Preprocedural Statin Medication Reduces the Extent of Periprocedural Non–Q-Wave Myocardial Infarction
Background— Stenting-related myocardial injury has been recognized as a frequent and prognostically important event, the extent of which depends on microcirculatory impairment in association with platelet aggregation, inflammation, and increased oxidative stress. Recent studies underscored the non–lipid-lowering effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) with antithrombotic, antiinflammatory, and antioxidative aspects. Thus, we tested the hypothesis that preprocedural statin therapy is associated with a reduction in the extent of stenting-related myocardial injury.
Methods and Results— We stratified 296 consecutive patients who were undergoing stenting of a de novo stenosis according to the preprocedural status of statin therapy (229 statin-treated and 67 control patients). Incidence of periprocedural myocardial injury was assessed by analysis of creatine kinase (CK; upper limit of normal [ULN] 70 IU/L for women, 80 IU/L for men) and cardiac troponin T (cTnT; bedside test; threshold 0.1 ng/mL) before and 6, 12, and 24 hours after the intervention. Relative to control patients, the incidence of CK elevation >3× ULN was more than 90% lower in statin-treated patients (0.4% versus 6.0%, P=0.01). Statin therapy was the only factor independently associated with a lower risk of CK elevation >3× ULN (OR: 0.08, 95% CI: 0.01 to 0.75; P=0.03). The overall incidences of CK and cardiac troponin T elevation were slightly lower in statin-treated than in control patients (14.4% versus 20.9%, P=0.3, and 17.9% versus 22.4%, P=0.5, respectively).
Conclusions— Preprocedural statin therapy is associated with a reduction in the incidence of larger-sized, stenting-related myocardial infarctions. Prospective, randomized trials are warranted to further assess this cardioprotective effect of statins in coronary intervention.
Received August 9, 2002; revision received September 4, 2002; accepted September 5, 2002.
Ischemic myocardial injury still remains the most common complication associated with percutaneous coronary intervention (PCI), particularly with new device interventions such as stenting.1 Importantly, an increase in subsequent cardiac events has been identified as the most important clinical implication of periprocedural myocardial injury in various clinical trials.1 Currently, postprocedural elevation of creatine kinase (CK) more than 3-fold above the upper limit of normal (ULN) is considered as periprocedural myocardial infarction.1,2⇓
Various clinical trials demonstrated the clinical benefit of treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for primary and secondary prevention in cardiovascular disease.3 Furthermore, there is increasing evidence for various non–lipid-lowering effects of statins, including improvement in endothelial function, as well as reduction in oxidative stress, inflammation, and platelet activation.4 These pleiotropic effects explain the cardioprotective profile of statins in ischemia/reperfusion models.5 Reduction in peri-interventional myocardial injury might relate to the recently reported improvement in long-term outcome after intervention for patients on statin therapy before intervention.6 Thus, the current study was performed to test the hypothesis that preprocedural statin treatment is associated with a reduction in the extent of periprocedural myocardial injury.
This study examined a series of 296 consecutive patients with successful coronary stenting for routine clinical indication,2 stratified according to the status of preprocedural statin medication (229 patients receiving 1 of the following statins for more than 1 week before PCI: 0.4% fluvastatin, 4.4% cerivastatin, 4.8% lovastatin, 14.9% simvastatin, 27.9% pravastatin, and 47.6% atorvastatin). Procedural success was defined as a reduction of lumen diameter stenosis to <30% residual lumen narrowing without the incidence of death, coronary artery bypass grafting (CABG), or Q-wave acute myocardial infarction (AMI). Exclusion criteria were (1) elevation of CK and cardiac troponin T (cTnT) before PCI, (2) AMI during the last 4 weeks before PCI, (3) terminal renal insufficiency, hypothyroidism, or skeletal muscle injury, (4) in-stent restenosis, (5) periprocedural glycoprotein IIb/IIIa receptor (GP IIb/IIIa) inhibition, and (7) contraindication to antiplatelet medication. The local ethics committee approved the study, and all patients gave written informed consent for the coronary procedure.
Implantation of tubular-slotted stents was performed, and target lesions and procedural complications were defined as previously reported.7,8⇓ All patients received either ticlopidine (500 mg/d) or clopidogrel (75 mg/d, 300 mg as loading dose) for 4 weeks in addition to continued aspirin medication (100 mg/d).
Cardiac Marker Analysis
Venous blood samples were scheduled before and 6, 12, and 24 hours after PCI. Cardiac serum markers were analyzed as described previously.8 Determination of CK-MB serum activity was made available in case of CK elevation.
Follow-up data were obtained by telephone or mail inquiry with the patient, their relatives, their primary physician, and/or their cardiologist. AMI was defined by a minimum rise of CK >2× ULN or by the development of new Q waves. Cardiac origin of death was considered if associated with congestive heart failure, arrhythmia, AMI, sudden death, or any other cardiac malady.
Continuous variables were reported as mean±SD, and categorical variables were presented as percentages. U-test or t test was used for group comparison with continuous, nonparametric or parametric variables. In case of categorical variables, group comparison was made by Yates’ corrected χ2 or, for expected frequencies <5, by the Fisher’s exact test. Multivariate analyses were performed in logistic regression and forward stepping manner. Survival analysis was performed by the Kaplan-Meier method with log-rank test group comparison. A probability value <0.05 was considered statistically significant.
Clinical and procedural variables for the study population are presented in Tables 1 and 2⇓. Serum concentration of fibrinogen was similar (380±99 versus 380±88 mg/dL), whereas serum concentration of C-reactive protein (CRP) tended to be lower among statin-treated patients than among control patients (0.5±0.9 versus 0.8±1.4 mg/dL, P=0.09).
Cardiac Marker Outcome
The overall incidences of postprocedural elevation of cTnT and CK were 18.9% and 15.9%, respectively, with no significant difference between statin-treated and control patients. Peak postprocedural CK serum activity was slightly lower among statin-treated patients than among control patients (54±43 versus 64±61 IU/L, P=0.5). The incidence of postprocedural elevation of CK elevation >3× ULN was significantly lower among statin-treated patients than among control patients (Figure 1). Preprocedural statin therapy was identified as the only independent negative predictor (OR: 0.08, 95% CI: 0.01 to 0.75, P=0.027) and unstable angina pectoris as the only independent positive predictor (OR: 7.9, 95% CI: 1.14 to 55.05, P=0.037) of postprocedural CK elevation >3× ULN.
Patient groups identified to benefit from preprocedural statin therapy were (incidence CK elevation >3× ULN statin-treated versus control patients) men (0.6% versus 7.0%, P=0.01), patients with low-density lipoprotein >100 mg/dL (1.2% versus 5.8%, P=0.04), those with total cholesterol >180 mg/dL (0.0% versus 4.7%, P=0.04), and those with type C lesion (0.0% versus 15.4%, P=0.04), as well as, tentatively, patients with multivessel coronary artery disease (0.6% versus 5.6%, P=0.07) and those with diabetes mellitus (0.0% versus 11.1%, P=0.07).
Follow-up data were available for 90.2% of the patients for a postprocedural period of 13±7 months (Figure 2).
The current study demonstrates a more than 90% reduction in the incidence of postprocedural elevation of CK >3× ULN in patients with preprocedural statin treatment relative to patients without preprocedural statin therapy, supporting a cardioprotective effect of statin pretreatment in coronary intervention.
Statins and Myocardial Infarction
Experimental studies consistently demonstrated that administration of statins before induction of myocardial ischemia improves myocardial viability.5 Preprocedural statin treatment substantially reduced the extent of inflammatory cell accumulation in the ischemic myocardium in association with preservation of coronary blood flow, which was attributed to a reduction in leukocyte adherence to the microvascular endothelium secondary to a reduction in adhesion molecule expression of the endothelial monolayer and increase in the bioavailability of nitric oxide.5 These antiinflammatory, procirculatory effects of statins might be tremendously beneficial in clinical situations, in which the integrity of the myocardial microvasculature is set at risk by microembolization of atherothrombotic debris, for instance during PCI.8–10⇓⇓ Indeed, the current study demonstrates a reduction in periprocedural myocardial infarction by preprocedural statin therapy. As in the experimental studies, statin pretreatment resulted in a substantial reduction in the extent rather than in the overall incidence of periprocedural myocardial infarction. Thus, in experimental models of ischemia/reperfusion injury and in the clinical setting of PCI, preprocedural statin treatment seems to exert a cardioprotective effect.
Statins and Coronary Intervention
Recent clinical studies indicate that patients with preprocedural elevation of C-reactive protein (CRP) serum concentrations are at higher risk of adverse cardiac events during follow-up after PCI, particularly ischemic events during the first postprocedural days.11,12⇓ Furthermore, a combination of anatomic lesion characteristics with this inflammatory index was found to be superior to procedural risk assessment by American College of Cardiology/American Heart Association lesion criteria alone.12 Given these implications that intervention of “unstable” lesions enhances the risk of periprocedural ischemic complications, preprocedural statin therapy might also improve postprocedural outcome by “stabilizing” the target lesion before PCI. Of note, a recent study pointed out that preprocedural statin therapy abolished the negative prognostic impact of baseline CRP elevation, potentially by interference with vascular inflammation, endothelial dysfunction, and overall atherosclerosis disease progression.13 These beneficial vascular effects of statins cannot be excluded; in fact, the trend toward lower CRP serum concentrations among patients with preprocedural statin therapy supports this theory, at least in part. Also, a reduction in circulating levels of CRP might result in less severe postprocedural microvascular impairment, given the direct proinflammatory effect of CRP on endothelial cells.14 Thus, preprocedural statin therapy might improve postprocedural outcome by modulating the target lesion and/or the myocardial microcirculation.
Various clinical trials have demonstrated worse long-term clinical outcome in association with periprocedural myocardial injury. In the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing trial (EPISTENT), postprocedural elevation of CK/CK-MB >3× ULN was associated with an increased risk of cardiac mortality during follow-up.15 Importantly, patients receiving periprocedural GP IIb/IIIa inhibition experienced not only a 55% reduction in the acute incidence of large-sized, periprocedural non–Q-wave myocardial infarction but also a 57% reduction in 1-year mortality.9,15⇓ This sustained clinical benefit was attributed to a preventive effect on platelet aggregation and a preserving effect on microvascular perfusion, attenuating myocardial necrosis and arrhythmic myocardial foci.9 As outlined above, protection of the integrity of the myocardial microvasculature has been identified as an important effect of statins in experimental studies. This might relate to recent reports on the detrimental effect of statin withdrawal in patients with acute coronary syndromes and the early and sustained postprocedural clinical benefit for patients receiving statin treatment before PCI.6,16⇓ In line with these findings are the current results of a 56% lower incidence of death/AMI among patients with preprocedural statin therapy during follow-up (2.4% versus 5.4%), which did not reach significance level because of the overall small number of cases. Thus, preprocedural statin therapy might improve postprocedural clinical outcome by reducing periprocedural AMI.
The major study limitations are the small size and the retrospective, nonrandomized nature of the method. Nevertheless, statin-treated patients did not have less severe coronary artery disease, less extensive risk factor and lipid profiles, or less complex lesions, interventions, and complications than control patients. Thus, despite the nonrandomized design, the 2 study groups were comparable in demographic and procedural profiles. Although patients with GP IIb/IIIa inhibitors were not included in this study, a potential interference with other drugs, especially β-blockers and angiotensin-converting enzyme-inhibitors, cannot be fully excluded.17 Also, the effects of dose and duration of treatment before PCI need to be addressed in a future randomized trial. Another limitation is the use of CK instead of CK-MB; yet CK analysis was combined with cTnT and available CK-MB values in cases of CK elevation.
Preprocedural statin treatment is associated with a reduction in the extent of stenting-related myocardial injury. Future prospective, randomized trials are warranted to further assess this cardioprotective effect of statin drugs in coronary intervention.
This study was supported in part by a Deutsche Forschungsgemeinschaft grant (DFG 155/4-2).
- ↵Smith SC Jr, Dove JT, Jacobs AK, et al. ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines): executive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2001; 103: 3019–3041.
- ↵Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001; 21: 1712–1719.
- ↵Chan AW, Bhatt DL, Chew DP, et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation. 2002; 105: 691–696.
- ↵Haude M, Caspari G, Baumgart D, et al. Comparison of myocardial perfusion reserve before and after coronary balloon predilatation and after stent implantation in patients with postangioplasty restenosis. Circulation. 1996; 94: 286–297.
- ↵Herrmann J, Haude M, Lerman A, et al. Abnormal coronary flow velocity reserve after coronary intervention is associated with cardiac marker elevation. Circulation. 2001; 103: 2339–2345.
- ↵Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation. 2000; 101: 570–580.
- ↵Chew DP, Bhatt DL, Robbins MA, et al. Incremental prognostic value of elevated baseline C-reactive protein among established markers of risk in percutaneous coronary intervention. Circulation. 2001; 104: 992–997.
- ↵Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.
- ↵Heeschen C, Hamm CW, Laufs U, et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002; 105: 1446–1452.
- ↵Sharma SK, Kini A, Marmur JD, et al. Cardioprotective effect of prior beta-blocker therapy in reducing creatine kinase-MB elevation after coronary intervention: benefit is extended to improvement in intermediate-term survival. Circulation. 2000; 102: 166–172.