1Department of Medicine and Care, Internal Medicine, University of Linköping, SE-58185 Linköping, Sweden
2VA Medical Center and University of Colorado Health Sciences Center, Denver, CO, USA
3Pfizer, New York, NY, USA
4MCP Hahnemann University, Philadelphia, PA, USA
5Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA
612 Narrow Street, London, UK
7San Francisco General Hospital and University of California, San Francisco, CA, USA
8Johann Wolfgang Goethe University, Frankfurt, Germany
Received 20 October 2004; revised 25 January 2005; accepted 27 January 2005; online publish-ahead-of-print 11 March 2005.
* Corresponding author. Tel: +46 13 222102; fax: +46 13 149991. E-mail address: andol{at}imv.liu.se
See page 853 for the editorial comment on this article (doi:10.1093/eurheartj/ehi218)
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Abstract |
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Methods and results Cox proportional hazards models were constructed to determine relations between lipoproteins and clinical endpoint events. Baseline LDL cholesterol (LDL-C) did not predict outcome. In contrast, baseline HDL-C predicted outcome with a hazard ratio of 0.986 per mg/dL increment in HDL-C, P<0.001, indicating 1.4% reduction in risk for each 1 mg/dL increase in HDL-C. Atorvastatin treatment profoundly lowered LDL-C, but had minimal effect on HDL-C. Neither Week 6 LDL-C nor absolute change of LDL-C from baseline by Week 6 had any significant impact on clinical endpoints occurring between Week 6 and Week 16 after randomization.
Conclusion Plasma HDL-C, but not LDL-C, measured in the initial stage of ACS predicts the risk of recurrent cardiovascular events over the ensuing 16 weeks. LDL-C reduction does not account for the clinical risk reduction with atorvastatin treatment after ACS. This finding may suggest that the clinical benefit of atorvastatin after ACS is mediated by qualitative changes in the LDL particle and/or by non-lipid (pleiotropic) effects of the drug.
Key Words: Acute coronary syndrome Intervention study Lipoprotein Statin
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Introduction |
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Acute coronary syndrome (ACS), including acute myocardial infarction and unstable angina pectoris, is associated with a high short-term risk for recurrent ischaemic events.3,4 There has been no prior study concerning the relationship between the serum lipoproteins at the time of ACS and the risk of early, recurrent ischaemic events following ACS. Nor has there been any analysis to determine whether pharmacological modulation of lipoproteins affects short-term risk after ACS. Because of different physiology of unstable vs. stable atherosclerotic plaques, it is possible that the relationship between serum lipoproteins and events may differ in acute and chronic CHD.
Statins may act rapidly to improve vascular endothelial function, attenuate vascular inflammation, and correct prothrombotic tendencies.5 Such effects have been observed within a few weeks of initiating treatment with statins in experimental animals or human subjects. These effects of statins may be related to their lipid-lowering actions and/or mechanisms unrelated to circulating lipoproteins.
The Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial demonstrated that treatment with atorvastatin 80 mg daily, initiated early after presentation with ACS and maintained for 16 weeks, resulted in a significant reduction of early recurrent ischaemic events, including both cardiac events and strokes when compared with treatment with placebo.6
The present analysis of data from the MIRACL trial had two objectives: first, we sought to determine the relationship between baseline serum lipoproteins (i.e. prior to randomized treatment assignment) and 16 week outcomes following ACS. Secondly, we sought to determine the relationship between the changes in serum lipoproteins during randomized treatment and the short-term risk of recurrent cardiovascular events.
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Methods |
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Most important exclusion criteria were serum cholesterol >7.0 mmol/L (270 mg/dL), anticipated coronary revascularization, Q-wave myocardial infarction within the previous month, coronary artery bypass grafting within 3 months, percutaneous coronary intervention within 6 months of enrolment, or treatment with other lipid-lowering drugs. There was no lower limit for total or LDL-C or upper limit for HDL-cholesterol (HDL-C) at entry.
All patients provided informed consent. The protocol was approved by local institutional review boards.
Study design
Between 24 and 96 h after hospital admission, patients were randomly assigned to double-blind treatment with atorvastatin 80 mg/day or matching placebo for 16 weeks. The dose was chosen to allow for maximal effects on LDL-C and possible pleiotropism in this proof-of-concept trial. Follow-up visits were scheduled at 2, 6, and 16 weeks. Plasma lipid and lipoprotein concentrations were measured at baseline, 6, and 16 weeks. Apolipoprotein B (apoB) and A-1 (apoA-1) were determined at baseline and at 16 weeks.
The primary efficacy measure was the time to first occurrence of death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation, or worsening angina with new objective evidence of ischaemia and requiring emergency rehospitalization.7
Lipid and lipoprotein analysis
Venous blood was collected after subjects had fasted for 1214 h. For analysis of changes in lipids, frozen sera obtained immediately before the start of active treatment and at the Week 6 and Week 16 visits were assayed. The central laboratory (Medical Research Laboratories, Cincinnati, OH, USA, and Brussels, Belgium) utilized assay methods standardized by the Centers for Disease Control, USA. In all samples where serum triglyceride levels did not exceed 4.40 mmol/L (400 mg/dL), LDL-C values were calculated on the basis of the Friedewald formula.8 If the serum triglyceride level exceeded 4.40 mmol/L, plasma LDL-C was measured directly.
Statistical analysis
Pre-specified Cox proportional hazards models stratified by country and inclusion event (unstable angina or non-Q-wave myocardial infarction) were constructed to determine relationships between lipoprotein fractions (total cholesterol, LDL-C, HDL-C, triglycerides, apoA-1, and apoB), randomized treatment assignment, and time to occurrence of clinical endpoint events (death, non-fatal acute myocardial infarction, cardiac arrest, or urgent rehospitalization for recurrent myocardial ischaemia). Two analysis populations were considered (Figure 1).
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Hazard ratios were expressed as the relative hazard for each 1 mg/dL increase in a specific lipid parameter, using a linear model. Absolute changes in concentrations were used in the models to maintain the same continuous scale as the baseline and Week 6 analyses. The validity of the proportional hazard assumption was tested by adding a time-dependent variable to each model to confirm that the hazard ratio for each lipid parameter did not increase or decrease over time. To determine whether non-linear relationships existed between lipid and lipoprotein concentrations and events, baseline, Week 6, and absolute change from baseline to Week 6 concentrations of total cholesterol, LDL-C, HDL-C, and triglycerides were also analysed in quartiles. In each model, the relative hazard of an event in quartiles 2, 3, and 4 was expressed with quartile 1 serving as the reference category (hazard ratio=1.000). All hypothesis testing was two-sided, and statistical significance was declared if P<0.05. Owing to the exploratory nature of the analyses, there was no adjustment to maintain an overall Type I error rate of 5%.
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Results |
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Lipid and lipoprotein concentrations at baseline and on randomized treatment
At the time of randomization, mean (SD) baseline LDL-C was 3.22 (0.86) mmol/L. There was no difference in baseline LDL-C between placebo and atorvastatin groups (Table 1). Mean baseline LDL-C in the non-Q-wave myocardial infarction group and in the unstable angina group were 3.15 and 3.33 mmol/L, respectively. This difference is probably related to greater tissue damage, more pronounced acute phase reaction, and thereby lower LDL-C among patients with non-Q-wave myocardial infarction than among patients with unstable angina. Six weeks after randomization, LDL-C had increased by 10% to a mean concentration of 3.46 mmol/L in the placebo group. Six weeks after randomization, LDL-C decreased by 46% to a mean concentration of 1.69 mmol/L in the atorvastatin group.
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Mean (SD) baseline HDL-C was 1.22 (0.32) mmol/L for the whole cohort and showed only minute changes in both groups 6 weeks after randomization.
Mean (SD) baseline triglyceride concentration for this cohort was moderately elevated at 2.01 (1.02) mmol/L. At Week 6, triglycerides remained essentially unchanged in the placebo group, but decreased by 21% in the atorvastatin group.
At Week 16, mean plasma lipid measurements were similar to those at Week 6; in both groups, total cholesterol, LDL-C, HDL-C, and triglycerides increased by 26% between the Week 6 and the Week 16 measurement (data not shown).
Relation of baseline lipids to 16 week risk of ischaemic events
Relationships among baseline lipids, lipoproteins, and apolipoproteins, and endpoints are shown in Figure 2. Between Week 0 and Week 16, a primary endpoint event occurred in 491 patients or 16.2% of patients (Figure 1). In a model incorporating treatment assignment and baseline LDL-C, assignment to treatment with atorvastatin was associated with a decreased risk of a primary endpoint event [hazard ratio 0.835, 95% confidence interval (CI) 0.6990.999, P=0.049].
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In contrast to LDL-C, baseline HDL-C was significantly related to outcome at 16 weeks. In a model incorporating treatment assignment, baseline HDL-C, and their interaction, for each mg/dL increment in baseline HDL-C, the hazard ratio for an event was 0.986 (95% CI 0.9790.994; P<0.001). Expressed another way, the risk of an event diminished by 1.4% for each 1 mg/dL increment in baseline HDL-C. An analysis by quartiles of baseline HDL-C suggests a linear relationship; hazard ratios [(95% CI), P-value] for events in quartiles 24 (relative to quartile 1) were 0.896 [(0.706, 1.136), 0.364], 0.822 [(0.642, 1.053), 0.121], and 0.620 [(0.477, 0.806), <0.001]. Owing to the unexpected non-significant relationship between baseline LDL-C and outcome, the relationship of baseline HDL-C and atorvastatin treatment to outcome was further explored in a post hoc analysis by level of LDL-C (below or above median of 3.17 mmol/L). The protective effect of HDL-C was more pronounced for those patients with baseline LDL-C below median, indicating that each mg/dL increase in baseline HDL-C was associated with a 2.2% reduction in risk (95% CI 1.23.3%; P<0.001). In contrast, among those with baseline LDL-C above median, there was no significant relationship between baseline HDL-C and risk of an ischaemic event between Week 0 and Week 16 [hazard ratio (95% CI)=0.998 (0.987, 1.010); P=0.744]. Baseline apoA-1 was inversely related to 16 week risk (P<0.001).
There was no evidence against the proportional hazards assumption in all of the models involving baseline lipid parameters.
Relationship between on-treatment lipids and outcome
The relationship between modification of lipids by randomized treatment and outcomes was studied using lipid values at baseline and Week 6 and clinical events occurring from Week 6 to Week 16 (n=121). Although this analysis excluded events occurring from baseline to Week 6, the alternative approach (relating lipid changes between baseline and Week 16 to events during the same period) would be logically invalid as it would use future lipid values (at Week 6) to predict past clinical events (prior to Week 6). The proportion of fatal events was greater in the period after 6 weeks than in the period prior to 6 weeks, even though the overall event rate was lower after 6 weeks. Therefore, we do not believe that by excluding events between 0 and 6 weeks, this resulted in a population at lower risk.
Assignment to treatment with atorvastatin tended to lower the risk of an ischaemic event between Week 6 and Week 16, with hazard ratio of 0.721 (95% CI 0.5011.037; P=0.077 and model including Week 6 HDL-C). However, neither Week 6 LDL-C or HDL-C nor absolute changes of these lipoproteins from baseline to Week 6 had any significant relationship to the risk of a clinical endpoint between Week 6 and Week 16, Figure 2. In addition, interactions between Week 6 lipoprotein levels and treatment assignment were not statistically significant, indicating that atorvastatin treatment did not modify the relationships between on-treatment LDL-C, HDL-C, or absolute change in these parameters and the incidence of recurrent events.
We also computed the univariate hazard ratio for the effect of LDL-C at 6 weeks (or change from Week 0 to Week 6) on the risk of an event between Week 6 and Week 16. This univariate hazard ratio was 1.003 (95% CI 0.9991.007) when compared with the multivariate hazard ratio for LDL-C of 1.001 (95% CI 0.9961.007), i.e. in a model also including treatment assignment.
If the Week 6 plasma samples were divided into quartiles of LDL-C with the lowest quartile serving as a reference, there was no discernible relationship between quartile of LDL-C at Week 6 or absolute change to Week 6 and events between Week 6 and Week 16. This was true both for quartiles defined across both treatment groups and for quartiles defined within treatment groups. Thus, there was no linear relationship between Week 6 or absolute change in LDL-C and events between Week 6 and Week 16, nor did analysis by quartiles suggest a threshold or quadratic relationship.
In contrast, patients in the highest quartile of HDL-C at Week 6 had a substantially reduced risk of an event between Week 6 and Week 16 with a hazard ratio of 0.520 (95% CI 0.3050.886; P<0.02 vs. the lowest quartile). Neither Week 6 values of total cholesterol or triglycerides nor changes in these values from baseline to Week 6 bore a relation to outcomes between Week 6 and Week 16.
In all of the models involving on-treatment lipid parameters, the proportional hazards assumption appeared to be valid.
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Discussion |
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Interpretation of a relationship between baseline LDL-C and risk of early, recurrent ischaemic events after ACS is complicated by acute phase effects on this lipoprotein.9 In the present study, this phenomenon is demonstrated in two ways. First, after 6 weeks on placebo, LDL-C increased significantly by 10% from baseline, suggesting recovery from an initial acute phase depression of plasma lipid levels. Secondly, those patients with more severe initial myocardial injurywhose index event was non-Q-wave myocardial infarctionhad lower baseline LDL-C and higher levels of inflammatory markers, such as C-reactive protein,10 than those with less severe injuryindex event unstable angina. Thus, as a result of the acute phase response, baseline LDL-C may be lower among patients with a poorer prognosis owing to greater initial myocardial injury. This relationship is directionally opposite to the relationship of LDL-C to long-term risk for CHD events. Operating concurrently, these two relationships may negate one another, resulting in no net relationship between LDL-C close to the time of ACS and short-term risk of recurrent events after ACS.
In contrast to LDL-C, acute phase effects on HDL-C were minimal in MIRACL. The cause of this, which is at variance with some other observations indicating that HDL-C and apoA-1 decrease in ACSs, was probably owing to the early blood sampling during the index event and to the relatively minor myocardial damage sustained. Therefore, levels of HDL-C measured shortly after ACS may more accurately reflect the physiological role of this lipoprotein in promoting plaque stability through mechanisms including reverse cholesterol transport and protection of LDL-C from oxidative stress.
Our second key finding was a highly significant relationship between baseline levels of HDL-C and 16 week risk of recurrent events after ACS. Because atorvastatin treatment had minimal effect on HDL-C in MIRACL, it is not possible to determine whether the relationship between HDL-C and risk would apply if HDL-C were modulated by drug therapy. Of particular interest is that atorvastatin, with unchanged apoA-1 concentrations, has been demonstrated to shift the HDL subpopulation profile of CHD patients towards that observed in subjects without CHD.11 The observed relationship raises the possibility that HDL might be an attractive target for modifying the high-risk state following ACS. The striking effect of direct apolipoprotein A-I infusions on coronary atherosclerosis in patients with ACS supports this view.12
The third finding, the absence of a discernible relation between changes in lipoproteins and the reduction in ischaemic events resulting from statin treatment is unexpected. It should be borne in mind that estimation of LDL-C with the Friedewald formula is a crude measure of the lipoprotein. Despite similar LDL-C concentrations, LDL particles may differ in their susceptibility to oxidation and thereby their ability to elicit an inflammatory response. It is possible that changes in the physicochemical properties of LDL-C (e.g. size, chemical composition, or oxidation state) by atorvastatin,13 rather than changes in the concentration of LDL-C, could account for the beneficial effect on ischaemic events observed in MIRACL. This explanation for the positive outcome on MIRACL is supported by our suggestion that atorvastatin promotes mobilization and clearance of proinflammatory oxidized phospholipids, which may contribute to a reduction in ischaemic events after ACS.14
Alternatively, our data are also consistent with the hypothesis that atorvastatin produces beneficial clinical effects after ACS entirely independent of effects on LDL-C or other lipoproteins, acting instead through non-lipid, or pleiotropic mechanisms. In experimental studies, many of the potentially beneficial effects of statins, such as enhanced expression of endothelial nitric oxide synthase, reduced expression of matrix metalloproteinases, and attenuation of ischaemia/reperfusion injury, may be demonstrated independently of any changes in the lipid milieu.15 The lipid-independent mechanisms of action may include modulation of the rho/rho-kinase pathway. By inhibiting 3-hydroxy-3-methyl glutaryl CoA reductase, statins reduce the intracellular pool of isoprenoid compounds. Reduced prenylation of the rho protein may attenuate vascular inflammation through a combination of different actions.16 We have previously demonstrated that atorvastatin treatment potentiates the decline in inflammation as estimated by CRP in MIRACL, a finding supporting the concept of an anti-inflammatory effect mediating the beneficial clinical effect in ACS.10 We demonstrated significant effects by atorvastatin on non-fatal and fatal strokes in the MIRACL trial.17 When the outcome measure included non-fatal stroke in addition to primary endpoint events in the present analysis, assignment to atorvastatin was associated with a hazard ratio of 0.824 (95% CI 0.6930.979; P<0.028). As the risk of stroke bears little relation to LDL-C in epidemiological studies, this finding favours the view of a pleiotropic effect to explain the clinical benefit in MIRACL.
Several limitations of the present analysis should be considered. Our analysis of relationships between changes in lipoproteins on randomized treatment and events utilized lipid values at Week 6 (or changes from Week 0 to Week 6) and events occurring between Week 6 and Week 16. Events occurring between Week 0 and Week 6 were not considered. This resulted in considerably fewer endpoints and diminished statistical power when compared with an analysis including all events between Week 0 and Week 16. However, the latter analysis would be logically flawed, as it would use future lipid values (at Week 6) to predict past events (prior to Week 6).
This analysis of the MIRACL trial may provide the first evidence of a clinically significant effect induced by non-lipid or pleiotropic effect(s) of statins. Regardless of the underlying mechanism, the practical message from this analysis is that, within the lipoprotein ranges included in MIRACL, the benefit of statin treatment after ACS is not influenced by LDL-C levels either at baseline or on treatment, and measurements of serum lipoproteins should not guide the use of this therapeutic intervention in the high-risk period immediately following ACS.
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Acknowledgement |
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References |
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