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Macrovascular Residual Risk Studies

8 July 2015
Triglyceride-rich lipoproteins: an important contributor to residual cardiovascular risk in acute coronary syndrome
Fasting triglyceride levels were predictive of recurrent cardiovascular events in statin-treated patients with acute coronary syndrome (ACS), according to this analysis of the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial.
Schwartz GG, Abt M, Bao W, DeMicco D, Kallend D, Miller M, Mundl H, Olsson AG. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol 2015;65:2267-75.


Objective: To investigate the relationship of fasting triglyceride (TG) levels to cardiovascular outcomes after ACS in patients treated with statins
Study design: Analysis of the dal-OUTCOMES and atorvastatin arm of the MIRACL trials. Both trials were randomised and double-blind in design.
Study population: Dal-OUTCOMES included 15,871 patients with recent ACS and fasting TG levels <400 mg/dL (4.5mmoll/L) who were randomised to treatment with dalcetrapib or placebo starting 4 to 12 weeks after ACS, against a background of best evidence-based treatment including statin (97% of patients). Patients were followed for a median of 31 months.
The atorvastatin arm of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS. There were no exclusions in MIRACL on the basis of fasting TG levels. Patients were followed for 16 weeks.
Primary variable: The primary outcome in dal-OUTCOMES was a composite of coronary heart disease (CHD) death, nonfatal myocardial infarction (MI), ischaemic stroke, unstable angina with objective evidence of myocardial ischemia requiring urgent re-hospitalisation, and cardiac arrest with resuscitation.
The primary endpoint in MIRACL was the composite of death, nonfatal MI, unstable angina with objective evidence of myocardial ischaemia requiring urgent re-hospitalisation, or cardiac arrest with resuscitation.
Methods: In each trial, hazard ratios (HRs) were determined for a 10 mg/dL (0.11 mmol/L) increase in fasting TG at baseline, both in univariate analyses and analyses adjusted for age, sex, history of hypertension, current smoking, diabetes, high-density lipoprotein (HDL) cholesterol and body mass index. Univariate and adjusted HRs for occurrence of endpoint events were determined for each quintile (dal-OUTCOMES) or tertile (MIRACL) of TGs.
Main results:

Compared with MIRACL, a larger proportion of patients in dal-OUTCOMES were male (80% versus 66%) or hypertensive (67% versus 55%). The use of platelet P2Y12 antagonists, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was more frequent in dal-OUTCOMES than in MIRACL. Median fasting TG levels at randomisation were 115 mg/dL (1.30 mmol/L) in dal-OUTCOMES and 160 mg/dL (1.80 mmol/L) in MIRACL.
In dal-OUTCOMES, 1,289 patients (8.1%) had at least one primary outcome event after the follow-up period. In the atorvastatin arm of MIRACL, 220 patients (14.7%) had at least one outcome event during the 16-week follow-up.
• Baseline fasting TG was a determinant of both short-risk (MIRACL) and long-term risk (dal-OUTCOMES) of a primary event in ACS patients (see Table and Figure).
• The HR associated with increasing fasting TG levels was similar in univariate analysis and after adjustment for age, sex, hypertension, smoking, diabetes, HDL cholesterol and body mass index.
• In both studies, the relationship of fasting TG level to cardiovascular risk was independent of LDL cholesterol.

Table 1. Impact of baseline TG on risk for the primary outcome; HR (95% CI)




Each 10 mg/dL TG increase

Unadjusted: 1.016 (1.010 to 1.022), p<0.001

Adjusted:      1.018 (1.011 to 1.024), p<0.001


Highest versus lowest TG quintile*

1.61 (1.34-1.94)

*Highest TG quintile >175 mg/dL (2.0 mmol/L) and lowest TG quintile £80 mg/dL (0.90 mmol/L)



Each 10 mg/dL TG increase

Adjusted       1.014 (0.996 to 1.032)

Highest versus lowest tertile*

1.50 (1.05 to 2.15)

Highest TG tertile >195 mg/dL (2.20 mmol/L), lowest TG tertile £135 mg/dL (1.5 mmol/L)

Figure. Baseline TG level was a determinant of short-term risk of a primary outcome in MIRACL (left), as well as long-term risk of a primary outcome in dal-OUTCOMES (right)

Baseline TG level was a determinant of short-term risk of a primary outcome in MIRACL, as well as long-term risk of a primary outcome in dal-OUTCOMES

Authors’ conclusion: Among patients with ACS treated effectively with statins, fasting TG levels predict long-term and short-term cardiovascular risk. TG-rich lipoproteins may be an important additional target for therapy.


The findings from this report strengthen the case implicating TG-rich lipoproteins, for which TG are a marker, as a contributor to residual cardiovascular risk in ACS patients. Despite the fact that MIRACL was conducted about 10 years earlier than dal-OUTCOMES,1,2 both analyses showed a strong association between fasting TG levels and short-term (MIRACL) and long-term (dal-OUTCOMES) risk of a recurrent cardiovascular event in ACS patients. As shown in the above Table, the hazard associated with increasing TG levels was nearly identical in univariate analyses and in analyses adjusted for risk factors usually associated with TG levels, including diabetes, HDL cholesterol and body mass index, and was independent of LDL cholesterol. Importantly, the incremental long-term cardiovascular risk associated with a 10-mg/dL increment in TG levels was similar to that for a 10-mg/dL increment in LDL cholesterol reported for dal OUTCOMES (adjusted HR 1.018, 95% CI 1.011 to 1.024 versus 1.083, 95% CI 1.063 to 1.103, respectively),

In the 10 year interim between MIRACL and dal-OUTCOMES, best treatment of ACS has evolved considerably. Unlike in MIRACL in which patients were statin-naive, ACS patients in dal-OUTCOMES were almost all (97%) on background statin therapy, and more patients were also treated with platelet P2Y12 antagonists (89% versus 11%), beta-blockers (87% versus 78%), and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (79% versus 49%). With a total ACS population of 17,372 these analyses extend the findings of previous reports to both short- and long-term residual cardiovascular risk.3,4

What then is the cause of residual cardiovascular risk in high risk patients? The fact that residual cardiovascular risk is still evident in ACS patients well treated with statins suggests that it is not the TG but rather the cholesterol contained in TG-rich lipoproteins that confers atherogenicity. In support, Mendelian randomisation studies, a ‘natural randomisation’ approach, have shown remnant cholesterol to be causal for incident risk of coronary heart disease.5 The advent of novel treatments, such as potent omega-3 fatty acid derivatives or antisense oligonucleotides to apolipoprotein CIII, will allow for testing whether lowering of elevated TG-rich lipoproteins, against a background of best evidence-based treatment, will reduce residual cardiovascular risk in such high-risk patients.


1. Schwartz GG, Olsson AG, Ezekowitz MD et al, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–8.

2. Schwartz GG, Olsson AG, Abt M et al, for the dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089–99.

3. Sacks FM, Alaupovic P, Moye LA et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 2000;102:1886–92.

4. Miller M, Cannon CP, Murphy SA et al, for the PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724–30.

5. Varbo A, Benn M, Tybjaerg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61: 427–36.

Key words  triglycerides; acute coronary syndrome; dal-OUTCOMES; MIRACL