Macrovascular Residual Risk Studies

COMMENT

CARDS was conducted to assess the effectiveness of 10 mg atorvastatin daily versus placebo in primary prevention of CV disease in patients with type 2 diabetes. The trial was stopped 2 years earlier than planned because of the significant benefits observed at the second interim analysis.

Significant reduction in major CV events but inconclusive results on mortality
According to the authors, the CARDS trial demonstrated that atorvastatin 10 mg daily was safe and effective in reducing the risk of first CV disease events, including stroke, in patients with type 2 diabetes at the lower end of the cholesterol distribution of untreated patients (Figure 1). A substantial reduction in major CV events (37%) (Figure 2), acute CHD events (36%), coronary revascularization (31%, non significant), risk of stroke (48%), and risk of all-cause mortality (27%, close to statistical significancy) was observed.
The investigators speculated that because of early termination and lesser time span for numerical events accretion, the trial lacked statistical power to demonstrate a significant reduction in all-cause mortality.
CHD mortality was not a pre-specified endpoint and thus was not subjected to analysis. Of the 42 CHD deaths reported during the study period, 18 occurred in the atorvastatin group (8 fatal myocardial infarctions and 10 other acute coronary deaths) and 24 in the placebo group (20 and 4, respectively).

The treatment effect did not vary by pretreatment cholesterol level. On-treatment LDL-C levels were substantially lower than current target amounts in most treatment guidelines (median LDL-C less than 2 mmol/L (80 mg/dL). No safety concerns were raised, with adverse event rates similar in the atorvastatin and placebo groups, and no cases of rhabdomyolysis were observed.

Statins for all diabetic patients or all high-risk diabetic patients only?
The authors argue that the data challenge the use of a particular threshold level of LDL-cholesterol as the sole arbiter by which patients with type 2 diabetes should receive statin therapy, as is the case in most of the current guidelines. This conclusion has however been criticized on the grounds that CARDS participants were not representative of the general population of patients with type 2 diabetes for several reasons.
First and foremost, although they had no documented previous history of CV disease, these patients were nevertheless at very high cardiovascular risk, since the presence of at least one of the following complications of diabetes or risk factor was a sine qua non study entry criteria: retinopathy, albuminuria, current smoking, or hypertension, the latter three of which being established CHD risk factors. In addition, mean known diabetes duration was 8 years. This resulted in an average 10-year risk of major cardiovascular events of about 25%.
Secondly, mean baseline high-density lipoprotein cholesterol (HDL-C) levels were surprisingly high in both groups (1.42 and 1.39 mmol/L in the placebo and atorvastatin group, respectively), whereas abnormally low levels of HDL-C would have been expected from a representative population of diabetic patients. In addition, HDL-C levels decreased over time in both groups during the study period, while statins generally increase, albeit modestly, HDL-C levels.
The “statin for all diabetic patients” approach recommended by the authors has been further challenged by the negative results of ASPEN,¹ a randomized trial in which no clinical benefits of atorvastatin 10 mg could be demonstrated in a low-risk diabetic population with low LDL-C.

Conclusions
The main result of CARDS is the observation that statin therapy can reduce major cardiovascular events in high-risk diabetic patients with low LDL-C and high HDL-C. Applied in this rather specific population, this treatment leaves 63% of events not prevented, while its effect on mortality is unclear.

Figure 1: Effect of treatment on primary and secondary endpoints


Figure 2:Cumulative hazard of primary end point