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Macrovascular Residual Risk Studies

1 October 2012
PROVE IT-TIMI 22: In patients treated with statins, on-treatment TG <150 mg/dL is independently associated with a lower risk of recurrent CHD events
Impact of Triglycerides Levels Beyond Low-Density Lipoprotein Cholesterol After Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial. J Am Coll Cardiol 2008;51:724
Miller M, Cannon CP, Murphy SA, et al. for the PROVE IT-TIMI 22 Investigators
Objective: To assess the impact of on-treatment triglycerides (TG) levels on coronary heart disease (CHD) risk after acute coronary syndrome (ACS).
Inclusion criteria: Hospitalization for ACS and total cholesterol
Exclusion criteria: Patients with events within 30 days of the initial ACS event.
Study population:
3,718 of the 4,162 patients included in the PROVE IT-TIMI 22 trial.
Intervention: Patients were randomly allocated to receive atorvastatin 80 mg/day or pravastatin 40 mg/day
Primary endpoint:
Composite endpoint of death, myocardial infarction, and recurrent ACS.
Secondary endpoint:
Time to first occurrence of individual components of the primary composite endpoint; all-cause mortality.
Study design:
Post-hoc analysis of the PROVE IT-TIMI 22 trial.
Follow up: 2 years
Method: - Kaplan-Meier’s survival probability events rate for the composite endpoint determined during follow-up.<br />
- Hazard ratios and 95% confidence intervals calculated using cut-points derived from the NCEP-ATP III guidelines: LDL-C <70 mg/dl, (optional target goal in ACS patients); TG <150 mg/dl.
- For adjusted analyses of the effect of on-treatment LDL-C and TG, Cox proportional hazards model including clinically important variables, potential confounders or effect, and intervention.
Main results: Significant 20% decrease in CHD risk in patients with on-treatment TG <150 mg/dL compared with higher TG (adjusted analysis, p=0.025).
Significant 1.6% reduction in CHD risk for each 10-mg/dl decrement in on-treatment TG (adjusted for LDL-C and other covariates, p < 0.001).
Author's conclusion: - On-treatment TG <150 mg/dl was independently associated with a lower risk of recurrent CHD events after ACS.
- Achieving low TG may be an additional consideration beyond LDL-C lowering in patients with ACS.


The PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) 22 trial1 was conducted in patients hospitalized for acute coronary syndrome (ACS) - either acute myocardial infarction (with or without electrocardiographic evidence of ST-segment elevation) or unstable angina. The trial demonstrated that, compared with LDL-C <100 mg/dL (<2.6 mmol/l), LDL-C <70 mg/dL (<1.8 mmol/l) was associated with a significant 28% reduction (p <0.046 for the overall study population) in relative risk of recurrent CHD events after inaugural ACS.

For the PROVE IT-TIMI 22 investigators, the next step was to determine what could be done to further reduce the residual risk of CHD events persisting after optimal statin therapy. As they write, “one potential impediment limiting further reduction in CHD events despite low on-treatment LDL-C is residual elevation in serum triglyceride (TG) levels.” Indeed, major population studies have shown that hypertriglyceridemia is an independent CHD risk factor.2

This post-hoc analysis of the PROVE IT-TIMI 22 trial showed that, compared with LDL-C ≥70 mg/dL and TG ≥150 mg/dL (≥1.7 mmol/l), there were significantly fewer events with LDL-C <70 mg/d and TG <150 mg/dL during the 2-year follow-up (Figure 1 represents unadjusted results).

However, the main result was the 20% reduction in relative risk of CHD associated with low on-treatment TG (<150 mg/dL) after adjustment for LDL-C and other covariates.

The impact of TG levels on risk of recurrent events was also truly impressive in patients who achieved very low levels of LDL-C (<70 mg/dL). Among them, those with TG ≥200 mg/dL had a 50% higher absolute risk of recurrent events compared to those with TG <200 mg/dL (events rate: 20.3% and 13.5%,respectively).

Lowering both LDL-C and TG might markedly reduce the residual CHD risk persisting after optimal statin therapy

There was a 1.6% reduction in CHD risk for each 10-mg/dL decrement in on-treatment TG. Translating this effect in terms of absolute CHD risk reduction, the investigators found that each 10% decrease in TG concentration was associated with a 2.3% lower incidence of recurrent CHD events.

Practical implications: new treatment approaches are needed

One limitation of statin therapy is that it acts mainly through LDL-C reduction but has only limited effects in terms of reduction of TG levels. Therefore, the authors conclude that lowering both LDL-C and TG could reduce the residual CHD risk which remains elevated despite recent diagnostic and therapeutic advancements. Interventions aiming at lowering TG levels include replacement of saturated and trans fats with mono- and polyunsaturated fats, especially omega-3 fatty acids at high doses and niacin or fibrate therapy.

The ongoing ACCORD trial is currently assessing the rates of incident CHD events in patients with type 2 diabetes receiving either a simvastatin-fenofibrate combination or simvastatin alone. Demonstration of a clinical benefit beyond LDL-C lowering would represent a major step in residual CHD risk reduction.



Estimates of death, myocardial infarction, and recurrent acute coronary syndrome between 30 days
and 2 years of follow-up based on (Figure 1) achieved low-density lipoprotein cholesterol (LDL-C) <70 mg/dL
and (Figure 2) triglycerides (TG) <150 mg/dL. The 95% confidence intervals are in parentheses. HR=hazard ratio.
  1. Cannon CP, Braunwald E, McCabe CH et al. for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.
  2. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450-8.