Eur J Cardiothorac Surg 2005;27:1051-1056
© 2005 Elsevier Science NL
Preoperative statin use and in-hospital outcomes following heart surgery in patients with unstable angina
Imtiaz S. Alia,b,c,*,
Karen J. Butha
a Division of Cardiac Surgery, Dalhousie University, Halifax, NS, Canada
b Department of Surgery, Dalhousie University, Halifax, NS, Canada
c Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada
Received 9 October 2004;
received in revised form 11 February 2005;
accepted 14 February 2005.
* Corresponding author. Address: QEII HSC, Room 2263, New Infirmary Site, 1796 Summer St., Halifax, NS, Canada B3H 3A7. Tel.: +1 902 473 3808; fax: +1 902 473 4448. (E-mail: imtiaz.ali{at}dal.ca).
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Abstract
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Objective: Unstable angina (UA) is characterized by a state of coronary artery vascular inflammation and endothelial dysfunction. Statins mitigate inflammation and endothelial dysfunction and decrease mortality associated with percutaneous interventions for UA. We determined whether preoperative statin use is associated with decreased mortality and morbidity following coronary artery bypass±valve surgery for UA. Methods: Patients with CCS Class IV angina having CABG±valve surgery were identified (n=1706). A logistic regression model determined the association of preoperative statin use with in-hospital mortality (IHM). Propensity score analysis was used to match two sub-groups of patients (GrpI, on statins, n=534; GrpII, not on statins, n=534) on factors known to affect outcomes. Outcomes were IHM, intra-aortic balloon pump (IABP) use, perioperative myocardial infarction (PMI), prolonged (>24h) ventilation (p-vent), stroke, and a composite outcome (comp) defined as any one or more of the above. Results: Of the 1706 patients, 1075 were on statins and 631 were not. Patients on statins were more likely to have isolated CABG, EF>40%, and be on a ß-blocker (P=0.0001); and less likely to have renal failure, MI<7 days, CHF, and undergoing urgent/emergent surgery (P=0.0001). Unadjusted rates of IHM (9 vs. 5%, P=0.001), stroke (4.4 vs. 2.3%, P=0.015), p-vent (28.4 vs. 19%, P=0.0001), and comp (32.5 vs. 22.8%, P=0.0001) were lower in patients receiving statins. After adjustment, statin use was not associated with a reduction in IHM (OR=1.0, 95% CI=0.6–1.5, P=0.85) or comp (OR=1.1, 95% CI=0.8–1.4, P=0.69). No significant differences were found in any of the propensity-adjusted outcomes for GrpI vs. GrpII: IHM (7.1 vs. 6.4%), PMI (2.8 vs. 1.7%), IABP use (3 vs. 3.8%), stroke (3.8 vs. 3.9%), p-vent (26.4 vs. 23.8%), comp (31.5 vs. 27.5%). Conclusions: Preoperative statin use is not associated with a reduction in IHM or major morbidity following CABG±valve surgery in patients with UA.
Key Words: Coronary artery bypass grafting • Statins • Outcomes
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1. Introduction
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The class of drugs referred to as statins exert their effect on cholesterol metabolism by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase catalyzes the rate-limiting step in the synthesis of cholesterol in the liver [1]. Statins are widely used in the treatment of dyslipidemia and coronary artery disease [2]. Large clinical trials [3,4] have clearly shown that statin therapy reduces the risk of coronary events and total mortality in patients with stable coronary artery disease (CAD). Although the survival benefit of statin treatment in patients with CAD is clearly related to their cholesterol-lowering ability, recent analyses have demonstrated that mechanisms beyond cholesterol reduction may also contribute [5]. Such ‘pleiotropic’ effects of statins which may contribute to improved survival include plaque stabilization, attenuation of thrombogenesis, normalization of endothelial dysfunction, and mitigation of oxidative stress, inflammation, and reperfusion injury [6]. It is now hypothesized that these pleiotropic effects of statins may be especially important in mediating the improved clinical outcomes of patients receiving these drugs immediately following the occurrence of an acute coronary syndrome [7] or preceding percutaneous coronary interventions (PCI).
Despite advances in cardiopulmonary bypass technology and myocardial protection, the mortality and morbidity of patients undergoing coronary artery bypass grafting (CABG) for unstable angina (UA) remains higher than for patients undergoing CABG for stable coronary artery disease [8]. Statin use prior to major vascular surgery significantly reduces the incidence of major adverse cardiovascular events [9] and has been associated with a reduction in mortality [10]. Furthermore, statin administration prior to PCI minimizes procedure-related MI's [11] and may increase survival [12]. It is unknown whether preoperative statin use alters the in-hospital morbidity and/or mortality of patients undergoing cardiac surgery. Much of the increased perioperative mortality and morbidity of patients undergoing revascularization for UA is due to cardiac causes such as arrhythmias, low-output syndrome, myocardial infarction (MI), myocardial stunning, and reperfusion injury. Statins attenuate thrombogenesis, normalize endothelial dysfunction and mitigate the oxidative stress and reperfusion injury characteristic of such complications. We hypothesized that the unique pleiotropic effects of statins may lead to a reduction in major morbidity/mortality in patients undergoing CABG and/or valve surgery for UA.
Thus, we undertook the current study utilizing multivariable logistic regression and propensity score analyses to determine whether the preoperative use of statins was associated with a reduction in mortality/morbidity in patients undergoing CABG or CABG+valve surgery specifically for unstable angina.
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2. Materials and methods
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2.1. Patient selection
The computerized database from the Maritime Heart Center Division of Cardiac Surgery (Dalhousie University, Halifax, Nova Scotia) was utilized to identify consecutive patients with CCS Class IV angina undergoing isolated CABG, or combined CABG/valve surgery between May 1 1998 and May 31 2003. Perioperative data were collected by full time research assistants and maintained in a computer database format. One of the data elements explicitly collected on all patients is whether or not they are receiving statin medication preoperatively. The end-points of interest analyzed were in-hospital mortality (IHM), intra- or post-operative intra-aortic balloon pump (IABP) use, perioperative myocardial infarction (PMI), prolonged (>24h) ventilation (p-vent), stroke, and a composite outcome (comp) defined as any one or more of the above. Perioperative MI was defined as a rise in creatine kinase MB fraction >5% and the presence of new Q waves or regional wall motion abnormalities as determined by radionuclide imaging or echocardiography. Stroke was defined as a new permanent neurologic deficit confirmed by physical examination by a neurological consultant and corroborated by ancillary computed tomography (CT) or magnetic resonance imaging (MRI). Transient ischemic attacks (TIA's) and reversible ischemic neurologic deficits (RIND's) were not included as a stroke end-point. All the end-points assessed are captured in the computerized database and chart reviews were not performed. Urgency status was determined according to standard Society of Thoracic Surgeons (STS) guidelines. An elective case was defined as a patient being stable for more than 24h prior to the procedure, urgent operation required surgery to be performed within 24h to prevent further clinical deterioration, and emergent/emergent salvage in patients who required an immediate operation. Cardiopulmonary bypass (CPB) was performed in a standardized fashion. Body temperature during the procedure was allowed to drift to approximately 32°C. Standard intermittent antegrade and/or retrograde cold blood cardioplegia was used for myocardial protection.
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3. Data analysis and statistics
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Statistical analysis was performed using the SAS software package (SAS, Release 8.2, SAS Institute, Inc., Cary, NC). Categorical variables were analyzed univariately with chi-square test or Fisher's exact test where appropriate, and continuous variables were examined by t-test or Wilcoxon rank sum test. Fully adjusted logistic regression models were generated to determine the association of preoperative statin use with IHM and the composite outcome in the entire group of study patients. A separate logistic regression model was generated to predict the probability of receiving statins preoperatively and the propensity scores obtained from this model were used to match two sub-groups of patients on type of procedure, age, gender, diabetes (type I or II), renal failure (defined as a serum creatinine>176µmol/L), presence of cerebrovascular or peripheral vascular disease (CVD, PVD), ejection fraction (EF), redo CABG, urgency status, recent MI (<7 days), history of congestive heart failure (CHF), presence of left main disease >50%, COPD, and use of ß-blockers and intravenous nitroglycerin. Propensity scores, expressed as predicted probability, were matched within 0.05 units. Outcomes were assessed in the two matched groups. Finally, the propensity scores were used to stratify the patients into quartiles and the propensity-stratified outcomes analyzed according to quartiles. Based on the hypothesis that patients receiving preoperative statin therapy are at lower risk of adverse outcome, our study has the statistical power of 80% to detect a 20% difference in relative risk for the composite outcome and a 40% difference in relative risk for in-hospital mortality.
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4. Results
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The baseline characteristics of the patients receiving and not receiving preoperative statin therapy are listed in Table 1. In the entire population studied (n=1706), 1075 patients were receiving statins preoperatively and 631 were not. Patients receiving statins were more likely to have isolated CABG and less likely to have CABG+valve surgery (P=0.0001). In addition, patients receiving statins were more likely to have EF
40% (P=0.0001), and undergoing non-urgent in-house surgery (P=0.0001). On the contrary, patients receiving statins were less likely to be 70 years of age (P=0.0001), have pre-existing renal failure (P=0.0001), left main disease >50% (P=0.004) and have an MI<7 days of surgery or a history of CHF (P=0.0001). The unadjusted outcomes are listed in Table 2, which shows that IHM, stroke, p-vent, median length of stay (LOS), and the composite outcome were all significantly lower in the group of patients receiving statins preoperatively. However, after adjusting for several co-variates, preoperative statin use did not emerge as an independent predictor of either IHM (OR=1.0, 95% CI=0.6–1.5, P=0.85, see Table 3) or the composite outcome (OR=1.1, 95% CI=0.8–1.4, P=0.69, see Table 4).
Because statin treatment was not randomized, a propensity model to predict the probability of receiving statins preoperatively was generated and the propensity scores were then used to match two sub-groups of patients. The goal was to match the 631 patients not on statins with 631 patients on statins in a 1:1 fashion. We achieved a match for 534 of the 631 (85%) patients not on statins with 534 of the 1075 patients that were receiving statins based on several factors known to impact outcome (Table 5). The outcomes of these propensity-matched patients are shown in Table 6, which demonstrates that preoperative statin therapy was not associated with a reduction in IHM, IABP use, stroke, PMI, p-vent, or the composite outcome. The propensity scores were then utilized to stratify the entire study population into quartiles (Table 7). Baseline characteristics of patients receiving and not receiving statins within each quartile were similar. The propensity-stratified outcomes are shown in Table 8, which shows that preoperative statin use was not associated with a reduction in any of the outcomes of interest.
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5. Discussion
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The higher mortality associated with surgical revascularization for UA may be partly explained by the pathophysiological differences which exist between the nature of the coronary artery plaque and state of accompanying vascular inflammation between patients with stable angina and UA [13]. Unlike the former, UA is characterized by the ‘vulnerable’ plaque exhibiting prominent macrophage accumulation in its atheromatous core and a thin fibrous cap prone to rupture and subsequent thrombosis. The macrophages produce matrix metalloproteinases which degrade the fibrous cap and secrete tissue factor and plasminogen activator inhibitor-1, resulting in accelerated thrombogenesis and an inhibition of fibrinolysis at the sites of plaque rupture [13]. In addition, UA is characterized by a state of generalized vascular inflammation with elevated levels of inflammatory cytokines and C-reactive protein (CRP) as well as endothelial dysfunction secondary to a decreased bioavailability of nitric oxide [14]. Thus, unlike the coronary vasculature of the patient with stable angina, the coronary vasculature of the patient with UA is ‘primed’ to experience a further oxidative, thrombogenic, and ischemia–reperfusion stress characteristic of surgical cardioplegic arrest and CPB.
The ability of statins to stabilize the vulnerable plaque, increase the bioavailability of nitric oxide, reduce markers of vascular inflammation, mediate an anti-oxidant effect, attenuate myocardial reperfusion injury, arrhythmias, and myocardial infarction, and improve coronary artery endothelial function (see Refs. [15,16] for review), suggests that these agents may be ideally suited to reduce in-hospital postoperative morbidity and mortality in patients undergoing surgical revascularization±valve surgery for UA.
In a laboratory study, Lazar et al. examined whether pretreatment with atorvastatin would minimize ischemic injury during revascularization of the acutely ischemic pig heart [17]. After 90min of ischemia, followed by 45min of cardioplegic arrest and 3h of reperfusion, ischemic damage was assessed by histologic quantification, echocardiographic regional wall motion analysis as well as coronary artery endothelial function. Statin treated animals demonstrated smaller infarct volumes, improved wall-motion scores and preserved endothelium-dependent coronary vasodilatation [17], raising the possibility that preoperative statin use may be protective in the setting of cardiac surgery. Subsequent work has demonstrated that the beneficial effects of statin pretreatment in the setting of ischemia/reperfusion injury are independent of lipid lowering and related to the ability of these drugs to enhance vascular endothelial nitric oxide (NO) production [18] and up-regulate growth factor-mediated pro-survival signaling pathways [19].
Based upon such theoretical concerns regarding the pleiotropic effects of statins, we conducted the current analyses to specifically determine whether preoperative statin use was associated with reduced in-hospital mortality or major morbidity in patients undergoing CABG and/or valve surgery for UA. We chose to analyze only in-hospital patients who were experiencing CCS Class IV angina because the operative risk in such patients is known to be elevated and such patients are known to have a significant coronary and systemic inflammatory component to their pathology. Hence, we surmised that any potential benefit of preoperative statin use attributable to their pleiotropic effects would most likely be evident in such patients. The outcomes analyzed included PMI, intra- or post-operative IABP use, stroke, prolonged (>24h) ventilation, IHM, and a composite outcome defined as any one or more of the above. Such short-term outcomes are recognized to be surrogate end-points of perioperative myocardial ischemia–reperfusion injury [20].
Significant differences were evident in the baseline characteristics of the patients receiving and not receiving preoperative statins (Table 1). Our results (Table 2) demonstrate that the unadjusted rates of IHM (9.0 vs. 5.0%, P=0.001), stroke (4.4 vs. 2.3%, P=0.015), p-vent (28.4 vs. 19.0%, P=0.0001), and the composite outcome (32.5 vs. 22.8%, P=0.0001) were lower in the group of patients receiving preoperative statins. However, after adjustment for baseline differences, preoperative statin therapy was not associated with a reduction in either IHM (OR=1.0, 95% CI=0.6–1.5, P=0.85, Table 3) or the comp (OR=1.1, 5% CI=0.8–1.4, P=0.69, Table 4). Furthermore, when the data were analyzed using propensity-matched sub-groups (Table 6) and propensity-stratified techniques (Tables 7 and 8), preoperative statin therapy did not emerge as a significant predictor of any of the outcomes of interest.
We recognize that patients with CCS Class IV angina may vary substantially in their presentation, treatment and eventual prognosis [21]. Although our database is not sufficiently sophisticated to allow analysis based on such newer and validated classification schemes, we have attempted to control for major differences by including preoperative intravenous nitroglycerin as a co-variate in the propensity-matched sub-groups (Table 5).
Our results contradict those of a recent small observational study [22] comprising a total of 323 patients (103 on statins, 219 not on statins) which concluded that preoperative statin use improved cardiovascular outcomes after CABG with regard to death, MI, unstable angina recurrence and arrhythmias at 60 days and 1 year. The discrepancy may be partly due to differences in the timing of assessment of the outcomes in the two studies. We chose to report only adverse in-hospital outcomes which we believed could possibly be mitigated by the pleiotropic effects of statins. It may be that the patients need to be followed longer term before a potential beneficial association between preoperative statin use and outcomes becomes apparent. However, it is likely that such longer term benefits of statin treatment prior to CABG are due to their lipid-lowering properties and ability to retard the development of vein-graft disease [23] as opposed to their pleiotropic effects. Furthermore, it should be recognized that differences in sex distribution, prevalence of hypertension, presence or severity of hyperlipidemia, as well as other unmeasured factors, may have resulted in relevant biases in the previous study [22].
Another explanation of our results may be that the magnitude of the inflammatory response to CPB and cardioplegic arrest during cardiac surgery is too great for preoperative statin use to have any impact on. In this regard, it has recently been reported that preoperative oral atorvastatin therapy failed to limit the inflammatory response to CPB as evidenced by its inability to diminish plasma levels of several inflammatory mediators [24]. In addition, it should be recognized that the majority of experimental animal studies have shown statins to minimize the extent of irreversible myocyte injury as reflected by infarct size. In the clinical scenario of cardiac surgery, reversible myocardial injury or ‘stunning’ is far more common and this type of injury may not be ameliorated by pretreatment with statins [25].
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6. Limitations
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Several limitations are apparent with our current analyses. The precise statin used (i.e. hydrophilic vs. hydrophobic), the exact dose, and the precise duration of therapy preoperatively is not known. It is possible that the pleiotropic effects of this class of medications may vary between individual drugs and be dose specific. We do not believe that a lack of knowledge regarding exact duration of therapy is critical to our analysis because the pleiotropic effects likely to exert myocardial protection (antithrombotic, anti-inflammatory, endothelial protective, anti-oxidant) and hence improved in-hospital outcomes are known to accrue rapidly (hours to days) after statin exposure [11,18]. Because the vast majority of patients on statins had a history of dyslipidemia, we assume that they had been receiving statins for at least several days if not months prior to surgery. We do acknowledge that the precise LDL, HDL and triglyceride levels of the patients are not known and thus we cannot relate outcomes to preoperative lipid profile. Our study is a retrospective analysis of prospectively collected data and despite the use of logistic regression and propensity analyses, factor(s) unaccounted for in our models could have introduced relevant bias(es). Despite such limitations, we believe our study is one of the first to date which attempts to answer whether preoperative statin use is associated with improved mortality/morbidity following cardiac surgery.
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7. Conclusion
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Despite the abundance of experimental and observational clinical data suggesting that statins mitigate myocardial reperfusion injury and infarction via their pleiotropic effects, we did not demonstrate an association between preoperative statin use and improved in-hospital morbidity/mortality in patients undergoing CABG±valve surgery for UA. A prospective randomized trial is necessary to determine conclusively whether preoperative statin use alters the short-term outcomes of cardiac surgery.
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Abstract
1. Introduction
