28th March 2011
The ROADMAP trial found olmesartan delayed the onset of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. While this disease-oriented outcome (DOO) suggested a potential benefit for olmesartan, of greater concern is that more patients taking olmesartan compared with placebo had fatal cardiovascular events — 15 patients (0.7%) vs. 3 patients (0.1%) (P=0.01).
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
This trial provides a safety signal about a possible increased risk of fatal cardiovascular (CV) events in people with type 2 diabetes taking the angiotensin-2 receptor antagonist (A2RA), olmesartan, particularly if they have pre-existing coronary heart disease (CHD). However, due to the inherent limitations of the data, this cannot be regarded as definitive. The FDA has an ongoing safety review of these concerns, and we anticipate that regulatory authorities in the UK/Europe will also be examining these data.
In the meantime, this safety concern adds weight to the argument that ACE inhibitors, not A2RAs, are the first-line choice when a renin-angiotensin system (RAS) drug is indicated. ACE inhibitors have a more robust evidence base than A2RAs for all indications in terms of evidence for efficacy, safety and most patient factors. The major benefit of A2RAs over ACE inhibitors is a slightly lower rate of cough. Hence, A2RAs are an alternative where a RAS drug is indicated, but an ACE inhibitor has to be discontinued because of an intolerable ACE inhibitor-induced cough.
What is the background to this?
Controlling blood pressure (BP) in patients with diabetes is beneficial with regard to both early and advanced stages of nephropathy. It is widely accepted (but not without contention) that inhibition of the renin-angiotensin system is particularly important for these patients. Indeed, NICE guidance recommends a once-daily, generic ACE inhibitor first line in preference to other classes of antihypertensives for the initial management of BP in most patients with type 2 diabetes because of their greater renal benefits.
The authors of the current study state that RAS drug treatment may be beneficial in the early stages of type 2 diabetes, as ACE inhibitors have been shown to delay the onset of microalbuminuria in type 2 diabetes patients with hypertension but normoalbuminuria. Hence the rationale for this study, to ascertain whether the A2RA, olmesartan, could also be beneficial in delaying the onset of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. The renal results from this study are interesting and add to the debate about the renal benefits of RAS drugs in people with type 2 diabetes. However, the onset and progress of microalbuminuria is a disease oriented outcome (DOO), and in itself does not tell us if patients are likely to live longer or better as a result of this (only measuring patient oriented outcomes [POOs] can tell us this). The main reason we are interested in this paper is because of the unexpected finding that olmesartan was associated with an increased risk of fatal CV events, a POO.
What does this study claim?
In the ROADMAP randomised controlled trial (RCT), 4,447 patients with type 2 diabetes, normoalbuminuria and at least one other CV risk factor were randomised to olmesartan 40mg daily or placebo for a median follow-up of 3.2 years. Additional antihypertensives (except ACE inhibitors or A2RAs) were used as needed to lower BP to <130/80mmHg. Mean BP during follow-up was 3.1/1.9mmHg lower in the olmesartan group.
The primary outcome, time to first onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.63 to 0.94)., Microalbuminuria developed in 8.2% of olmesartan patients compared with 9.8% of the placebo group, absolute risk reduction (ARR) 1.6%, number needed to treat (NNT) 63 over a median of 3.2 years.
The secondary composite outcome of CV complications or death from CV causes was similar in both groups (4.3% with olmesartan vs. 4.2% with placebo; HR 1.00, 95%CI 0.75 to 1.33). However, death from CV causes (primarily fatal myocardial infarction [MI] and sudden cardiac death) was higher in the olmesartan group (15 patients [0.7%] with olmesartan vs. 3 patients [0.1%] with placebo, HR 4.94, 95%CI 1.43 to 17.06, P=0.01, absolute risk increase (ARI) 0.6%, number needed to harm [NNH] 167 over a median of 3.2 years). The majority of deaths from CV causes (12 of 18) occurred in people with pre-existing CHD, where there was a significantly higher risk in the olmesartan group (11 patients [2.0%] with olmesartan vs. 1 patient [0.2%] with placebo, HR 10.57, 95%CI 1.37 to 81.88, P=0.02, ARI 1.8%, NNH 56 over a median of 3.2 years).
The unexpected findings from ROADMAP that olmesartan was associated with an increased risk of fatal CV events, particularly in people with pre-existing CHD, need to be viewed with caution. The trial was not powered for CV events, and the very small numbers of patients affected means these findings could simply be due to the play of chance. Having said this, another trial (ORIENT) also found the addition of olmesartan to pre-existing antihypertensive treatment in patients with type 2 diabetes and nephropathy was associated with a higher rate of death from CV causes (10 cases with olmesartan vs. 3 cases with placebo).
The authors of ROADMAP and the accompanying editorial suggest the increased risk of death from CV causes seen with olmesartan in this study may be due to reducing blood pressure too low in certain patients at high risk. The dose used in ROADMAP was 40mg once daily, the maximum recommended dose. However, they also state that a direct effect of olmesartan cannot be ruled out. The FDA has an ongoing safety review of both these trials to try and better understand this worrying safety signal about olmesartan. There is also an ongoing FDA safety review of A2RAs and a possible association with an increased risk of cancer. This issue has been discussed in more detail in MeReC Rapid Review Nos. 1525 and 2491.
Until the FDA or UK/European regulatory authorities announce their findings, we should bear this potential safety signal in mind when prescribing decisions are being made. Due to the inherent limitations of the data, the results from these trials cannot be regarded as definitive, but this safety concern adds weight to the argument that ACE inhibitors, not A2RAs, are the first-line choice when a RAS drug is indicated. ACE inhibitors have a more robust evidence base than A2RAs for all indications in terms of evidence for efficacy, safety and most patient factors. The major benefit of A2RAs over ACE inhibitors is a slightly lower rate of cough (with a NNH of around 30). Hence, A2RAs are an alternative where a RAS drug is indicated, but an ACE inhibitor has to be discontinued because of an intolerable ACE inhibitor-induced cough.
RAS drugs are one of the key therapeutic topics outlined in the NPC’s Quality, Innovation, Productivity and Prevention (QIPP) document for review and, where appropriate, revision to ensure prescribing is in line with NICE guidance. A set of 13 prescribing comparators, including one relating to RAS drugs, have recently been developed to support QIPP implementation, and data from the NHS Business Services Authority are now available on these.
Randomised, double-blind, multicentre, controlled trial.
4,447 patients with type 2 diabetes, normoalbuminuria (urine albumin:creatinine ratio [mg/g]: <35 for females, <25 for males) and at least one other CV risk factor.
Intervention and comparison
Olmesartan 40mg once daily or placebo for a median of 3.2 years.
Outcomes and results
Study funded by Daiichi Sankyo.
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