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Macrovascular Residual Risk THROUGH LANDMARK STUDY

9 March 2015
Atherogenic dyslipidaemia is associated with higher residual cardiovascular risk in patients with previous stroke

Results 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 involving subjects with stroke or transient ischaemic attack (TIA) who were receiving best medical therapy, including statin, showed that those with atherogenic dyslipidaemia had a higher residual cardiovascular risk compared with those without this lipid profile.

Sirimarco G, Labreuche J, Bruckert E et al; on behalf of the PERFORM and SPARCL Investigators and Committees. Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients. Stroke 2014;45:1429-36.
Summary
Comments & References

 

STUDY SUMMARY
Objective: To investigate whether atherogenic dyslipidaemia, characterised by low high-density lipoprotein cholesterol (≤40 mg/dL or 1.01 mmol/L) and high triglycerides (≥150 mg/dL or 1.7 mmol/L), was associated with residual cardiovascular risk in patients with a previous stroke or TIA who were receiving optimal statin therapy.
Study design: Post hoc analysis of data from the PERFORM (n= 19,100) and SPARCL (n= 4,731) studies
Study population: After at least 3 months on statin treatment, 1,057 (10%) patients in PERFORM and 259 patients (9%) in SPARCL had atherogenic dyslipidaemia. Across both studies, these patients tended to be younger, male, and had a higher prevalence of hypertension, diabetes mellitus and smoking, and higher body mass index and 3-month low-density lipoprotein cholesterol levels than those without atherogenic dyslipidaemia. LDL-C levels in patients with and without atherogenic dyslipidaemia were £100 mg/dL or 2.6 mmol/L. 
Primary variable: The primary outcome was the occurrence of major cardiovascular events, a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death.  
Methods: Patients were categorised according to the presence or absence of the atherogenic dyslipidaemia phenotype, as defined above. The impact of atherogenic dyslipidaemia on cardiovascular risk was analysed by hazard ratios (HRs) using univariate and multivariate Cox proportional hazard regression models.
Main results:

·       After a median follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1,123 and 485 patients, respectively.

·       The risk of major cardiovascular events was 36% and 40% higher, respectively in patients with atherogenic dyslipidaemia compared with those without this phenotype.  This association was attenuated by multivariate analyses (Table). 

Study

Unadjusted HR

Adjusted HR

 

 

 

PERFORM

1.36 (1.14–1.63; p<0.001)

1.23 (1.03–1.48; p=0.02)

SPARCL

1.40 (1.06–1.85; p=0.017)

1.24 (0.93–1.65; p=0.15)

Authors’ conclusion: The presence of atherogenic dyslipidaemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischaemic attack receiving statin therapy. Specific therapeutic interventions should now be trialled to address this residual risk.

COMMENT

Despite the limitations inherent with a post hoc exploratory analysis, the findings from this report reaffirm the importance of atherogenic dyslipidaemia as a contributor to lipid-related residual cardiovascular risk, inclusive of cerebrovasvular disease. It is also highly relevant that these results are also consistent with evidence from trials with fibrates and niacin that this dyslipidaemic profile exacerbates cardiovascular risk in patients on best medical therapy including statins.1,2 Indeed, the magnitude of increase in cardiovascular risk is remarkably consistent across these analyses, in the range of 35-40%.

The outstanding question is how best to manage atherogenic dyslipidaemia so as to reduce lipid-related residual risk in these patients. Clinical trials of current therapies, including fibrates and niacin, have been less than definitive, although the strongest evidence to date is for fibrates. For example, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study, simvastatin-treated patients with type 2 diabetes and atherogenic dyslipidaemia (defined here as baseline triglycerides in the upper third of the population (≥204 mmg/dL or 2.3 mmol/L) and baseline HDL-C levels in the lower third (£34 mg/dL or 0.9 mmol/L), derived benefit from the addition of fenofibrate, whereas the overall study population did not.3 Additionally, the Acute Coronary Syndrome Israeli Survey (ACSIS) registry showed that the combination of statin plus fibrate was independently associated with a 46% reduction in risk of major vascular events, with greatest impact in patients with diabetes and atherogenic dyslipidaemia.4

Novel therapies undergoing development may offer potential for targeting atherogenic dyslipidaemia. Options include cholesteryl ester transfer protein (CETP) inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). However, trials so far have not specifically focused on patients with a prior history of stroke/TIA. Clearly, as highlighted by the authors, there is a need for prospective evaluation of treatments in this high cardiovascular risk patient population. This aim is also consistent with the key missions of the Residual Risk Reduction Initiative.

References

1. Sacks FM, Carey VJ, Fruchart JC: Combination lipid therapy in type 2 diabetes. N Engl J Med 2010,363:692-84.

2. Guyton JR, Slee AE, Anderson T et al. Relation of lipoprotein levels to cardiovascular events in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) Trial [abstract]. Circulation 2012; 126:1450.

3. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC et al: Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med 2010,362:1563–74.

4. Tenenbaum A, Medvedofsky D, Fisman EZ et al. Cardiovascular events in patients received combined fibrate/statin treatment versus statin monotherapy: Acute Coronary Syndrome Israeli Surveys data. PLoS One 2012;7:e35298.

Key words atherogenic dyslipidaemia; triglycerides; high-density lipoprotein cholesterol; stroke; residual cardiovascular risk