Aliskiren increased adverse events in patients with diabetes and kidney disease who were receiving ACE inhibitors or ARBs

de Leeuw PW. — Tue, 19 Mar 2013 00:00:00 GMT

Question

In patients with type 2 diabetes and chronic kidney disease, with or without cardiovascular (CV) disease, what are the relative efficacy and safety of adding aliskiren to standard therapy?

Methods

Design

Randomized placebo-controlled trial (Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints [ALTITUDE]). ClinicalTrials.gov NCT00549757.

Allocation

{Concealed}*.†

Blinding

Blinded† (patients, clinicians, and outcome assessors).

Follow-up period

Median 33 months.

Setting

838 centers in 36 countries.

Patients

8606 adults ≥ 35 years of age (mean age 64 y, 68% men, 98% with chronic kidney disease) who had type 2 diabetes and albuminuria, or CV disease with reduced estimated glomerular filtration rate (30 to < 60 mL/min/1.73 m²), and were treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Exclusion criteria included serum potassium > 5.0 mmol/L or unstable renal or CV status.

Intervention

Aliskiren, 150 mg/d, increased to 300 mg/d at 4 weeks (n = 4274), or placebo (n = 4287), added to standard therapy with ACE inhibitors or ARBs.

Outcomes

Primary composite: death from CV causes, cardiac arrest, nonfatal MI, nonfatal stroke, unplanned heart failure hospitalization, need for renal replacement therapy with no dialysis or transplantation available or initiated, or serum creatinine level ≥ 2 times the baseline value. Secondary outcomes included a CV composite outcome (CV components of the primary outcome), a renal composite outcome (renal components of the primary outcome), all-cause mortality, albumin-to-creatinine ratio, and adverse events. 8600 patients (1620 events) were needed to detect a 15% reduction from 8% with placebo (90% power, α = 0.05).

Patient follow-up

97% (intention-to-treat analysis).

Main results

The trial was stopped early because of excess risk for adverse events in the aliskiren group and improbability of an offsetting benefit. The main results are in the Table. The aliskiren group had greater reduction in albumin-to-creatinine ratio (14% between-group difference in reduction, 95% CI 11 to 17) but higher rates of hyperkalemia (39% vs 29%, P < 0.001) and hypotension (12% vs 8%, P <0.001) than the placebo group.

Conclusion

In patients with type 2 diabetes and chronic kidney disease, with or without cardiovascular disease, adding aliskiren to standard therapy did not improve outcomes and increased adverse events.Aliskiren vs placebo added to standard therapy for patients with type 2 diabetes and chronic kidney disease, with or without CV disease‡Outcomes§AliskirenPlaceboAt a median 33 moRRI (95% CI)NNH (CI)Primary composite outcome||18%17%7% (−2 to 18)Not significantCV composite14%13%10% (−1 to 23)Not significantRenal composite6.0%5.9%3% (−13 to 22)Not significantAll-cause mortality8.8%8.4%6% (−8 to 22)Not significant‡CV = cardiovascular; other abbreviations defined in Glossary. RRI, NNH, and CI calculated from control event rates and hazard ratios in article.§Components of composite outcomes are defined in Outcomes section.||The only significant component was cardiac arrest with resuscitation (RRI 140%, CI 5 to 446).

Annals of Internal Medicine: Diabetic Nephropathy Topic Collection

Aliskiren increased adverse events in patients with diabetes and kidney disease who were receiving ACE inhibitors or ARBs