Diabetes, aliskiren, and heart failure: let's bring ASTRONAUT down to earth.

ASTRONAUT (Aliskiren Trial on Acute Heart Failure Outcomes) failed to show that aliskiren was superior to placebo in reducing cardiovascular events when prescribed to patients with a reduced left ventricular ejection fraction who had recently recovered from worsening heart failure requiring hospital admission. Clinicians are tempted to look at outcome in patient subgroups because they are required to evaluate the efficacy and safety of an intervention for individual patients and believe that such analyses may help them in their practice. Unfortunately, subgroup analyses are commonly misinterpreted and often misleading. 5 In ASTRONAUT, interactions between the effects of treatment and patient characteristics were sought in 21 subgroups, including two separate analyses by age. For the primary endpoint, cardiovascular death or re-hospitalization for heart failure at 6 months, no statistically significant subgroup interactions were identified, although a trend (P 1⁄4 0.08) was noted for diabetes. The analysis was then repeated for four secondary endpoints; now potentially 105 subgroup analyses. For all-cause mortality, this identified a nominally statistically significant interaction (P , 0.01) between treatment assigned and diabetes; patients who did not have diabetes who were assigned to aliskiren appeared to fare better. This led the investigators to speculate that the neutral outcome in ASTRONAUT might be due to a lack of effect, or even harm, amongst patients bearing a diagnosis of diabetes mellitus and that substantial benefit may have accrued in other patients. However, the simplest explanation for most subgroup effects is a chance observation due to multiple testing. Some corroborative evidence can be found suggesting that aliskiren might be harmful in patients with diabetes. ALTITUDE (Aliskiren Trial In Type 2 Diabetes Using Cardio-Renal Disease Endpoints) investigated the effects of aliskiren in 8561 patients with type 2 diabetes (T2DM) and chronic kidney or cardiovascular disease. The study was stopped prematurely because the risk/benefit ratio was considered unattractive after a median follow-up of almost 3 years. Trends to an excess of cardiovascular deaths (5.8% vs. 5.0%), stroke (3.4% vs. 2.8%), and end-stage renal disease (2.8% vs. 2.6%) were noted in patients assigned to aliskiren. Although the study did not provide conclusive evidence of harm from aliskiren, it provided no evidence of benefit. An excess of hyperkalaemia, hypotension, diarrhoea, and renal impairment was observed in those assigned to aliskiren. As a consequence of the results of ALTITUDE and ASTRONAUT, regulatory authorities required investigational treatment to be withdrawn from patients with diabetes in ATMOSPHERE (Aliskiren Trial to Minimize OutcomeS in Patients with HEart failure), a study of .7000 patients with heart failure and left ventricular systolic dysfunction comparing aliskiren and enalapril alone and in combination. This decision was made against the recommendation of the data monitoring committee that had full access to the data, implying that theyhadnoconcernsabout the safetyof addingaliskiren to enalapril in patients with diabetes. Thepossibilityof an interactionbetweentheeffectsof aliskirenand diabetes raises at least three important issues. (i) What was the definition of diabetes? (ii) What was the mechanism of benefit in patients without diabetes? (iii) Why was this benefit lost or reversed in those with diabetes? As the authors admit, the diagnosis of diabetes was not robust. Indeed, it is not clear that T2DM, as currently defined, should be considered a discrete disease entity. Classical, type 1 diabetes mellitus due to insulin deficiency causes symptoms, morbidity, and death unless treated by insulin. In contrast, patients labelled as having T2DM have high plasma concentrations of insulin due to resistance to its effects and is usually asymptomatic. Although T2DM augurs an increase in long-term cardiovascular risk, there is scant evidence that ‘improving’ glucose control is beneficial, except in extreme cases. The current definition of T2DM is arbitrary, based on laboratory tests. However, there is a continuous spectrum of insulin resistance. It is not a question of whether someone has insulin resistance or not, just a question of how much; patients with heart failure will generally have more. Insulin resistance is strongly related to the health and mass of skeletal muscle. Inactivity, by choice