Adjunctive Aliskiren Gives No Benefits, Possibly Harmful

Daniel M. Keller, PhD

November 06, 2012

SAN DIEGO, California — Aliskiren as an adjunct to renin–angiotensin–aldosterone system (RAAS) blockade not only failed to provide benefit in patients with type 2 diabetes at high risk for cardiovascular and renal events, it might actually have been harmful, according to a new study.

The results of the double-blind, randomized, international, multicenter Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial of aliskiren in dual RAAS blockade was presented by Hans-Henrik Parving, MD, DMSc, professor and chief physician in the Department of Endocrinology at Rigshospitalet, University of Copenhagen, Denmark, here at Kidney Week 2012: American Society of Nephrology 45th Annual Meeting.

The results were also published online November 3 in the New England Journal of Medicine to coincide with Kidney Week. Dr. Parving explained that the study was terminated early (in December 2011) because of futility and adverse effects.

Even with RAAS blockade, mortality risk remains unacceptably high for patients with type 2 diabetes. Previous trials of dual RAAS blockade with an angiotensin-converting-enzyme (ACE) inhibitor and an angiotensin-receptor blocker (ARB) have been disappointing. In patients with diabetes, the renin inhibitor aliskiren, alone or in combination with an ARB, has been shown to reduce albuminuria, compared with an ARB alone. However, evidence of the effect of dual RAAS blockade on cardiovascular disease and on hard renal end points, such as end-stage renal disease (ESRD) and death from renal failure, has been lacking.

In the ALTITUDE study, 8561 patients receiving background therapy of an ACE inhibitor or an ARB for approximately 4 years were randomly assigned to aliskiren (n = 4274) or placebo (n = 4287). After 4 weeks of aliskiren 150 mg once daily, the dose was increased to 300 mg once daily.

Eligible participants 35 years or older had type 2 diabetes and evidence of micro- or macroalbuminuria or cardiovascular disease. The aliskiren and placebo groups were well matched for age (mean, 64 years), sex (about 67% men), body mass index (29.9 kg/m²), glycated hemoglobin (7.8%), blood pressure (about 137/74 mm Hg), estimated glomerular filtration rate (eGFR) (mean, 57 mL/min per 1.73 m²), and urinary albumin-to-creatinine ratio (geometric mean, 206 to 208 mg/g). Most of the patients (82%) had had diabetes for 5 years or more. The groups were also well matched for cardiovascular disease history.

The primary end point was a composite of cardiovascular death, resuscitation from sudden death, nonfatal myocardial infarction or stroke, unplanned hospitalization for heart failure, ESRD, renal death, and a doubling of serum creatinine for at least 1 month.

As an event-driven trial, the total number of primary events was 93.5% of the expected number when the trial was stopped.

No Overall Benefit From Aliskiren in Dual Blockade

There was no significant difference between the aliskiren and placebo groups in terms of time to reach the primary composite end point or the secondary composite end points.

At a median follow-up of 32.9 months, 18.3% of the aliskiren group had experienced a primary end point event, as had 17.1% of the placebo group (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = .12).

Similarly, 13.8% of the aliskiren group reached the cardiovascular composite end point, as did 12.6% of the placebo group (HR, 1.11; 95% CI, 0.99 to 1.25; P = .09). The renal composite outcome was 6.0% in the aliskiren group and 5.9% in the placebo group (HR, 1.03; 95% CI, 0.87 to 1.23; P = .74), and death from any cause was 8.8% and 8.4%, respectively (HR, 1.06; 95% CI, 0.92 to 1.23; P = .42). All P values are unadjusted for multiple comparisons.

The only significant component of the primary composite end point was resuscitation from sudden death, which favored aliskiren over placebo (0.4% vs 0.2%; HR, 2.40; 95% CI, 1.05 to 5.48; P = .04).

Systolic and diastolic blood pressure increased over the course of the trial, but less so with aliskiren (P < .001 for both). The urinary albumin-to-creatinine ratio edged up, especially with placebo, but it remained lower with aliskiren at all time points (P < .001).

The adjusted least-squares mean decrease from baseline to 6 months in eGFR was greater with aliskiren than with placebo (2.45 vs 1.29 mL/min per 1.73 m²; P < .001). The eGFR values were equivalent after 24 months.

Evidence of Harm With Aliskiren

More patients in the aliskiren group than in the placebo group permanently discontinued the study drug for a reason other than death (33.8% vs 28.4%). Discontinuations related to an adverse event were also more common in the aliskiren group (13.2% vs 10.2%; P < .001).

Potassium levels increased in patients receiving dual blockade. Patients with baseline potassium levels of 5 mEq/L or more were at greater risk for the primary composite end point (P = .0114) if they received dual blockade. The same was true for the cardiovascular composite end point (P = .039).

Dr. Parving said the patients with the higher potassium levels should have been excluded from the trial, but "all the values for inclusion were measured through the screening period, [whereas these values] are referring to the baseline period, which is occurring later on," he said.

Hyperkalemia was the most common adverse event reported in both the aliskiren and placebo groups and the most common reason for discontinuation (P < .001 for both). Hypotension was the next most common reason for discontinuation (P < .02) and was more frequent in the aliskiren group than in the placebo group (P < .001). Stroke risk was higher in the aliskiren group at an interim analysis, but the difference disappeared with the inclusion of additional patients.

In summary, Dr. Parving said there was no statistical difference in the primary end point between the treatment groups, but the aliskiren group experienced more adverse events, especially hyperkalemia and hypertension. He concluded that the addition of aliskiren to standard RAAS blockade in patients with type 2 diabetes at high risk for cardiovascular and renal events "is not supported by these data, and may even be harmful."

Session cochair Julie Ingelfinger, MD, senior consultant in pediatric nephrology at the Massachusetts General Hospital, professor of pediatrics at Harvard Medical School in Boston, and deputy editor of the New England Journal of Medicine, who was not involved in the study, told Medscape Medical News that one has to look at how the trial was conducted.

In this study, "people were to be excluded if they had an estimated GFR of less than 15 mL/min per 1.73 m² or were hyperkalemic. At baseline, some of those patients had converted to what would have been exclusion criteria," she noted. "If those people hadn't been in the trial, would it have made a difference? I don't know," she said. Patients who should have been excluded accounted for less than 3% in each of the study groups.

Dr. Ingelfinger explained that the use of aliskiren as a second blocker of the RAAS system "is something we shouldn't do. I think there were signals here that are concerning." It is clear from these data that the use of 2 agents is associated with more hyperkalemia, which "is something to be concerned about in this fragile population," she added.

This trial was supported by Novartis. Dr. Parving reports receiving honoraria from, being a consultant for, and being a scientific advisor to Novartis, Reata, and Abbott; and being a scientific advisor to Takeda. Dr. Ingelfinger has disclosed no relevant financial relationships.

N Engl J Med. Published online November 3, 2012. Abstract

Kidney Week 2012: American Society of Nephrology 45th Annual Meeting. Abstract HI-OR01. Presented November 3, 2012.