In addition to their lipid-lowering capabilities, HMG-CoA reductase inhibitors (statins) modulate inflammation, inhibit thrombosis, and augment endothelial cell function.1 These additional benefits of statins have generated considerable interest in their efficacy as an early treatment for patients with acute coronary syndromes (ACS). The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial demonstrated a modest reduction in recurrent ischemia in ACS patients treated with early high-dose statin therapy.2 A substudy of the Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) trial not only showed better short-term outcomes in ACS patients pretreated with statins compared with those not receiving statin therapy prior to presentation, but also showed that statin withdrawal during hospitalization was associated with increased event rates.3 Using the data from the Global Registry of Acute Coronary Events (GRACE) project,4 we assessed the effects of prior statin therapy on hospital presentation and outcomes of ACS patients and also evaluated the association between early administration or withdrawal of statin therapy during hospitalization and subsequent outcomes.
Patients and methods
The GRACE project is a large, multinational study of patients presenting with ACS to 94 hospitals in 14 countries. The details of this project have been previously discussed.5 A total of 19,537 men and women with ACS were enrolled and categorized into the following groups: (1) no previous statin use and no in-hospital statin therapy, (2) no previous statin use but in-hospital statin therapy, (3) previous statin use and in-hospital statin therapy, and (4) previous statin use but no in-hospital statin therapy. To analyze the differences between these four groups, we used chi-square tests and Wilcoxon rank-sum tests for discrete variables (individual characteristics, diagnostic methods, treatment practices, hospital complications, and mortality) and for continuous variables, respectively. Multivariate regression analyses were used to evaluate the association between prior statin use and hospital presentation, as well as any association between prior or in-hospital statin therapy and hospital outcomes including death, while controlling for potential confounding variables. We used the Hosmer—Lemeshow test to analyze final models for goodness of fit.
Of 19,537 men and women, 4,056 (21%) were receiving statin therapy prior to presentation; 428 (11%) of these patients did not receive statins during the index hospitalization.
Effect of previous statin therapy on hospital presentation. Compared with patients who were not taking statins prior to hospitalization, patients receiving previous statin therapy were similar in age but more likely to have vascular risk factors or known vascular disease; they were slightly less ill at presentation, but more likely to already be receiving certain cardiac medications or to receive certain in-hospital cardiac therapies and procedures. At presentation (after controlling for potentially confounding variables), the patient group receiving prior statin therapy was found to be less likely to have ST-segment elevation myocardial infarction (MI) (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.71—0.88), to develop creatine phosphokinase (CPK) levels greater than twice normal (OR, 0.78; 95% CI, 0.70–0.86), or to develop certain clinical complications or die during hospitalization than those patients not previously receiving statins (Table 1, Figure).
Continuation or withdrawal of statins during hospitalization and outcomes. Patients who received statins before presentation and continued
to receive them during hospitalization were younger, more likely to be male, more likely to smoke, and more likely to receive other effective cardiac therapies in the hospital or undergo percutaneous coronary intervention (Table 2). They were less likely to have a history of diabetes or hypertension. After controlling for potential confounding variables, it was found that patients who received both previous and in-hospital statin therapy were significantly less likely to die in the hospital (OR, 0.38; CI, 0.28—0.52) or to have a composite end point of death or in-hospital
MI and/or stroke (OR, 0.66; CI, 0.56—0.77) than patients who never received statins. Patients who had received previous statin therapy but did not receive it during hospitalization, however, were no less likely to die during their hospital stay (OR, 1.39; CI, 0.91–2.14) than patients who never received statin therapy (Table 3).
Early in-hospital statin initiation in statin-naive patients. A total of 5,959 (38%) of the 15,481 statin-naive patients received in-hospital statin therapy. When compared with those who never received statin therapy, these patients were more likely to be male, were younger with fewer comorbidities, were less likely to be receiving other cardiac medications before presentation, were less ill at presentation, but were more likely to present with ST-segment elevation MI, and were more likely to receive in-hospital cardiac therapies and procedures such as cardiac catheterization (Table 2). After controlling for potentially confounding variables, statin-naive patients who were started on statin therapy in-hospital were less likely to suffer in-hospital complications (with the exception of recurrent MI), were less likely to die (OR, 0.38; 95% CI, 0.30—0.48), and were less likely to suffer the composite end point of death, MI, and/or stroke (OR, 0.87; 95% CI, 0.78–0.97) when compared with patients who never received statins (Table 3).
In summary, data from the GRACE project suggest that patients who received previous statin therapy had a less severe ACS presentation, despite having more comorbidities when compared with those not previously receiving statins. Patients previously receiving statin therapy who continued to receive statins in-hospital had significantly lower rates of in-hospital complications and death than those never treated with statins. However, any favorable association between prior statin therapy and hospital outcomes was lost if statin treatment was discontinued during hospitalization.
This abrogation of the protective benefit of statin pretreatment associated with early withdrawal of therapy was first described in a substudy analysis of the PRISM database.3 Patients in whom statins were discontinued had an almost threefold higher short-term event rate (death and nonfatal MI) than patients continuing therapy. Interestingly, most of the adverse events occurred early (0—7 days) before any impact on serum lipid levels would be anticipated. Similarly, our data suggest increased rates of several in-hospital complications, including death, for ACS patients discontinuing statin therapy initiated before hospitalization. In addition, these patients had event rates as high as or higher than patients never receiving statin therapy at all (before or during hospitalization).
These data suggest that while previous statin therapy may attenuate the severity of the early course of ACS, withdrawal of therapy may have a det-rimental impact. The mechanism(s) responsible for this observation remain unclear, but it is unlikely to reflect alterations in lipid levels, which can take days to weeks to manifest. There is emerging clinical and basic science data that statin agents modulate processes beyond low-density lipoprotein lowering. It has been hypothesized that statin agents may favorably impact a variety of inflammatory, thrombotic, and endothelial processes. Sudden withdrawal of statin therapy may result in a rebound in one or more of these processes, which may in turn contribute to further destabilization of a recently ruptured atherosclerotic plaque.
In a small study of atorvastatin (Lipitor) therapy in eight healthy men with normal cholesterol levels, a significant augmentation in endothelial-dependent blood flow and concomitant decrease in high-sensitivity C-reactive protein (hs-CRP) was detected within 24 to 48 hours of statin therapy.6 Although hs-CRP did not change appreciably after cessation of therapy, endothelial-dependent blood flow returned to below baseline values within 1 day of statin cessation. In a subsequent series of experiments, the same investigators were able to demonstrate in a mouse model that withdrawal of statin therapy can result in 90% suppression of endothelial nitric oxide production within 2 days.7 Other alternative mechanisms by which early statin therapy, and conversely, withdrawal, might impact the early course of ACS include altered platelet aggregability, inhibition of thrombus formation/growth, reduction in matrix metalloproteinase activity, and enhanced endothelial function.8-11
It must be acknowledged that ours was not a randomized trial of early statin treatment or discontinuation. Although we attempted to rigorously control for potential confounding variables, differences in the outcomes for early statin therapy may still be af-
fected by unmeasured differences in baseline characteristics, clinical presentation, or concomitant therapies. As such, no firm conclusions can be drawn about a causal relationship between early statin therapy (and withdrawal) and hospital outcomes based on this study.
That said, this study adds to an increasing literature supporting the aggressive utilization of early statin therapy in patients with ACS. Data from the previously published Cardiac Hospitalization Atherosclerosis Management Program12 as well as the Swedish Register of Cardiac Intensive Care13 document enhanced long-term adherence to statins, as well as reduced 1-year mortality in ACS patients who are initiated on therapy before hospital discharge.
The results of our study suggest that patients with ACS were less likely to suffer in-hospital complications and/
or death if they were already receiving statins before hospitalization. If statin therapy was discontinued during hospitalization, however, these benefits were lost. Our findings reinforce the hypothesis that statin therapy can modulate a variety of non—lipid-lowering pathophysiologic mechanisms in ACS patients. Future randomized trials are needed to address the effect of previous and early in-hospital statin therapy on clinical outcomes in patients with ACS.