effect, although most mechanisms are based on the assumption that anisodamine ultimately acts by improving blood flow in the microcirculation [18]. Anisodamine is vasoactive in relieving microvascular spasm, improving and dredging the microcirculation, and increasing the tolerance to ischemia in patients with microcirculatory disorder [19]. Our current study has shown that intracoronary administration of anisodamine before administration of diltiazem is effective in preventing the no-reflow phenomenon following PCI in STEMI patients, especially in patients with bradycardia or
hypotension. This study is the first to show that one kind of acetylcholine receptor blockers in combination with calcium antagonists can improve slow or no reflow. In the present study, administration was safe and well tolerated. Poupko et al. [18] reported that the cardiovascular properties of anisodamine include depression of cardiac conduction and the ability to protect against arrhythmia induced by various agents, whereas our data showed that anisodamine combined with diltiazem showed the tendency to reduce bradycardiac arrhythmia. Moreover, use of a temporary pacemaker was decreased and the thus the side effects would be reduced. It is interesting to note that accelerated idioventricular rhythm and tachyarrhythmia were observed more frequently in patients randomized to intracoronary diltiazem. Accelerated idioventricular rhythm is the most frequent arrhythmia occurring during primary PCI in patients with STEMI. However, it is not a marker of successful reperfusion, but is associated with extensive myocardial damage and delayed microvascular reperfusion [20]. High-sensitivity C-reactive protein was an independent correlate of in-hospital MACEs and may play a crucial role in both the pathogenesis and the development of slow coronary flow [21]. In this study, high-sensitivity C-reactive protein levels were lower in the COM group than in the diltiazem group after 1 week of PCI, which indicated that intracoronary anisodaminereflected and diltiazem-reflected ischemic burden was reduced, reperfusion was a success, and prognosis would improve. The physiological effects of anisodamine are multifactorial and still not fully understood. In addition to
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Intracoronary anisodamine and diltiazem Peng et al. 651
Angiographic procedure and outcomes of patients randomized to intracoronary combination administration of anisodamine and diltiazem or only diltiazem
Table 2
Procedural Thrombus aspiration [n (%)] Use of temporary pacemaker [n (%)] Use of glycoprotein IIb/IIIa inhibitor [n (%)] Balloon predilatation [n(%)] Stent implantation [n(%)] Stent diameter (mm) Stent length (mm) ST-segment resolution [n (%)] Complete (>70%) Partial (70–30%) No improvement (< 30%) cTnI maximum(U/l) CK-MB maximum(U/l) Time to CK-MB maximum (h) One week post-PCI N-terminal prohormone brain natriuretic peptide (pg/ml) High-sensitivity C-reactive protein (mg/l) Echo of 1 week post-PCI Left ventricular ejection fraction (%) Left ventricular end diastolic volume (ml) Left ventricular end systolic volume (ml)
COM group (n = 54)
Diltiazem group (n = 54)
5 (9.3) 3 (5.6) 30 (55.6) 51 (94.4) 54 (100) 3.3 ± 0.6 22.3 ± 12.8
11 (20.4) 11 (20.4) 37 (68.5) 52 (96.3) 54 (100) 3.3 ± 0.8 25.1 ± 11.3
40 (74.1) 10 (18.5) 4 (7.4) 2.2 (IQR 0.5–5.7) 264 (IQR 220–317) 6.4 (IQR 3.4–9.9)
25 (46.3) 15 (27.8) 14 (25.9) 3.9 (IQR 1.0–7.8) 255 (IQR 198–330) 6.9 (IQR 3.4–13.0)
1306 (IQR 255–2578) 7.7 ± 0.8
2334 (IQR 1221–3224) 9.3 ± 1.1
54.2 ± 10.3 159 ± 40 109 ± 39
50.2 ± 12.8 150 ± 45 105 ± 49
P 0.176 0.045 0.234 1.0 – 0.819 0.231 0.007
0.165 0.555 0.055 0.067 < 0.001 0.077 0.275 0.640
Data are expressed as mean ± SD, median [25–75% interquartile range (IQR)], or as number (%). CK-MB, creatine phosphokinase-MB; cTnI, cardiac troponin I; PCI, percutaneous coronary intervention.
Side effects unassociated with the heart in patients randomized to the COM group or diltiazem
Table 3
COM group (n = 54) Hypotension Flushing Thirst Blurred vision Retention of urine
8 3 8 1 8
(14.8) (5.6) (14.8) (1.9) (14.8)
Diltiazem group (n = 54) 5 6 3 1 4
(9.35) (11.1) (5.6) (1.9) (7.4)
P 0.556 0.489 0.202 1 0.359
Data are expressed as number (%).
Fig. 4
MACEs free survival rate (%)
100 95 90 85 80
Clinical outcomes after PCI did not differ significantly between patients randomized to the COM group and intracoronary diltiazem, except left ventricular ejection fraction. Why does intracoronary administration of anisodamine and diltiazem not improve MACEs? The first explanation may be that the sample size was relatively small and the dose of the bolus intracoronary anisodamine and diltiazem may not have been adequate to induce maximal vasodilatation. Second, the systematic performance of thrombus aspiration and the administration of the glycoprotein IIb/IIIa inhibitor abciximab during primary PCI resulted in an improvement in myocardial reperfusion. Third, it can be discussed whether intracoronary infusion was administered in the right time window or by the correct route. Previous studies have reported performing intracoronary infusion after no reflow occurred; some studies have reported on the safety and efficacy of the administration of intracoronary drugs by micro or aspiration catheters distal to the culprit lesion.
75 Group COM group Diltiazem group
70 65 60 0
1
2 3 4 Follow-up time (months)
5
6
Kaplan–Meier curve of MACEs free survival rate. MACEs, major adverse cardiac events.
vasodilatation, experimental studies have documented anisodamine as an antioxidant that may protect against free radical-induced cellular damage.
Our study has several limitations. First, the study was limited by the small sample size, and there was no drugfree group for comparison. Additional large-scale research is required to confirm the impact of anisodamine and diltiazem before reperfusion on clinical outcomes and a placebo group should be included. In addition, although we excluded patients with cardiac shock, anisodamine is used widely in the treatment of septic shock because of its protective effects on many organs [14–16]. Anisodamine can reduce fibrinogen, increase fibrinolytic activity, and inhibit microthrombosis, but we did not test hemagglutination. Furthermore, intracoronary anisodamine and diltiazem boluses may be too short-acting for any beneficial effect and we cannot exclude the efficacy of prolonged
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
652 Coronary Artery Disease 2014, Vol 25 No 8
intracoronary administration. Trial drug doses were according to the previous test and literature [3,6]. However, 1 mg anisodamine might be too small for some patients; injection according to patients’ body weight might be more appropriate. Moreover, we should assess the infarction size by MRI, which is considered the ‘gold’ standard criterion of no reflow. It is difficult to define the exact mechanism of anisodamine or diltiazem and to differentiate antivasospasm and vasoconstriction effects. Therefore, further studies are required to explore these factors.
5 6
7
8
9
Conclusion
Intracoronary anisodamine and diltiazem administration before stenting improved the angiographic and electrocardiographic results and decreased reperfusion arrhythmia in patients with acute STEMI undergoing PCI. However, the definite clinical benefits of anisodamine and diltiazem were not found; additional large-scale research is required to confirm the impact of anisodamine and diltiazem on clinical outcomes.
10 11
12
Acknowledgements
13
The authors are very grateful to the physicians and staff members of the Department of Cardiology, Bethune International Peace Hospital.
14
This work was partially funded by the Natural Science Foundation of China No. 81350003. 15
Conflicts of interest
16
There are no conflicts of interest. 17
References 1
2
3
4
Resnic FS, Wainstein M, Lee MK, Behrendt D, Wainstein RV, OhnoMachado L, et al. No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention. Am Heart J 2003; 145:42–46. Harrison RW, Aggarwal A, Ou FS, Klein LW, Rumsfeld JS, Roe MT, et al. Incidence and outcomes of no-reflow phenomenon during percutaneous coronary intervention among patients with acute myocardial infarction. Am J Cardiol 2013; 111:178–184. Huang D, Qian J, Ge L, Jin X, Jin H, Ma J, et al. REstoration of COronary flow in patients with No-Reflow Phenomenon after primary coronary interVEntion of acute myocaRdial infarction (RECOVER). Am Heart J 2012; 164:394–401. Ozdogru I, Zencir C, Dogan A, Orscelik O, Inanc MT, Celik A, et al. Acute effects of intracoronary nitroglycerin and diltiazem in coronary slow flow phenomenon. J Investig Med 2013; 61:45–49.
18 19
20
21
Berg R, Buhari C. Treating and preventing no reflow in the cardiac catheterization laboratory. Curr Cardiol Rev 2012; 8:209–212. Fu XH, Fan WZ, Gu XS, Wei YY, Jiang YF, Wu WL, et al. Effect of intracoronary administration of anisodamine on slow reflow phenomenon following primary percutaneous coronary intervention in patients with acute myocardial infarction. Chin Med J (Engl) 2007; 120:1226. Brodie BR, Stuckey TD, Hansen C, VerSteeg DS, Muncy DB, Moore S, et al. Relation between electrocardiographic ST-segment resolution and early and late outcomes after primary percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 2005; 95:343–348. Tanzilli G, Greco C, Pasceri V, Pelliccia F, Arrivi A, Placanica A, Mangieri E. Dipyridamole versus verapamil for treatment of no-reflow during primary angioplasty. Catheter Cardiovasc Interv 2010; 76:787–793. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Barron HV, Braunwald E. TIMI Study Group. Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 2002; 105:1909–1913. Konidala S, Gutterman DD. Coronary vasospasm and the regulation of coronary blood flow. Prog Cardiovasc Dis 2004; 46:349–373. Li L, Gu Y, Liu T, Bai Y, Hou L, Cheng Z, et al. A randomized, single-center double-blinded trial on the effects of diltiazem sustained-release capsules in patients with coronary slow flow phenomenon at 6-month follow-up. PLoS One 2012; 7:e38851. Bai Y, Hu L, Wu J, Gu Y, Li L, Gao B, Jiang H. Effects of intravenous diltiazem in a rat model of experimental coronary thrombotic microembolism. Exp Ther Med 2013; 6:873–882. Zhang ZX, Wang P, Zhang QS, Pan X, Zhao QX, Wang XK. Effects of anisodamine on the expressions of vascular endothelial growth factor and intercellular adhesion molecule 1 in experimental infusion phlebitis. Chin Med J (Engl) 2012; 125:300–305. Sun L, Zhang GF, Zhang X, Liu Q, Liu JG, Su DF, Liu C. Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors. Acta Pharmacol Sin 2012; 33:761–766. Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med J (Engl) 1992; 105:976–979. Zhou Q. Severe acute mountain sickness complicated by multiple organ dysfunction syndrome. Emerg Med 2012; 2:2. Yin XL, Shen H, Zhang W, Yang Y. Inhibition of endoplasm reticulum stress by anisodamine protects against myocardial injury after cardiac arrest and resuscitation in rats. Am J Chin Med 2011; 39:853–866. Poupko JM, Baskin SI, Moore E. The pharmacological properties of anisodamine. J Appl Toxicol 2007; 27:116–121. Wang Y, Fu X, Wang X, Jia X, Gu X, Zhang J, et al. Protective effects of anisodamine on renal function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Tohoku J Exp Med 2011; 224:91–97. Terkelsen CJ, Sørensen JT, Kaltoft AK, Nielsen SS, Thuesen L, Bøtker HE, Lassen JF. Prevalence and significance of accelerated idioventricular rhythm in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2009; 104:1641–1646. Yurtdaş M, Yaylali YT, Kaya Y, Ozdemir M. Increased plasma high-sensitivity C-reactive protein and myeloperoxidase levels may predict ischemia during myocardial perfusion imaging in slow coronary flow. Arch Med Res 2014; 45:63–69.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
645
Effect of intracoronary anisodamine and diltiazem administration during primary percutaneous coronary intervention in acute myocardial infarction Yuhong Penga, Xianghua Fua, Wei Lia, Wei Genga, Kun Xinga, Leisheng Rub, Jiaan Sunb and Yuying Zhaob Objective The aim of this study was to examine the role of intracoronary anisodamine and diltiazem administration performed before stenting on the immediate angiographic and clinical outcome in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods STEMI patients during primary PCI were randomized to two bolus injections of intracoronary anisodamine (1 mg/5 ml) and diltiazem (2 mg/5 ml) (COM group, n = 54) or saline (5 ml) and diltiazem (2 mg/5 ml) (diltiazem group, n = 54) before stenting. The primary endpoint was the incidence of no/slow reflow [thrombolysis in myocardial infarction (TIMI) flow grade ≤ 2] immediately after stenting. TIMI myocardial perfusion grade and corrected TIMI frame count were assessed. The secondary endpoints were major adverse cardiac events including death, nonfatal myocardial infarction, and target vessel revascularization. Results The percent of TIMI flow grade 3 was found to be higher in the COM group than in the diltiazem group (92.6 vs. 75.9%, P = 0.032). The percent of TIMI myocardial perfusion grade 3 was 46.3% in the diltiazem group and improved in the COM group (68.5%, P = 0.032). Corrected TIMI frame count was significantly lower in the COM group
Introduction The no-reflow performance is a predictive factor of continuous myocardial ischemia, ventricular remodeling, and cardiac dysfunction during primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) [1]. A higher incidence was identified in men, older patients, those with diabetes mellitus, those with a prolonged interval from symptom onset to admission, those with cardiogenic shock, and patients with longer lesions, bifurcation lesions, proximal left anterior descending coronary artery lesions, pre-PCI thrombus score of at least 4, collateral circulation 0–1, and impaired preprocedure thrombolysis in myocardial infarction (TIMI) flow [2]. Intracoronary infusion of diltiazem can reverse no reflow during primary PCI for STEMI [3]. After the application of intracoronary 5 mg diltiazem, heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP), and corrected TIMI frame counts (cTFC) were found to be 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
than in the diltiazem group (P < 0.0001). The COM group showed low incidences of bradyarrhythmia and rapid arrhythmia (7.4 vs. 24.1% and 3.7 vs. 18.5%, respectively, P = 0.032, P = 0.029). In addition, there were no significant differences in the secondary outcome measures. Conclusion Intracoronary anisodamine and diltiazem administration before stenting improved the angiographic results and prevented reperfusion arrhythmia in patients with STEMI undergoing PCI. Coron Artery Dis 25:645–652 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:645–652 Keywords: anisodamine, arrhythmias, cardiac, diltiazem, myocardial infarction, myocardial reperfusion injury, no-reflow phenomenon, percutaneous coronary intervention a
Department of Cardiology, Second Hospital of Hebei Medical University and Department of Cardiology, Bethune International Peace Hospital, Hebei, People’s Republic of China b
Correspondence to Xianghua Fu, MD, PhD, Department of Cardiology, Second Hospital of Hebei Medical University, 215 Heping West Road; Shijiazhuang, Hebei 050000, People’s Republic of China Tel: + 86 138 331 31680; fax: + 86 0311 8361 5346; e-mail: [email protected] Received 18 May 2014 Revised 2 August 2014 Accepted 4 August 2014
significantly lower than predrug values [4]. Calcium channel blockers work by several mechanisms including endothelium-mediated vasodilatation, reduction of myocardial oxygen demand by negative inotropic and chronotropic effects, and may reduce oxygen free radical damage during reperfusion [5]. It is important to note that although no reflow partly results from microvascular spasm, capillary destruction and microemboli to small arteries are likely to be major factors. However, diltiazem is mainly limited by side effects (bradycardia/hypotension) and shrunk by vasomotion effects. Therefore, we need drugs with broader pharmacological effects to prevent no reflow. Anisodamine is a nonspecific cholinergic antagonist. Many basic and clinical studies have proved that anisodamine can exert a significant effect on relieving microvascular spasm, and improving and dredging the coronary microcirculation. Intracoronary administration of anisodamine is effective in reversing no reflow following PCI DOI: 10.1097/MCA.0000000000000167
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
646
Coronary Artery Disease 2014, Vol 25 No 8
in STEMI patients; it is especially suitable for patients with bradycardia or hypotension [6]. Benefit beyond vasodilation makes it a potentially useful drug for the treatment of no reflow. Therefore, we hypothesize that intracoronary administration of these two vasodilate drugs might result in synergistic effects in STEMI patients. The aim of our study was to examine the role of intracoronary anisodamine and diltiazem administration during primary angioplasty on the immediate angiographic results and clinical course.
Methods Study design and population
This study is a prospective, randomized, control study. Patients presenting with STEMI were selected among 150 patients consecutively referred to the catheterization laboratory of our institution for emergency primary coronary angioplasty between January 2012 and January 2014. The study was approved by the local medical ethics committee and was carried out in accordance with the Helsinki II declaration. All patients provided written informed consent. The femoral and radial artery accesses were obtained, and heparin was administered at a dose of 100 IU/kg to maintain an activated clotting time greater than 250 s. Selection of a bare-metal or a drug-eluting stent was made according to the clinical and angiographic characteristics and considering financial limitations. The inclusion criteria were as follows: (1) Symptoms suggesting acute myocardial ischemia lasting 30 min. (2) Ischemic chest pain associated with ST-segment elevation of 0.1 mV in two or more leads on the ECG. (3) Patients with STEMI with symptom onset within the previous 12 h or symptom onset within the previous 12–24 h who had clinical and/or ECG evidence of ongoing ischemia. (4) Culprit coronary artery abnormalities: initial TIMI grade of 2 or less. The exclusion criteria were bradycardia (heart rate ≤ 60 bpm) or hypotension (SBP ≤ 90 mmHg or DBP ≤ 60 mmHg); atrioventricular block; previous myocardial infarction resulting in left ventricular dysfunction (previous of left ventricular ejection fraction ≤ 0.50); history of any malignancy within the past 5 years; cardiogenic shock; nonmelanoma skin cancer or cervical cancer in situ; history of thrombocytosis (platelets ≥ 500 000/mm3); history of thrombocytopenia; history of stroke or transient ischemic attack within the past 6 months; chronic liver disease that might interfere with survival; chronic renal insufficiency as defined by a creatinine level of at least 2 mg/dl; and inability to provide informed consent.
Randomization and treatment
After the performance of an initial coronary angiography, patients who fulfilled the eligibility criteria were randomly allocated in a ratio of 1 : 1 to two groups: COM group (n = 54, received anisodamine, 1 mg/5 ml and diltiazem, 2 mg/5 ml; first anisodamine, then diltiazem) and diltiazem group (n = 54, received saline 5 ml and diltiazem, 2 mg/5 ml). Randomization concealment was carried out by the sealed envelope technique. Administration was by an injection through the guiding catheter: the injection was administered immediately after we crossed the lesion of the infarct-related artery with the guidewire, or after the balloon passed the lesion, or after the balloon inflation before stenting (TIMI > 0 before the intracoronary injection). Electrocardiogram analysis
A 12-lead ECG was assessed at baseline and 90 min after primary PCI. The existing ST-segment deviation in the single ECG had a maximum deviation of 90 min on judging myocardial reperfusion after primary angioplasty [7]. A decrease in the single lead with a maximum deviation of ST-segment elevation was categorized as complete (>70%), partial (70–30%), or no improvement (< 30%) in ST-segment resolution, and was used as an indirect measure of myocardial reperfusion. Angiographic analysis
Coronary angiograms were reviewed by two experienced interventional cardiologists who were blinded to the therapy that the patients received. PCI was considered successful when the residual stenosis was 10%, in the absence of dissection, thrombosis, or distal vessel embolization. During PCI, TIMI, cTFC, and TIMI myocardial perfusion grade (TMPG) were assessed at an angiographic core laboratory as defined previously [8,9]. Two-dimensional echocardiography and laboratory data
We performed an echocardiography to assess the severity of left ventricular remodeling. At baseline, within a week after PCI, 2D echocardiography was used to assess conventional parameters such as left ventricular end systolic volume, left ventricular end diastolic volume, and left ventricular ejection fraction. At the 6-month follow-up, 2D echocardiography was performed again. Blood samples were obtained at 4, 8, 12, 16, and 24 h in all patients after the intervention for creatine kinase-MB, and after 12 h for cardiac troponin I. The levels above the cut-off points were considered markers of myonecrosis. Biochemical indicators including high-sensitivity C-reactive protein and N-terminal prohormone brain natriuretic peptide were detected before PCI and 1 week after PCI. Clinical follow-up
Side effects that were specifically documented were bradycardia (including symptomatic bradycardia,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Intracoronary anisodamine and diltiazem Peng et al. 647
atrioventricular block) and tachyarrhythmia (including ventricular fibrillation, ventricular tachycardia, accelerated idioventricular rhythm, and frequent ventricular premature beats), hypotension, flushing, thirst, blurred vision, and retention of urine. The primary endpoint was the incidence of no/slow reflow (TIMI flow grade ≤ 2) after stenting; TMPG and cTFC were also observed. The secondary endpoints were major adverse cardiovascular events (MACEs) including death, nonfatal myocardial infarction, and target vessel revascularization. All patients were followed for 6 months. Follow-up data after primary PCI were collected from hospital records, written questionnaires, and telephone interviews.
Sample size
On the basis of a clinical audit in our hospital and a literature review, we estimated that the incidence of no/ slow reflow (TIMI ≤ 2) during primary PCI would be 35% in the diltiazem group and 10% in the COM group. A minimum of 108 patients (n = 54 per group) would provide 90% power to reject the null hypothesis with a type 1 error of 0.05.
Statistical analysis
Categorical variables were presented as frequency values and proportions and were compared using the χ2-test or the Fisher exact test. Continuous normally distributed variables were presented as mean values and SDs and were compared using the two-tailed Student’s t-test. For skewed distributed variables, median values with interquartile range were calculated and the variables were compared using the Mann–Whitney U-test. Kaplan–Meier plots were generated to determine the clinical follow-up data differences over time among different groups. For all analyses, a P-value less than 0.05, two-tailed, was considered statistically significant. Statistical analysis was carried out using the Statistical Package for IBM SPSS Statistics 16.0 (IBM Corporation, Chicago, Illinois, USA) and MedCalc statistical software 12.3.0 (MedCalc Software bvba, Brussels, Belgium). Data were presented as mean ± SD, n/N (%), or interquartile range.
Results Patient characteristics
After the initial angiography, 108 patients, 78 men and 30 women, who fulfilled the inclusion criteria and followed up in the end were randomized to the COM group and the diltiazem group (Fig. 1). There was no statistically significant difference in the clinical characteristics, laboratory examination results, and drug treatment between the two groups before the operation (Table 1).
Myocardial reperfusion as assessed by angiography and electrocardiography
Before PCI, the angiographic characteristics of the two groups were similar. After coronary reperfusion, TIMI flow grade 3 occurred in 50 patients in the COM group and 41 patients in whom anisodamine was not administered (92.6 vs. 75.9%; P = 0.032) (Fig. 2). TMPG 3 was found to be higher in 37 patients in the anisodamine and the diltiazem administration group and 25 patients in the diltiazem group (68.5 vs. 46.3%; P = 0.032) (Fig. 2) immediately after PCI. An intracoronary injection with combination resulted in greater cTFC than injection with diltiazem after PCI (Fig. 3). Table 2 shows the angiographic procedure and outcomes. Resolution of single-lead ST-segment elevation (>70%) was more frequently observed in the COM group than in the diltiazem group. However, a Q-wave myocardial infarction developed in 46 patients in the COM group and in 48 patients in the diltiazem group (85.2 vs. 88.9%, P = 0.775). Patients in the diltiazem group were more likely to use a temporary pacemaker. The highsensitivity C-reactive protein level in patients of the COM group was higher than that of the control group. There was no significant difference in left ventricular ejection fractions in those in whom drugs were or were not administered within 1 week after PCI (Table 2). From the baseline to 1 week after PCI, there was a significant increase in the levels of N-terminal prohormone brain natriuretic peptide and high-sensitivity C-reactive protein level in the entire patient population (P < 0.0001). However, no difference was observed between the two groups in the levels of N-terminal prohormone brain natriuretic peptide between baseline and 1 week. Side effects
Side effects were reported during the PCI procedure. Symptomatic bradycardia, and II and III degree atrioventricular blocks were observed in four patients in the COM group and in 13 patients in the diltiazem group (7.4 vs. 24.1%; P = 0.032). In the COM group, two patients (3.7%) developed accelerated idioventricular rhythm and tachyarrhythmia, whereas the frequency of rapid reperfusion arrhythmias was higher in 10 patients (18.5%) administered diltiazem (P = 0.029). However, the incidence of adverse effects unassociated with the heart did not differ between the two groups (Table 3). All side effects disappeared within 2–3 h and no clinical sequela was observed. Follow-up
Left ventricular ejection fraction at 6 months after PCI was 59.2 ± 12.3% in patients randomized to intracoronary anisodamine and diltiazem versus 51.2 ± 13.4% in the group with only diltiazem (P = 0.002). Only one patient (1.9%) randomized to the COM group died compared
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
648
Coronary Artery Disease 2014, Vol 25 No 8
Fig. 1
Assessed for eligibility (n=150)
Initial angiogram
Excluded (n=19); not meeting inclusion criteria (n=16); declined to participate (n=3); other reasons (n=2)
Randomized (n=110)
Diltiazem group
COM group
Wire passage (n=55) Ballon angioplasty (n=55)
Wire passage (n=55) Ballon angioplasty (n=55)
Intracoronary anisodamine (1 mg/5 ml) and diltiazem (2 mg/5 ml)
Intracoronary saline (5 ml) and diltiazem (2 mg/5 ml)
Follow-up (n=110) Lost to follow-up (n=1) Discontinued intervention (n=0)
Lost to follow-up (n=1) Discontinued intervention (n=0) Analysis (n=108)
Flow diagram: randomization, treatment, and angiographic recordings during primary, percutaneous coronary intervention.
with two patients (3.7%) randomized to the diltiazem group (P = 1.000). Reinfarction occurred in one patient (1.9%) in every group (P = 1.000). Target vessel revascularization was performed in two patients (3.7%) randomized to the COM group and in seven patients (13.0%) randomized to the diltiazem group (P = 0.161). Fig. 4 shows the Kaplan–Meier curve of MACEs free survival rate. There was no difference in MACEs in the two groups at 6 months (log-rank χ2 = 2.853, P =0.091).
Discussion In the present study, we have evaluated the combined administration of anisodamine and diltiazem during primary PCI in STEMI patients. The major findings of our study are as follows: (a) the percent of TIMI flow grade 3 and TMPG 3 was found to be higher after intracoronary anisodamine and diltiazem infusion. cTFC was significantly lower in the COM group than in the diltiazem group; (b) during the PCI procedure, reperfusion
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Intracoronary anisodamine and diltiazem Peng et al. 649
Table 1 Baseline clinical characteristics of patients randomized to an intracoronary combined administration of anisodamine and diltiazem or only diltiazem
Age (years) Male [n(%)] Risk factors Hypertension [n (%)] Smoking [n (%)] Diabetes mellitus [n (%)] Dyslipidemia [n (%)] BMI (kg/m2) Family history of coronary artery disease [n (%)] Killip grade [n (%)] I II III Pain-to balloon time (h) Door-to-balloon time(min) Infarct-related vessel [n(%)] Left artery descendent Left circumflex artery Right coronary artery Thrombus grade [n (%)] 0/1 2 3 4 TIMI flow pre-PCI [n(%)] 0 or 1 2 Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) N-terminal prohormone brain natriuretic peptide (pg/ml) High-sensitivity C-reactive protein (mg/l) Creatinine clearance (ml/min)
COM group (n = 54)
Diltiazem group (n = 54)
P
63.1 ± 4.3 40 (74.1)
63.2 ± 10.1 45 (83.3)
0.947 0.347
23 (42.6) 31 (57.4) 32 (59.3) 16 (29.6) 28.1 ± 2.6 12 (22.2)
21 (38.9) 36 (66.7) 25 (46.3) 22 (40.7) 27.3 ± 2.9 18 (33.3)
0.845 0.428 0.248 0.386 0.134 0.283 0.413
40 (74.1) 11 (20.4) 3 (5.6) 8.5 ± 1.7 69 (IQR 48–84)
45 (83.3) 8 (14.8) 1 (1.9) 8.9 ± 1.8 61 (IQR 50–79)
26(48.1) 5 (9.3) 23 (42.6)
23 (42.6) 8 (14.8) 23 (42.6)
4 (7.4) 10 (18.5) 12 (22.2) 28 (51.9)
9 (16.7) 13 (24.1) 9 (16.7) 23 (42.6)
38 (70.4) 6 (11.1) 126.5 ± 23.4 77.9 ± 11.3 72.9 ± 10.8 222 (IQR 128–255) 27.6 ± 5.8 89.2 ± 28.6
32 (59.3) 15 (27.8) 128.9 ± 24.7 78.1 ± 11.6 70.1 ± 17.6 212 (IQR 123–555) 28.3 ± 5.1 87.4 ± 24.5
0.238 0.238 0.645
0.357
0.086
0.605 0.928 0.321 0.627 0.507 0.726
Data are expressed as mean ± SD, median [25–75% interquartile range (IQR)], or as number (%). Creatinine clearance less than 70 ml/min is defined as renal damage. PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.
arrhythmia rates were significantly lower for the patients in the COM group. No reflow following primary PCI, despite the presence of a patent epicardial vessel, is a serious complication resulting in increased mortality. There is considerable evidence suggesting that no reflow is mainly because of dysfunctional microcirculation and the presence of vasospasm at the level of the resistance arterioles. Some researchers suggested that distal end occlusion resulting from microthrombus, lipoids, or plaque fragments may be relevant. Among these, microvascular spasm is one of the main causes [10]. Upfront strategies to reduce the incidence of no reflow could be considered for high-risk patients to improve outcomes. Clinical and basic studies have shown that calcium antagonists could attenuate microvascular spasm [11,12]. As a vasodilator, diltiazem has been shown to improve myocardial microcirculation by dilating the coronary arteriole [11]. Intravenous diltiazem treatment improved cardiac function and microvascular thrombotic injury in a rat model of coronary thrombotic microembolism [12]. Intracoronary infusion of diltiazem or verapamil can reverse no reflow more effectively than nitroglycerin during primary PCI for acute myocardial infarction [4].
The efficacy of diltiazem and verapamil is similar, and diltiazem seems to be safer [3]. However, these favorable results should be interpreted with caution because they are limited by a small sample size, potential selection bias, or a nonrandomized trial design. Although intracoronary verapamil and diltiazem have been utilized during PCI to maximize coronary blood flow, both have dose-limiting chronotropic, dromotropic, and negative inotropic effects on the heart. Intensive lowering of blood pressure in most STEMI is associated with an increase in the risk of low cardiac output. Reduced heart rate or blood pressure has limited the use of diltiazem. Our previous studies showed that the SBP, DBP, and mean pressures of intracoronary artery after intracoronary administration of anisodamine increased from 115 to 123, 75 to 84, and 88 to 95 mmHg, respectively, along with an increase in heart rate from 68 to 84 beats/min [6]. Thus, we hypothesized that intracoronary administration of anisodamine before administration of diltiazem might exert synergistic effects on myocardial reperfusion while offsetting these side effects. Anisodamine is a naturally occurring atropine derivative that has been isolated, synthesized, and characterized by scientists in China. Anisodamine alleviates inflammatory
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
650
Coronary Artery Disease 2014, Vol 25 No 8
Fig. 2
Fig. 3
(a)
P =0.03
100 90 70
75.90%
60 50 40
92.60%
TIMI3 TIMI≤2
30 20 24.10%
10 0
Diltiazem group
(b) 90
Patients (%)
70
46.30% 68.50%
60 40 30
53.70% 31.50%
10 0
10
TMPG3 TMPG≤2
50
20
5 Time after PCI (min)
Myocardial reperfusion as assessed by cTFC in patients randomized to intracoronary two drugs and intracoronary diltiazem, 30 (interquartile range, 27–32) versus 44 (interquartile range, 40–48) immediately after PCI (P < 0.0001), 24 (interquartile range, 21–27) versus 30 (interquartile range, 27–32) after 5 min (P < 0.0001), 16 (interquartile range, 14–20) versus 24 (interquartile range, 21–28) after 10 min (P < 0.0001). cTFC, corrected TIMI frame count; PCI, percutaneous coronary intervention.
P =0.03
80
Group COM group Diltiazem group
0
7.40% COM group
100
cTFC
Patients (%)
80
50 45 40 35 30 25 20 15 10 5 0
COM group
Diltiazem group
Myocardial reperfusion as assessed by angiography in patients randomized to intracoronary anisodamine and diltiazem and intracoronary placebo. The percentages of patients according to (a) thrombolysis in myocardial infarction (TIMI), (b) TIMI myocardial perfusion grade (TMPG) are shown.
damage and exerts protective effects in an animal model of infusion phlebitis [13]. Many studies have shown that it improves microcirculation by relieving vasospasms, reducing microthrombosis, inhibiting inflammation, and protecting the vascular endothelium [14–16]. Yin et al. [17] assumed that the cellular protective effect of anisodamine is partially attributable to its inhibition of the endoplasm reticulum stress response in cardiomyocytes; this activity may also be associated with its improvement of microcirculation blood current. Several mechanisms have been proposed to explain its beneficial effect, although most mechanisms are based on the assumption that anisodamine ultimately acts by improving blood flow in the microcirculation [18]. Anisodamine is vasoactive in relieving microvascular spasm, improving and dredging the microcirculation, and increasing the tolerance to ischemia in patients with microcirculatory disorder [19]. Our current study has shown that intracoronary administration of anisodamine before administration of diltiazem is effective in preventing the no-reflow phenomenon following PCI in STEMI patients, especially in patients with bradycardia or
hypotension. This study is the first to show that one kind of acetylcholine receptor blockers in combination with calcium antagonists can improve slow or no reflow. In the present study, administration was safe and well tolerated. Poupko et al. [18] reported that the cardiovascular properties of anisodamine include depression of cardiac conduction and the ability to protect against arrhythmia induced by various agents, whereas our data showed that anisodamine combined with diltiazem showed the tendency to reduce bradycardiac arrhythmia. Moreover, use of a temporary pacemaker was decreased and the thus the side effects would be reduced. It is interesting to note that accelerated idioventricular rhythm and tachyarrhythmia were observed more frequently in patients randomized to intracoronary diltiazem. Accelerated idioventricular rhythm is the most frequent arrhythmia occurring during primary PCI in patients with STEMI. However, it is not a marker of successful reperfusion, but is associated with extensive myocardial damage and delayed microvascular reperfusion [20]. High-sensitivity C-reactive protein was an independent correlate of in-hospital MACEs and may play a crucial role in both the pathogenesis and the development of slow coronary flow [21]. In this study, high-sensitivity C-reactive protein levels were lower in the COM group than in the diltiazem group after 1 week of PCI, which indicated that intracoronary anisodaminereflected and diltiazem-reflected ischemic burden was reduced, reperfusion was a success, and prognosis would improve. The physiological effects of anisodamine are multifactorial and still not fully understood. In addition to
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Intracoronary anisodamine and diltiazem Peng et al. 651
Angiographic procedure and outcomes of patients randomized to intracoronary combination administration of anisodamine and diltiazem or only diltiazem
Table 2
Procedural Thrombus aspiration [n (%)] Use of temporary pacemaker [n (%)] Use of glycoprotein IIb/IIIa inhibitor [n (%)] Balloon predilatation [n(%)] Stent implantation [n(%)] Stent diameter (mm) Stent length (mm) ST-segment resolution [n (%)] Complete (>70%) Partial (70–30%) No improvement (< 30%) cTnI maximum(U/l) CK-MB maximum(U/l) Time to CK-MB maximum (h) One week post-PCI N-terminal prohormone brain natriuretic peptide (pg/ml) High-sensitivity C-reactive protein (mg/l) Echo of 1 week post-PCI Left ventricular ejection fraction (%) Left ventricular end diastolic volume (ml) Left ventricular end systolic volume (ml)
COM group (n = 54)
Diltiazem group (n = 54)
5 (9.3) 3 (5.6) 30 (55.6) 51 (94.4) 54 (100) 3.3 ± 0.6 22.3 ± 12.8
11 (20.4) 11 (20.4) 37 (68.5) 52 (96.3) 54 (100) 3.3 ± 0.8 25.1 ± 11.3
40 (74.1) 10 (18.5) 4 (7.4) 2.2 (IQR 0.5–5.7) 264 (IQR 220–317) 6.4 (IQR 3.4–9.9)
25 (46.3) 15 (27.8) 14 (25.9) 3.9 (IQR 1.0–7.8) 255 (IQR 198–330) 6.9 (IQR 3.4–13.0)
1306 (IQR 255–2578) 7.7 ± 0.8
2334 (IQR 1221–3224) 9.3 ± 1.1
54.2 ± 10.3 159 ± 40 109 ± 39
50.2 ± 12.8 150 ± 45 105 ± 49
P 0.176 0.045 0.234 1.0 – 0.819 0.231 0.007
0.165 0.555 0.055 0.067 < 0.001 0.077 0.275 0.640
Data are expressed as mean ± SD, median [25–75% interquartile range (IQR)], or as number (%). CK-MB, creatine phosphokinase-MB; cTnI, cardiac troponin I; PCI, percutaneous coronary intervention.
Side effects unassociated with the heart in patients randomized to the COM group or diltiazem
Table 3
COM group (n = 54) Hypotension Flushing Thirst Blurred vision Retention of urine
8 3 8 1 8
(14.8) (5.6) (14.8) (1.9) (14.8)
Diltiazem group (n = 54) 5 6 3 1 4
(9.35) (11.1) (5.6) (1.9) (7.4)
P 0.556 0.489 0.202 1 0.359
Data are expressed as number (%).
Fig. 4
MACEs free survival rate (%)
100 95 90 85 80
Clinical outcomes after PCI did not differ significantly between patients randomized to the COM group and intracoronary diltiazem, except left ventricular ejection fraction. Why does intracoronary administration of anisodamine and diltiazem not improve MACEs? The first explanation may be that the sample size was relatively small and the dose of the bolus intracoronary anisodamine and diltiazem may not have been adequate to induce maximal vasodilatation. Second, the systematic performance of thrombus aspiration and the administration of the glycoprotein IIb/IIIa inhibitor abciximab during primary PCI resulted in an improvement in myocardial reperfusion. Third, it can be discussed whether intracoronary infusion was administered in the right time window or by the correct route. Previous studies have reported performing intracoronary infusion after no reflow occurred; some studies have reported on the safety and efficacy of the administration of intracoronary drugs by micro or aspiration catheters distal to the culprit lesion.
75 Group COM group Diltiazem group
70 65 60 0
1
2 3 4 Follow-up time (months)
5
6
Kaplan–Meier curve of MACEs free survival rate. MACEs, major adverse cardiac events.
vasodilatation, experimental studies have documented anisodamine as an antioxidant that may protect against free radical-induced cellular damage.
Our study has several limitations. First, the study was limited by the small sample size, and there was no drugfree group for comparison. Additional large-scale research is required to confirm the impact of anisodamine and diltiazem before reperfusion on clinical outcomes and a placebo group should be included. In addition, although we excluded patients with cardiac shock, anisodamine is used widely in the treatment of septic shock because of its protective effects on many organs [14–16]. Anisodamine can reduce fibrinogen, increase fibrinolytic activity, and inhibit microthrombosis, but we did not test hemagglutination. Furthermore, intracoronary anisodamine and diltiazem boluses may be too short-acting for any beneficial effect and we cannot exclude the efficacy of prolonged
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
652 Coronary Artery Disease 2014, Vol 25 No 8
intracoronary administration. Trial drug doses were according to the previous test and literature [3,6]. However, 1 mg anisodamine might be too small for some patients; injection according to patients’ body weight might be more appropriate. Moreover, we should assess the infarction size by MRI, which is considered the ‘gold’ standard criterion of no reflow. It is difficult to define the exact mechanism of anisodamine or diltiazem and to differentiate antivasospasm and vasoconstriction effects. Therefore, further studies are required to explore these factors.
5 6
7
8
9
Conclusion
Intracoronary anisodamine and diltiazem administration before stenting improved the angiographic and electrocardiographic results and decreased reperfusion arrhythmia in patients with acute STEMI undergoing PCI. However, the definite clinical benefits of anisodamine and diltiazem were not found; additional large-scale research is required to confirm the impact of anisodamine and diltiazem on clinical outcomes.
10 11
12
Acknowledgements
13
The authors are very grateful to the physicians and staff members of the Department of Cardiology, Bethune International Peace Hospital.
14
This work was partially funded by the Natural Science Foundation of China No. 81350003. 15
Conflicts of interest
16
There are no conflicts of interest. 17
References 1
2
3
4
Resnic FS, Wainstein M, Lee MK, Behrendt D, Wainstein RV, OhnoMachado L, et al. No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention. Am Heart J 2003; 145:42–46. Harrison RW, Aggarwal A, Ou FS, Klein LW, Rumsfeld JS, Roe MT, et al. Incidence and outcomes of no-reflow phenomenon during percutaneous coronary intervention among patients with acute myocardial infarction. Am J Cardiol 2013; 111:178–184. Huang D, Qian J, Ge L, Jin X, Jin H, Ma J, et al. REstoration of COronary flow in patients with No-Reflow Phenomenon after primary coronary interVEntion of acute myocaRdial infarction (RECOVER). Am Heart J 2012; 164:394–401. Ozdogru I, Zencir C, Dogan A, Orscelik O, Inanc MT, Celik A, et al. Acute effects of intracoronary nitroglycerin and diltiazem in coronary slow flow phenomenon. J Investig Med 2013; 61:45–49.
18 19
20
21
Berg R, Buhari C. Treating and preventing no reflow in the cardiac catheterization laboratory. Curr Cardiol Rev 2012; 8:209–212. Fu XH, Fan WZ, Gu XS, Wei YY, Jiang YF, Wu WL, et al. Effect of intracoronary administration of anisodamine on slow reflow phenomenon following primary percutaneous coronary intervention in patients with acute myocardial infarction. Chin Med J (Engl) 2007; 120:1226. Brodie BR, Stuckey TD, Hansen C, VerSteeg DS, Muncy DB, Moore S, et al. Relation between electrocardiographic ST-segment resolution and early and late outcomes after primary percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 2005; 95:343–348. Tanzilli G, Greco C, Pasceri V, Pelliccia F, Arrivi A, Placanica A, Mangieri E. Dipyridamole versus verapamil for treatment of no-reflow during primary angioplasty. Catheter Cardiovasc Interv 2010; 76:787–793. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Barron HV, Braunwald E. TIMI Study Group. Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 2002; 105:1909–1913. Konidala S, Gutterman DD. Coronary vasospasm and the regulation of coronary blood flow. Prog Cardiovasc Dis 2004; 46:349–373. Li L, Gu Y, Liu T, Bai Y, Hou L, Cheng Z, et al. A randomized, single-center double-blinded trial on the effects of diltiazem sustained-release capsules in patients with coronary slow flow phenomenon at 6-month follow-up. PLoS One 2012; 7:e38851. Bai Y, Hu L, Wu J, Gu Y, Li L, Gao B, Jiang H. Effects of intravenous diltiazem in a rat model of experimental coronary thrombotic microembolism. Exp Ther Med 2013; 6:873–882. Zhang ZX, Wang P, Zhang QS, Pan X, Zhao QX, Wang XK. Effects of anisodamine on the expressions of vascular endothelial growth factor and intercellular adhesion molecule 1 in experimental infusion phlebitis. Chin Med J (Engl) 2012; 125:300–305. Sun L, Zhang GF, Zhang X, Liu Q, Liu JG, Su DF, Liu C. Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors. Acta Pharmacol Sin 2012; 33:761–766. Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med J (Engl) 1992; 105:976–979. Zhou Q. Severe acute mountain sickness complicated by multiple organ dysfunction syndrome. Emerg Med 2012; 2:2. Yin XL, Shen H, Zhang W, Yang Y. Inhibition of endoplasm reticulum stress by anisodamine protects against myocardial injury after cardiac arrest and resuscitation in rats. Am J Chin Med 2011; 39:853–866. Poupko JM, Baskin SI, Moore E. The pharmacological properties of anisodamine. J Appl Toxicol 2007; 27:116–121. Wang Y, Fu X, Wang X, Jia X, Gu X, Zhang J, et al. Protective effects of anisodamine on renal function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Tohoku J Exp Med 2011; 224:91–97. Terkelsen CJ, Sørensen JT, Kaltoft AK, Nielsen SS, Thuesen L, Bøtker HE, Lassen JF. Prevalence and significance of accelerated idioventricular rhythm in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2009; 104:1641–1646. Yurtdaş M, Yaylali YT, Kaya Y, Ozdemir M. Increased plasma high-sensitivity C-reactive protein and myeloperoxidase levels may predict ischemia during myocardial perfusion imaging in slow coronary flow. Arch Med Res 2014; 45:63–69.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
