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Macrovascular Residual Risk Studies

1 June 2009
Residual risk of macrovascular events after intensive therapy with atorvastatin in patients with stable coronary heart disease
Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease N Engl J Med 2005;352:1425-35.
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJP, Shepherd J and Wenger NK, for the Treating to New Targets (TNT) Investigators.
Objective To assess the effect of lowering low-density lipoprotein cholesterol (LDL-C) below 100 mg/dL (2.6 mmol/L) with atorvastatin 80 mg/day in patients with stable coronary heart disease (CHD).
Study population
10,001 patients with stable CHD and LDL-C levels <130 mg/dL (3.4 mmol/L) at enrolment or after an 8-week period of treatment with atorvastatin 10 mg.
Primary endpoint First occurrence of major cardiovascular (CV) event (death from CHD, non-fatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or non-fatal stroke).
Secondary enpoint Individual components of the primary endpoint plus any CV event.
Study design Randomized, double-blind, parallel-group, multicenter.
Median follow-up
4.9 years.
Main results
  • Mean LDL-C 77 mg/dL (2.0 mmol/L) with atorvastatin 80 mg vs 101 mg/dL (2.6 mmol/L) with 10 mg.
  • Persistent elevations in liver aminotransferase 1.2% with atorvastatin 80 mg vs 0.2% with 10 mg (p<0.001).
  • Primary event in 434 patients (8.7%) receiving atorvastatin 80 mg vs 548 patients (10.9%) receiving 10 mg, amounting to an absolute 2.2% reduction in rate of major CV events, and a 22% reduction in relative risk (hazard ratio (HR), 0.78; 95% CI: 0.69, 0.89; p <0.001).
  • No significant difference in death from CHD (HR, 0.80; 95%CI: 0.61–1.03; p= 0.09) between the two drug regimens.
  • No significant difference in death from any cause (HR, 1.01; 95% CI: 0.85 to 1.19; p=0.92).
Author's conclusion Atorvastatin 80 mg/day in stable CHD provides significant clinical benefit beyond that of 10 mg/day, with a greater incidence of elevated aminotransferase levels.


Using data collected from the Treating to New Targets (TNT) study, the benefit of reducing LDL-C levels to well below 100 mg/dL (2.6 mmol/L) was investigated in patients with stable CHD and slightly elevated LDL-C levels (despite previous therapy with low-dose atorvastatin) over a median period of 4.9 years, given what had been recommended in the guidelines.1,2

LDL-C levels approached goal of 75 mg/dL with atorvastatin 80 mg/day
High-dose statin therapy with atorvastatin 80 mg/day produced a mean LDL-C level of 77 mg/dL (2.0 mmol/L) (n = 5006) within 3 months, which approached the goal of 75 mg/dL (1.9 mmol/L) (Figure 1). The atorvastatin 10 mg/day treatment resulted in a mean LDL-C level of 101 mg/dL (2.6 mmol/L) (n = 4995), close to the 100 mg/dL target. Total cholesterol and triglyceride levels decreased significantly in the first 3 months of atorvastatin 80 mg therapy and then remained stable. Both statin doses produced non-significant increases in high-density lipoprotein (HDL) cholesterol.
The adverse event profiles of the two doses of atorvastatin were consistent with previous studies.3,4 The respective rates of discontinuation due to treatment-related adverse events were 7.2% and 5.3% with the 80 and 10 mg doses respectively (p<0.001). Despite exclusion of patients with abnormal liver function tests, there was a significant incidence of persistent elevations in liver aminotransferase levels. There was a low rate of muscle-related adverse events and 5 cases of rhabdomyolysis
(2 with 80 mg and 3 with 10 mg).

Absolute residual risk of macrovascular events after 5 years of atorvastatin therapy
The TNT study tested the limits of LDL-C lowering and gives an approximate idea of the absolute macrovascular residual risk after intensive statin therapy. A major cardiovascular (CV) event occurred in 8.7% of patients receiving atorvastatin 80 mg, as compared with 10.9% of those receiving 10 mg daily (Figure 2). Thus increasing the dose by
8-fold resulted in a 2.2% absolute reduction in the rate of major CV events.
Thus, the absolute residual risk of macrovascular events after 5 years of intensive statin therapy is at least 8.7% according to this study. Indeed, patients with LDL-C between 130 and 250 mg/dL (3.4 and 6.5 mmol/L) at enrolment entered an 8-week run-in period of open-label treatment with atorvastatin 10 mg/day; only those who achieved
a mean LDL-C ≤130 mg/dL (3.4 mmol/L), i.e. responders to treatment, could participate in the study. One may speculate that the real macrovascular residual risk is higher in unselected patients in the real world.

Intensive blood glucose control does not prevent macrovascular disease in type 2 diabetic patients

Despite an impressive figure of patients-years of follow-up, inconclusive evidence of a 16% risk reduction (p=0·052) for myocardial infarction (MI), which included non-fatal and fatal MI and sudden death was seen. Furthermore, diabetes-related mortality and all cause mortality did not significantly differ between the intensive and conventional groups. The data did not support the suggestion of adverse cardiovascular effects from sulphonylureas or insulin.

Tight blood glucose control alone leaves a substantial unaddressed residual risk of micro- and macrovascular events

The evidence suggests that intensive blood glucose control alone does not prevent most microvascular complications, and is not effective in reducing the risk of macrovascular events. Other therapeutic approaches may therefore be required to decrease cardiovascular morbidity and mortality. These findings and data from subsequent trials, such as STENO-2,3 support the case for additional strategies to reduce the residual risk of micro- and macrovascular events.


Figure 1: Mean LDL cholesterol levels during the study

Figure 1: Cumulative incidence of first major CV event during the study

  1. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. Eur Heart J 2003;24:1601-10
  2. Grundy SM, Cleeman JI, Merz CN, et al. Circulation 2004;110:227-39.
  3. Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med 2004;350:1495-504.
  4. Sever PS, Dahlof B, Poulter NR, et al. Lancet 2003;361:1149-58.
Key words Atorvastatin – LDL cholesterol – cardiovascular risk reduction