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Macrovascular Residual Risk Studies

8 February 2015
Residual cardiovascular risk similar in men and women
A new analysis from the Cholesterol Treatment Trialists’ (CTT) Collaboration confirms the benefit of statin therapy is in both men and women. Despite statin treatment, however, substantial residual risk of major cardiovascular events persists.
Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials.
Lancet Published Online January 9, 2015
Objective: To compare the effects of statin therapy between women and men
Study design: Meta-analyses based on data from 22 trials of statin therapy versus control (n=134,537) and 5 trials of more-intensive versus less-intensive statin therapy (n=39,612)
Study population: The analysis included 174,149 subjects, of whom 46,675 (27%) were women. Compared with men, women were older (mean age 65.1 vs 61.8 years), had a higher prevalence of hypertension (60% vs 48%) and diabetes mellitus (24% vs 18%), but were less likely to smoke (16% vs 20%) or have a history of vascular disease (47% vs 65%). Mean low-density lipoprotein cholesterol (LDL-C) at baseline was similar in men and women (3.3 versus 3.4 mmol/L).
Primary endpoint:
  • The primary outcome was major vascular events (a composite of major coronary events, coronary revascularisation, stroke)
  • Other outcomes included major coronary events (defined as non-fatal myocardial infarction or coronary death), coronary revascularisation (angioplasty or bypass grafting), stroke (subdivided by type), and cause-specific mortality
Methods: Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1.0 mmol/L reduction in LDL-C. A Cox model that adjusted for non-sex differences was used to compare the effects of statin therapy in men and women. The median duration of follow-up of survivors was 4.9 years, range 2-7 years.
Main results:

Among all 27 trials, statins reduced the risk of major vascular events by 21% for each 1.0 mmol/L reduction in LDL-C (rate ratio 0·79, 95% CI 0·77–0·81, p<0·0001). The proportional reduction in major vascular events was similar in men and women (Table). Overall, each 1 mmol/L reduction in LDL-C with statin therapy reduced major coronary events or coronary revascularisation each by 24%, and stroke by 15%. Proportional reductions in these outcomes were similar in men and women.

As shown in the Table, however, 11,284 statin-treated subjects (3.3%), 8,943 men and 2,341 women, continued to experience major vascular events each year.

Table. Proportional reduction in major vascular events per 1 mmol/L reduction in LDL-C


Events (% per year)



Statin or more intensive statin

Control or less intensive statin

Rate ratio (confidence interval, CI)

All subjects

11,284 (3.3%)

13,673 (4.0%)

0.79 (95% CI 0.77–0.81)


8,943 (3.5%)

10,979 (4.4%)

0·78 (99% CI 0.75–0.81)


2,341 (2.6%)

2,694 (3.0%)

0.84 (99% CI 0.78–0.91)

Authors’ conclusion: In men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major vascular events.


This meta-analysis aimed to dispel uncertainty as to whether women benefit from statin therapy to the same extent as men. The findings clearly indicate that, for similar baseline cardiovascular risk, the benefits accrued from statin therapy in terms of reduction in major vascular events, were similar in men and women.

However, as for previous reports from the CTT Collaboration,1,2 it is also clear that statin therapy fails to eliminate the risk of cardiovascular events. In this analysis, the overall annual cardiovascular event rate was 3.3% in statin-treated subjects (higher in higher-risk individuals), and similar in men and women. Thus, while statin therapy is indisputably effective in lowering LDL-C and reducing the risk of major vascular events, residual cardiovascular risk persists.

Inspection of the data shows that median triglycerides at baseline were 1.5-1.6 mmol/L (upper limit 2.1 to 2.2 mmol/L). Consistent with evidence highlighted this month, targeting triglyceride-rich lipoproteins is potentially an effective strategy for reducing this residual cardiovascular risk among statin-treated subjects, both men and women.3-5 Indeed, this strategy has been recommended by the Residual Risk Reduction Initiative, in a recent Position Statement.6 Novel treatments that target different pathways influencing the metabolism of triglyceride-rich lipoproteins may offer future benefit in reducing residual cardiovascular risk.7


1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.

2. Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.

3. Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor Cardiovascular Diabetology 2014, 13:159.

4. Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk. New insights from human genetics. Arterioscler Thromb Vasc Biol 2015 [Epub ahead of print].

5. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2014 [Epub ahead of print]

6. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.

7. Huynh K. Gene therapy: Targeting apoc-III to lower triglycerides. Nat Rev Cardiol 2014 [Epub ahead of print]

Key words  statin; major vascular events; residual cardiovascular risk; women