Lipoprotein-Associated Phospholipase A2 and Its Association With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction) Trial
Background— Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with the risk of cardiovascular (CV) events in population-based studies. The prognostic value of Lp-PLA2 in patients with acute coronary syndromes (ACS) has not been established.
Methods and Results— Plasma levels of Lp-PLA2 activity were measured at baseline (n=3648) and 30 days (n=3265) in patients randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d after ACS in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction) trial. The primary end point was death, myocardial infarction, unstable angina, revascularization, or stroke (mean follow-up 24 months). At baseline after ACS, the risk of recurrent CV events was similar across all quintiles of Lp-PLA2 activity (Ptrend=0.88). Overall, mean levels of Lp-PLA2 were lower at 30 days of follow-up than at baseline (35.7 versus 40.9 nmol · min−1 · mL−1, P<0.001). In particular, treatment with atorvastatin 80 mg/d was associated with a 20% reduction in Lp-PLA2 activity (P<0.001), whereas Lp-PLA2 rose 3.6% with pravastatin 40 mg/d (P<0.001). Patients with 30-day Lp-PLA2 activity in the highest quintile were at significantly increased risk of recurrent CV events compared with those in the lowest quintile (26.4% versus 17.6%, Ptrend=0.002). After adjustment for cardiac risk factors, treatments, achieved low-density lipoprotein (LDL), and C-reactive protein, Lp-PLA2 activity in the highest quintile remained independently associated with a higher risk of recurrent CV events (adjusted hazard ratio 1.33, 95% confidence interval [CI] 1.01 to 1.74).
Conclusions— Lp-PLA2 is not useful for risk stratification when measured early after ACS. At 30 days, Lp-PLA2 activity is significantly lowered with high-dose statin therapy and is associated with an increased risk of CV events independent of C-reactive protein and LDL cholesterol levels.
Received January 25, 2006; revision received March 2, 2006; accepted March 3, 2006.
Inflammation has been established as a key contributor to atherothrombosis.1 As such, circulating levels of inflammatory biomarkers may provide important prognostic information beyond that obtained from traditional risk factors.2 As new insights are gained about the pathophysiology of athero- genesis and plaque rupture, additional markers of inflammation may be identified that provide incremental value for assessing risk and guiding therapy.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a 45-kD enzyme, also known as platelet-activating factor acetylhydrolase (PAF-AH), that is produced predominantly by macrophages and lymphocytes.3,4 In plasma, more than two thirds of Lp-PLA2 circulates bound to low-density lipoprotein (LDL), with much of the enzyme’s activity concentrated in atherogenic small, dense LDL.5 Early studies suggested the enzyme may have an antiinflammatory role,6,7 whereas growing evidence suggests that it acts in several pathways that contribute to atherogenesis.8,9 In addition, Lp-PLA2 has been identified in atherosclerotic plaques10 and is strongly expressed in macrophages found in lesions prone to rupture.11 As such, there has been interest in the inhibition of the Lp-PLA2 enzyme as a therapeutic target.12 Although lipid-lowering therapies that include statins may lower circulating Lp-PLA2,13–15 the clinical implications of this observation outside of LDL reduction remain unclear.
Clinical Perspective p 1752
At least 4 large studies have shown an independent association between Lp-PLA2 and the risk of future cardiovascular (CV) events in candidates for primary prevention.16–19 In addition, Lp-PLA2 has been shown to be elevated in patients with coronary artery disease20–23 and to be associated with an increased risk of coronary events in patients with preexisting stable CV disease.24,25 In contrast, few data exist on the association of Lp-PLA2 with prognosis in acute coronary syndromes (ACS).
We therefore investigated the prognostic utility of Lp-PLA2 in a large cohort of patients presenting across the spectrum of ACS and assessed its incremental value to existing clinical risk factors. We also examined the association between Lp-PLA2, randomized types of statin therapies, and subsequent outcomes in PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction).
Study Population and Design
The design and results of PROVE IT-TIMI 22 have been reported previously.26 In brief, PROVE IT-TIMI 22 was a multicenter, randomized, double-blind trial of 4162 patients to evaluate the effects of intensive (atorvastatin 80 mg daily) versus moderate (pravastatin 40 mg daily) statin therapy for the prevention of major adverse cardiac events after ACS. Randomization occurred in the first 10 days after the index event (median 7 days).
Patients were followed for 18 to 36 months after randomization (mean 24 months). The primary end point of the trial was a composite of death, myocardial infarction (MI), unstable angina that required hospitalization, revascularization (>30 days after randomization), or stroke. Elements of the primary end point were adjudicated by a clinical events committee.26
Blood Sampling and Analysis
As part of the study protocol, a sample of venous blood was obtained in EDTA-treated tubes from the subjects at the time of enrollment and at 30 days’ follow-up. The plasma component was frozen and shipped to a central laboratory where samples were stored at −70°C or colder. Lp-PLA2 activity was measured with [3H]-PAF as reaction substrate, using previously described methodology18 at GlaxoSmithKline (Research Triangle Park, NC). Enzyme activity is expressed as nanomoles of PAF hydrolyzed per minute per mL of plasma samples (nmol · min−1 · mL−1). An aliquot of each sample and 2 aliquots of 3 plasma controls were each analyzed in 2 duplicate plates. The average intraplate and interplate coefficient of variations were both <7%, whereas the mean Lp-PLA2 activity determined for each sample had an average coefficient of variation of 9.4% within the normal dynamic range of the assay.
After determination of Lp-PLA2 activity, samples were frozen and subsequently thawed for determination of Lp-PLA2 mass. Lp-PLA2 mass measurements were performed with the PLAC Test at diaDexus Inc (South San Francisco, Calif). This assay consists of a sandwich-type immunoassay that uses 2 anti-Lp-PLA2 monoclonal antibodies standardized to recombinant Lp-PLA2 as described previously.20,27
Available plasma samples from baseline and after 30 days’ follow-up were also measured for high-sensitivity C-reactive protein (CRP) (Denka Seiken, Tokyo, Japan) at the TIMI Biomarker Core Laboratory (Boston, Mass).28 All biomarker testing was performed by personnel who were blinded to treatment arms, outcomes, and results of other biomarker testing.
Continuous variables were compared with the Student t test, and categorical variables were compared with the χ2 test. Correlations between levels of Lp-PLA2 activity, Lp-PLA2 mass, lipids, and CRP were examined with the Spearman correlation coefficient.
To evaluate its association with clinical outcomes, Lp-PLA2 was analyzed as a continuous variable and categorized into quintiles according to Lp-PLA2 level at baseline and after 30 days of follow-up. For this analysis, we defined achieved LDL, CRP, and Lp-PLA2 as the levels obtained 30 days after initiation of study drug. Patients with an event before 30 days of follow-up were excluded from the 30-day analyses. Event rates were estimated by the Kaplan-Meier method.
Cox proportional hazards models were constructed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for clinical events associated with levels of Lp-PLA2. The variables that were tested for inclusion in the model were age, gender, tobacco use, index diagnosis, prior MI, diabetes mellitus, prior renal disease, prior statin use, treatment arm, LDL, high-density lipoprotein (HDL), and CRP. With a stepwise approach to modeling (P=0.1 for entry, P=0.05 for retention), the final model consisted of age, index diagnosis, prior MI, diabetes mellitus, prior renal disease, treatment arm, LDL, and CRP. Analyses at 30 days included achieved CRP and achieved LDL as covariates in the model. We tested for an interaction of Lp-PLA2 with the randomized statin regimen by entering an interaction term in the model. Stratified analyses were also performed based on treatment arm, statin use before index event, and LDL concentration above or below the median. For all analyses, a probability value <0.05 was considered to be statistically significant. Statistical analyses were performed with Stata version 8.2 (StataCorp, College Station, Tex).
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
Baseline Demographics and Clinical Presentation
Measurements of Lp-PLA2 activity were available for 3648 participants (87.7%) at baseline. After 30 days’ follow-up, 3265 participants (78.4%) were alive and free from a recurrent event and had a serum sample for measurement of Lp-PLA2.
In the study population, the index event was evenly divided between ST-elevation MI, non–ST-elevation MI, and high-risk unstable angina. More than two thirds of patients underwent percutaneous coronary intervention for management of their ACS before randomization, and one quarter were taking a statin before their event. The characteristics of the study population and achieved Lp-PLA2 are displayed in Table 1. Mean levels of Lp-PLA2 at 30 days were higher among patients who were younger, male, white, or current smokers or who had a prior history of MI or hyperlipidemia. Mean levels of Lp-PLA2 activity were lower in patients with a history of hypertension and were lowest in patients with ST-elevation MI as their index diagnosis.
Baseline Lp-PLA2 Activity and Clinical Outcomes
At baseline after ACS, no significant association was evident between Lp-PLA2 and the risk of subsequent outcomes (Table 2). Event rates for the primary end point were similar across all quintiles of Lp-PLA2 activity (Ptrend=0.88). Mean Lp-PLA2 activity was similar in patients both with and without recurrent CV events (41.2 versus 40.8 nmol · min−1 · mL−1, P=0.76), including the individual elements of the composite end point. In addition, no significant associations were observed after adjustment for baseline demographics, risk factors, and medications (adjusted HR, quintile 5:quintile 1, for the primary end point 1.08; 95% CI 0.86 to 1.36) or when analyses were stratified by prior statin use, LDL concentration, or randomized treatment arm.
Lp-PLA2 Activity and Statin Therapy
After 30 days’ follow-up, overall mean Lp-PLA2 activity had decreased by 12.7% compared with mean activity at baseline (35.7 versus 40.9 nmol · min−1 · mL−1, P<0.001). Notably, mean Lp-PLA2 activity declined by 20% after treatment with high-dose atorvastatin (P<0.001), whereas mean Lp-PLA2 activity rose by 3.6% in patients taking pravastatin (P<0.001; P<0.001 for the difference between treatment arms; Figure 1). For patients who were statin naïve before the index event, mean Lp-PLA2 activity declined by 24% after 30 days in atorvastatin-treated patients (P<0.001) and remained unchanged in patients treated with pravastatin (P=0.55; P<0.001, for the difference between treatment arms). In a linear regression model, treatment with high-dose atorvastatin was associated with a larger reduction in Lp-PLA2 activity independent of the change in LDL (P<0.001).
Both mean Lp-PLA2 activity and LDL concentration were reduced after 30 days compared with baseline, and the correlation between the achieved values of these variables was significant (r=0.50, P<0.001), such that 25% of the variance in achieved Lp-PLA2 was explained by achieved plasma LDL. A very weak correlation was evident between achieved Lp-PLA2 activity and achieved CRP (r=0.07, P<0.001). Achieved Lp-PLA2 activity did not correlate with HDL (r=−0.02, P=0.21) and correlated modestly with achieved triglycerides (r=0.36, P<0.001).
Thirty-Day Lp-PLA2 Activity and Clinical Outcomes
Patients with Lp-PLA2 activity in the highest quintile at 30 days were at significantly increased risk of recurrent CV events compared with patients with Lp-PLA2 activity in the lowest quintile (26.4% versus 17.7%, Ptrend=0.002, Figure 2). Notably, there was directional consistency across the individual end points of death, MI, and need for revascularization (Table 3). Moreover, after we controlled for relevant clinical predictors including achieved LDL and achieved CRP, patients with Lp-PLA2 activity in the highest quintile remained at significantly increased risk of the primary end point (adjusted HR 1.33, 95% CI 1.01 to 1.74), death or MI (adjusted HR 1.70, 95% CI 1.08 to 2.68), and recurrent MI (adjusted HR 1.98, 95% CI 1.17 to 3.34; Table 3).
For the purpose of placing the prognostic performance of Lp-PLA2 in the context of our prior evaluation of CRP,28 Lp-PLA2 was also evaluated separately along with LDL and each of the relevant clinical predictors and was associated with a 1.69-fold (95% CI 1.08 to 2.65) higher risk of death or MI in the highest quintile of Lp-PLA2. By comparison, patients with CRP in the highest quintile were at 1.90-fold (95% CI 1.33 to 2.72) higher risk of death or MI after adjusting for the same variables.
When the association between Lp-PLA2 activity and clinical outcomes was analyzed by treatment arm, Lp-PLA2 was a significant predictor of MI (Ptrend=0.004), revascularization (P=0.04), and the primary end point (P=0.04) among patients assigned to treatment with pravastatin, thereby eliminating the possibility of confounding by statin allocation. In patients treated with high-dose atorvastatin, the association appeared attenuated, with no statistically significant relationships observed between Lp-PLA2 and the risk of subsequent CV events (Ptrend=0.23); however, formal testing did not yield definitive statistical evidence of an interaction between treatment groups (Table 3).
Lp-PLA2 Mass and Clinical Outcomes
To compare our findings with a commercially available assay, Lp-PLA2 mass was also measured in all available samples with the PLAC test (diaDexus, South San Francisco, Calif) mass assay. Samples were available for measurement in 3625 participants (87.1%) at baseline and 3263 participants (78.4%) at 30-day follow-up.
Only a modest correlation was apparent between Lp-PLA2 activity and Lp-PLA2 mass both at baseline (r=0.35, P<0.001) and at 30-day follow-up (r=0.36, P<0.001; Figure 3). When measured at baseline after an ACS, we observed no independent association between Lp-PLA2 mass and the risk of future CV events.
At 30-day follow-up, patients with Lp-PLA2 mass in the highest quintile had a statistically higher incidence of CV events than those with Lp-PLA2 mass in the lowest quintile (22.8% versus 20.3%, Ptrend=0.03). However, this association was no longer significant after adjustment for achieved LDL and other clinical risk indicators (adjusted HR 0.98, 95% CI 0.76 to 1.25). These results were similar across each element of the composite end point and when stratified by LDL concentration either above or below the median.
This large-scale study of Lp-PLA2 in a well-characterized population of patients with ACS provides several findings of clinical importance with respect to this emerging biomarker. In particular, we found that Lp-PLA2 is not useful for risk stratification when measured in the early days after presentation with unstable coronary disease. However, when measured during follow-up, Lp-PLA2 activity provides prognostic information that is incremental to that obtained from traditional risk factors, including both LDL and CRP.
Use of Lp-PLA2 for Risk Assessment
Although elevated levels of Lp-PLA2 have been shown to be associated with CV outcomes in population-based studies,16–19 few data are available with regard to its prognostic utility in patients with ACS. When measured early after an event, we found no independent association between Lp-PLA2 activity or mass and the risk of recurrent CV events, regardless of prior statin use, treatment arm, or baseline LDL concentration.
There are several possible explanations for our findings that should be considered. As LDL concentrations fall unpredictably early after onset of ACS,29 Lp-PLA2 may variably diminish in tandem, thereby dampening the apparent association of both LDL and Lp-PLA2 with outcomes. To that end, Stephens and colleagues30 observed a reduction in both LDL and Lp-PLA2 activity during the first several days after ACS compared with the time of presentation. Another factor that could theoretically influence the prognostic utility of the marker is the widespread inflammation that accompanies ACS.31,32 Yet, it remains unclear whether Lp-PLA2 is an acute-phase reactant, because enzyme levels have been shown to rise or fall in response to inflammatory stimuli in both human and animal models.33–35 Another consideration is randomized statin use in the PROVE IT-TIMI 22 cohort. Although lipid-lowering therapy can variably influence levels of Lp-PLA2 and its predominant carrier LDL, it is unlikely that our baseline findings can be explained by treatment effect alone, because they were confirmed in an additional 2351 patients with ACS who were on much lower rates of lipid-lowering therapy (see online-only Data Supplement at http://circ.ahajournals.org/cgi/content/full/ CIRCULATIONAHA.105.612630/DC1).
Importantly, we found that elevated levels of Lp-PLA2 activity are independently associated with an increased risk of recurrent CV events, but only when measured at a time when patients were distanced from the acute inflammatory response to the index event. This observation resolves the potential discordance between the lack of prognostic value of the baseline measurement in the present study and prior studies that have shown an association between Lp-PLA2, prevalent coronary artery disease, and future vascular events.20–25 Comparable to prior studies, the relative hazard for subsequent CV events for patients with the highest levels of Lp-PLA2 activity was ≈1.3 after we accounted for traditional risk factors. Notably, directional consistency was observed across most of the individual end points, including death, recurrent MI, and the need for coronary revascularization. Moreover, determination of Lp-PLA2 activity provided incremental prognostic information to that provided by traditional risk factors, including LDL and CRP.
Influence of Intensive Statin Therapy
The PROVE IT-TIMI 22 trial provided the opportunity to explore the effects of moderate and intensive statin therapies on levels of Lp-PLA2 in a randomized design. Intensive statin therapy with atorvastatin 80 mg/d was associated with a mean 20% reduction in Lp-PLA2 activity and a 23% reduction in Lp-PLA2 mass. In contrast, patients treated with pravastatin 40 mg/d observed a much smaller change in Lp-PLA2 activity (3.6%) or mass (−4.5%). Importantly, the larger reduction in Lp-PLA2 activity observed with atorvastatin 80 mg/d was only partially explained by the change in LDL. Although a definitive interaction with treatment group was not observed, the present findings are hypothesis generating, raising the possibility that intensive statin therapy may help to partially attenuate the risk associated with higher levels of Lp-PLA2. Moreover, pharmacological interventions aimed at inhibiting the Lp-PLA2 enzyme may provide incremental benefit to intensive lipid-lowering therapy and are now under investigation.12
Lp-PLA2 Activity Versus Mass
Our finding of a modest correlation between Lp-PLA2 as measured by the mass and activity assays (r=0.36) contrasts with a much stronger correlation (r=0.86) that was previously reported in a smaller study of 148 males, which used an earlier version of the mass assay.20 To date, there have been limited data comparing assay performance on a large scale across different patient populations. The present findings raise important questions about factors that may influence Lp-PLA2 enzyme activity independently of its quantified mass, including various therapies and disease states. Lipoproteins have been shown to alter the catalytic behavior of Lp-PLA2 in human plasma,36 with enhanced enzyme activity seen in association with LDL as opposed to enzyme bound to HDL. One could speculate that changes in lipoprotein distribution and particle size after ACS could lead to a differential effect on enzyme mass and activity. Moreover, Lp-PLA2 enzyme activity is determined by the rate of PAF hydrolysis in vitro, yet the ability to hydrolyze PAF is not limited to Lp-PLA2. Various other plasma enzymes, including lecithin cholesterol acyltransferase (LCAT), are capable of PAF hydrolysis and may upregulate this function during periods of oxidative stress.37–39
Many of the larger primary prevention studies explored the association between Lp-PLA2 and CV events using measurements of Lp-PLA2 mass.16,17,19,40 The WOSCOPS (West Of Scotland COronary Prevention Study) and MONICA (MONItoring trends and determinants in CArdiovascular disease) studies both found an independent association between Lp-PLA2 and the risk of coronary heart disease,16,19 whereas in the ARIC (Atherosclerosis Risk In Communities) study, an independent association was observed in patients with an LDL concentration <130 mg/dL.17 However, in our study of patients with recent ACS, the association between achieved Lp-PLA2 mass and CV outcomes was largely attenuated after controlling for baseline variables. Similarly, no independent association was observed between Lp-PLA2 mass and future coronary events in the Women’s Health Study population after other risk indicators were taken into consideration.40 As such, possible differences in assay performance in various clinical settings are of interest and should be addressed in future studies.
Limitations of the present study include the randomization of patients to statin therapies soon after ACS, which differentially influenced Lp-PLA2, LDL, and outcomes. Although we evaluated the prognostic utility of Lp-PLA2 by treatment arm and LDL concentration, the presence of statin use may have partially attenuated the relationship between Lp-PLA2 and subsequent events. However, the utility of Lp-PLA2 testing in the setting of statin use remains particularly relevant because intensive statin therapy is frequently used in post-ACS management.41 In addition, although 2 distinct time points were available for analysis, it is possible that stronger associations would be observed at different lengths of time after ACS. Owing to the absence of a placebo arm or plasma samples from the time of initial presentation, we are unable to ascertain whether Lp-PLA2 levels were acutely elevated at the time of ACS and subsequently returned to baseline by 30 days.
In conclusion, in the present study, Lp-PLA2 was not associated with an increased risk of recurrent CV events when measured early after ACS. As such, Lp-PLA2 cannot be advocated for risk stratification at that time. Rather, the present data suggest that Lp-PLA2 activity can offer additional prognostic information when assessed at a time significantly distanced from the acute coronary event. Additional understanding of available assay types is warranted to better understand the incremental utility of this biomarker. Moreover, intensive statin therapy is associated with significant lowering of Lp-PLA2 independent of LDL. Future investigation will help to determine whether inhibition of the Lp-PLA2 enzyme will prove to be a valuable therapeutic target.
Drs O’Donoghue, Morrow, and Sabatine are supported by National Institutes of Health grant U01 HL083-1341. Grant support for PROVE IT–TIMI 22 was provided by Bristol-Myers Squibb. Funding for the current analysis was supported by GlaxoSmithKline.
Dr O’Donoghue has received honoraria from GlaxoSmithKline. Dr Morrow has received research grants from GlaxoSmithKline, AstraZeneca, Merck, Pfizer, Schering-Plough, Bayer, Biosite, Dade-Behring, and Roche, all via the TIMI Study Group, and serves as a consultant/advisory board member to GlaxoSmithKline. Dr Sabatine has received research grants from AstraZeneca and Schering-Plough via the TIMI Study Group and from BristolMyers Squibb, other research support from diaDexus and Roche, and honoraria from BristolMyers Squibb and Sanofi-Aventis and serves as a consultant/advisory board member for Sanofi-Aventis and Bristol-Myers Squibb. Sabina A. Murphy has no disclosures to report. Carolyn H. McCabe has received research grants from GlaxoSmithKline, AstraZeneca, Merck, Pfizer, and Schering-Plough, all via the TIMI Study Group. Dr Cannon has received research grants from AstraZeneca, Merck, and Schering-Plough via the TIMI Study Group and serves as a consultant to or on the advisory boards of AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Schering-Plough, Pfizer, and Sanofi-Aventis. Dr Braunwald has received research grants from GlaxoSmithKline, AstraZeneca, Merck, and Pfizer via the TIMI Study Group and from Schering-Plough and serves as a consultant to or on the advisory boards of Bristol-Myers Squibb, Pfizer; Merck, and Schering-Plough.
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We examined the association between the novel marker lipoprotein-associated phospholipase A2 (Lp-PLA2) and cardiovascular (CV) outcomes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction) trial, a randomized trial of intensive versus moderate statin therapy after acute coronary syndrome (ACS). Both Lp-PLA2 activity and Lp-PLA2 mass were ascertained at 2 distinct time points in the trial. When measured early after ACS, we found no independent association between Lp-PLA2 and CV outcomes. In contrast, when measured during follow-up, higher levels of Lp-PLA2 were associated with an increased risk of recurrent CV events. After adjustment for relevant clinical predictors that included low-density lipoprotein (LDL) and C-reactive protein, 30-day Lp-PLA2 activity in the highest quintile was associated with a statistically significant 33% increase in the relative risk of CV events. In contrast, the association between 30-day Lp-PLA2 mass and outcomes was statistically attenuated. As such, the present study suggests that clinicians should not use Lp-PLA2 for risk assessment during hospitalization for ACS; however, when measured during ambulatory follow-up, Lp-PLA2 activity offered prognostic information incremental to that provided by traditional risk markers, including LDL and C-reactive protein. Further study will be needed to determine whether inhibition of the Lp-PLA2 enzyme will prove to be a valuable therapeutic target.
The online-only Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.612630/DC1.
Guest Editor for this article was Robert O. Bonow, MD.