ROADMAP Published, But No News on FDA Safety Review of ARB

March 11, 2011

March 11, 2011 (Hannover, Germany) — Results of a large multicenter trial showing that the angiotensin-receptor blocker (ARB) olmesartan (Benicar, Daiichi Sankyo) delays onset to microalbuminuria in patients with type 2 diabetes have been published [1]. The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study findings were first reported last summer amid controversy, because the US FDA had announced a safety review on olmesartan just the week before, due to concerns about an excess risk of cardiac death seen in the olmesartan arm of ROADMAP and in another smaller study, Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial (ORIENT).

Nine months later, not much appears to have changed. ROADMAP, led by Dr Hermann Haller (University of Hannover Medical School, Germany), is published in the March 10, 2011 issue of the New England Journal of Medicine, and an accompanying editorial [2] by one of the deputy editors for the journal, Dr Julie R Ingelfinger, observes: "The FDA has not yet announced any conclusions concerning the risk of death with olmesartan."

Alyssa Dargento, a public-affairs spokesperson at Daiichi Sankyo, told heartwire : "A complete data package and analyses were submitted to the FDA in response to the June 11, 2010 FDA drug safety communication.  The FDA is currently reviewing the data, and we continue to work collaboratively with the agency as their review progresses."

The FDA has not yet announced any conclusions concerning the risk of death with olmesartan

The lack of any boxed warning for this drug in the eight months since the safety review was announced, plus the fact that, prior to this, olmesartan had been on the market since 2002 with no cardiovascular risk signal, means that "most nephrologists and cardiologists" contend that the benefits of this drug outweigh any small risks, Ingelfinger says. However, "others would argue that there are many ACE inhibitors and ARBs that have not been associated with a signal of increased cardiovascular death, so why not prescribe one of those agents?"

Excess CV Deaths Due to Chance, J-Curve, or Direct Effect of Olmesartan?

Although it has been available for almost 10 years, there had been no large outcome trials with olmesartan prior to ROADMAP--one of the reasons the finding of excess cardiac deaths in the active-treatment arm of this trial and the smaller ORIENT study prompted some concern.

ROADMAP is a randomized, double-blind, multicenter study conducted in Europe, including 4447 patients with diabetes and at least one additional cardiovascular risk factor, but no evidence of renal dysfunction. The participants were randomized to receive either olmesartan at 40 mg/day (n=2232) or placebo (n=2215), and all were allowed to take additional non–renin-angiotensin-system (RAS) antihypertensives to reach target BP (<130/80 mm Hg), until the predefined number of adjudicated microalbuminuria events occurred at a median follow-up of 3.2 years. The primary end point was renal: time to onset of albuminuria.

Haller told heartwire , "The data [published in the journal] are the same" as were presented at the European Society of Hypertension (ESH) meeting in Oslo last summer, but some of the analyses reported there do not appear in the manuscript; "there will be follow-up publications."

The results show there was a cumulative incidence of microalbuminuria of 8.2% with olmesartan and 9.8% with placebo; the primary end point, time to onset of microalbuminuria, was delayed by 23% with olmesartan (hazard ratio 0.77, p=0.01), with the majority of this effect being BP independent.

But in ROADMAP, there were 15 cardiovascular deaths in the olmesartan group--seven cases of sudden death, five fatal MIs, two fatal strokes, and one death related to coronary revascularization--compared with a total of three CV deaths--one sudden death and two fatal strokes--in the control group (0.7% vs 0.1%, p=0.01).

Most of the excess cardiovascular mortality in the olmesartan group occurred in those with preexisting cardiovascular disease (11 events vs one with placebo, p=0.03) and among patients in the lowest quartile of BP, the investigators point out.

In contrast, fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events, 3.6% vs 4.1% (p=0.37), they note.

"The fact that these signals go in opposite directions, together with the feeling that the study was underpowered to determine cardiovascular risk, has led many to comment that these results may well be due to chance," says Ingelfinger in her editorial. Haller et al agree, and last year, at the ESH meeting, Haller told heartwire : "It's clear-cut, it's not a problem of olmesartan; we are sure about that."

Nevertheless, Haller et al now appear to be hedging their bets somewhat, admitting in their paper that the CV mortality finding is "of concern." Excessive reduction of BP in some high-risk patients may confer a predisposition to an increased risk of death, a finding that is consistent with the well-known, somewhat-controversial "J-curve-effect," they observe, pointing out that the ESH states that doctors should avoid lowering BP excessively to values below 120/70 mm Hg in people with underlying CVD.

They also concede that "a direct effect of olmesartan cannot be ruled out" and point out that the FDA is currently reviewing the existing data on the drug.

Ingelfinger adds that olmesartan has been promoted as a medication that helps patients reach BP goals rapidly and that the dose used in ROADMAP, 40 mg, was higher than that used in many other studies. In the other smaller trial being looked at by the FDA, ORIENT, 500 patients were randomized to receive olmesartan at 10 mg/day to 40 mg/day or placebo. There were 10 cardiovascular deaths in the olmesartan group compared with three in the control group.

Target Those With High BP, Low eGFR or Albuminuria for Most Benefit

Haller et al say their findings extend the results of other trials and suggest that olmesartan delays the time to onset of microalbuminuria in type 2 diabetes, "even when BP control is excellent according to current recommendations."

"These results provide hope that it may be possible to prevent chronic kidney disease in the many persons worldwide who have type 2 diabetes mellitus," says Ingelfinger in her editorial.

Haller says Ingelfinger's editorial is "balanced" and "stresses the two points we have mentioned. That olmesartan delays or prevents microalbuminuria, which may result in a delay or prevention of diabetic nephropathy. But when one uses this strategy, it is clear that we have a problem with blood pressure."

It is not possible to draw definite conclusions from a short-term prevention study about the way in which changes in microalbuminuria may affect the rates of renal and CV event rates in the long term.

Also, as noted last year at ESH, Haller says that in the overall patient population, although the difference was significant, it was small, so the question becomes which diabetic patients should be targeted.

Subgroup analyses suggest those with high systolic blood pressure (above 138 mm Hg), a low estimated glomerular filtration rate (eGFR) of under 90 mL/min, or those who have the first trace of albumin in the urine, even before microalbuminuria, will benefit most, he told heartwire .

And he and his colleagues also note that ROADMAP has some limitations. "It is not possible to draw definite conclusions from a short-term prevention study about the way in which changes in microalbuminuria may affect the rates of renal and CV event rates in the long term," they observe, pointing out also that the follow-up period "was too short."

Roadmap was supported by Daiichi Sankyo. Haller reports receiving payment for board membership from Novartis; consulting fees from Bayer Schering Pharma and Daiichi Sankyo; lecture fees from Bayer Schering Pharma, Roche, and Menarini; payment for development of educational presentations from Daiichi Sankyo and Bayer Schering Pharma; and travel support from Amgen and Daiichi Sankyo. Disclosures for the coauthors are listed in the paper. Ingelfinger reports receiving travel, accommodation, and/or meeting expenses from the National Institutes of Health and the Cystinosis Research Foundation and receiving royalties from various book publishers.

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