Effect of Statin Use Within the First 24 Hours of Admission for Acute Myocardial Infarction on Early Morbidity and Mortality†
Article Outline
We determined the effects of early statin treatment in acute myocardial infarction (AMI) on in-hospital morbidity and mortality. Experimental models of ischemia and reperfusion have shown that statins have early cardioprotective effects. However, the effect of statin use within the first 24 hours of admission on early morbidity and mortality in AMI has not been well studied. Data were collected on 300,823 patients who had AMI in the National Registry of Myocardial Infarction 4. In-hospital events were compared between patients who continued statin therapy received before the index AMI hospitalization (n = 17,118) or newly started statin therapy within the first 24 hours of hospitalization (n = 21,978) and patients who did not receive early statin treatment (n = 126,128) or whose statin therapy was discontinued (n = 9,411). New or continued treatment with a statin in the first 24 hours was associated with a decreased risk of mortality compared with no statin use (4.0% and 5.3% compared with 15.4% no statin). Discontinuation of statin treatment was associated with a slightly increased risk of mortality (16.5%). Early statin use was also associated with a lower incidence of cardiogenic shock, arrhythmias, cardiac arrest, rupture, but not recurrent myocardial infarction. Propensity analysis yielded mortality odds ratios of 0.46 for continued therapy, 0.42 for newly started therapy, and 1.25 for discontinued therapy for matched pairs versus no statin therapy (all p values <0.0001). In conclusion, the use of statin therapy within the first 24 hours of hospitalization for AMI is associated with a significantly lower rate of early complications and in-hospital mortality.
Experimental models of ischemia and reperfusion have shown that statins significantly decrease reperfusion injury and limit myocardial infarction size.1, 2 We hypothesized that patients who were hospitalized with acute myocardial infarction (AMI) and received statin treatment within 24 hours of hospital admission would have lower in-hospital morbidity and mortality risks than patients who did not receive statins or whose statins were discontinued. This study used data from the National Registry of Myocardial Infarction 4 (NRMI 4) to test this hypothesis.
Methods
NRMI 4 is a prospective, observational database of consecutive patients who were admitted with AMI to 1,230 participating hospitals throughout the United States. A total of 300,823 patients was enrolled from July 2000 to January 2002. The data collection process used in this study and quality control features have been previously described.3 To be included in the NRMI, patients must have had an AMI before hospital discharge according to prescribed criteria. These criteria included a supportive clinical history, increases in serial cardiac biomarkers, and the presence of electrocardiographic findings consistent with AMI. To avoid incomplete information with regard to prehospital and first 24-hour treatment and incomplete follow-up, we excluded transfer-in and transfer-out patients. A total of 174,635 patients who had AMI was included in this analysis. Detailed demographic data, hospital characteristics, risk factors for coronary artery disease, presenting clinical characteristics, initial diagnosis, electrocardiogram, location and type of AMI, and cardiac procedures were recorded, as previously described.3 The use of medications on an outpatient basis before the index hospitalization, during the first 24 hours of hospitalization, and at discharge were recorded.
Data on in-hospital mortality and major clinical adverse events were collected on each patient. For this study the primary outcome was the association of statin use with in-hospital death. Secondary outcomes included in-hospital cardiogenic shock, cardiac arrest, ventricular fibrillation or sustained ventricular tachycardia, cardiac rupture, heart failure, and reinfarction.
Patients were categorized into 4 groups based on whether statin treatment was provided before the index hospitalization (defined as having received a statin within 24 hours before hospitalization) and whether statin therapy was administered within the first 24 hours of hospitalization. Patients were classified as “continued” on a statin (yes/yes) if they had been receiving a statin before the index hospitalization and if the patient received a statin within 24 hours of admission. Patients were classified as “newly started” on a statin (no/yes) if they had not been receiving statin therapy before the index hospitalization and if they were started on statin therapy within 24 hours of hospital admission. Patients were classified as statin “discontinued” (yes/no) if patients were previously on statin therapy but were not prescribed statin therapy within 24 hours of admission. The comparison group for the analyses were patients “not started” (no/no) who did not previously receive statin treatment and did not receive statin treatment during the first 24 hours of hospitalization.
Statistical analysis
SAS 8.02 (SAS Institute, Cary, North Carolina) was used for statistical analysis and the SAS/STAT logistic procedure was used to perform the logistic and propensity score analyses. Descriptive statistics were generated for baseline demographics and clinical characteristics across patient groups. Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) for in-hospital mortality and major clinical events were determined. For the matched analysis, differences between matched pairs were evaluated with McNemar’s test for binary data.
To control for differences in confounding variables that were associated with in-hospital mortality and other secondary outcomes, logistic regression analysis was performed. In the first block demographic and medical history variables were controlled for. Presentation and AMI characteristics were added to the second block, administration of prehospital therapies to the third block, and administration of hospital therapies during the first 24 hours to the fourth block. A fifth block included cardiovascular procedures during hospitalization. The addition of the final block included the propensity score and formed the full model. Blocks were entered cumulatively until the complete model was produced.
To minimize any bias inherent in the choice to newly start or continue statin treatment during the first 24 hours in this study, a propensity analysis was performed to adjust for confounding.4 A multivariable logistic regression model was developed with available demographic, clinical, and treatment variables and any plausible interaction terms and variable transformations to estimate for each patient the probability of receiving statins. This probability was the propensity score. Demographic and clinical variables entered into the model included age, gender, medical history, admission characteristics, type of AMI, and hospital characteristics. Medications used before and during the first 24 hours of admission were also included. Using the model, patients were classified by quintiles of increasing probability of early statin initiation. Primary and secondary outcomes for the matched population subsets were calculated. Propensity scores were then added to the logistic regression analysis to complete the final model. Analyses restricted to patients who had ST-segment elevation and non-ST-segment elevation AMI and the subset of patients who were treated at hospitals with interventional capability were also performed.
Results
Statin therapy was used in the first 24 hours of hospitalization in 39,096 of 174,635 patients (22.4%). There were 21,978 patients who were newly started on statin therapy (no/yes, 12.6%) and 17,118 patients who were continued on statin therapy (yes/yes, 9.8%). Statin therapy was discontinued in 9,411 patients (yes/no, 5.4%). There were 126,128 patients (no/no, 72.2%) who did not receive statin treatment before or within the first 24 hours of hospitalization. Characteristics of patients by statin treatment groups are presented in Table 1.
Table 1. Baseline demographics and clinical characteristic by statin use cohort
| Characteristic | Yes/Yes (n = 17,118) | No/Yes (n = 21,978) | No/No (n = 126,128) | Yes/No (n = 9,411) | p Value |
|---|---|---|---|---|---|
| Age (yrs) | 69.5 ±12.1 | 65.6±14.0 | 72.2±14.5 | 70.2±11.7 | <0.0001 |
| Women | 38.9% | 36.1% | 46.6% | 39.6% | <0.0001 |
| Black | 6.1% | 7.2% | 8.3% | 6.0% | <0.0001 |
| Medicare | 63.3% | 48.7% | 64.6% | 62.9% | <0.0001 |
| Teaching hospital | 11.0% | 13.9% | 10.6% | 10.7% | <0.0001 |
| Diabetes mellitus | 42.5% | 28.6% | 30.2% | 41.1% | <0.0001 |
| Hypertension | 71.6% | 59.2% | 60.2% | 69.6% | <0.0001 |
| Chronic renal insufficiency | 15.3% | 8.2% | 13.1% | 16.7% | <0.0001 |
| Current tobacco use | 17.6% | 29.8% | 21.1% | 18.9% | <0.0001 |
| Previous AMI | 44.0% | 22.8% | 23.4% | 40.3% | <0.0001 |
| Congestive heart failure | 23.9% | 12.1% | 23.0% | 24.0% | <0.0001 |
| Previous coronary bypass | 32.5% | 14.4% | 11.7% | 28.4% | <0.0001 |
| Aspirin outpatient therapy | 61.8% | 31.1% | 31.0% | 55.0% | <0.0001 |
| β-Blocker outpatient therapy | 49.2% | 13.0% | 18.2% | 43.7% | <0.0001 |
| Presentation | |||||
| Chest pain | 65.2% | 74.8% | 53.5% | 57.4% | <0.0001 |
| ST elevation | 19.6% | 36.0% | 25.8% | 23.5% | <0.0001 |
| Anterior AMI | 13.9% | 21.3% | 19.5% | 16.9% | <0.0001 |
| Systolic blood pressure | 145.6±31.0 | 147±31.2 | 147.1±33.7 | 140.1±33.9 | <0.0001 |
| Heart rate | 86.2±23.3 | 84.2±22.4 | 90.5±25.3 | 88.1±25.4 | <0.0001 |
| Killip’s class I | 73.2% | 81.6% | 69.4% | 71.3% | <0.0001 |
| Killip’s class II/III | 26.4% | 17.9% | 29.1% | 27.4% | <0.0001 |
| Killip’s class IV | 0.4% | 0.5% | 1.6% | 1.4% | <0.0001 |
| TIMI risk STEMI low | 61.2% | 71.9% | 54.5% | 54.2% | <0.0001 |
| TIMI risk STEMI high | 4.1% | 2.3% | 7.2% | 6.4% | <0.0001 |
| TIMI risk non-STEMI low | 25.3% | 31.3% | 26.2% | 23.8% | <0.0001 |
| TIMI risk non-STEMI high | 17.1% | 11.9% | 14.8% | 18.8% | <0.0001 |
| LVEF <0.40 | 23.6% | 19.1% | 23.6% | 26.2% | <0.0001 |
| Hospitalization | |||||
| Thrombolytic | 6.4% | 13.0% | 7.8% | 7.4% | <0.0001 |
| Direct coronary intervention | 10.5% | 21.2% | 9.8% | 11.4% | <0.0001 |
| Cardiac catheterization | 55.3% | 69.0% | 43.8% | 52.8% | <0.0001 |
| Coronary bypass (all) | 8.1% | 8.8% | 7.5% | 11.2% | <0.0001 |
| Medications in first 24 h | |||||
| Aspirin | 87.6% | 91.6% | 75.9% | 72.6% | <0.0001 |
| β Blocker | 74.5% | 80.9% | 57.7% | 56.6% | <0.0001 |
| ACE inhibitor | 47.5% | 49.0% | 30.4% | 27.3% | <0.0001 |
| Calcium blocker | 23.2% | 13.4% | 15.1% | 13.9% | <0.0001 |
| Glyprotein IIb/IIIa receptor blocker | 22.9% | 35.6% | 17.2% | 22.0% | <0.0001 |
| Low-molecular-weight heparin | 31.4% | 30.7% | 27.5% | 25.6% | <0.0001 |
| Nonstatin lipid-lowering agent | 4.9% | 4.6% | 4.5% | 1.5% | <0.0001 |
| Statin at discharge | 91.2% | 85.2% | 21.8% | 70.6% | <0.0001 |
New initiation of statin treatment within the first 24 hours of admission for AMI was associated with a substantially decreased risk of in-hospital mortality compared with no statin use (4.0% vs 15.4%, unadjusted OR 0.23, 95% CI 0.22 to 0.25). Continuation of statin therapy in the first 24 hours of hospitalization for AMI was also associated with a decreased risk of mortality compared with no statin use (5.3% vs 15.4%, OR 0.31, 95% CI 0.29 to 0.33). In contrast, patients who had been treated with statin therapy before hospitalization but whose therapy was discontinued had a mortality risk that was slightly higher than the risk in patients who did not use statins (16.5% vs 15.4%, OR 1.09, 95% CI 1.03 to 1.15). Early statin use, whether newly initiated or continued, was also associated with a lower incidence of cardiac arrest, cardiogenic shock, cardiac rupture, and ventricular tachycardia/ventricular fibrillation but not with recurrent AMI (Figure 1).
Figure 1.
Clinical events by statin use before hospitalization and within the first 24 hours after hospitalization (unadjusted). VT/VF = ventricular tachycardia/ventricular fibrillation.
Propensity modeling identified several variables that independently predicted the likelihood of newly starting, continuing, or discontinuing statin therapy in the first 24 hours of hospitalization. Model c-statistics for the yes/yes, no/yes, and yes/no versus no/no matching were 0.81, 0.69, and 0.77, respectively. Analysis of outcomes in each patient group matched by propensity to newly receiving or being continued on statins in the first 24 hours (using demographic, clinical, and hospital characteristics) continued to indicate a significant association of early statin use with improved outcomes. Propensity-matched patients in whom statin therapy was newly started in the first 24 hours of hospitalization developed significantly decreased rates of in-hospital mortality, cardiogenic shock, ventricular tachycardia/ventricular fibrillation, and cardiac arrest compared with patients in whom early statin therapy was not started (no/no group; Table 2). This population had a similar rate of recurrent myocardial infarction. Patients whose statin therapy was continued had similar decreased rates of in-hospital mortality, cardiogenic shock, cardiac arrest, ventricular tachycardia/ventricular fibrillation, and cardiac rupture as did patients who did not receive early statins (Table 2). In contrast, patients whose statins were discontinued had increased rates of mortality, cardiogenic shock, cardiac arrest, ventricular tachycardia/ventricular fibrillation, and heart failure/pulmonary edema compared with patients in whom early statin therapy was not started.
Table 2. In-hospital outcomes for propensity-matched patient groups
| No/Yes vs No/No | Yes/Yes vs No/No | Yes/No vs No/No | ||||
|---|---|---|---|---|---|---|
| (n = 21,513) | (n = 21,513) | (n = 16,408) | (n = 16,408) | (n = 9,076) | (n = 9,076) | |
| In-hospital death | 3.9%⁎ | 8.6% | 5.2%⁎ | 10.7% | 15.5%⁎ | 12.8% |
| Cardiogenic shock | 2.3%⁎ | 4.1% | 2.3%⁎ | 4.2% | 7.8%⁎ | 5.1% |
| Cardiac arrest | 2.9%⁎ | 5.2% | 2.8%⁎ | 5.0% | 7.8%⁎ | 5.8% |
| Ventricular tachycardia/ventricular fibrillation | 4.4%⁎ | 5.1% | 3.7%⁎ | 4.7% | 7.0%‡ | 6.0% |
| Cardiac rupture | 0.2%⁎ | 0.5% | 0.2% | 0.3% | 0.8% | 0.6% |
| Congestive heart failure/pulmonary edema | 15.5% | 15.4% | 22.7%† | 23.7% | 28.3%⁎ | 25.7% |
| Recurrent myocardial infarction | 1.5% | 1.5% | 1.6% | 1.9% | 1.6% | 1.8% |
⁎ p <0.001 |
† p <0.05 |
‡ p <0.005. |
After adjusting for potential confounding demographic, clinical, hospital, prehospital, and in-hospital therapy variables and statin propensity, patients in whom statin therapy was newly started continued to have a significantly decreased risk of in-hospital mortality (OR 0.62, 95% CI 0.57 to 0.67) compared with patients who were not treated. After adjustment, patients who continued on statins also had a significant decreased risk of in-hospital mortality (OR 0.58, 95% CI 0.54 to 0.63) compared with patients who did not start treatment. Compared with patients who never received statins, those who used statins before hospitalization but did not receive treatment within the first 24 hours of hospitalization had a slightly increased risk of dying during hospitalization after adjustment for demographic, clinical, and treatment factors and propensity score (OR 1.12, 95% CI 1.05 to 1.20). Similar findings were observed when analyses were confined to patients who had ST-segment elevation and those who had non-ST-segment elevation myocardial infarction (Figure 2). Models for all hospitals and those confined to hospitals with interventional capabilities yielded similar results (Table 3), but with improved model statistics for interventional hospital analyses.
Figure 2.
ORs for in-hospital mortality by statin use before hospitalization and within the first 24 hours after hospitalization after matching on propensity score.
Table 3. In-hospital mortality by statin therapy groups
| OR (95% CI) | ||
|---|---|---|
| All Hospitals | Interventional Hospitals | |
| No/yes vs no/no | ||
| Unadjusted | 0.23(0.22–0.25) | 0.26(0.24–0.28) |
| Covariate adjusted—blocks 1–4* | 0.58(0.54–0.63) | 0.62(0.56–0.68) |
| Propensity score and covariate adjusted | 0.62(0.57–0.67) | 0.66(0.60–0.72) |
| Yes/yes vs no/no | ||
| Unadjusted | 0.31(0.29–0.33) | 0.34(0.31–0.37) |
| Covariate adjusted—blocks 1–4 | 0.58(0.54–0.62) | 0.59(0.54–0.66) |
| Propensity score and covariate adjusted | 0.58(0.54–0.63) | 0.60(0.54–0.66) |
| Yes/no vs no/no | ||
| Unadjusted | 1.09(1.03–1.15) | 1.07(1.00–1.15) |
| Covariate adjusted—blocks 1–4 | 1.13(1.05–1.21) | 1.07(0.98–1.16) |
| Propensity score and covariate adjusted | 1.12(1.05–1.20) | 1.06(0.97–1.16) |
Discussion
In this study of >170,000 patients who had AMI, 22.4% received statin therapy within the first 24 hours of hospitalization. If continued or newly started on statin therapy, patients were at substantially lower risk for in-hospital mortality and other complications of AMI compared with patients who were not treated. The association between the use of statin therapy within the first 24 hours of hospitalization and significantly improved clinical outcomes persisted even after extensive covariate and propensity risk adjustments. Patients who had received statin therapy before hospitalization but whose therapy was not continued in the first 24 hours of hospitalization derived no associated protective effect and were actually at a somewhat higher risk compared with patients who did not receive statin treatment before or early during hospitalization.
The potential for a direct cardioprotective effect of statins was first reported more than a decade ago by Osborne et al1 who demonstrated that lovastatin decreased the extent of myocardial injury after ischemia and reperfusion in hypercholesterolemic rabbits. More recent experimental studies have consistently demonstrated that statin treatment significantly decreases the extent of myocardial necrosis, preserves myocardial viability, and results in increased ventricular function in models of myocardial ischemia reperfusion injury.2, 5 This cardioprotective effect of statins in attenuating myocardial ischemia reperfusion injury has been shown to involve increased bioavailability of nitric oxide.6 Investigations of the effects of nitric oxide donors in myocardial ischemia reperfusion injury have indicated that they can attenuate the extent of myocardial ischemia reperfusion injury in vivo. Statins have been demonstrated to activate the Akt pathway, resulting in a rapid increase in nitric oxide bioavailability.7
Statins also have been shown to attenuate ventricular remodeling in the early period after AMI. Statin administration that started 6 hours after coronary ligation was associated with amelioration of left ventricular structural remodeling, attenuation of increased matrix metalloproteinase activity, and decreased contractile failure over the next 28 days.8 Moreover, there was significantly improved survival soon after myocardial infarction, with survival curves that diverged 3 to 4 days after infarction. Other potential mechanisms of early benefit in AMI with statins include decreases in inflammatory cell accumulation in the ischemic myocardium, oxidative stress, and monocyte adhesion.5, 9 Collectively, these findings provide plausible biologic mechanisms by which statins could exert a mortality-decreasing cardioprotective effect very early in the course of AMI.
This analysis provides the strongest clinical evidence to date to support the hypothesis of early, direct cardioprotective effects of statins in AMI. However, adequately powered prospective randomized clinical trials are needed to confirm these findings before it can be concluded that there are direct cardioprotective effects of statins in AMI.
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- † A complete list of participating hospitals is available from ClinTrials Research, 1100 Weston Parkway, Cary, North Carolina 27513.
The National Registry of Myocardial Infarction 4 is supported by Genentech, Inc., South San Francisco, California.
PII: S0002-9149(05)00925-2
doi:10.1016/j.amjcard.2005.04.029
© 2005 Elsevier Inc. All rights reserved.
