Aliskiren/Valsartan Combination Trial Published: What Does It Mean?

July 23, 2007 — A study showing that combination of the new direct renin inhibitor, aliskiren (Tekturna, Novartis), and an angiotensin receptor blocker (ARB), valsartan (Diovan, Novartis), was more effective at lowering blood pressure (BP) than either drug alone has been published. The trial was first reported at the American College of Cardiology meeting in New Orleans, by the principal investigator, Dr Suzanne Oparil (University of Alabama at Birmingham School of Medicine), and appears in The Lancet this week.
However, in a commentary accompanying the publication, Dr Willem H Birkenhäger (Erasmus University, Rotterdam, the Netherlands) and Dr Jan A Staessen (University of Leuven, Belgium) take issue with a number of things. For example, they wonder why aliskiren was combined with an ARB rather than a diuretic or calcium channel blocker (CCB), and they point out that hyperkalemia appears to be an issue with the combination tested in this trial, concluding that aliskiren is unlikely to ever be used in general practice or even in primary prevention in specialist care.
But in an interview with heartwire, Oparil rebuffed most of their criticisms as unfounded, commenting, "It is very aggressive and very negative... they have picked on the wrong things." She admitted, however, that it would take time to see how aliskiren fares in relation to all other antihypertensives: "Nobody knows exactly how it should be used and that's being honest." Nevertheless, the drug is a new tool in the armamentarium for hypertension doctors, she said, and it has some advantages, such as a very good tolerability profile.
Blocking Renin-Angiotensin System in Two Parts
Aliskiren was approved by the US Food and Drug Administration in March and is the first in a new class of antihypertensives and the first new agent for reducing BP in 10 years. Novartis funded the study by Oparil et al and four of the co-authors are employees of the company.
1797 difficult-to-treat hypertensive patients were randomized to one of four arms: aliskiren alone, valsartan alone, a combination of the two, or placebo. For the first four weeks, patients took aliskiren 150 mg once daily, valsartan 160 mg once daily, a combination of the two, or placebo. They were then titrated to double the initial dose for four weeks, the maximum therapeutic dose of both drugs.
The primary end point was a reduction in mean sitting diastolic BP from baseline to week 8, and analysis was on an intention-to-treat basis. Secondary end points included reduction in mean sitting systolic BP, the proportion of responders, the proportion of patients achieving BP control, and the change in 24-hour BP profile as assessed by ambulatory BP monitoring (ABPM).
The combination lowered diastolic and systolic BP more than either aliskiren or valsartan alone, BP control rates were significantly greater with the two drugs together than either drug alone, and 24-hour ABPM showed superior reductions with the combination. The study is particularly interesting, Oparil said, "because we blocked the renin-angiotensin system in two parts with full doses."
Comments About Hyperkalemia "Inaccurate and Unfair"
Birkenhäger and Staessen's first criticism of the study is that its generalizability "is limited by the selective recruitment and the use of diastolic rather than systolic BP as the main selection criterion and primary efficacy variable."
"That's a ridiculous criticism," Oparil responded to heartwire. She says that the people in her study "genuinely did have high BP, because they were screened using ABPM." Also, she notes, "using diastolic BP is quite standard, even though we the experts tend to use systolic BP now." Nevertheless, she points out that systolic BP was in any case a secondary criterion and endpoint, "They can't say it was ignored."
The editorialists move on to discuss the subject of hyperkalemia, which they note was above 5.5 mmol/L at any time post-baseline in 4% of patients in the combination group, compared with 2% in both monotherapy groups and 3% in the placebo group. But again Oparil takes issue with this, saying their comments are "inaccurate and unfair."
"In fact, what you find is that frequently, on retest, hyperkalemia goes away because it's a laboratory artifact which is the result of red blood cells getting a little hemolysed," she noted, adding that this was the case in most people in this study. Of the 18 patients on the combination therapy who had increases in serum potassium > 5.5 mmol/L during double-blind treatment, 13 had potassium concentrations within the normal range at the end of the study without the need for treatment disruption, she notes. And 'serious' hyperkalemia, which is considered dangerous when it exceeds 6 mmol/L, was seen in only two patients on the combination therapy, compared with 5 in the valsartan alone arm, 4 in the aliskiren alone arm and 6 in the placebo group, she noted.
"There was no increase in the danger level, they have tremendously overinterpreted this and it's unfair." She said it is well-known that patients taking angiotensin-converting enzyme (ACE) inhibitors or ARBs or drugs such as spironolactone are prone to develop hyperkalemia, "but this drug [aliskiren] doesn't seem to be any worse." She added that she has gone through the sponsors' files "and hyperkalemia has not popped up." However, she noted that there have not been any studies done in patients with renal dysfunction and that Novartis will likely be looking at this issue in more detail.
One of the editorialists, Staessen, responded to Oparil: "We based our comments on the combination of the highest dose of aliskiren with an unusually high dose of valsartan. The dose of 320 mg/day of valsartan is unavailable in many countries, including Belgium. Previous trials of valsartan, such as VALUE (Valsartan Antihypertensive Long-term Use Evaluation), did not include the 320 mg dose. Oparil might clarify whether the issue at stake is aliskiren, valsartan, or the combination [and] give us access to the Novartis company database to assess how quality control of the serum potassium measurements was handled. Under these conditions, we can substantiate or negate our independent points of view."
"The only way forward is to use the scientific way to clarify issues.... via peer-reviewed medical journals. If Prof Oparil is dissatisfied with our commentary, I would invite her to writie a letter-to-the-editor with her objections," he added.
BP Reduction With Combination Not Much Better Than Either Agent Alone
Birkenhäger and Staessen go on to say in their editorial that the additional BP reduction, over and beyond that provided by the single components "was not as large as might be expected from combining any two antihypertensive agents from different classes." Hence they question why Oparil and colleagues opted to combine aliskiren with valsartan, rather than with a diuretic or a CCB "as recommended by current guidelines."
Oparil told heartwire that a study has been conducted with aliskiren in combination with a diuretic (hydrochlorothiazide), and this is published in the Journal of Hypertension. Others have looked at the drug in combination with an ACE inhibitor, ramipril, and in combination with a CCB, amlodipine. All trials showed that the combination reduced BP more than either agent alone, she noted, but added "it's really not fair to do these cross-comparisons... it is difficult to make direct comparisons across trials with different patient populations."
"You have to give the sponsor credit for studying this," she added, noting that the diuretic, ACE inhibitor and CCB chosen for the trials were not Novartis products but rather one of the most commonly used agents in each respective class.
The only drug class that aliskiren had not been tested in combination with is beta-blockers, she added, because they inhibit renin release.
Will Aliskiren Prevent End-Organ Damage? Novartis Hopes So
The editorialists move on to discuss Phase III trials that are ongoing with aliskiren in high-risk patients with left ventricular hypertrophy, heart failure or renal dysfunction but that these will not be easy to interpret.
"From a strategic point of view, the sponsor is looking for an area of superiority," Oparil says, talking about the hope that there will be improved organ protection with aliskiren, both alone and in combination. "That will be the brass ring for them if they can show a better effect, as we do need things that are better at protecting target organs."
In conclusion, Oparil admitted that she has not used aliskiren much in her everyday practice because she is involved in so many trials and has so many other protocols to try.
"But I wouldn't hesitate to use it. The kind of patient I would use it in would be one in whom BP is not controlled, and they have a lot of drug intolerances and a lot of nuisance side-effects from other agents. This is pretty clean." The only downside with aliskiren is that you can get diarrhoea, but only at a dose of 600 mg, which is twice the recommended daily dose, she adds.
"Aliskiren is new and interesting. Some physicians like new things and some are wary of them. The position of this drug relative to everything else won't be settled for a few years. It has been tested in several thousand patients but it's not a million patients. Time will tell," she concluded.
Oparil is the recipient of a number of grants-in-aid from various companies, including Novartis. She is also a consultant for a number of companies, including Novartis, and is a member of the board of Encysive Pharmaceuticals. SAY has served as a speaker for Novartis. Coauthor Dr Steven A Yarows (University of Michigan Health System, Ann Arbor) has served as a speaker for Novartis. The remaining four authors — Drs Samir Patel, Hui Fang, Jack Zhang, and Andrew Satlin — are employees of Novartis. Birkenhager reports no financial disclosures. Staessen has consulted for AstraZeneca, Daiichi-Sankyo, Pfizer, Sigma-Tau, and Tanave and received funding for studies, seminars, or travel from these companies.
Lancet. 2007;370:195-196, 221-229.