- Email: [email protected]
Relation of Preprocedural Statin Therapy to In-Hospital Procedural Complications Following Percutaneous Coronary Interventions in Patients With Hyperlipidemia
Relation of Preprocedural Statin Therapy to In-Hospital Procedural Complications Following Percutaneous Coronary Interventions in Patients With Hyperlipidemia Mandeep Singh, MDa,*, Ryan J. Lennon, MSb, Veronique L. Roger, MDa, Charanjit S. Rihal, MDa, Sean Halligan, MDa, Amir Lerman, MDa, Eric Yang, MDa, and David R. Holmes, Jr., MDa We investigated whether the observed protective effect of hyperlipidemia is stronger in patients who take statins and, if so, whether that effect is likely due to patient characteristics associated with statin use. In-hospital complications and long-term outcomes of patients with hyperlipidemia (cholesterol level >240 mg/dl) undergoing percutaneous coronary interventions (PCI) on statins (group Ia, n ⴝ 2,052) and not on statins (group Ib, n ⴝ 1,650) were compared with 726 patients with lower cholesterol levels (group II). Despite a higher prevalence of co-morbidities and worse angiographic characteristics in patients with hyperlipidemia, patients in group Ia had significantly lower in-hospital mortality (0% vs 2% in the other 2 groups, p <0.001), a lower increase in the postprocedure creatine kinase-MB fraction (14% vs 27% in group Ib and 28% in group II, p <0.001), and fewer PCI complications (15% vs 30% in groups Ib and II, p <0.001). After adjustment, patients in group Ia had a significant decrease in complications (odds ratio 0.72, 95% confidence interval 0.65 to 0.92, p ⴝ 0.009). In contrast, those in group Ib had outcomes similar to those of patients with lower cholesterol. After application of propensity analysis to adjust for the likelihood of receiving statins based on clinical, angiographic, and procedural characteristics, group Ia had fewer in-hospital complications (odds ratio 0.75, 95% confidence interval 0.62 to 0.90, p ⴝ 0.002) and lower in-hospital mortality (odds ratio 0.32, 95% confidence interval 0.12 to 0.84, p ⴝ 0.021). After successful PCI, overall survival after dismissal and survival free of myocardial infarction and target vessel revascularization were similar. In conclusion, hyperlipidemia per se is not associated with lower in-hospital complications after PCI. The benefit is largely limited to patients on statin treatment. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98:325–330)
Risk models for prediction of major adverse cardiovascular complications after percutaneous coronary interventions (PCIs) have traditionally not included pretreatment with hydroxymethyl glutaryl coenzyme-A reductase inhibitors (statins).1–5 In the few models that included hyperlipidemia, it was found to be protective.6 Moreover, hyperlipidemia has been listed as 1 variable associated with lowered risk of complications in an analysis from an aggregation of 8 PCI databases and in current guidelines for PCI from the American College of Cardiology/American Heart Association (ACC/AHA).7,8 Data from the few observational studies and randomized trials in the setting of PCI have demonstrated significant decreases in short- and long-term mortality and other ischemic end points in patients who receive statins.9 –12 However, many important subgroups that would have derived the most benefit from statins, such as patients with cardiogenic shock or acute myocardial infarction, were
The Divisions of aCardiovascular Diseases and Internal Medicine and Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota. Manuscript received October 26, 2005; revised manuscript received and accepted February 9, 2006. * Corresponding author: Tel: 507-255-2548; fax: 507-255-2550. E-mail address: [email protected] (M. Singh).
b
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.02.036
excluded in most studies.9,13–15 Therefore, it is likely that statin pretreatment, rather than hyperlipidemia, provides protection to patients who undergo PCI. In the present study, we examined whether the observed protective effect of hyperlipidemia is stronger in patients who take statins and, if so, whether that effect is likely due to statin use or other patient characteristics associated with statin use. Methods Study population: Under a protocol approved by the institutional review board, we included all patients who underwent PCI from August 1, 2000, to February 29, 2004, at the Mayo Clinic (Rochester, Minnesota). We compared the procedural success, in-hospital complications, and longterm outcome of patients with hyperlipidemia (fasting cholesterol level ⱖ240 mg/dl, group I) with patients with lower cholesterol levels (fasting cholesterol level ⬍240 mg/dl, group II) at the time of PCI. Group I was further subdivided into groups Ia (patients on statins) and Ib (patients not on statins). Because preprocedural statin use was not explicitly recorded, patients who were on any lipid-lowering agents before PCI and at discharge were included in the statin group if 1 of the drugs at discharge was a statin. Patients www.AJConline.org
326
The American Journal of Cardiology (www.AJConline.org)
Table 1 Baseline characteristics Variable
Age (yrs) Men Current smoker Diabetes mellitus Hypertension Canadian Heart Classification ⱖ3 Unstable angina MI 1–7 d MI ⬍24 h Congestive heart failure (ever) Congestive heart failure at presentation Previous coronary bypass graft surgery Previous percutaneous transluminal coronary angioplasty Peripheral arterial disease Renal disease
High Cholesterol Statin Use (n ⫽ 2,052)
No Statins (n ⫽ 1,650)
67.1 ⫾ 11.2 1,472 (72%) 281 (14%) 581 (29%) 1,567 (79%) 1,127 (55%) 1,208 (59%) 306 (15%) 185 (9%) 335 (18%) 235 (11%) 620 (30%) 705 (34%) 276 (14%) 84 (4%)
66.6 ⫾ 12.2 1,102 (67%) 300 (18%) 425 (26%) 1,177 (75%) 774 (47%) 853 (52%) 196 (12%) 419 (26%) 264 (17%) 201 (12%) 298 (18%) 420 (25%) 148 (9%) 43 (3%)
Lower Cholesterol (n ⫽ 726)
p Value
67.6 ⫾ 13.3 534 (74%) 147 (21%) 144 (20%) 426 (60%) 285 (39%) 359 (49%) 134 (18%) 162 (23%) 130 (19%) 112 (15%) 53 (7%) 115 (16%) 58 (8%) 47 (7%)
0.19 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.64 0.019 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
Values are means ⫾ SD or numbers of patients (percentages).
with unknown lipid status before PCI and who denied research authorization were excluded from analysis. End point and definitions: The outcome of interest was major in-hospital complications, defined as ⱖ1 of the following: (1) death, (2) Q-wave myocardial infarction (MI), (3) urgent or emergency coronary artery bypass surgery, (4) cerebrovascular accident or transient ischemic attack, or (5) postprocedural increase in the creatine kinase-MB fraction. Follow-up events were analyzed for overall survival and survival free of MI and target vessel revascularization. A significant (measured at 8 and 16 hours) increase in creatine kinase-MB was defined as ⱖ3 times the upper limit of normal. MI by enzyme increase criteria occurred if either measurement or the 2 measurements were increased. Any in-hospital death that occurred after PCI was considered related to the procedure. Lesion success was defined as achievement of a residual luminal diameter stenosis of ⬍50% by visual estimation. Procedural success was defined as ⱖ1 successful lesion without in-hospital death, Q-wave MI, stroke, or emergency coronary artery bypass surgery. Lesions were classified according to ACC/AHA lesion classification into types A, B1, B2, and C.16 Single-vessel disease was defined as ⬎70% luminal diameter stenosis in 1 major epicardial vessel, and multivessel disease as ⬎70% stenosis in 1 major epicardial vessel and ⬎50% stenosis in ⱖ1 other major epicardial vessel. Statistical analysis: Continuous variables are presented as mean ⫾ SD and were compared by Student’s t test or Mann-Whitney rank-sum test. Discrete variables are summarized as frequencies and percentages. Pearson’s chisquare test was used for bivariate analysis for categorical data. Logistic regression was used to estimate odds ratios and associated p values for the primary end point. KaplanMeier estimation for time to event and Cox’s proportional
hazards modeling were used for unadjusted and adjusted survival analyses, respectively. Follow-up analyses included only events after discharge and excluded patients with unsuccessful procedures. All analyses were conducted with SAS 8.2 (SAS Institute, Cary, North Carolina). To determine whether the observed protective nature of hyperlipidemia was associated with statin use within that group, multiple logistic regression was used to estimate the adjusted odds ratios of in-hospital complications for patients with hyperlipidemia with and without statins versus patients with normal lipid levels. Covariates for the model were selected using backward selection on variables significantly different across the 3 groups. Within patients with hyperlipidemia, a propensity score analysis was conducted to assess whether the observed statin effect could be explained by risk factors related to statin use. Logistic regression models were used to estimate the likelihood of a subject being on statins based on baseline, angiographic, and procedural characteristics. Variables that were significantly different between the 2 groups were used in the model. Patients were classified into groups based on the estimated probability of receiving statins according to the logistic regression model. We excluded patients if their propensity score fell outside the range of propensity scores common to the 2 treatments. The propensity score was based on 18 clinical, 3 angiographic, and 5 procedural variables plus 11 2-way interactions. The ability of the propensity score model to balance covariate distributions within propensity score groups was tested for continuous covariates by fitting a linear model with the covariate as the dependent variables and statin use, propensity score groups, and their interaction as the independent variables. For binary covariates, the Cochran-MantelHaenszel statistic was used to estimate if an association persisted between statin use and the covariate across groups; the
Coronary Artery Disease/Prediction of Complications Following Coronary Interventions
327
Table 2 Angiographic characteristics Variable
Multivessel disease ACC/AHA B2/C lesion Thrombus in any lesion Calcium in any stenosis Eccentric lesion Bifurcation lesion Ostial disease Maximum balloon length (mm) Maximum device size (mm) PCI exigency Elective Urgent Emergency Vein graft intervention Total no. of stents placed Glycoprotein IIb/IIIa receptor inhibitors
Lower Cholesterol (n ⫽ 726)
High Cholesterol
p Value
Statin Use (n ⫽ 2,052)
No Statins (n ⫽ 1,650)
451 (65%) 492 (76%) 229 (34%) 221 (34%) 489 (84%) 85 (13%) 99 (19%) 16.5 ⫾ 6.2 3.4 ⫾ 0.7
1,369 (70%) 1,518 (78%) 383 (20%) 686 (37%) 1,457 (84%) 234 (12%) 310 (22%) 16.3 ⫾ 6.8 3.4 ⫾ 0.8
1,131 (72%) 1,171 (79%) 510 (33%) 503 (34%) 1,144 (85%) 194 (13%) 239 (22%) 16.5 ⫾ 6.0 3.4 ⫾ 0.6
212 (29%) 342 (47%) 172 (24%) 28 (4%) 1.5 ⫾ 1.1 454 (63%)
858 (42%) 1,022 (50%) 171 (8%) 233 (11%) 1.4 ⫾ 1.0 1,170 (57%)
484 (29%) 729 (44%) 436 (26%) 96 (6%) 1.4 ⫾ 1.0 1,005 (61%)
0.006 0.49 ⬍0.001 0.12 0.61 0.90 0.37 0.65 0.11 ⬍0.001
⬍0.001 0.58 0.009
Table 3 Procedural success and in-hospital complications Variable
Procedural success TIMI grade 3 flow after procedure in all lesions Death Q-wave MI Emergency coronary bypass graft surgery Cerebrovascular accident/transient ischemic attack Any creatine kinase-MB fraction increase Any complication
Lower Cholesterol (n ⫽ 726)
688 (95%) 651 (94%) 18 (2%) 5 (1%) 4 (1%) 5 (1%) 201 (28%) 219 (30%)
High Cholesterol Statin Use (n ⫽ 2,052)
No Statins (n ⫽ 1,650)
1,956 (95%) 1,854 (95%) 5 (0%) 35 (2%) 8 (0%) 8 (0%) 283 (14%) 306 (15%)
1,547 (94%) 1,466 (93%) 40 (2%) 25 (2%) 10 (1%) 7 (0%) 451 (27%) 487 (30%)
p Value
0.11 0.07 ⬍0.001 0.14 0.63 0.57 ⬍0.001 ⬍0.001
TIMI ⫽ Thrombolysis In Myocardial Infarction.
Breslow-Day test was used to assess heterogeneity of odds ratios across groups. Within each propensity score group, unadjusted odds ratios and hazard ratios were calculated. The logs of these estimates were combined across groups using an inverse-variance weighted mean. This estimator is the maximum likelihood estimator under the assumption of a fixed effect across groups. The adjusted odds and hazard ratios were then calculated with the exponential function of the combined estimate. Results There were 5,980 PCIs performed in 5,159 patients; 129 refused use of their records for medical research and were excluded. Of the remaining 5,030 patients, 438 had no data on their history of high cholesterol and 164 had no data on the use of statins, and these were excluded. Thus, the study sample consisted of 4,428 unique patients. Table 1 presents significant differences in the baseline demographics of the 3 groups. Patients with hyperlipidemia
in general had a higher prevalence of co-morbid conditions (diabetes mellitus, hypertension), severe angina class, and previous percutaneous or surgical revascularization. Patients on statins presented less frequently with MI. In contrast, patients with lower cholesterol levels had higher prevalences of current smoking and renal disease. Table 2 presents the angiographic characteristics of the 3 groups. Multivessel disease and vein graft interventions were more common, whereas the presence of angiographic thrombus was less frequent in patients on statins. Emergency PCI and glycoprotein IIb/IIIa inhibitor use was less common in patients on statins. Any major PCI complication was seen in 15% of patients in group Ia and 30% of those in groups Ib and II (p ⬍0.001). In-hospital mortality was significantly lower in patients treated with statins (0% in group Ia vs 2% in groups Ib and II, p ⬍0.001). In addition, significant creatine kinase-MB increases after PCI were seen in 14% of patients on statins in group Ia after PCI compared with 27% in group Ib and
328
The American Journal of Cardiology (www.AJConline.org)
Table 4 Multiple logistic regression model for in-hospital complications Variable
Odds Ratio
95% Confidence Interval
p Value
Group II Group Ia Group Ib Age (per 10 yrs) MI ⬍24 h MI 1–7 d previously Shock before PCI Unstable angina Thrombus Emergency PCI Elective PCI Glycoprotein IIb/IIIa receptor inhibitor use Previous cerebrovascular accident/transient ischemic attack Prophylactic intra-aortic balloon pump Diabetes mellitus
1.00 0.72 0.91 1.15 7.15 1.93 2.09 0.68 2.67 2.22 0.80 1.46
(Reference) 0.56–0.92 0.71–1.17 1.06–1.24 5.42–9.44 1.50–2.37 1.23–3.54 0.56–0.82 2.17–32.9 1.70–2.90 0.63–1.02 1.19–1.78
1.32
1.01–1.73
0.041
2.60
1.25–5.40
0.010
0.78
0.64–0.97
0.023
0.009 0.46 ⬍0.001 ⬍0.001 ⬍0.001 0.006 ⬍0.001 ⬍0.001 ⬍0.001 0.067 ⬍0.001
28% in group II (p ⬍0.001). Other in-hospital complications were not significantly different in the 3 groups (Table 3). Median follow-up was 23 months and 1-year follow-up was complete in 75%. After successful PCI, overall longterm survival and survival free of MI and target vessel revascularization were not significantly different in patients with hyperlipidemia with or without the use of statins at the time of PCI and in patients with lower cholesterol levels. In the multivariable analysis, patients in group Ia had a significant decrease in the rate of in-hospital complications (odds ratio 0.72, 95% confidence interval 0.56 to 0.92, p ⫽ 0.009) compared with group II. In contrast, patients in group Ib had outcomes similar to those with lower cholesterol levels (odds ratio 0.91, 95% confidence interval 0.71 to 1.17, p ⫽ 0.46; Table 4). Other variables associated with in-hospital complications are listed in Table 4. After adjusting for propensity score groups, patients in group Ia had significantly fewer in-hospital complications, including increased creatine kinase-MB (odds ratio 0.75, 95% confidence interval 0.62 to 0.90, p ⫽ 0.002) than did those not on statins (Table 5). Statin use was also significantly protective against in-hospital mortality in the propensity score adjustment analysis (odds ratio 0.32, 95% confidence interval 0.12 to 0.84, p ⫽ 0.021). In patients with successful procedures, statin use was not associated with any decrease in long-term follow-up major adverse cardiovascular events (after adjustment for propensity score). Discussion In this report, treated hyperlipidemia was associated with lower in-hospital mortality and postprocedural cardiac biomarker increases only in patients who used statins at the time of PCI. The decrease in mortality in patients who used
statins at the time of PCI persisted after adjustment for propensity to receive statin therapy and for factors that might be associated with in-hospital mortality. One-year survival, or survival free of MI and target vessel revascularization, in patients with a successful PCI procedure was similar in patients who were or were not on statins at the time of PCI. The available risk models that determine outcome after PCI in general do not list hyperlipidemia as a significant factor that influences outcome.1,2,5 Hyperlipidemia was protective in a conglomerate of 8 large databases of ⬎150,000 patients that was aimed to determine variables associated with adverse outcomes after PCI8; only 1 database had hyperlipidemia listed as a protective variable.17 The current ACC/AHA guidelines list hyperlipidemia as a protective variable during PCI.7 In the recent ACC/National Cardiovascular Data Registry (ACC-NCDR), hyperlipidemia, a protective univariate variable, lost its significance after adjustment of other variables.6 In contrast, Qureshi et al18 reported hyperlipidemia as 1 variable in the multivariate analysis that was associated with in-hospital mortality. In contrast, we demonstrated improved in-hospital outcome of PCI with a history of hyperlipidemia that was limited to patients on statins at the time of angioplasty. However, it is likely that patients with lower cholesterol levels have higher rates of presentation with MI, which lowers cholesterol at presentation. In addition, patients with lower cholesterol levels are associated with frailty and poor long-term outcome.19 Previous angioplasty studies in patients with stable and unstable coronary syndromes have demonstrated significant decreases in the increase of cardiac biomarkers in patients who take statins.11,14 Early (30-day) and 6-month survival benefits were also noted in nonrandomized data on patients who used statins at the time of PCI.9,10,20 Even in patients who did not undergo PCI, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial reported significant decreases in death, nonfatal MI, cardiac resuscitation, or recurrent symptomatic myocardial ischemia in patients with unstable angina or non–Q-wave MI who were randomized to atorvastatin.21 The marked and very early benefit of statins in the present study is likely due to inclusion of high-risk subgroups, including those with cardiogenic shock and MI, that were excluded in previous studies.9,10,15 In the Lescol Intervention Prevention Study (LIPS), the statin advantage in decreasing major adverse cardiovascular complications in a group of patients with stable or unstable angina was seen at 18 months, when statins were initiated ⬎2 days after PCI.13 In other studies, pretreatment with statins, in a nonrandomized, single-center experience with PCI in patients with stable and unstable angina (patients with shock and acute MI were excluded) demonstrated decreased mortality as soon as 30 days and was sustained until 6 months.9,10 It is also plausible that patients on statins were more aggressively treated, had residual selection bias, and were more
Coronary Artery Disease/Prediction of Complications Following Coronary Interventions
329
Table 5 Multivariate analysis after adjustment for propensity analysis* Group
1 (unlikely to be on statin) 2 3 4 5 6 (likely to be on statin) Overall
No. of Patients
Event Rate (%)
Controls
Statin
Controls
Statin
173 341 373 290 251 209 1637
30 193 365 447 487 528 2050
86.1 51.3 14.7 13.8 13.1 11.5 29.1
73.3 38.3 14.2 10.1 10.1 11.9 14.9
Odds Ratio†
95% Confidence Interval
0.44 0.59 0.96 0.70 0.74 1.04 0.75
0.18–1.11 0.41–0.85 0.64–1.45 0.44–1.10 0.46–1.18 0.63–1.72 0.62–0.90
* Analysis for in-hospital death, Q-wave MI, emergency coronary artery bypass graft surgery, stroke, and increased creatine kinase-MB fraction. † p ⫽ 0.002.
adherent to therapy and a lifestyle that positively influences outcome. The higher prevalence of inflammatory markers in patients with acute coronary syndrome, the salutary role of statins in plaque stabilization, and modulation of the inflammatory response are some of the likely pathophysiologic mechanisms that account for such an early benefit.22 The dissociative effects of statins between rates of mortality and other ischemic end points, as previously shown,9 have been reaffirmed by the present study. The likely reasons are intriguing and speculative and are attributed to differential expression of inflammation on mortality and ascertainment bias for MI.9,10,20,23–25 Treatment with statins was nonrandomized and duration of treatment before PCI is unknown. Discharge medications and compliance with statins during follow-up are unknown. Many patients who were not on statins at the time of coronary interventions likely received these medications subsequent to discharge and probably underestimated the treatment benefit with statins for follow-up events. Despite careful adjustment of potential confounders, there may still be some unmeasured factors, including better socioeconomic status, health care, and so forth, that may have favorably affected outcome in patients who used statins at the time of PCI. We used hyperlipidemia with a cholesterol level ⱖ240 mg/dl as a dichotomous variable. Therefore, it is unknown whether a lower threshold or reliance on other fractions of the lipid panel would have similarly affected in-hospital mortality. We have no information on the inflammatory markers in these patients. Previous studies have demonstrated a beneficial effect of statins in patients with higher C-reactive protein levels at the time of PCI.10 1. Singh M, Lennon RJ, Holmes DR Jr, Bell MR, Rihal CS. Correlates of procedural complications and a simple integer risk score for percutaneous coronary intervention. J Am Coll Cardiol 2002;40:387–393. 2. Resnic FS, Ohno-Machado L, Selwyn A, Simon DI, Popma JJ. Simplified risk score models accurately predict the risk of major inhospital complications following percutaneous coronary intervention. Am J Cardiol 2001;88:5–9. 3. Moscucci M, Kline-Rogers E, Share D, O’Donnell M, Maxwell-Eward A, Meengs WL, Kraft P, DeFranco AC, Chambers JL, Patel K, et al. Simple bedside additive tool for prediction of in-hospital mortality after percutaneous coronary interventions. Circulation 2001;104:263– 268.
4. Kimmel SE, Berlin JA, Strom BL, Laskey WK. Development and validation of simplified predictive index for major complications in contemporary percutaneous transluminal coronary angioplasty practice. The Registry Committee of the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol 1995;26:931–938. 5. Ellis SG, Weintraub W, Holmes D, Shaw R, Block PC, King SB III. Relation of operator volume and experience to procedural outcome of percutaneous coronary revascularization at hospitals with high interventional volumes. Circulation 1997;95:2479 –2484. 6. Shaw RE, Anderson HV, Brindis RG, Krone RJ, Klein LW, McKay CR, Block PC, Shaw LJ, Hewitt K, Weintraub WS. Development of a risk adjustment mortality model using the American College of Cardiology–National Cardiovascular Data Registry (ACC-NCDR) experience: 1998 –2000. J Am Coll Cardiol 2002;39:1104 –1112. 7. Smith SC Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO, et al. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)— executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol 2001;37:2215–2239. 8. Block PC, Peterson ED, Krone R, Kesler K, Hannan E, O’Connor GT, Detre K, Peterson EC. Identification of variables needed to risk adjust outcomes of coronary interventions: evidence-based guidelines for efficient data collection. J Am Coll Cardiol 1998;32:275–282. 9. Chan AW, Bhatt DL, Chew DP, Quinn MJ, Moliterno DJ, Topol EJ, Ellis SG. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation 2002;105:691– 696. 10. Chan AW, Bhatt DL, Chew DP, Reginelli J, Schneider JP, Topol EJ, Ellis SG. Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation 2003;107:1750 –1756. 11. Chang SM, Yazbek N, Lakkis NM. Use of statins prior to percutaneous coronary intervention reduces myonecrosis and improves clinical outcome. Catheter Cardiovasc Interv 2004;62:193–197. 12. Walter DH, Fichtlscherer S, Britten MB, Auch-Schwelk W, Schachinger V, Zeiher AM. Benefits of immediate initiation of statin therapy following successful coronary stent implantation in patients with stable and unstable angina pectoris and Q-wave acute myocardial infarction. Am J Cardiol 2002;89:1– 6. 13. Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, Branzi A, Bertolami MC, Jackson G, Strauss B, Meier B. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 287:3215–3222. 14. Mulukutla SR, Marroquin OC, Smith C, Varghese R, Anderson WD, Lee JS, Cohen HA, Counihan PJ, Lee AB, Gulati V, McNamara D. Effect of statin therapy prior to elective percutaneous coronary intervention on
330
15.
16.
17.
18.
19.
The American Journal of Cardiology (www.AJConline.org) frequency of periprocedural myocardial injury. Am J Cardiol 2004; 94:1363–1366. Ellis SG, Chew D, Chan A, Whitlow PL, Schneider JP, Topol EJ. Death following creatine kinase-MB elevation after coronary intervention: identification of an early risk period: importance of creatine kinase-MB level, completeness of revascularization, ventricular function, and probable benefit of statin therapy. Circulation 2002;106: 1205–1210. Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Multivessel Angioplasty Prognosis Study Group. Circulation 1990;82:1193–1202. O’Connor GT, Malenka DJ, Quinton H, Robb JF, Kellett MA Jr, Shubrooks S, Bradley WA, Hearne MJ, Watkins MW, Wennberg DE, et al. Multivariate prediction of in-hospital mortality after percutaneous coronary interventions in 1994 –1996. Northern New England Cardiovascular Disease Study Group. J Am Coll Cardiol 1999;34:681– 691. Qureshi MA, Safian RD, Grines CL, Goldstein JA, Westveer DC, Glazier S, Balasubramanian M, O’Neill WW. Simplified scoring system for predicting mortality after percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1890 –1895. Brescianini S, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, Inzitari D. Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly? Results from the Italian Longitudinal Study on Aging. J Am Geriatr Soc 2003;51:991– 996.
20. Aronow HD, Topol EJ, Roe MT, Houghtaling PL, Wolski KE, Lincoff AM, Harrington RA, Califf RM, Ohman EM, Kleiman NS, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357:1063–1068. 21. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711– 1718. 22. Gottsauner-Wolf M, Zasmeta G, Hornykewycz S, Nikfardjam M, Stepan E, Wexberg P, Zorn G, Glogar D, Probst P, Maurer G, Huber K. Plasma levels of C-reactive protein after coronary stent implantation. Eur Heart J 2000;21:1152–1158. 23. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000; 343:1139 –1147. 24. Muhlestein JB, Horne BD, Carlquist JF, Madsen TE, Bair TL, Pearson RR, Anderson JL. Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. Circulation 2000;102:1917–1923. 25. Horne BD, Muhlestein JB, Carlquist JF, Bair TL, Madsen TE, Hart NI, Anderson JL. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol 2000;36:1774 –1780.
Risk models for prediction of major adverse cardiovascular complications after percutaneous coronary interventions (PCIs) have traditionally not included pretreatment with hydroxymethyl glutaryl coenzyme-A reductase inhibitors (statins).1–5 In the few models that included hyperlipidemia, it was found to be protective.6 Moreover, hyperlipidemia has been listed as 1 variable associated with lowered risk of complications in an analysis from an aggregation of 8 PCI databases and in current guidelines for PCI from the American College of Cardiology/American Heart Association (ACC/AHA).7,8 Data from the few observational studies and randomized trials in the setting of PCI have demonstrated significant decreases in short- and long-term mortality and other ischemic end points in patients who receive statins.9 –12 However, many important subgroups that would have derived the most benefit from statins, such as patients with cardiogenic shock or acute myocardial infarction, were
The Divisions of aCardiovascular Diseases and Internal Medicine and Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota. Manuscript received October 26, 2005; revised manuscript received and accepted February 9, 2006. * Corresponding author: Tel: 507-255-2548; fax: 507-255-2550. E-mail address: [email protected] (M. Singh).
b
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.02.036
excluded in most studies.9,13–15 Therefore, it is likely that statin pretreatment, rather than hyperlipidemia, provides protection to patients who undergo PCI. In the present study, we examined whether the observed protective effect of hyperlipidemia is stronger in patients who take statins and, if so, whether that effect is likely due to statin use or other patient characteristics associated with statin use. Methods Study population: Under a protocol approved by the institutional review board, we included all patients who underwent PCI from August 1, 2000, to February 29, 2004, at the Mayo Clinic (Rochester, Minnesota). We compared the procedural success, in-hospital complications, and longterm outcome of patients with hyperlipidemia (fasting cholesterol level ⱖ240 mg/dl, group I) with patients with lower cholesterol levels (fasting cholesterol level ⬍240 mg/dl, group II) at the time of PCI. Group I was further subdivided into groups Ia (patients on statins) and Ib (patients not on statins). Because preprocedural statin use was not explicitly recorded, patients who were on any lipid-lowering agents before PCI and at discharge were included in the statin group if 1 of the drugs at discharge was a statin. Patients www.AJConline.org
326
The American Journal of Cardiology (www.AJConline.org)
Table 1 Baseline characteristics Variable
Age (yrs) Men Current smoker Diabetes mellitus Hypertension Canadian Heart Classification ⱖ3 Unstable angina MI 1–7 d MI ⬍24 h Congestive heart failure (ever) Congestive heart failure at presentation Previous coronary bypass graft surgery Previous percutaneous transluminal coronary angioplasty Peripheral arterial disease Renal disease
High Cholesterol Statin Use (n ⫽ 2,052)
No Statins (n ⫽ 1,650)
67.1 ⫾ 11.2 1,472 (72%) 281 (14%) 581 (29%) 1,567 (79%) 1,127 (55%) 1,208 (59%) 306 (15%) 185 (9%) 335 (18%) 235 (11%) 620 (30%) 705 (34%) 276 (14%) 84 (4%)
66.6 ⫾ 12.2 1,102 (67%) 300 (18%) 425 (26%) 1,177 (75%) 774 (47%) 853 (52%) 196 (12%) 419 (26%) 264 (17%) 201 (12%) 298 (18%) 420 (25%) 148 (9%) 43 (3%)
Lower Cholesterol (n ⫽ 726)
p Value
67.6 ⫾ 13.3 534 (74%) 147 (21%) 144 (20%) 426 (60%) 285 (39%) 359 (49%) 134 (18%) 162 (23%) 130 (19%) 112 (15%) 53 (7%) 115 (16%) 58 (8%) 47 (7%)
0.19 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.64 0.019 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
Values are means ⫾ SD or numbers of patients (percentages).
with unknown lipid status before PCI and who denied research authorization were excluded from analysis. End point and definitions: The outcome of interest was major in-hospital complications, defined as ⱖ1 of the following: (1) death, (2) Q-wave myocardial infarction (MI), (3) urgent or emergency coronary artery bypass surgery, (4) cerebrovascular accident or transient ischemic attack, or (5) postprocedural increase in the creatine kinase-MB fraction. Follow-up events were analyzed for overall survival and survival free of MI and target vessel revascularization. A significant (measured at 8 and 16 hours) increase in creatine kinase-MB was defined as ⱖ3 times the upper limit of normal. MI by enzyme increase criteria occurred if either measurement or the 2 measurements were increased. Any in-hospital death that occurred after PCI was considered related to the procedure. Lesion success was defined as achievement of a residual luminal diameter stenosis of ⬍50% by visual estimation. Procedural success was defined as ⱖ1 successful lesion without in-hospital death, Q-wave MI, stroke, or emergency coronary artery bypass surgery. Lesions were classified according to ACC/AHA lesion classification into types A, B1, B2, and C.16 Single-vessel disease was defined as ⬎70% luminal diameter stenosis in 1 major epicardial vessel, and multivessel disease as ⬎70% stenosis in 1 major epicardial vessel and ⬎50% stenosis in ⱖ1 other major epicardial vessel. Statistical analysis: Continuous variables are presented as mean ⫾ SD and were compared by Student’s t test or Mann-Whitney rank-sum test. Discrete variables are summarized as frequencies and percentages. Pearson’s chisquare test was used for bivariate analysis for categorical data. Logistic regression was used to estimate odds ratios and associated p values for the primary end point. KaplanMeier estimation for time to event and Cox’s proportional
hazards modeling were used for unadjusted and adjusted survival analyses, respectively. Follow-up analyses included only events after discharge and excluded patients with unsuccessful procedures. All analyses were conducted with SAS 8.2 (SAS Institute, Cary, North Carolina). To determine whether the observed protective nature of hyperlipidemia was associated with statin use within that group, multiple logistic regression was used to estimate the adjusted odds ratios of in-hospital complications for patients with hyperlipidemia with and without statins versus patients with normal lipid levels. Covariates for the model were selected using backward selection on variables significantly different across the 3 groups. Within patients with hyperlipidemia, a propensity score analysis was conducted to assess whether the observed statin effect could be explained by risk factors related to statin use. Logistic regression models were used to estimate the likelihood of a subject being on statins based on baseline, angiographic, and procedural characteristics. Variables that were significantly different between the 2 groups were used in the model. Patients were classified into groups based on the estimated probability of receiving statins according to the logistic regression model. We excluded patients if their propensity score fell outside the range of propensity scores common to the 2 treatments. The propensity score was based on 18 clinical, 3 angiographic, and 5 procedural variables plus 11 2-way interactions. The ability of the propensity score model to balance covariate distributions within propensity score groups was tested for continuous covariates by fitting a linear model with the covariate as the dependent variables and statin use, propensity score groups, and their interaction as the independent variables. For binary covariates, the Cochran-MantelHaenszel statistic was used to estimate if an association persisted between statin use and the covariate across groups; the
Coronary Artery Disease/Prediction of Complications Following Coronary Interventions
327
Table 2 Angiographic characteristics Variable
Multivessel disease ACC/AHA B2/C lesion Thrombus in any lesion Calcium in any stenosis Eccentric lesion Bifurcation lesion Ostial disease Maximum balloon length (mm) Maximum device size (mm) PCI exigency Elective Urgent Emergency Vein graft intervention Total no. of stents placed Glycoprotein IIb/IIIa receptor inhibitors
Lower Cholesterol (n ⫽ 726)
High Cholesterol
p Value
Statin Use (n ⫽ 2,052)
No Statins (n ⫽ 1,650)
451 (65%) 492 (76%) 229 (34%) 221 (34%) 489 (84%) 85 (13%) 99 (19%) 16.5 ⫾ 6.2 3.4 ⫾ 0.7
1,369 (70%) 1,518 (78%) 383 (20%) 686 (37%) 1,457 (84%) 234 (12%) 310 (22%) 16.3 ⫾ 6.8 3.4 ⫾ 0.8
1,131 (72%) 1,171 (79%) 510 (33%) 503 (34%) 1,144 (85%) 194 (13%) 239 (22%) 16.5 ⫾ 6.0 3.4 ⫾ 0.6
212 (29%) 342 (47%) 172 (24%) 28 (4%) 1.5 ⫾ 1.1 454 (63%)
858 (42%) 1,022 (50%) 171 (8%) 233 (11%) 1.4 ⫾ 1.0 1,170 (57%)
484 (29%) 729 (44%) 436 (26%) 96 (6%) 1.4 ⫾ 1.0 1,005 (61%)
0.006 0.49 ⬍0.001 0.12 0.61 0.90 0.37 0.65 0.11 ⬍0.001
⬍0.001 0.58 0.009
Table 3 Procedural success and in-hospital complications Variable
Procedural success TIMI grade 3 flow after procedure in all lesions Death Q-wave MI Emergency coronary bypass graft surgery Cerebrovascular accident/transient ischemic attack Any creatine kinase-MB fraction increase Any complication
Lower Cholesterol (n ⫽ 726)
688 (95%) 651 (94%) 18 (2%) 5 (1%) 4 (1%) 5 (1%) 201 (28%) 219 (30%)
High Cholesterol Statin Use (n ⫽ 2,052)
No Statins (n ⫽ 1,650)
1,956 (95%) 1,854 (95%) 5 (0%) 35 (2%) 8 (0%) 8 (0%) 283 (14%) 306 (15%)
1,547 (94%) 1,466 (93%) 40 (2%) 25 (2%) 10 (1%) 7 (0%) 451 (27%) 487 (30%)
p Value
0.11 0.07 ⬍0.001 0.14 0.63 0.57 ⬍0.001 ⬍0.001
TIMI ⫽ Thrombolysis In Myocardial Infarction.
Breslow-Day test was used to assess heterogeneity of odds ratios across groups. Within each propensity score group, unadjusted odds ratios and hazard ratios were calculated. The logs of these estimates were combined across groups using an inverse-variance weighted mean. This estimator is the maximum likelihood estimator under the assumption of a fixed effect across groups. The adjusted odds and hazard ratios were then calculated with the exponential function of the combined estimate. Results There were 5,980 PCIs performed in 5,159 patients; 129 refused use of their records for medical research and were excluded. Of the remaining 5,030 patients, 438 had no data on their history of high cholesterol and 164 had no data on the use of statins, and these were excluded. Thus, the study sample consisted of 4,428 unique patients. Table 1 presents significant differences in the baseline demographics of the 3 groups. Patients with hyperlipidemia
in general had a higher prevalence of co-morbid conditions (diabetes mellitus, hypertension), severe angina class, and previous percutaneous or surgical revascularization. Patients on statins presented less frequently with MI. In contrast, patients with lower cholesterol levels had higher prevalences of current smoking and renal disease. Table 2 presents the angiographic characteristics of the 3 groups. Multivessel disease and vein graft interventions were more common, whereas the presence of angiographic thrombus was less frequent in patients on statins. Emergency PCI and glycoprotein IIb/IIIa inhibitor use was less common in patients on statins. Any major PCI complication was seen in 15% of patients in group Ia and 30% of those in groups Ib and II (p ⬍0.001). In-hospital mortality was significantly lower in patients treated with statins (0% in group Ia vs 2% in groups Ib and II, p ⬍0.001). In addition, significant creatine kinase-MB increases after PCI were seen in 14% of patients on statins in group Ia after PCI compared with 27% in group Ib and
328
The American Journal of Cardiology (www.AJConline.org)
Table 4 Multiple logistic regression model for in-hospital complications Variable
Odds Ratio
95% Confidence Interval
p Value
Group II Group Ia Group Ib Age (per 10 yrs) MI ⬍24 h MI 1–7 d previously Shock before PCI Unstable angina Thrombus Emergency PCI Elective PCI Glycoprotein IIb/IIIa receptor inhibitor use Previous cerebrovascular accident/transient ischemic attack Prophylactic intra-aortic balloon pump Diabetes mellitus
1.00 0.72 0.91 1.15 7.15 1.93 2.09 0.68 2.67 2.22 0.80 1.46
(Reference) 0.56–0.92 0.71–1.17 1.06–1.24 5.42–9.44 1.50–2.37 1.23–3.54 0.56–0.82 2.17–32.9 1.70–2.90 0.63–1.02 1.19–1.78
1.32
1.01–1.73
0.041
2.60
1.25–5.40
0.010
0.78
0.64–0.97
0.023
0.009 0.46 ⬍0.001 ⬍0.001 ⬍0.001 0.006 ⬍0.001 ⬍0.001 ⬍0.001 0.067 ⬍0.001
28% in group II (p ⬍0.001). Other in-hospital complications were not significantly different in the 3 groups (Table 3). Median follow-up was 23 months and 1-year follow-up was complete in 75%. After successful PCI, overall longterm survival and survival free of MI and target vessel revascularization were not significantly different in patients with hyperlipidemia with or without the use of statins at the time of PCI and in patients with lower cholesterol levels. In the multivariable analysis, patients in group Ia had a significant decrease in the rate of in-hospital complications (odds ratio 0.72, 95% confidence interval 0.56 to 0.92, p ⫽ 0.009) compared with group II. In contrast, patients in group Ib had outcomes similar to those with lower cholesterol levels (odds ratio 0.91, 95% confidence interval 0.71 to 1.17, p ⫽ 0.46; Table 4). Other variables associated with in-hospital complications are listed in Table 4. After adjusting for propensity score groups, patients in group Ia had significantly fewer in-hospital complications, including increased creatine kinase-MB (odds ratio 0.75, 95% confidence interval 0.62 to 0.90, p ⫽ 0.002) than did those not on statins (Table 5). Statin use was also significantly protective against in-hospital mortality in the propensity score adjustment analysis (odds ratio 0.32, 95% confidence interval 0.12 to 0.84, p ⫽ 0.021). In patients with successful procedures, statin use was not associated with any decrease in long-term follow-up major adverse cardiovascular events (after adjustment for propensity score). Discussion In this report, treated hyperlipidemia was associated with lower in-hospital mortality and postprocedural cardiac biomarker increases only in patients who used statins at the time of PCI. The decrease in mortality in patients who used
statins at the time of PCI persisted after adjustment for propensity to receive statin therapy and for factors that might be associated with in-hospital mortality. One-year survival, or survival free of MI and target vessel revascularization, in patients with a successful PCI procedure was similar in patients who were or were not on statins at the time of PCI. The available risk models that determine outcome after PCI in general do not list hyperlipidemia as a significant factor that influences outcome.1,2,5 Hyperlipidemia was protective in a conglomerate of 8 large databases of ⬎150,000 patients that was aimed to determine variables associated with adverse outcomes after PCI8; only 1 database had hyperlipidemia listed as a protective variable.17 The current ACC/AHA guidelines list hyperlipidemia as a protective variable during PCI.7 In the recent ACC/National Cardiovascular Data Registry (ACC-NCDR), hyperlipidemia, a protective univariate variable, lost its significance after adjustment of other variables.6 In contrast, Qureshi et al18 reported hyperlipidemia as 1 variable in the multivariate analysis that was associated with in-hospital mortality. In contrast, we demonstrated improved in-hospital outcome of PCI with a history of hyperlipidemia that was limited to patients on statins at the time of angioplasty. However, it is likely that patients with lower cholesterol levels have higher rates of presentation with MI, which lowers cholesterol at presentation. In addition, patients with lower cholesterol levels are associated with frailty and poor long-term outcome.19 Previous angioplasty studies in patients with stable and unstable coronary syndromes have demonstrated significant decreases in the increase of cardiac biomarkers in patients who take statins.11,14 Early (30-day) and 6-month survival benefits were also noted in nonrandomized data on patients who used statins at the time of PCI.9,10,20 Even in patients who did not undergo PCI, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial reported significant decreases in death, nonfatal MI, cardiac resuscitation, or recurrent symptomatic myocardial ischemia in patients with unstable angina or non–Q-wave MI who were randomized to atorvastatin.21 The marked and very early benefit of statins in the present study is likely due to inclusion of high-risk subgroups, including those with cardiogenic shock and MI, that were excluded in previous studies.9,10,15 In the Lescol Intervention Prevention Study (LIPS), the statin advantage in decreasing major adverse cardiovascular complications in a group of patients with stable or unstable angina was seen at 18 months, when statins were initiated ⬎2 days after PCI.13 In other studies, pretreatment with statins, in a nonrandomized, single-center experience with PCI in patients with stable and unstable angina (patients with shock and acute MI were excluded) demonstrated decreased mortality as soon as 30 days and was sustained until 6 months.9,10 It is also plausible that patients on statins were more aggressively treated, had residual selection bias, and were more
Coronary Artery Disease/Prediction of Complications Following Coronary Interventions
329
Table 5 Multivariate analysis after adjustment for propensity analysis* Group
1 (unlikely to be on statin) 2 3 4 5 6 (likely to be on statin) Overall
No. of Patients
Event Rate (%)
Controls
Statin
Controls
Statin
173 341 373 290 251 209 1637
30 193 365 447 487 528 2050
86.1 51.3 14.7 13.8 13.1 11.5 29.1
73.3 38.3 14.2 10.1 10.1 11.9 14.9
Odds Ratio†
95% Confidence Interval
0.44 0.59 0.96 0.70 0.74 1.04 0.75
0.18–1.11 0.41–0.85 0.64–1.45 0.44–1.10 0.46–1.18 0.63–1.72 0.62–0.90
* Analysis for in-hospital death, Q-wave MI, emergency coronary artery bypass graft surgery, stroke, and increased creatine kinase-MB fraction. † p ⫽ 0.002.
adherent to therapy and a lifestyle that positively influences outcome. The higher prevalence of inflammatory markers in patients with acute coronary syndrome, the salutary role of statins in plaque stabilization, and modulation of the inflammatory response are some of the likely pathophysiologic mechanisms that account for such an early benefit.22 The dissociative effects of statins between rates of mortality and other ischemic end points, as previously shown,9 have been reaffirmed by the present study. The likely reasons are intriguing and speculative and are attributed to differential expression of inflammation on mortality and ascertainment bias for MI.9,10,20,23–25 Treatment with statins was nonrandomized and duration of treatment before PCI is unknown. Discharge medications and compliance with statins during follow-up are unknown. Many patients who were not on statins at the time of coronary interventions likely received these medications subsequent to discharge and probably underestimated the treatment benefit with statins for follow-up events. Despite careful adjustment of potential confounders, there may still be some unmeasured factors, including better socioeconomic status, health care, and so forth, that may have favorably affected outcome in patients who used statins at the time of PCI. We used hyperlipidemia with a cholesterol level ⱖ240 mg/dl as a dichotomous variable. Therefore, it is unknown whether a lower threshold or reliance on other fractions of the lipid panel would have similarly affected in-hospital mortality. We have no information on the inflammatory markers in these patients. Previous studies have demonstrated a beneficial effect of statins in patients with higher C-reactive protein levels at the time of PCI.10 1. Singh M, Lennon RJ, Holmes DR Jr, Bell MR, Rihal CS. Correlates of procedural complications and a simple integer risk score for percutaneous coronary intervention. J Am Coll Cardiol 2002;40:387–393. 2. Resnic FS, Ohno-Machado L, Selwyn A, Simon DI, Popma JJ. Simplified risk score models accurately predict the risk of major inhospital complications following percutaneous coronary intervention. Am J Cardiol 2001;88:5–9. 3. Moscucci M, Kline-Rogers E, Share D, O’Donnell M, Maxwell-Eward A, Meengs WL, Kraft P, DeFranco AC, Chambers JL, Patel K, et al. Simple bedside additive tool for prediction of in-hospital mortality after percutaneous coronary interventions. Circulation 2001;104:263– 268.
4. Kimmel SE, Berlin JA, Strom BL, Laskey WK. Development and validation of simplified predictive index for major complications in contemporary percutaneous transluminal coronary angioplasty practice. The Registry Committee of the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol 1995;26:931–938. 5. Ellis SG, Weintraub W, Holmes D, Shaw R, Block PC, King SB III. Relation of operator volume and experience to procedural outcome of percutaneous coronary revascularization at hospitals with high interventional volumes. Circulation 1997;95:2479 –2484. 6. Shaw RE, Anderson HV, Brindis RG, Krone RJ, Klein LW, McKay CR, Block PC, Shaw LJ, Hewitt K, Weintraub WS. Development of a risk adjustment mortality model using the American College of Cardiology–National Cardiovascular Data Registry (ACC-NCDR) experience: 1998 –2000. J Am Coll Cardiol 2002;39:1104 –1112. 7. Smith SC Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO, et al. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)— executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol 2001;37:2215–2239. 8. Block PC, Peterson ED, Krone R, Kesler K, Hannan E, O’Connor GT, Detre K, Peterson EC. Identification of variables needed to risk adjust outcomes of coronary interventions: evidence-based guidelines for efficient data collection. J Am Coll Cardiol 1998;32:275–282. 9. Chan AW, Bhatt DL, Chew DP, Quinn MJ, Moliterno DJ, Topol EJ, Ellis SG. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation 2002;105:691– 696. 10. Chan AW, Bhatt DL, Chew DP, Reginelli J, Schneider JP, Topol EJ, Ellis SG. Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation 2003;107:1750 –1756. 11. Chang SM, Yazbek N, Lakkis NM. Use of statins prior to percutaneous coronary intervention reduces myonecrosis and improves clinical outcome. Catheter Cardiovasc Interv 2004;62:193–197. 12. Walter DH, Fichtlscherer S, Britten MB, Auch-Schwelk W, Schachinger V, Zeiher AM. Benefits of immediate initiation of statin therapy following successful coronary stent implantation in patients with stable and unstable angina pectoris and Q-wave acute myocardial infarction. Am J Cardiol 2002;89:1– 6. 13. Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, Branzi A, Bertolami MC, Jackson G, Strauss B, Meier B. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 287:3215–3222. 14. Mulukutla SR, Marroquin OC, Smith C, Varghese R, Anderson WD, Lee JS, Cohen HA, Counihan PJ, Lee AB, Gulati V, McNamara D. Effect of statin therapy prior to elective percutaneous coronary intervention on
330
15.
16.
17.
18.
19.
The American Journal of Cardiology (www.AJConline.org) frequency of periprocedural myocardial injury. Am J Cardiol 2004; 94:1363–1366. Ellis SG, Chew D, Chan A, Whitlow PL, Schneider JP, Topol EJ. Death following creatine kinase-MB elevation after coronary intervention: identification of an early risk period: importance of creatine kinase-MB level, completeness of revascularization, ventricular function, and probable benefit of statin therapy. Circulation 2002;106: 1205–1210. Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Multivessel Angioplasty Prognosis Study Group. Circulation 1990;82:1193–1202. O’Connor GT, Malenka DJ, Quinton H, Robb JF, Kellett MA Jr, Shubrooks S, Bradley WA, Hearne MJ, Watkins MW, Wennberg DE, et al. Multivariate prediction of in-hospital mortality after percutaneous coronary interventions in 1994 –1996. Northern New England Cardiovascular Disease Study Group. J Am Coll Cardiol 1999;34:681– 691. Qureshi MA, Safian RD, Grines CL, Goldstein JA, Westveer DC, Glazier S, Balasubramanian M, O’Neill WW. Simplified scoring system for predicting mortality after percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1890 –1895. Brescianini S, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, Inzitari D. Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly? Results from the Italian Longitudinal Study on Aging. J Am Geriatr Soc 2003;51:991– 996.
20. Aronow HD, Topol EJ, Roe MT, Houghtaling PL, Wolski KE, Lincoff AM, Harrington RA, Califf RM, Ohman EM, Kleiman NS, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 2001;357:1063–1068. 21. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711– 1718. 22. Gottsauner-Wolf M, Zasmeta G, Hornykewycz S, Nikfardjam M, Stepan E, Wexberg P, Zorn G, Glogar D, Probst P, Maurer G, Huber K. Plasma levels of C-reactive protein after coronary stent implantation. Eur Heart J 2000;21:1152–1158. 23. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000; 343:1139 –1147. 24. Muhlestein JB, Horne BD, Carlquist JF, Madsen TE, Bair TL, Pearson RR, Anderson JL. Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. Circulation 2000;102:1917–1923. 25. Horne BD, Muhlestein JB, Carlquist JF, Bair TL, Madsen TE, Hart NI, Anderson JL. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol 2000;36:1774 –1780.