European Heart Journal Advance Access originally published online on July 4, 2006
European Heart Journal 2006 27(15):1799-1804; doi:10.1093/eurheartj/ehl125
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Patients using statin treatment within 24 h after admission for ST-elevation acute coronary syndromes had lower mortality than non-users: a report from the first Euro Heart Survey on acute coronary syndromes
1 Atrium Medical Centre, Heerlen, The Netherlands
2 Department of Cardiology, Thoraxcentre, Erasmus University Medical Center, Room H560, Dr Molewaterplein 40, 3015 GD Rotterdam, Rotterdam, The Netherlands
3 Klinikum der Stadt Ludwigshafen Germany
4 University of Uppsala, Uppsala, Sweden
5 Gasthuisberg University Hospital, Leuven, Belgium
6 Rabin Medical Center, Petah Tikwa, Israel
7 Neufeld Cardiac Research Institute, Tel Hashomer, Israel
Received 27 September 2005; revised 28 April 2006; accepted 1 June 2006; online publish-ahead-of-print 4 July 2006.
* Corresponding author. Tel: +31 10 4633938; fax: +31 10 4635258. E-mail address: m.simoons{at}erasmusmc.nl
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Abstract |
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Aims Statins provide effective secondary prevention in cardiovascular disease. However, it remains uncertain how soon statins should be started after an acute coronary syndrome (ACS). Recently published trials suggest starting before discharge. We hypothesize that statins should be initiated without delay.
Methods and results Data from a large cohort of 10 484 consecutive patients with an ACS were analysed. Of this cohort, 1426 first-time statin receivers and survivors of the first 24 h were compared with 6771 first-day survivors not receiving statin therapy. A propensity score for the likelihood of receiving statin therapy within 24 h was developed and used with other established risk factors in a multivariable analysis. There was a significantly reduced all-cause 7-day mortality in patients receiving early statin therapy [0.4 vs. 2.6%, unadjusted hazard ratio (HR) 0.16, 95% confidence interval (CI) 0.08–0.37, adjusted HR 0.34, 95% CI 0.15–0.79]. Statistical significance was observed in patients presenting with STE-ACS (adjusted HR 0.17, 95% CI 0.04–0.70) and not in NSTE-ACS patients. However, no statistical evidence of heterogeneity in treatment effect was observed between these groups.
Conclusion These data suggest that very early statin therapy is associated with reduced mortality in patients presenting with STE-ACS; however, these findings have to be confirmed by prospective, randomized controlled trials before firm treatment recommendations can be given.
Key Words: Statin • Acute coronary syndrome • Mortality • Prevention
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Introduction |
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Since publication of the landmark trials 4S, CARE and LIPID, HMG-coA reductase inhibitors (statins) are recognized as effective treatment for secondary prevention of cardio-vascular events.1–3 In these trials, statin therapy was started late (months) after a coronary event, and the benefit became apparent only after long-term use. Beyond a favourable effect on serum lipids, statins may also directly stabilize coronary plaques.4,5 Accordingly, in acute coronary syndrome (ACS) patients, presenting with (STE-ACS) or without (NSTE-ACS) ST-elevation, it might be advantageous to start statin therapy early after hospital admission. Two observational studies confirmed this hypothesis. In the Swedish myocardial infarction registry,6 and in the combined data sets of the GUSTO IIb and PURSUIT trials in ACS, patients who received statin therapy before hospital discharge had lower mortality than the remaining patients.7 In contrast, in the SYMPHONY studies, statin therapy within 3 days after admission was not associated with improved outcome.8
Randomized trials of early statin therapy vs. control in ACS patients that are conducted so far showed mixed results. The MIRACL trial, which enrolled NSTE-ACS patients, reported a statistically significant 16% lower rate of death and non-fatal major cardiac events at 4 months follow-up in patients receiving 80 mg/day of atorvastatin compared with placebo.9 In MIRACL, study medication was initiated within 24–96 h after admission. In the small FLORIDA trial, which enrolled patients presenting with STE-ACS, fluvastatin therapy (80 mg/day) did not affect the incidence of major adverse cardiac events when compared with placebo. The median time to the initiation of study medication after the onset of symptoms was 8 days. The larger A to Z trial, which included NSTE-ACS as well as STE-ACS patients, showed a favourable, but statistically non-significant trend towards reduction of major cardiovascular events during 6–24 months follow-up in patients receiving an intensive simvastatin regimen (40 mg/day for 1 month followed by 80 mg/day thereafter) when compared with those receiving a less intensive regimen (placebo for 4 months followed by 20 mg/day of simvastatin).10 Study medication in the A to Z trial was started after patients were stabilized for at least 12 h. A trend towards better outcome after early statin therapy (0.4 mg/day of cerivastatin) was also observed in the PRINCESS trial STE-ACS, but again statistical significance was not reached (data presented at the Annual Congress of the European Society of Cardioloy, August 2004). Study medication in the PRINCESS trial was initiated within 48 h of symptom onset.
We suppose that the relative late start of statin treatment, especially in patients with ST-elevation, is one of the reasons for the lack of benefit in these trials, as the beneficial non-lipid lowering effects might be optimal very early in the process of plaque destabilization. Therefore, we postulate that statin therapy that is initiated within 24 h after admission is associated with improved outcome in ACS patients. We studied this hypothesis in the large cohort of patients who were enrolled in the first Euro Heart Survey on ACS and were not receiving statins before hospitalization.
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Euro Heart Survey ACS
The details of the Euro Heart Survey ACS have been previously described in detail.11 The survey was performed in clusters composed of academic and non-academic hospitals and hospitals with and without cardiac catheterization laboratories and cardiac surgery facilities. The enrolment period was planned from 4 September to 31 December 2000. Because of technical delays (primarily delays in approval by Ethic Committees in several countries), the Expert Committee decided to extend the duration of the survey to 15 May 2001.
All patients with suspected ACS, screened at the emergency room, chest pain units, catheterization laboratory, or otherwise were registered on a screening log (after acquisition of written informed consent if required), but they were not enrolled until the diagnosis of ACS was confirmed. Patients who had been in another hospital for a short (<12 h) observation period and were transferred for diagnosis and management were also registered, and information from the referring hospital was sought. However, patients who were referred only for a specific treatment (i.e. cardiac catheterization or coronary bypass surgery) were not included. For all logged patients, we recorded the tentative initial diagnosis made by the attending physicians based on the initial electrocardiographic pattern: ACS with ST-elevation, ACS without ST-elevation, and ACS with an undetermined electrocardiographic pattern. The full case report form was filled out for patients with a discharge diagnosis of unstable angina or myocardial infarction. The case report form included details regarding the demographic, clinical, and electrocardiographic characteristics of the patient, the diagnostic and treatment modalities, the in-hospital complications, and the discharge status. A total of 10 484 patients were enrolled.
Study population
As chronic use before hospitalization might influence its early effects, we excluded 2099 patients already receiving statin treatment before hospitalization from this analysis, because this is not a randomized trial and decisions regarding the initiation of early (statin) treatment might be influenced by the physician's anticipation of the patient's condition. Specifically, estimates of the effectiveness of early statin therapy might be biased by the fact that moribund patients are less likely to receive such early therapy than their thriving counterparts. In order to partly adjust for this phenomenon, we excluded the 188 (2.2%) patients who died within the first 24 h after admission. Thus, a total of 8197 patients who survived the first 24 h were available for analysis.
Endpoint definition
The Euro Heart Survey ACS was designed to evaluate the application of treatment guidelines in patients with ACSs during routine clinical practice. With regard to patient outcome, the survey mainly focused on major adverse cardiac events that occurred during hospital stay, including myocardial (re)infarction and death. Adverse events were reported by the local investigators and not adjudicated by an independent endpoint committee. Furthermore, the survey protocol did not mandate serial electrocardiograms (ECG) or blood sampling for determination of cardiac enzymes (as per design, it was the intention to minimize the impact of the survey protocol on routine procedures). As we realize the survey design is susceptible to observer bias, especially with regard to ‘soft’ endpoints, we choose the incidence of all-cause mortality at 7 days and at 30 days after admission as the endpoints of this study.
Data analysis
Continuous data are presented as mean value and standard deviation (SD), whereas dichotomous data are presented as numbers and percentages. Differences in baseline characteristics between patients who received statin therapy within 24 h after admission (statin users) and those who did not receive statin therapy within this time period (statin non-users) were evaluated by unpaired Student's t-tests and 
2 tests, as appropriate.
We developed a propensity score for the likelihood of receiving statin therapy within 24 h. Multivariable logistic regression analysis was applied to identify baseline factors that were associated with such early statin use. We considered a broad range of patient baseline characteristics, including age, sex, diabetes, hypertension, dislipidaemia, family history of coronary artery disease (CAD), smoking, history of myocardial infarction, history of heart failure, history of coronary artery bypass grafting, history of percutaneous coronary intervention (PCI), history of renal insufficiency, ST-segment changes at the qualifying ECG, Killip class at admission, heart rate at admission, systolic blood pressure at admission, reperfusion therapy within 24 h, and the use of aspirin, heparin, ticlopidin, beta-blockers, ACE-inhibitors, and glycoprotein IIb/IIIa inhibitors during the first 24 h. Potential interactions between these variables were not considered. All variables entered the multivariable stage. In general, for the development of a propensity score, it is recommended to use an extensive model, to ensure that any predictors (true and chance) are accounted for. Hence, no model reduction procedures were applied. We report adjusted odds ratios (ORs) and 95% confidence intervals (CI) of the variables that compose the final propensity model. The performance of the propensity score model was studied with respect to discrimination and calibration. Discrimination refers to the ability to distinguish statin users from non-users; it was quantified by the c-statistic. Calibration refers to whether the predicted probability of statin use is in agreement with the observed probability; calibration was measured with the Hosmer–Lemeshow goodness-of-fit test. In an attempt to optimize the discriminatory power of the propensity model, first order interactions between the variables that compose the model were considered. Furthermore, second-order terms for continuous variables were considered. However, both attempts did not result in an improvement of the c-statistic. Therefore, we decided to apply the model without interaction terms and based on first-order terms for continuous variables.
The method of Kaplan–Meier was used to describe the incidence of death over time. Log-rank tests were applied to study differences in survival between statin users and non-users. These relations were further evaluated by multivariable Cox' proportional hazards regression analyses, with adjustment for confounders. We considered a broad range of potential confounders, including the propensity for early statin use (the propensity of statin use was determined for each patient, based on the obtained regression formula; discussed earlier), age, sex, risk factors for coronary disease, medical history, ECG changes, haemodynamic condition, and medication use. The multivariable models were constructed by backward deletion of the least significant characteristics, while applying the Akaike information criterion [that is, the applied threshold of significance depended on the degrees of freedom (DF) associated with the variable at hand; if DF=1, then P
0.157].12 We report crude and adjusted hazard ratios (HRs) and corresponding 95% CI.
We speculated that treatment effects of statin therapy might be different in patients presenting with STE-ACS vs. NSTE-ACS. In order to study a potential heterogeneity in treatment effect, we included the ECG changes*statin use interaction-term in the final multivariable model. No other interactions between statin use and clinical characteristics were studied.
Clinical variables were missing for 2702 patients (1689, 63%, had missing values for only one clinical variable and in 2214 patients, 82%, values for two variables). This subset had higher 7-day (5.3 vs. 2.1%) and 30-day (8.8 vs. 3.8%) mortality than the patients with complete data. Excluding patients with missing data, therefore, could lead to biased risk estimates.13 To partly correct for this, all multivariable analyses were performed on a data set that included imputed predictive variables. A simple imputation algorithm was used, and missing variables were replaced with the mean value of the variable at hand, as observed in the data set. [Dichotomous variables were coded as 0 (factor absent) or 1 (factor present). Thus, the imputed value for patients with missing data corresponds with the prevalence of the factor in the patients with non-missing data.]
Statistical significance of all tests was stated at the 0.05 probability level. All tests were two-sided.
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Propensity score for early statin use
A total of 1426 (17%) patients received statin therapy within 24 h after admission. There were relevant differences in clinical baseline characteristics between the statin users and non-users (Table 1). Statin users were younger and more often men than non-users. Patients receiving early statin therapy were more often diagnosed as NSTE-ACS and less often as STE-ACS, whereas the undetermined ECG pattern was equally distributed. Traditional risk factors for CAD, including diabetes mellitus, hypercholesterolaemia, a family history of coronary disease, and cigarette smoking as well as a prior history of coronary disease (previous myocardial infarction or coronary intervention) were also more prevalent in the group of statin users. Patients receiving early statins more often received standard treatment for ACS within 24 h after admission, including aspirin, heparin, and beta-blockers. Gender, diabetes, history of renal insufficiency, systolic blood pressure at admission, and the use of ticlopidin during the first 24 h were not included in the propensity score because of a P>0.5. Variables that compose the propensity score for the likelihood of receiving statin therapy within 24 h are presented in Table 1. The propensity score model adequately discriminated between early statin users and non-users (c-statistic 0.75) and the predicted frequencies agreed with the observed frequencies (Hosmer–Lemeshow P-value 0.75; Figure 1).
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Statin use within 24 h and early mortality
Seven-day follow-up was complete for 7696 (94%) patients, and 30-day follow-up was complete for 6899 (84%) patients. All-cause mortality at 7 days was 1.3% in patients presenting with NSTE-ACS patients (Kaplan–Meier estimate; 52 events in 4021 patients), 2.8% in those presenting with STE-ACS (100/3583), and 5.1% in patients with an undetermined ECG (25/504). At 30 days, these figures were 3.3% (123/4021), 5.1% (174/3583), and 9.6% (45/504). All-cause mortality at 7 days was significantly lower in the group of patients receiving early statin therapy (0.4 vs. 2.6% events; absolute difference 2.2%; unadjusted HR 0.16; 95% CI 0.08–0.37; adjusted HR 0.34; 95% CI 0.15–0.79) (Table 2 and Figure 2). There was no statistical evidence of heterogeneity in treatment effect between subgroups of patients according to ST-segment changes on the presenting ECG (P-value for heterogeneity 0.11, based on the ECG changes*statin use interaction-term in the multivariable model). However, after adjustment for multiple confounders, early statin therapy was not associated with reduced mortality in patients presenting with NSTE-ACS. The propensity score for early statin use was a significant contributor in all multivariable models, indicating that it acted as an important confounder of the relation between statin use and clinical outcome.
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The absolute difference in all-cause mortality between early statin users and non-users observed at 7 days follow-up had increased at 30 days. Hence, at 30 days, early statin therapy was still associated with reduced mortality, although statistical significance was not reached after adjustment for multiple confounders (unadjusted HR 0.44 and 95% CI 0.31–0.64; adjusted HR 0.90 and 95% CI 0.60–1.3). Statistical significance was observed in patients presenting with STE-ACS (adjusted HR 0.49 and 95% CI 0.25–0.95). There was statistical evidence of a heterogeneity in treatment effect between subgroups of patients according to ST-segment changes on the presenting ECG (P-value for heterogeneity 0.01, based on the ECG changes*statin use interaction-term in the multivariable model).
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Discussion |
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Statin therapy that is initiated within 24 h after hospitalization was associated with reduced short-term mortality in patients admitted with ACS. This treatment effect was already present after 7 days follow-up. The beneficial effects of early statin use were mainly observed in patients presenting with ST-segment elevation.
Several randomized clinical trials have demonstrated the effectiveness of long-term statin therapy in patients with established coronary disease. Statin therapy was associated with a 20–42% reduction in long-term mortality.1–3 Hence, current treatment guidelines indicate that (life-long) statin therapy should be considered for secondary prevention in CAD patients.14,15 Still, it should be appreciated that in these landmark trials patients were enrolled several months after CAD was diagnosed (the majority of patients was enrolled after they experienced a myocardial infarction), whereas the benefits of statin therapy only became apparent after the first year of treatment. Recently published randomized trials in which patients are treated with statins before discharge when compared with placebo show an event reduction that became already apparent during the first 6 months.9,10 Our data support the hypothesis that a much earlier start of statin therapy (i.e. within the first 24 h after an ACS) may result in a mortality reduction within 7 days and confirm the results of the analysis done by the NRMI-4 investigators.16
The benefits of long-term statin treatment can largely be explained by its cholesterol-lowering effects (especially the reduction of low density lipoprotein cholesterol) and the associated retardation of the progression of atherosclerosis.5,17 In contrast, the short-term benefits of statins are most likely due to the non-cholesterol-lowering vascular effects, like plaque stabilization, improvement of endothelial function, inhibiting monocyte recruitment, and decreasing the pro-thrombotic state, which have been demonstrated in vitro as well as in vivo studies.4,18 Support for these vascular effects is provided by the recently published analysis from the PROVE-IT study in which patients with high levels of hs-C-reactive protein had better clinical outcomes independent of LDL lowering.19 Also reduction of peri-procedural (not a late effect) myocardial injury by statin therapy is demonstrated in patients undergoing PCI.20 Finally, a reduction of peri-operative mortality after statin therapy was also observed in patients undergoing non-cardiac vascular surgery.21
We do not fully understand why the association between early statin therapy and reduced mortality was particularly observed in patients presenting with ST-elevation, whereas this association was absent in those presenting without ST-elevation. It is true that there was no (strong) statistical evidence for heterogeneity in treatment effect between subgroups according to abnormalities on the presenting ECG, and a chance effect cannot be excluded. In contrast, statistical tests of heterogeneity often lack power to detect clinically relevant differences between subgroups. More importantly, such tests may also fail to reveal differences in the pathophysiological processes underlying subgroups of patients with STE or NSTE-ACS, which could have been the case in our analysis. A proposed mechanism could be an effect of statins on the acute activated stage in ST-elevation coronary syndromes, where they might exert an anti-thrombogenic or plaque stabilizing effect reducing further thrombotic occlusion with subsequent myocardial damage and risk for death. This effect could be the result of the inhibition of plasminogen activator inhibitor I (PAI-I) or reduction of expression of procoagulant tissue factor.22 Another mechanism could be a reduction in lethal arrhythmias as was observed by Lorenz et al.23 This might also be a reason why in the A to Z trial and in the SYMPHONY analysis, in which patients were included after stabilization, these anti-thrombogenic effects of statins were no longer as strong as in the acute phase, and statin therapy was less effective. Noteworthy, data from the A-Z trial also suggest a stronger effect of early statin therapy in patients presenting with STE-ACS when compared with NSTE-ACS. More research to address this issue, however, is needed. Finally, the lower event rate in the NSTE-ACS group could also explain the absence of power to detect a difference in effect.
Our analysis has several limitations. Most importantly, this study was not designed as a randomized trial of statin therapy within 24 h vs. placebo or control therapy. In fact, our data were derived from an observational database of patients who were admitted for ACS, and we do not know why early statin therapy was initiated in some patients and withheld in others. The treating physician's perception of the patient's risk and clinical risk profiling likely played an important role in this respect. Indeed, important differences in clinical characteristics and medication use were observed between early statin users and non-users. We accounted for these differences by means of a propensity score for early statin use. It is known that the accuracy of this score is highly dependent on the accuracy and the extent of the model that generates it. Therefore, in the regression analysis to develop the score, we applied the backward selection approach and used a liberal threshold for statistical significance of the candidate components to remain in the model, as suggested by Akaike.12 Still, although the use of a propensity score resembles randomization, we realize that it cannot be considered as good as randomization. Thus, we cannot exclude the possibility that the estimate of treatment effect is still biased due to differential patient selection.
Conclusions and clinical implications
These data suggest that very early statin therapy is associated with reduced mortality in patients presenting with STE-ACS. It is true that our findings have to be confirmed by prospective, randomized controlled trials before firm treatment recommendations can be given. Still, on the basis of our observational data and recently published randomized trials, we conclude that statin therapy should be started in patients admitted with (STE-)ACS, preferably as soon as possible, and regardless of their lipid levels.
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The Euro Heart Survey ACS was supported by Schering-Plough and Centocor. These sponsors had no role in study design, data collection, data interpretation, or writing of the manuscript.
Conflict of interest: none declared.
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This paper was guest edited by Prof. Dr Markus Schwaiger, Klinik r.d. Isar der TU Muenchen, Nuklearmed. Klinik u. Poliklinik, Munich 81675, Germany
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[Abstract/Free Full Text]
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