Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design

Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Nephrology Dialysis Transplantation (Impact Factor: 3.49). 04/2009; 24(5):1663-71. DOI: 10.1093/ndt/gfn721
Source: PubMed

ABSTRACT Patients with type 2 diabetes are at increased risk of macro- and microvascular disease, and the presence of albuminuria and/or reduced kidney function further enhances macrovascular risk. Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events, yet the residual renal and cardiovascular risk still remains high. Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs, lowers plasma renin activity, angiotensin I and angiotensin II levels, may thereby provide greater benefit compared to ACEi or ARB alone.
The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily, reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB). ALTITUDE is an international, randomized, double-blind, placebo-controlled, parallel-group study, which will include three categories of high-risk patients with type 2 diabetes (aged > or =35 years): those with either urinary albumin/creatinine ratio (UACR) > or =200 mg/g; microalbuminuria (UACR) > or =20 <200 mg/g and eGFR > or =30 <60 mL/min/1.73 m2; and thirdly, those with a history of cardiovascular disease and eGFR > or =30 <60 mL/min/1.73 m2 with or without microalbuminuria. ALTITUDE is an event driven trial that aims to randomize 8600 patients with a planned follow-up time of 48 months. The primary outcome measure is time to first event for the composite endpoint of cardiovascular death, resuscitated death, myocardial infarction, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline serum creatinine concentration. Secondary endpoints include a composite CV endpoint and a composite renal endpoint.
ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes.

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Available from: Mathieu M Ghadanfar, Jul 18, 2014
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    ABSTRACT: Tesis Univ. Granada. Departamento de Medicina. Leída el 2 de julio de 2009
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    ABSTRACT: Nephropathy is a potentially devastating complication of diabetes causing much morbidity and associated with a considerable risk of premature cardiovascular mortality. Early identification and aggressive treatment is essential. The earliest phase is persistent microalbuminuria and this phased itself is associated with loss of renal function and increased cardiovascular risk especially in type 2 diabetes. At the phase of dipstick positive proteinuria so-called overt nephropathy these risks accelerate leading if untreated to end-stage renal failure or premature cardiovascular death. Treatment is by improved blood glucose control and antihypertensive therapy. Treatment with renin-angiotensin system inhibitors may be prescribed with a target BP of at least 130/80 mmHg (125/75 in younger patients). Lipid lowering therapy is indicated and smoking cessation should be advocated. Consideration of the development of anaemia and bone disease should be made. Joint care by diabetes and renal specialists should be considered when a patient’s serum creatinine concentration reaches 150 µmol/litre or eGFR around 30–50ml/min, and plans for renal replacement therapy should be made. Specialists should agree on management protocols for end-stage renal failure on a regional, district or institutional basis, and review and update them at regular intervals. Proteinuria during pregnancy and pregnancy in patients with diabetic proteinuria requires special attention and should be managed by a joint team of specialists. Counselling and education of patients and briefing of primary health care providers should be provided throughout all phases of diabetic kidney disease.
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