Verapamil

Background: Intracoronary calcium-channel blockers administered in the event of no reflow during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) have been shown to improve myocardial perfusion.

Study objective: To evaluate the effects of the administration of intracoronary verapamil before the occurrence of no reflow during direct PCI.

Design and setting: Single-center, nonrandomized, prospective study with a retrospective control group.

Patients and methods: From September 2001 to December 2003, 50 consecutive patients with AMI were prospectively enrolled for intracoronary verapamil treatment. Intracoronary verapamil was administered immediately prior to balloon inflation and at short intervals during the procedure thereafter. Retrospectively, 50 consecutive AMI patients who had undergone direct PCI and had not received intracoronary calcium-channel blockers were enrolled as control subjects. Patients with cardiogenic shock or platelet glycoprotein IIIb/IIIa inhibitor were excluded. Thrombolysis in Myocardial Infarction (TIMI) flow grade, corrected TIMI frame count (CTFC), and TIMI myocardial perfusion grade (TMPG) were assessed prior to and following PCI by two independent cardiologists blinded to the procedures.

Results: The two groups had similar baseline and postprocedural angiographic characteristics, although the patients who been administered verapamil received more stent implantations than the control subjects (84% vs 60%, p = 0.008). Postprocedural TIMI flow < 3 (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.12 to 1.30; p = 0.18) and TMPG (OR, 1.24; 95% CI, 0.46 to 3.34; p = 0.68) were not associated with the implantation of the stents. There were no significant difference in post-PCI TIMI flow (p = 0.68) and CTFC (p = 0.36) between patients treated with verapamil and the control subjects. Post-PCI TMPG was significantly better in patients treated with intracoronary verapamil (p = 0.003). Forty-two percent of the patients treated with verapamil were found to have TMPG-3, while only 14% of the control subjects were found to have the same degree of TMPG (p = 0.004). Treatment with intracoronary verapamil (OR, 0.26; 95% CI, 0.12 to 0.58; p = 0.001) and pre-PCI TIMI flow (OR, 0.54; 95% CI, 0.35 to 0.84; p = 0.006) were found by multiple logistic regression to be independent predictors of TMPG. Conclusions: Early administration of intracoronary verapamil during direct PCI improves postprocedural myocardial perfusion, as evaluated by TMPG.

Key words: angioplasty; coronary artery disease; intracoronary vempamil; myocardial infarction; no-reflow phenomenon.

Abbreviations: AMI = acute myocardial infarction; CI = confidence interval; CTFC = corrected Thrombolysis in Myocardial Infarction frame count; OR = odds ratio; PCI = percutaneous coronary intervention; TIMI = Thrombolysis in Myocardial Infarction; TMPG = Thrombolysis in Myocardial Infarction myocardial perfusion grade

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No-reflow phenomenon, defined as inadequate myocardial perfusion of the adequately dilated target vessel without evidence of angiographic mechanical obstruction, has been observed in 0.6 to 2% of all percutaneous coronary interventions (PCIs). (1-3) No-reflow phenomenon occurs more frequently in patients with acute coronary syndrome with total occlusion (3); in cases of acute myocardial infarction (AMI), no reflow results in prolonged myocardial ischemia after reperfusion of a target coronary artery. Angiographic no-reflow phenomenon has been reported in 10 to 44% of those undergoing PCI for AMI, (2,4-8) and it has been associated with microvascular reperfusion failure, (1,9,10) higher left ventricular dysfunction, and adverse clinical outcomes. (3,4,11,12)

Experimental and clinical studies (2,13) have shown microvascular spasm and reperfusion injury to be possible mechanisms behind the no-reflow phenomenon in myocardial infarction. Intracoronary calcium-channel blockers have been administered for no reflow during PCI for AMI and have been shown to improve microvascular perfusion and myocardial salvage. (14-16) However, once no reflow in AMI has developed and made it difficult for pharmacologic agents to reach the microvasculature, especially in a vessel with Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow, it can be resistant to such therapy. (17) In this study, we evaluate the effect of intracoronary verapamil before the no-reflow phenomenon occurs during PCI for AMI.

MATERIALS AND METHODS

From September 2001 to December 2003, 50 patients ready to undergo direct PCI within 12 h from the onset of AMI were prospectively and consecutively enrolled to receive intracoronary verapamil treatment. Intracoronary verapamil, 50 to 100 [micro]g, was administered just before the guidewire was advanced through the infarct-related vessel with TIMI flow grade > 0, just after guidewire was advanced through the distal portion of the totally occluded infarct-related vessel and, if improved TIMI flow developed, after the subsequent angiogram. Otherwise, verapamil was administered just as an uninflated balloon catheter was introduced through the totally occluded site of the infarct-related artery to the distal portion of the vessel. During the rest of the procedure, intracoronary verapamil, 50 to 100 [micro]g, was continued and administered in short intervals. For control subjects, we retrospectively enrolled from August 2000 to August 2001 50 consecutive patients who had undergone direct PCI within 12 h of AMI and who did not receive intracoronary calcium-channel blockers or platelet glycoprotein IIb/IIIa inhibitors.

AMI patients were included if they had continuous chest pain for at least 30 min, if they had been sent for PCI within 12 h of the onset of chest pain, and if they had been found to have ST-segment elevation [greater than or equal to] 1 mm (0.1 mV) in two or more contiguous leads on the 12-lead ECG. Patients who went into cardiogenic shock and patients treated with platelet glycoprotein IIb/IIIa inhibitors were excluded from the study. TIMI flow grade, corrected TIMI frame count (CTFC), and TIMI myocardial perfusion grade (TMPG) were assessed before and after PCI by two independent cardiologists blinded to the procedures. One month after the procedure, information on recurrent ischemic symptoms, death, target vessel myocardial infarction, or need for revascularization of the treated vessel was collected by chart check, outpatient visit, or telephone contact with the patient.

Angiographic Definitions

TIMI flow grade was classified into grade 0 (no flow), grade 1 (penetration without perfusion), grade 2 (partial perfusion), or grade 3 (complete perfusion). To objectively evaluate an index of coronary flow as a continuous quantitative variable, the number of cineframes required for contrast to first reach standardized distal coronary landinarks in the infarct-related artery (the TIMI frame count) was measured with a frame counter on the cineviewer (25 frames per second). A CTFC < 14 was defined as a CTFC that was faster then the 95% confidence interval (CI) for normal flow (0 to 13 frames, hyperemia, TIMI grade 4 flow). A CTFC of 40 has been previously identified as the cutoff point between TIMI grade 3 flow and TIMI grade 2 flow. (18)

The TMPG was used to assess the Idling and clearance of contrast in the myocardium. TMPG-0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery. TMPG-1 indicated a presence of myocardial blush but no clearance from the microvasculature (blush or a stain present on the next injection). TMPG-2 indicated that the blush cleared slowly (blush strongly persistent and diminished minimally or not at all during three cardiac cycles of the washout phase). TMPG-3 indicated that blush began to clear during washout (blush minimally persistent after three cardiac cycles of washout).

Statistical Analysis

Data are presented as mean [+ or -] SD unless otherwise noted. Differences between the two groups were examined by two-tailed Student t test, [chi square], and exact Mann-Whitney U rank test where appropriate. Variables entered into the logistic models were those with a univariate probability value of p < 0.20. Multivariate logistic models were used to identify the independent predictors of TMPG; p < 0.05 was considered significant.

RESULTS

Between September 2001 and December 2003, 50 consecutive patients undergoing direct PCI within 12 h from the onset of AMI were prospectively enrolled in the study. None of these patients received platelet glycoprotein IIb/IIIa inhibitors during the procedure. From August 2000 to August 2001, 50 consecutive patients who had undergone direct PCI within 12 h from onset of AMI and who had not received intracoronary calcium-channel blockers or platelet glycoprotein IIb/IIIa inhibitors were retrospectively enrolled as the control subjects. The two groups had similar baseline clinical characteristics, with the exception that significantly more verapamil patients received stent implantations (verapamil vs control, 84% vs 60%; p = 0.008) [Table 1].

Angiographic Analysis

Both groups had similar pre-PCI and post-PCI thrombus scores and TIMI flow grades, post-PCI CTFC, and post-PCI TIMI grade 3 flow (90% vs 84%, respectively) [Table 2]. The patients treated with intracoronary verapamil had significantly higher TMPG than the control subjects (p = 0.003) [Table 2]. TMPG-3 was observed in 21 of the patients (42%) who received intracoronary verapamil and in 7 of the control subjects (14%) who did not (p = 0.004) [Table 2].

Univariate analysis showed that the pre-PCI thrombus score (odds ratio [OR], 1.62; 95% CI, 1.03 to 2.54; p = 0.04), pre-PCI TIMI flow (OR, 0.51; 95% CI, 0.33 to 0.78; p = 0.002) and intracoronary verapamil (OR, 0.23; 95% CI, 0.11 to 0.51; p = 0.0003) were all independent predictors of TMPG (Table 3). However, the results of multiple logistic regression found only treatment with intracoronary verapamil (OR, 0.26; 95% CI, 0.12 to 0.58; p = 0.001) and pre-PCI TIMI flow (OR, 0.54; 95% CI, 0.35 to 0.84; p = 0.006) to be independent predictors of TMPG (Table 3). Postprocedural TIMI flow < 3 (OR, 0.39; 95% CI, 0.12 to 1.30; p = 0.18) and TMPG-3 (OR, 1.24; 95% CI, 0.46 to 3.34; p = 0.68) were not associated with the stenting procedure (Table 3).

Clinical Outcomes

One month clinical follow-up data for all patients can be found in Table 4. The patients treated with verapamil had no major adverse in-hospital cardiac events, including death, coronary artery bypass surgery, myocardial infarction, or revascularization. The control group had three in-hospital deaths. One of the patients who died was found to have neurologic deficits during the PCI procedure and died within 24 h due to brainstem stroke and heart failure. Another patient died of recurrent ventricular tachycardia and fibrillation, and the other patient had retroperitoncal bleeding complicated with hypovolemic shock and acute renal failure. He died of cardiogenic shock and ventricular fibrillation 4 days after the PCI procedure. One patient treated with verapamil died out of the hospital. He was dead on arrival 2 weeks after the PCI procedure. There were no other 30-day major adverse cardiac events in either of the groups.

DISCUSSION

AMI no-reflow phenomenon is associated with profound and broad myocardial damage, progressive left ventricular dilatation, and a high frequency of post-AMI complications. (4,5,11,12,19-21) Multiple factors (eg, microvascular spasm, endothelial cell damage, tissue edema, platelet aggregation, and neutrophil, clot, and atheromatous plaque plugging of the microvessels) contribute to the development of AMI no-reflow phenomenon. (1,2,14,22-29) Intracoronary calcium-channel blockers have been shown to be effective in the management of no-reflow phenomenon during PCI. (2,3,30) Moreover, administration of intracoronary calcium-channel blockers in both elective PCI and direct PCI revealed improvement of epicardial coronary flow and myocardial perfusion. (14,31,32)

In our study, patients treated with verapamil received more stent implantations than those who were not (42 patients, 84%; vs 30 patients, 60%; p = 0.008). The increase in the usage of stenting during the primary PCI after August 2001 was due to the general acceptance of stenting as an effective modality in the treatment of AMI by our interventional cardiologists. Although primary infarct-related artery stenting has been reported to better reduce the need for repeat target vessel revascularization than primary balloon angioplasty, infarct artery stenting has been associated with a trend toward a lower TIMI grade 3 flow at the end of the procedure. (33-35) This reduction in the normal angiographic flow achieved after initial primary balloon angioplasty may be caused by the increased distal embolization of the atherosclerotic and thrombotic material during the stent expansion. Studies (14,36) have shown a significant improvement in the TIMI flow after post-PCI intracoronary verapamil treatment. However, although the patients treated with verapamil received more stents, there was no statistical significant difference of the post-PCI TIMI grade 3 flow between the two groups.

In our study, patients who underwent preballoon inflation and early intracoronary verapamil administration and those who did not receive verapamil had similar post-PCI TIMI flow (90% vs 84%) and CTFC: CTFC < 14, 19 patients (38%) vs 24 patients (48%); CTFC [greater than or equal to] 14 to [less than or equal to] 40, 27 patients (54%) vs 20 patients (40%); CTFC > 40, 4 patients (8%) vs 6 patients (12%). However, as evidenced by the significantly improved TMPG, patients treated with verapamil had better myocardial reperfusion than control subjects: 21 patients (42%) vs 7 control subjects (14%) [p = 0.004]. Although univariate analysis revealed that the pre-PCI thrombus score, pre-PCI TIMI flow, and intracoronary verapamil (OR, 0.23) were independent predictors of TMPG (Table 3), multiple logistic regression found the only independent predictors of TMPG to be treatment with intracoronary verapamil (OR, 0.26; 95% CI, 0.12 to 0.58; p = 0.001) and pre-PCI TIMI flow (OR, 0.54; 95% CI, 0.35 to 0.84; p = 0.006). We found that the poorer pre-PCI TIMI flow predicted more frequent no-reflow phenomenon, a finding similar to that by Abbo et al. (3) Our study further supports the role of distal microvascular spasm in AMI no-reflow phenomenon.

Distal embolization of the thrombus and plaque debris might occur at the time of reperfusion, leading to mechanical capillary obstruction. (37) The distal emboli could produce endothelium dysfunction and local inflammatory reaction, which lead to suboptimal myocardial tissue reperfusion. (38,39) Mechanical devices, including distal protection devices, thrombus aspiration devices, and rheolytic thrombectomy devices, have been used successfully to reduce distal embolization during primary PCI. (28,41,42) In a randomized study conducted by Napodano et al, (40) intracoronary thrombectomy as an adjunct to stenting during primary PCI using a catheter system (X-Sizer; ev-3; Endicor Medical; White Bear Lake, MN) was found to improve myocardial reperfusion, as evidenced by their myocardial blush and ST-segment resolution results. However, their study showed no difference in the post-PCI TIMI grade 3 flow between the patients undergoing thrombectomy and patients undergoing conventional therapy (93.5% vs 95.7%). In our study, the patients treated with intracoronary verapamil had better TMPG and higher TMPG-3 rates than the control subjects. Likewise, in the study by Napodano et al, (40) thrombectomy patients were found to have significantly more post-PCI TMPG-3 than control subjects (71.7% vs 36.9%, p = 0.006). Furthermore, Giri et al (42) found abciximab, a platelet glycoprotein IIb/IIIa receptor antagonist, to be associated with a higher post-PCI TIMI grade flow and less no-reflow phenomenon. The above studies have suggested that platelet thrombus plays a crucial role in the development of AMI no-reflow phenomenon.

In our study, only one patient receiving stent implantation in the verapamil group had a major adverse cardiac event. He was found dead by his family at home 11 days after discharge. That patient had a post-PCI TIMI flow of 3, TMPG-3, and CTFC of 7. His death may have been a result of subacute thrombosis of the target vessel. Three of the control subjects died. One of the control subjects, who had received balloon angioplasty, died of ventricular tachycardia and fibrillation 1 day after the procedure. This patient had a post-PCI TIMI flow of 3, TMPG-3, and a CTFC of 8. His death may also have been a result of subacute thrombosis of the target vessel. Another control patient who died had retroperitional bleeding and died of cardiogenic shock and ventricular fibrillation 4 days after the PCI procedure. This patient had a post-PCI TIMI flow of 3, TMPG-1, and a CTFC of 23. The other control patient who died had brainstem stroke and heart failure. He had a post-PCI TIMI flow of 1, TMPG-0, and a CTFC of 99. Our study excluded the cardiogenic shock patients. Only two patients in the verapamil group and four patients in the control group were classified as Killip class III. This might explain the insignificant difference of the in-hospital and 30-day major adverse cardiac event rate in our two groups, although the patients treated with verapamil had significantly more post-PCI TMPG-3 than those not treated with verapamil.

This study has several limitations. Most importantly, the possibility of significant differences between study and control groups cannot be excluded in this small nonrandomized study. For instance, although the patients in the verapamil and the control groups were comparable, significantly more pre-PCI TIMI flow 2 or 3 was observed in the verapamil group (34%) than in the historical control group (14%) [p = 0.034]. Another limitation of this study is that the patients in the control group were retrospectively enrolled. Additionally, the evaluation of the myocardial perfusion by TMPG was not systematically verified by other markers of reperfusion success, such as myocardial contrast echocardiography, creatine kinase myocardial band release, ECG ST-segment resolution, or echocardiographic left ventricular function. This study spanned different periods, so the technique of the operators in the verapamil group might have been considerably improved over time. Finally, the visual densitometric assessment of TMPG was qualitative and subjective, and so may have been influenced by the amount and force of contrast injection, as well as observer variability. Further adequately powered randomized studies must be conducted to define better the efficacy of early administration of intracoronary verapamil for the improvement of the myocardial perfusion during direct PCI.

CONCLUSION

Early administration of intracoronary verapamil during direct PCI improves post-procedural myocardial perfusion as evaluated by TMPG.

Manuscript received July 9, 2004; revision accepted May 25, 2005.

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Chi-Ling Hang, MD; Cha-Ping Wang, MD; Hon-Kan Yip, MD; Cheng-Hsu Yang, MD; G. Bih-Fang Guo, MD, PhD; Chiung-Jen Wu, MD; and Shyh-Ming Chen, MD

* From the Section of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Hsien, Taiwan, Republic of China.

Correspondence to: Shyh-Ming Chen, MD, Chang Gung Memorial Hospital, 123 Ta-Pei Rd, Niao-Sung Hsiang, Kaohsiung Hsien 833, Taiwan, ROC; e-mail: syming99@seed.net.tw

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