On November 3, 2012 at the recent meeting of the American Society of Nephrology-Kidney Week in San Diego, the results of three important clinical trials in nephrology were presented during a special session on High Impact Clinical Studies.
The first report presented by Dr Hans-Henrik Parving , University of Copenhagen was the result of the ALITITUDE Trial. This study was undertaken to determine whether the addition of aliskiren, a direct renin inhibitor to either an ACE inhibitor or an angiotensin receptor blocker (ARB) in patients with type 2 diabetes and chronic kidney disease (CKD) would lead to a reduction in cardiovascular and renal events in this high-risk population. We reported that on December 20, 2011 the ALTITUDE Trial was discontinued on recommendation of the Data and Safety Monitoring Board [KDDD]. Therefore, the report on the final data was anxiously awaited. It was confirmed that, in patients with type 2 diabetes and CKD who are at high risk of cardiovascular and renal events, the addition of aliskiren to the standard therapy with RAS blockade does not provide additional benefit and may be harmful due to the increased risk of hyperkalemia. The results of the trial were simultaneously published in the New England Journal of Medicine. A summary of the trial and commentary can also be found at Heartwire.
The second report presented by Dr Vicente Torres, Mayo Clinic, Minnesota was the result of a phase 3 trial of tolvaptan, a vasopressin V2 receptor antagonist in patients with autosomal dominant polycystic kidney diseases (ADPKD). Tolvaptan is already approved and marketed by Otsuka under the brand name Samsca for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.
Previous work in animal models of ADPKD had shown that blockade of vasopressin V2 receptors slows cyst growth by down-regulating cAMP signaling (see Devuyst et al). The TEMPO 3:4 trial was a pivotal phase 3 multicenter trial including 1445 adult patients with ADPKD and relatively preserved GFR and a total kidney volume (TKV) of 750 ml or more. Patients with larger TKV have been shown to have more rapid increase in kidney size, and likely more rapid progression of disease. Over the 3 years treatment period, the decrease in TKV was lower in the tolvaptan-treated patients compared to placebo (2.8% vs 5.5% per year). There was also a lower incidence of kidney pain and slower decline in kidney function, as measured by the reciprocal of serum creatinine, in the tolvaptan group. Adverse events leading to discontinuation were higher in the tolvaptan group. Not surprisingly, thirst, polyuria and nocturia were reported more frequently in the tolvaptan group with a frequency more than double that of placebo group. The next step will be the submission of a New Drug Application (NDA) to the FDA. Otsuka had previously obtained fast track designation for tolvaptan in ADPKD, which will allow a faster review and approval process. Should tolvaptan be approved for treatment of ADPKD, it will be the first drug specifically developed for this indication. The results of TEMPO 3:4 trial were simultaneously published in New England Journal of Medicine as well. A summary of the results can also be found at the eAJKD blog.
The third report presented by Dr Glenn Chertow, Stanford University, California was the result of a phase 4 trial of the calcimimetic agent, cinacalcet (Sensipar, Amgen) called Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) Trial. The rationale to conduct this trial was based on reports from observational studies of patients receiving dialysis treatment that showed elevated serum phosphorus, calcium, parathyroid hormone and alkaline phosphatase were associated with increased risk of cardiovascular events and death (see here and here). The results of the EVOLVE Trial were also published in New England Journal of Medicine. The study enrolled 3883 hemodialysis patients with moderate hyperparathyroidism (median iPTH 693 pg/mL) to receive either cinacalcet or placebo. The patients were followed for up to 64 months and the median treatment duration was 21.2 months. The study results showed that cinacalcet did not significantly reduce the risk of death or major cardiovascular events in this high risk patient group. A summary of the results of this trial is also available at Heartwire.
Commentary: well designed randomized controlled trials (RCT) are considered the gold standard to evaluate the effect of a therapeutic intervention. Often epidemiological or observational studies may suggest a link between an abnormal laboratory test (e.g. phosphorus) or a biomarker (e.g. CRP) and a clinical outcome such as mortality. However, this does not mean that correcting the laboratory abnormality with a therapeutic intervention will necessarily alter the outcome. Only a well-conducted RCT will be able to provide a definitive answer. In this respect, we must congratulate the sponsors and the investigators of ALTITUDE and EVOLVE Trials for undertaking these well conducted studies without which these questions would not have been answered. We can now focus our attention on testing other hypotheses related to the causes of increased cardiovascular morbidity and mortality among CKD patients, especially those receiving chronic dialysis.