Effect of Chronic Angiotensin Converting Enzyme Inhibitor Therapy on Myocardial Injury in Patients Undergoing Percutaneous Coronary Interventions
Percutaneous coronary interventions (PCI) frequently produce increases in cardiac biomarkers. Using troponin as the biomarker, the incidence of myonecrosis after PCI may be as high as 30–50%.1 It has been shown that serum creatinine kinase (CK) and the cardiac isoform of CK (CK-MB) ≥ 3 times the upper limit of normal are associated with worsened long-term outcomes after PCI.1,2 A rise in CK-MB to that level has been defined as a myocardial infarction (MI) secondary to PCI,3 and various strategies have been evaluated to reduce its incidence.4–7
Little is known about the effect of chronic angiotensin converting enzyme inhibitor (ACE-I) therapy in reducing procedural myocardial injury. We hypothesized that preprocedural chronic ACE-I therapy, due to its multiple salutary effects on endothelial function and inflammatory and oxidant stress-related cascade,8–13 will reduce the incidence of procedural MI and decrease both short- and long-term adverse cardiac events.
Methods
We studied all patients who underwent PCI with stenting between January 2003 and August 2004 at a single institution (Central Arkansas Veterans Health System, Little Rock, Arkansas). Patients who underwent multiple interventions in the same session were regarded as having one PCI procedure. There were 138 patients on chronic ACE-I therapy, who had 140 PCI sessions, and 127 not on ACE-I therapy, who had 132 PCI sessions. Since post-PCI MI was the primary study endpoint, the number of sessions (n = 272) was used to determine the difference in MI between groups. MI from PCI was defined as elevation of serum CK-MB to ≥ 3 times the upper limit of normal by 24 hours after the procedure.3 Patients with increased CK-MB before catheterization were excluded (n = 50). Blood for CK-MB was collected in all patients at 6-hour intervals times 3 following PCI. Data were collected by chart review of preprocedural medications, patient age, coronary artery disease (CAD) risk factors, procedural characteristics including stent type, glycoprotein (GP) IIb/IIIa inhibitor use and angiographic characteristics, periprocedural cardiac biomarkers and long-term outcomes including major adverse cardiac events (MACE) at 51 ± 6 months of follow up. Chronic ACE-I use was defined as > 1 week duration of ACE-I therapy from the day of prescription distribution. The no chronic ACE-I group was defined as no ACE-I therapy prior to the procedure with no prescription for an ACE-I. MACE included cardiac death, MI and clinically-driven target lesion revascularization (TLR). MI after discharge was defined in accord with the Universal Definition of Myocardial Infarction.3 All patients were recommended to be on 6 months of dual-antiplatelet therapy for drug-eluting stents (DES) and 1 month for bare-metal stents (BMS) in accordance with guidelines current at the time of the study.
Statistical analysis. Continuous variables are presented as mean ± standard deviation (SD) and were compared by the unpaired Student’s t-test. The chi-square test (when an expected cell counts were > 5) or Fisher’s Exact test (when any expected cell count was
Results
A total of 341 patients underwent non-emergency PCI during the study period. Fifty patients were excluded, as they had baseline elevation in CK-MB, 8 patients were excluded 
because of missing data and 21 patients who were on angiotensin receptor blockers only were excluded. Data were obtained on a total of 265 patients who underwent PCI in 272 sessions (7 patients had staged procedures). Baseline clinical and angiographic characteristics are shown in Table 1. Not unexpectedly, ACE-I-treated patients had a higher prevalence of diabetes and drug use with beta-blockers, statins and oral hypoglycemic agents. There was a trend toward greater use of DES in the no-chronic ACE-I group.
The incidence of procedural MI in the chronic ACE-I group tended to be lower than the no ACE-I group (5.7% vs. 12%; p = 0.18). As expected, patients who underwent intervention in a saphenous vein graft had a higher incidence of procedural MI compared to those who had an intervention in a native vessel (17.8% vs. 6.2%; p = 0.013). A multiple logistic regression model identified preprocedural chronic ACE-I therapy has a protective effect on procedural MI (odds ratio = 0.36; 95% confidence intervals [CI] 0.13–0.99; p = 0.05). Univariate and 
multivariate predictors of procedural MI are shown in Table 2. The long-term (51 ± 6 months) incidence of death was higher in the chronic ACE-I therapy group on univariate analysis, which decreased to a trend only on multivariate analysis, likely due to the worsened baseline profile in the ACE-I group. There was a trend toward a higher incidence of MACE, which did not reach statistical significance in the ACE-I group, likely related to worsened baseline risk (Table 3). Procedural MI was associated with a higher MACE rate during long-term follow up (51 ± 4 months; 59% vs. 34%; p = 0.027). There was also a trend in diabetics toward a higher incidence of MACE (44.6% vs. 33%; p = 0.075). Of the 22 patients with procedural MI, 13 patients (59%) had MACE on long-term follow up: 5 with MI, 8 with TLR and 1 death in 
this group.
Discussion
The primary study finding is that patients on chronic ACE-I therapy prior to PCI show a 64% relative risk reduction in MI from PCI. This difference, by univariate analysis, was of borderline significance. The chronic ACE-I group had a worse baseline profile. When multivariate analysis was employed, ACE-I use became significant as a factor in decreased procedural MI. This study also confirmed that development of an MI during PCI is associated with worse long-term outcomes.1,2
The concept of using ACE-I during PCI has recently been explored. It has been shown that intracoronary ACE-I during primary PCI suppresses reperfusion-associated ventricular arrhythmias and improves coronary blood flow, which may be secondary to alleviation of postischemic neurohumoral and inflammatory stress.14,15 Leesar et al showed that intracoronary ACE-I during PCI attenuates the manifestation of myocardial ischemia and protects myocardium by preconditioning mimetic actions.16 Zhao et al suggested that chronic pretreatment with ACE-I could preserve the microvascular integrity and reduce no-reflow in patients with acute MI undergoing primary PCI.17
Recently, Shariff et al reported that pretreatment with a renin angiotensin system-blocker in patients with ST-segment elevation MI resulted in a reduction in infarct size.18 Aronow et al showed that the use of long-term ACE-I/angiotensin receptor-blockers was associated with a significantly lower risk of coronary atherothrombotic events following PCI. This risk reduction was of greater magnitude than that shown by clopidogrel.19
Ours is the first clinical study to primarily evaluate the effect of chronic ACE-I pre-PCI on reducing post-procedural myonecrosis. Previous studies have shown that treatment with ACE-I after acute MI has a beneficial effect on ventricular remodeling, improves ventricular function and reduces mortality.10,20–22 Vascular injury caused by PCI with distal microembolization and reperfusion of ischemic myocardium simulates the events that may occur after acute MI. Studies have shown that ACE-I reduces ischemia reperfusion injury and decreases infarct size in animal models following reperfusion after a brief period of ischemia.23–25 Our data suggest the possibility that ACE-I can protect the heart during PCI and may be a reasonable preprocedural therapy.
Study limitations. The major limitations of this study are its small sample size, baseline inequalities between study groups and the retrospective nature of the study including chart review as the sole method of data collection with unknown factors that may have influenced results. There were several baseline characteristics which were higher in the ACE-I group, favoring the no ACE-I group for long-term outcome. Despite these differences, multivariate analysis found that ACE-I patients had fewer MIs during PCI. The lack of beneficial effect on long-term outcomes in the ACE-I group may be accounted for in part by the baseline differences and sample size.
The relative decrease in MI frequency in this study with chronic ACE-I therapy is similar to other agents that have been shown to decrease MI after PCI including GP IIb/IIIa inhibitors,4 statins26–28 and intracoronary beta blockade.7 We suspect that the reason for the borderline statistical significance in our study is a type II beta error related to the small sample size. Previous studies26–28 have demonstrated that statins may decrease procedural MI, and the greater utilization of statin usage in the ACE-I group may explain in part the reduced incidence of procedural MI in the ACE-I group. However, on multivariate analysis, ACE-I showed significance, whereas statins did not.
Conclusion
In conclusion, we have shown that chronic therapy with ACE-I prior to PCI is associated with a 64% relative risk reduction of procedural MI. As the long-term outcome of PCI is adversely affected by the development of MI during PCI and ACE-I likely decreases MI during PCI, it is reasonable to postulate that with a larger sample size, a decreased incidence of procedural MI with an ACE-I may decrease the long-term incidence of MACE. These results demonstrate the need for a randomized trial to determine whether universal ACE-I use prior to PCI decreases MI and improves long-term outcomes.
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From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. The authors report no conflicts of interest regarding the content herein. Manuscript submitted August 30, 2010, provisional acceptance September 27, 2010, final version accepted October 27, 2010. Address for correspondence: Rajesh Sachdeva, MD, Central Arkansas Veterans Healthcare System, 4300 W 7th Street, Little Rock, AR 72205. E-mail: rrsachdeva@gmail.com
