One of the comments to the posting on the termination of the ALTITUDE trial was: "300 mg is a high dose when combining with ACE-I or ARB. At 150 mg I have not seen any issues when combining with standard care."
This statement made me want to look into the background to the ALTITUDE trial - why did they use the higher dose of aliskerin?
Some background facts for aliskerin:
1. Aliskiren is the first in a class of drugs called direct renin inhibitors. It's current approved indication is for the treatment of essential hypertension.
2. Aliskiren binds to the S3bp binding pocket of renin, essential for its activity (see link). Binding to this pocket prevents the conversion of angiotensinogen to angiotensin.
3. The hypothesis that was being tested in ALTITUDE was that Aliskiren may have renoprotective (and cardioprotective) effects that are independent of its blood pressure−lowering effect in patients who are already receiving the recommended treatment with ACEi or ARB.4. The key study to examine this issue was AVOID. This study by Parving et al was published in July 2008 in the NEJM.
- AVOID enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.
- The patient flow was as follows:
- n=1892 screened
- n=805 enter open label (run-in) phase
- n=599 undergo randomization
- Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001).
- The mean rate of decline in the estimated glomerular filtration rate during the 24-week study period was 2.4 ml per minute per 1.73 m2 (95% CI, 1.1 to 3.7) in the aliskiren group and 3.8 ml per minute per 1.73 m2 (95% CI, 2.5 to 5.1) in the placebo group (P=0.07).
- A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group).
- The total numbers of adverse and serious adverse events were similar in the groups. (9.0% and 9.4%, respectively), as was the percentage of patients who withdrew from the study owing to adverse events (5.6% and 6.4%, respectively). There were no deaths in the aliskiren group and two deaths in the placebo group. Hyperkalemia was reported in 5.0% of the patients in the aliskiren group and in 5.7% of the patients in the placebo group.
So what went wrong in ALTITUDE? Hard to say, since there is no public information on this yet, but perhaps we can speculate. The excess in adverse effects seem to related to hypotension - non-fatal stroke, renal complications, and possibly excessive renin-angiotensin blockade (hyperkalemia). Perhaps a dose of 150 mg/day rather than 300 mg/day of aliskerin would have been better tolerated?
The use of the higher dose of Aliskerin was based, at least in part, on the experience from AVOID in which the 300 mg dose was well tolerated but after the initial 3 month treatment with 150 mg/day - the run-in period. Perhaps, AVOID's run-in phase excluded many of the patients who might not tolerate aliskerin?
It is also possible that the patients enrolled in ALTITUDE were different (older, more vascular disease) than in AVOID. Certainly, ALTITUDE was 15 times the size of AVOID, so it is very possible that the patients in ALTITUDE could have been substantially more heterogenous compared to AVOID. Consequently, ALTITUDE subjects might respond more adversely to combination therapy to higher doses of aliskerin.
In ALTITUDE patients reportedly could be on either ACEi or ARB. Perhaps the use of aliskerin on top of losartan (in AVOID) was better tolerated than an ACE inhibitor?
In AVOID the biggest reduction in albuminuria came with the use of aliskerin at 150 mg/day -- with a reduction in albuminuria of approximately 15%. If the ALTITUDE study had utilized a lower dose of aliskerin, circumventing the adverse risks that have been reported (non-fatal stroke, renal complications, hypotension, and hyperkalemia) the trial could have gone to completion, and a benefit might have been demonstrated.
In the December 15th issue of the New England Journal Ranjana Srivastava writes: "The more medicine advances, the greater the glimpses we're allowed into the human body's complexities, and the more intrigued we are. We realize that there are layers upon layers of explanations, and it's sometimes exceedingly difficult to arrive at simple, understandable definitions of diseases and how they afflict us....Carefully performed trials benefit us in many ways: they deliver information about patient characteristics, drugs, and what will or won't work in the real world. They seldom crystallize what's best for a particular patient but usually educate us about what will harm the patient. There is nothing constructive about dismissing the available evidence about a disease, paltry as it may be, without trying to build on it."
So what do I plan to do? Since I wasn't using aliskerin very much - perhaps only one or two patients it won't affect my practice much, and since I was not using it as combination therapy on top of ACEi or ARB, ALTITUDE isn't going to affect my specific care of any patients. However, I will be cautious with aliskerin and as a precaution will stop the aliskerin in patient's as has been recommended by the drug manufacturer.
