Atherogenic Dyslipidemia and Residual Cardiovascular Risk in Statin-Treated Patients
Background and Purpose—Treatment with statins reduces the rate of cardiovascular events in high-risk patients, but residual risk persists. At least part of that risk may be attributable to atherogenic dyslipidemia characterized by low high-density lipoprotein cholesterol (≤40 mg/dL) and high triglycerides (triglycerides ≥150 mg/dL).
Methods—We studied subjects with stroke or transient ischemic attack in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM; n=19 100) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL; n=4731) trials who were treated with a statin and who had high-density lipoprotein cholesterol and triglycerides measurements 3 months after randomization (n=10 498 and 2900, respectively). The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We also performed a time-varying analysis to account for all available high-density lipoprotein cholesterol and triglyceride measurements.
Results—A total of 10% of subjects in PERFORM and 9% in SPARCL had atherogenic dyslipidemia after ≥3 months on start statin therapy. After a follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1123 and 485 patients in the 2 trials, respectively. The risk of major cardiovascular events was higher in subjects with versus those without atherogenic dyslipidemia in both PERFORM (hazard ratio, 1.36; 95% confidence interval, 1.14–1.63) and SPARCL (hazard ratio, 1.40; 95% confidence interval, 1.06–1.85). The association was attenuated after multivariable adjustment (hazard ratio, 1.23; 95% confidence interval, 1.03–1.48 in PERFORM and hazard ratio, 1.24; 95% confidence interval, 0.93–1.65 in SPARCL). Time-varying analysis confirmed these findings.
Conclusions—The presence of atherogenic dyslipidemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischemic attack receiving statin therapy. Specific therapeutic interventions should now be trialed to address this residual risk.
Treatment with statins reduces the rate of cardiovascular events in high-risk patients,1 but residual risk persists despite achieving low-density lipoprotein cholesterol (LDL-C) levels at or below recommended targets; the residual risk may in part be attributable to low high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels.2–5 The combination of these lipoprotein abnormalities, termed atherogenic dyslipidemia (AD), is highly prevalent in patients with diabetes mellitus or metabolic syndrome, and, in addition to high LDL-C, contributes independently to cardiovascular risk.6–19
Treatment with fibrates may reduce cardiovascular risk in patients with AD associated with metabolic syndrome and type 2 diabetes mellitus.20 However, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, the use of fenofibrate and simvastatin did not reduce the rates of cardiovascular events compared with simvastatin alone. However, a subgroup of individuals with both low HDL-C and high triglyceride levels seemed to benefit from the combination.21 This finding is consistent with post hoc subgroup analyses performed on data from previous fibrate trials.22–24 Data on the impact of AD on residual cardiovascular risk in stroke or transient ischemic attack (TIA) patients receiving otherwise best medical therapy are lacking.
We performed a post hoc analysis of data from the PERFORM (Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack) and SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trials to determine whether AD was associated with residual cardiovascular risk in stroke or TIA patients who were receiving optimal statin therapy.
Data from patients enrolled in 2 prospective randomized trials were analyzed retrospectively. We first analyzed data from PERFORM, an international multicenter randomized controlled trial designed to assess the superiority of terutroban compared with aspirin in the prevention of cardiovascular ischemic events in patients with recent noncardioembolic stroke. The design, baseline characteristics, and main findings have been reported.25–27 Briefly, PERFORM enrolled 19 100 subjects (between February 2006 and April 2008) ≥55 years of age with either an ischemic stroke (≤3 months) or a TIA (≤8 days). All participants provided written informed consent before enrollment. The present analysis is restricted to the subset of patients treated with any statin medication between the qualifying event and randomization. Follow-up visits were performed at 1, 3, and 6 months, and every 6 months thereafter; the minimum follow-up duration was 2 years. Blood samples were collected in fasting condition for evaluation of lipid profiles at enrollment, at 3 months, and then annually.
We also analyzed data from subjects enrolled in the SPARCL trial, designed to assess the superiority of 80 mg atorvastatin compared with placebo for the prevention of stroke in patients with recent noncardioembolic stroke or TIA.28 Briefly, SPARCL enrolled 4731 subjects (between September 1998 and March 2001), ≥18 years of age with a stroke or TIA (≤6 months).28,29 The present analysis is restricted to the subset of patients treated with any statin medication at randomization, including 601 patients using a nonstudy statin. All participants provided written informed consent before enrollment. Follow-up visits, including a clinical examination and lipid profile evaluation, were performed at 1, 3, and 6 months, and every 6 months thereafter; surviving patients had last study visits between March and June 2005.
For the primary analysis, we used the HDL-C and triglyceride levels assessed 3 months after randomization to define AD, because in addition to LDL-C lowering, statin therapy is associated with an increase in HDL-C and a decrease triglyceride levels.29,30 We defined AD using prespecified cut-off values for low HDL-C and high triglycerides. Based on a previous meta-analysis, these cut-offs were defined as HDL-C ≤40 mg/dL and triglycerides ≥150 mg/dL (primary definition), regardless of subject’s sex.2,4,23 Sensitivity analysis was performed using a more stringent cut-off value of 35 mg/dL for low HDL-C and 200 mg/dL for high triglycerides. In secondary analyses, we used all available measures of HDL-C and triglyceride levels (including those obtained at randomization and during follow-up period) using a time-varying AD phenotype; 45 650 HDL-C and triglycerides measurements (mean of 4.0 measurements per patient) were available in PERFORM trial, and 34 777 HDL-C and triglycerides measurements (mean of 11.7 measurements per patient) were available in SPARCL trial.
The main outcome was major cardiovascular events (MVE, a composite of nonfatal myocardial infarction [MI], nonfatal stroke and cardiovascular death). We also analyzed 2 secondary individual outcomes: (1) fatal or nonfatal MI and (2) fatal or nonfatal stroke. Events were adjudicated by blinded evaluation using medical records in both trials.
Data were expressed as mean (±SD) for continuous variables and counts (percentages) for qualitative variables. All analyses were conducted separately in the PERFORM and SPARCL cohorts using the same analytic strategy.
For the primary analysis, patients were divided into 2 groups on the basis of the AD phenotype at 3 months. Subjects’ characteristics were compared between the 2 groups using χ2 test (Fisher exact test was used when the expected cell frequency was <5) for categorical variables and Student t test for continuous variables. Characteristics associated with AD phenotype (P<0.10) were included in a stepwise selection logistic regression analysis. The characteristics that remained significantly associated with AD phenotype were subsequently used to adjust the association of AD phenotype with study outcomes. We investigated the impact of AD phenotype on cardiovascular risk through the calculation of hazard ratios (HRs) for the selected end points using univariate and multivariate Cox proportional hazard regression models. Event curves were calculated using the corrected group prognosis method,31 with adjustment for continuous variables (age, body mass index, and LDL-C) using the quartile values. The proportional hazard assumptions were assessed by examining the log–log survival plots and by introducing a time-dependent variable into models. The proportional hazard assumption was only violated for MI outcome in the SPARCL cohort (P=0.03).
For the secondary analyses, we assessed the impact of AD phenotype in a time-varying Cox regression analysis using all available HDL-C and triglycerides values (ie, baseline and follow-up values). This secondary analysis accounted for changes in AD phenotype over time by including a time-dependent covariate into the univariate and multivariate Cox models. The multivariate analyses also adjusted for LDL-C levels, which were included as a time-varying covariate.
Statistical tests were conducted, with a 2-tailed α-level of 0.05 considered significant. Data were analyzed using SAS software version 9.3 (SAS Institute; Cary, NC).
Of 11 457 subjects receiving statin therapy between the qualifying event and randomization in the PERFORM trial, 10 498 (91.6%) had available HDL-C and triglycerides levels measured at the 3-month postrandomization visit. A total of 2900 subjects receiving a statin at randomization had available 3-month postrandomization measurements of HDL-C and triglycerides levels in SPARCL (Figure I in the online-only Data Supplement). In both study samples, >80% of patients remained under statin during follow-up period, which was consistent with no change in LDL-C levels during the follow-up (Figure II in the online-only Data Supplement).
AD: Rates and Associated Risk Factors
In PERFORM, 10% (n=1057) of subjects had AD (primary definition; HDL-C ≤40 mg/dL and triglycerides ≥150 mg/dL) after ≥3 months of start statin therapy (Table 1). The proportion of subjects with AD decreased to 3% (n=302), using more stringent criteria (HDL≤35 mg/dL and triglyceride≥200 mg/dL). Using the primary definition, AD was associated with younger age, male sex, Asian ethnicity, hypertension, diabetes mellitus, smoking, prior history of coronary or peripheral artery disease, higher body mass index, and 3-month LDL-C levels (Table 2). In addition, patients with AD were more likely to have had an index stroke rather than TIA and had greater disability than patients without AD. All of these characteristics remained associated with AD phenotype in the multivariable analysis (Table I in the online-only Data Supplement).
In SPARCL, 9% of subjects had AD at 3 months using the primary definition, and 2% using the more stringent definition (Table 1). Using the primary definition, AD was associated with younger age, male sex, hypertension, diabetes mellitus, smoking, higher body mass index, and 3-month LDL-C level (Table 2). Table II in the online-only Data Supplement compares subjects in PERFORM and SPARCL with and without AD based on the more stringent definition. There were no substantial differences compared with using the primary definition of AD.
AD and MVEs
In PERFORM, 1123 subjects had ≥1 MVE during a median (interquartile range) follow-up of 2.3 (1.9–2.8) years. As shown in the Figure (A), the MVE rate was higher in subjects with AD than in those without AD (HR, 1.36; 95% confidence interval, 1.14–1.63; P<0.001). In unadjusted analyses, the AD phenotype (primary definition) was also associated with each of the 2 secondary outcomes (fatal/nonfatal stroke; fatal/nonfatal MI; Tables 3 and 4). The association between AD and MVEs remained significant after multivariable adjustment (Tables 3 and 4). Although the point estimates for risk remained higher for those with AD, the effect was not significant after covariate adjustment for the secondary outcomes (Tables 3 and 4). Sensitivity analysis using the more stringent AD definition showed higher, unadjusted risk MVEs and for fatal/nonfatal MI, but not stroke (Table III in the online-only Data Supplement). In secondary analyses using all available HDL-C and triglycerides values (ie, baseline and follow-up values), the AD phenotype was associated with MVEs and fatal/nonfatal stroke in both unadjusted and adjusted analyses (Table 5). AD phenotype was associated with the risk of fatal/nonfatal MI in the unadjusted but not adjusted analyses (Table 5).
In SPARCL, 485 subjects had ≥1 MVE during a median (interquartile range) follow-up of 4.9 (4.4–5.5) years. As in PERFORM, subjects with AD had a greater risk of a MVE than those without AD (Figure [B]; HR, 1.40; 95% confidence interval, 1.06–1.85; P=0.02). The HRs for AD using the primary definition were similar to those calculated in the PERFORM sample; however, after multivariate analysis, none were significant. In secondary analyses using all available HDL-C and triglycerides values, there was an increased risk of MI associated with AD in both unadjusted and adjusted analyses (adjusted HR, 2.26; 95% confidence interval, 1.46–3.50; Table 5).
In this post hoc analysis of 2 large clinical trials conducted in subjects with stroke or TIA while receiving a statin and otherwise best medical therapy, those having AD had a higher residual cardiovascular risk than those without AD. This finding was consistent across the 2 studies.
After ≥3 months of starting statin treatment after randomization, ≈1 in 10 patients had AD (primary definition, HDL ≤40 mg/dL and triglycerides ≤150 mg/dL). Compared with non-AD subjects, vascular risk factors were over-represented in those with AD, as previously observed in other populations.12–14 Of note, in both trial cohorts, AD patients had their baseline TIA or stroke at a younger age than non-AD patients. The AD phenotype was also more frequent in the Asian than in the non-Asian population in the PERFORM trial. These findings, together with the current pandemic of metabolic disorders (obesity, metabolic syndrome, and diabetes mellitus), highlight the potential importance of targeting this population for additional preventive interventions. Previous studies reported a higher prevalence of AD phenotype, despite lipid-modifying treatment. In a survey of 8548 European patients with dyslipidemia, low HDL-C (<40 mg/dL in men and <50 mg/dL in women) and high triglycerides (>150 mg/dL) were present in 21% of men and 25% of women receiving lipid-modifying treatment (statins in 85% of cases).32 In addition to heterogeneity in definitions and population settings, the lower AD prevalence observed in PERFORM and SPARCL trials may be explained by a better control of risk factors in the setting of randomized trials than in routine clinical practice.
Among subjects who were receiving a statin in PERFORM, AD phenotype was associated with a 36% increase risk in MVEs (P<0.01), which was reduced to 23% after adjusting for on-treatment LDL-C level, vascular risk factors (including age, sex, hypertension, diabetes mellitus, smoking, body mass index, prior history of coronary artery disease, and peripheral artery disease), ethnicity (Asian versus non-Asian), and severity of qualifying event (stroke versus TIA, and modified Rankin score). Similar trends were found in SPARCL subjects who were receiving a statin, although the increased risk of MVEs in subjects with AD did not reach significance in fully adjusted analyses (24%; 95% confidence interval, –7% to 65%).
Our findings are consistent with previous studies assessing the relationship between AD and coronary artery disease. In the Effect of Potentially Modifiable Risk Factors Associated With Myocardial Infarction in 52 Countries (INTERHEART) study, the risk associated with AD was independent and additive to LDL-C levels.33 During the past few years, mounting evidence has established both low HDL-C and elevated triglyceride levels as predictors of cardiovascular disease, independently of LDL-C levels.34–36 Indeed, 1 in 7 subjects with the combination of triglycerides >200 mg/dL and HDL-C <35 mg/dL had an MI in the Prospective Cardiovascular Münster (PROCAM) study.37
In our population, and particularly in the SPARCL trial, we also observed an increased risk of MI associated with AD. Elevated serum triglycerides associated with low HDL cholesterol levels have been observed in many patients with established coronary artery disease. The magnitude of increased cardiovascular risk associated with AD was estimated ≈1.6-fold in patients with angiographically documented coronary artery disease. This increased risk was higher than that associated with dyslipidemia involving isolated low HDL-C or high triglycerides alone.38
Our results are consistent with the results of fibrate trials. A greater benefit of fibrates was found for the prevention of coronary artery disease and the need for cardiac revascularization, confirming the strong relationship between AD phenotype and coronary events.22,23 Although intensive statin therapy represents a cornerstone of cardiovascular disease prevention, our analysis provides evidence that the risk of MVEs remains in patients with stroke or TIA and AD, despite statin therapy. Therefore, increasing HDL-C and reducing triglycerides concentrations may be a promising strategy to address this important residual risk, especially given the current pandemic of metabolic disorders. Compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the combination of a statin and a fibrate also has a major impact on triglycerides, HDL, and LDL particle size.39 Nevertheless, the risks, benefits, and cost effectiveness (because it is likely that the number who need treatment will be high) in patients with stroke with AD need to be prospectively evaluated.
Meta-analyses of randomized control trials suggest that fibrates may reduce cardiovascular events through an effect on AD.23 Analysis of data from the Acute Coronary Syndrome Israeli Survey (ACSIS) registry suggests that the fibrate/statin combination was independently associated with a 46% reduced risk in MVEs.40 In this analysis, the greatest impact was in patients with diabetes mellitus and AD. Combined fibrate/statin therapy may be more effective in achieving comprehensive lipid control and may lead to additional cardiovascular risk reduction.
The main limitation of the present study is that it is based on post hoc, exploratory analyses. The findings may not necessarily be generalizable to a more heterogeneous population because of the potential for residual, confounding despite multivariable adjustment.
We could not exclude that the association of AD and stroke recurrence was not apparent because blood samples were obtained in the fasting state, possibly reducing the impact of triglycerides (some data suggest a lower effect of fasting triglycerides on vascular risk41) because stroke subtypes vary and were not completely evaluated, and because statistical power for comparisons of individual end points was limited. Supporting our conclusions, the results were similar in the 2 separate trials. Although we could not be sure of adherence of patients to statin treatment, the adherence was likely high on the levels of LDL-C during follow-up and that the adjustment for on-treatment LDL level was sufficient to control the noncompliance effect.
In conclusion, in these 2 large clinical trials involving subjects with stroke or TIA who were receiving a statin and otherwise best medical therapy, those with AD had a higher residual cardiovascular risk compared with those without AD. Specific therapeutic interventions should target this residual risk.
Trials Executive Committee
PERFORM Executive Committee: Marie-Germaine Bousser (Chair), Pierre Amarenco, Angel Chamorro, Ian Ford, Kim Fox, Marc Fisher, Michael G. Hennerici, Heinrich Mattle, Peter M. Rothwell.
SPARCL Steering Committee: Pierre Amarenco, Fred Callahan III, Larry B. Goldstein, Henrik Sillesen, K. Michael A. Welch (Chair), Justin A. Zivin.
Sources of Funding
Funding for this study was provided in part by SOS-Attaque Cerebrale Association and supported by the Département Hospitalo-Universitaire FIRE (Fibrosis Inflammation Remodeling) of Université Paris-Diderot, France.
Dr Bruckert reports receipt of honorarium for consulting/presentation from Abbott, AstraZeneca, Genfit, Genzyme, MSD, Pfizer, Sanofi, Servier, AMT, Merck, Lilly, Novo-Nordisk, Pfizer, Aegerion, Amgen. Dr Goldstein reports consultancy fees and honoraria from Pfizer. Dr Fox reports receipt of consultancy and lecture fees from Servier. Dr Rothwell reports receipt of consultancy fees from Pfizer, Sanofi, Boehringer-Ingelheim, AstraZeneca, Bayer, and Daiichi-Sankyo. Dr Amarenco reports receipt of research grant support and lecture fees from Pfizer, Sanofi, Bristol-Myers-Squibb, Merck, AstraZeneca, Boehringer-Ingelheim, consultancy fees from Pfizer, BMS, Merck, Boehringer-Ingelheim, AstraZeneca, Bayer, Daiichi-Sankyo, Lundbeck, Edwards, Boston Scientific, Kowa, and lecture fees from Bayer, Boston Scientific, St Jude Medical, and research grants from the French government. The other authors report no conflicts.
* A list of all PERFORM and SPARCL Investigators and Committees is given in the Appendix.
Guest Editor for this article was Bruce Ovbiagele, MD, MSc, MAS.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.004229/-/DC1.
- Received November 21, 2013.
- Revision received March 7, 2014.
- Accepted March 11, 2014.
- © 2014 American Heart Association, Inc.
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