Physicians' Academy for Cardiovascular Education

Limited use of Lp(a) as a prognostic marker in established CAD

O'Donoghue et al. JACC Oct 2013 - J Am Coll Cardiol. 2013 Oct 10

Lipoprotein (a) For Risk Assessment in Patients with Established Coronary Artery Disease.

O'Donoghue M, Morrow DA, Tsimikas S et al.
J Am Coll Cardiol. 2013 Oct 10. doi: 10.1016/j.jacc.2013.09.042. [Epub ahead of print]


Lp(a) is a class of lipoprotein particles made up of a cholesterol-rich LDL part covalently linked to a apolipoprotein(a). Genetic studies suggest that Lp(a) may have a causal role in the development of atherosclerosis [1]. A doubling of Lp(a) levels throughout life associated with genetic variants of the Lp(a) (LPA) gene was found to be associated with 22% higher risk of myocardial infarction (MI)[2,3]. Increased risk of heart disease has also been linked to common LPA gene variants that are strongly associated with Lp(a) levels [2,3].
A large pooled analysis in primary prevention populations confirmed that Lp(a) is an independent but modest risk factor for death from coronary heart disease (CHD), nonfatal MI and stroke [4].
Data on the meaning of Lp(a) in secondary prevention populations are limited. However, some professional societies have now endorsed routine one-time screening for Lp(a) in individuals at intermediate or high risk of CV events [5,6].
New lipid-modifying therapies are in development that reduce Lp(a) [7-10]. This study therefore assessed the independent prognostic utility of Lp(a) and evaluated proposed screening cutpoints in three large clinical trial populations (PEACE trial: Prevention of Events with Angiotensin Converting Enzyme Inhibition, CARE trial: Cholesterol and Recurrent Event and PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and Infection Therapy- Thrombolysis in Myocardial Infarction 22)
of patients with either stable coronary artery disease (CAD) or after an acute coronary syndrome (ACS). Secondary prevention studies were also considered.

Main results

  • When modelled as a continuous variable per one SD increase in log-transformed Lp(a) concentration, there was no association with the risk or MACE, nor the odds of CV death or MI, in either one of three trials, nor when meta-analysed across the three trials.
  • There was no evidence for a threshold effect when analysing CV events across quintiles of Lp(a), in the separate trials or when taking all data together. Even comparison of patients with Lp(a) above the 95th percentile with those with levels below the median, did not show significantly increased HRs for CV events in separate and combined analyses.
  • In 2573 individuals (PROVE IT-TIMI 22) who were statin-naïve prior to randomisation, median Lp(a) levels rose by 13% and 25% respectively from baseline by day 30, in patients randomised to pravastatin 40 mg and atorvastatin 80 mg daily. Lp(a) change was not correlated to change in LDL-c levels, nor were the higher Lp(a) levels associated with increased CV event risk.
  • When combining data of these three studies with eight previously published studies of Lp(a) in secondary prevention, patients with Lp(a) in the highest quantile had significantly increased odds of MACE (OR: 1.40, 95%CI: 1.15-1.71, P=0.001), although there was a high degree of between-study heterogeneity (Q-statistic 34.0 (df 12), P=0.001, I2=65%).
  • When stratifying for average LDL-c concentration for each study, high Lp(a) was significantly associated with MACE if LDL-c was over 130 mg/dL (OR: 1.46, 95%CI: 1.23-1.73, P<0.001). This association was not seen in studies where LDL-c was lower, indicating effect modification of LDL-c concentrations.


The current findings suggest that high levels of Lp(a) may be of use to identify individuals at increased risk of CV events in patients with established CAD. However, marked heterogeneity is seen between studies, and particularly in patients with well controlled LDL-c levels the prognostic value of Lp(a) remains unclear. There is currently insufficient evidence to suggest that Lp(a) levels above a certain threshold level should be used to guide therapy.


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