Early termination of aliskiren study due to adverse events

HSA would like to update healthcare professionals on the recent early termination of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) as the results showed that there was no benefit with aliskiren and that there were more cases of stroke, renal complications, hyperkalemia and hypotension in patients who received aliskiren compared with patients who received a placebo.

Aliskiren is available in Singapore as a single-ingredient (Rasilez®, Novartis) and in combination with hydrochlorothiazide (Rasilez® HCT, Novartis). It is currently indicated to treat primary hypertension either as a monotherapy or in combination with other antihypertensives (diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and calcium channel blockers).

About the ALTITUDE study

The ALTITUDE study was a placebo controlled phase III trial aimed at evaluating the potential benefits of aliskiren, in addition to conventional therapy including an ACE inhibitor or an ARB, in reducing the risk of CV and renal events, when used in type 2 diabetic patients at high risk for fatal and non-fatal CV and renal events. This is the first long-term investigation of aliskiren with a planned follow up period of four years and involved 8,606 diabetic patients with renal impairment and/or CV disease from 36 countries. The primary endpoint of the ALTITUDE study was the first occurrence of one of the following events: CV death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalisation for heart failure, doubling of baseline serum creatinine concentration to above the upper limit of normal (sustained for at least one month), and onset of end stage renal disease or renal death. The secondary CV endpoint was the first occurrence of the above-mentioned CV outcomes while the secondary renal endpoint was the first occurrence of renal events.

ALTITUDE Interim results

In Dec 2011, the independent Data Monitoring Committee overseeing the study reviewed the second interim analysis for ALTITUDE. At that time, 69% of the projected total primary outcome events had been accrued. The results of this interim analysis are shown in Table 1.¹

Table 1. Preliminary results of ALTITUDE Primary and secondary composite outcomes and each component outcome based on adjudicated events; time-to-event analysis in a randomised population

Variable	Aliskiren (N=4283)	Placebo (N=4296)	Total (N=8579)	HR	95% CI	P-value
Primary composite outcome	581 (13.6%)	542 (12.6%)	1123 (13.1%)	1.09	(0.97, 1.22)	0.1663
Secondary composite outcome - CV	444 (10.4%)	396 (9.2%)	840 (9.8%)	1.14	(0.99, 1.30)	0.0664
Secondary composite outcome - renal	166 (3.9%)	180 (4.2%)	346 (4.0%)	0.93	(0.76, 1.15)	0.5178

The emergence of an imbalance in primary and CV composite endpoints was observed only after 18-24 months of treatment. There was an increased risk of primary outcome events associated with aliskiren with a hazard ratio (HR) of 1.09 (95% CI 0.97- 1.22). However, based on an assumption of a 15% risk reduction (HR = 0.85) of primary outcome events in the original study design, the conditional probability that the study would demonstrate benefit at the end of the trial was p < 0.0001.² Hence, the Data Monitoring Committee concluded from this interim analysis that the study patients were unlikely to achieve the primary objective of the study to benefit from aliskiren.

There was also a higher incidence of adverse events related to fatal or non-fatal stroke (2.6% vs. 2.0%), renal serious adverse events, i.e. renal impairment, acute renal failure, chronic renal failure, renal failure (4.7% vs. 3.3%), hyperkalaemia (36.9% vs. 27.1%) and hypotension (18.4% vs. 14.6%) in the aliskiren group as compared to placebo.

In view of the futility in meeting the final endpoint and the substantial safety concerns highlighted through the preliminary analyses of the interim results, the Data Monitoring Committee recommended that all subjects cease treatment with aliskiren. The information available at present is preliminary and additional analyses from ALTITUDE by Novartis are ongoing.

Actions taken by the European Medicines Agency (EMA)³

Following a review of data and analyses from the ALTITUDE study, alongside all data from other studies and spontaneous reports of suspected adverse drug reactions associated with aliskiren, the EMA's Committee for Medicinal Products for Human Use (CHMP) had concluded that the benefit-risk balance of Rasilez and combination products containing aliskiren remains positive for the treatment of essential hypertension but requested the inclusion of a contraindication against the use of aliskiren in patients with diabetes or moderate to severe renal impairment (GFR<60ml/min/1.73m²) who take ACE inhibitors or ARBs as well as to include a warning that the combination of aliskiren with an ACE inhibitor or ARB is not recommended in all other hypertensive patients patients because adverse outcomes cannot be excluded.

HSA's actions and advisory

To date, HSA has received 14 suspected adverse reaction reports associated with the use of aliskiren, of which four involved CV events (one case of hypotension, myocardial infarction and stroke and three cases of hypotension).

In view of the interim findings from ALTITUDE, HSA would like to remind healthcare professionals to review their patients on aliskiren therapy. As aliskiren or aliskiren-containing fixed combination products should not be used in combination with ACE inhibitors or ARBs in diabetic patients, healthcare professionals are advised to stop aliskiren-based treatments and not initiate new aliskiren treatment in diabetic patients who are taking an ACE inhibitor or an ARB. Alternative antihypertensive treatment should be considered as necessary.

A Dear Healthcare Professional Letter (DHCPL) was issued by Novartis, in consultation with HSA, in January 2012 to update on the safety concerns and above recommendations. HSA is currently working with Novartis to update the package inserts of Rasilez® and Rasilez® HCT to reflect this new information. Healthcare professionals are encouraged to report all suspected adverse reactions associated with aliskiren to the Vigilance Branch of HSA.

References

1. http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/rasilez_hpc-cps-eng.php
2. Data Monitoring Committee's recommendation letter for ALTITUDE, dated 14 Dec 2011
3. http://www.ema.europa.eu/ema/index.jspcurl=pages/medicines/human/public_health_alerts/2012/02/human_pha_detail_000055.jsp&mid=WC0b01ac058001d126

Published: 20 Apr 2012

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