The ALTITUDE trial: Aliskiren increases the risk of adverse events and stroke without any cardiovascular or renal improvements in patients with Type 2 Diabetes

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Key study points: 

1. There was no difference in the incidence of primary outcomes (cardiovascular death, cardiac arrest with resuscitation, nonfatal MI, nonfatal stroke, etc.) between patients taking Aliskiren vs placebo.

2. Patients using Aliksiren were more likely to suffer a stroke than patients on placebo (Relative Risk 1.34; 95% CI, 1.01 to 1.77, p=0.044).

Primer: Type 2 Diabetes Mellitus (T2DM) is one of the fastest growing diseases in the world. In 2011, it was estimated that 25.8 million children and adults have diabetes, with the majority having T2DM. Uncontrolled diabetes leads to several complications including retinopathy, peripheral neuropathy, nephropathy, cardiovascular disease, and renal disease. Heart and renal disease account for the majority of the deaths in diabetic patients. Fortunately, there are several drugs such as Angiontenin-Converting Enzyme (ACE) inhibitors and Angiotensin-Receptor Blockers (ARBs) that decrease the rate of cardiovascular mortality and renal disease progression. These drugs work by decreasing the effect of the renin-angiotensin system (RAS) thereby treating hypertension, which leads to decreased artherogenesis and proteinuria. Aliskiren is a new drug that affects the RAS by inhibiting the enzyme that cleaves prorenin into renin, and thus decreases hypertension as well. Previous research showed dual therapy of Aliskiren combined with an ARB significantly decreased albuminuria in diabetic renal disease compared to ARB alone. This purpose of this study was to determine whether a combination of Aliskiren with ARB or ACE inhibitor was safe and whether it decreased fatal and nonfatal renal and cardiovascular outcomes in patients with T2DM.

Background reading: 

1. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Andersen C; The ONTARGET Investigators. Telmisaratan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559. 

2. Parving HH, Persson F, Lewis JB, Hollenberg NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358:2433-2446. 

3. Ravandi A, Teo KK. Blocking the renin-angiotensin system: dual- versus mono- therapy. Expert Rev Cardiovasc Ther 2009;7:667-674. 

This [double-blind randomized controlled] study: evaluated the use of Aliskiren (300 mg) in combination with ACE inhibitors or ARBs in patients with type 2 diabetes.

The inclusion criteria were: (1) 35 years of age or older (2) diagnosis of type 2 diabetes (3) evidence of microalbuminuria, macroalbuminuria or cardiovascular disease. 8, 561 patients underwent a 4 to 12 week run-in phase in which they were given either Aliskiren or placebo. The primary outcome was death from cardiovascular disease or the first occurrence of cardiac arrest with resuscitation; nonfatal MI, nonfatal stroke, hospitalization for heart failure, end-stage renal disease, etc.

There was no difference in primary outcome between Aliskiren and placebo after the safety monitoring committee recommended the authors stop the study after 24 months. Furthermore, there was no difference in death from any cause between the two groups despite the drop in blood pressure in the Aliskiren group (between group differences, 1.3 and 0.6 mm Hg).

Significantly more patients discontinued the study due to Aliskiren use (13.2%) vs. placebo (10.2%), p<.001) due to adverse events. The most common adverse event was hyperkalemia. Furthermore, the Aliskiren group was at a higher risk of strokes than the placebo group (relative risk 1.34; 95% Ci 1.01-1.77, p=.044).

In sum: This double-blind, multi-centered, randomized control trial evaluated the use of Aliskiren in combination with either ACE inhibitors or ARBs in patients with type 2 diabetes. The independent safety committee recommended that the trial end early due to the increased adverse events (hyperkalemia and hypotension) and increased risk of stroke. The study showed that there was no benefit in cardiovascular and renal outcomes after adding Aliskiren to drug therapy. The outcome of this study is surprising as other drugs that inhibit the Renin-Angiotensin System (RAS) decrease the incidence of hypertension (a surrogate endpoint) as well as the rate of strokes and cardiovascular deaths. These results emphasize the importance of hard endpoints such as death, because surrogate endpoints can be misleading.

Click to read the study in the NEJM (New England Journal of Medicine)

By [JC] and [MP] 

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