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Azilsartan: the new sartan on the block

By Gareth Malson, MRPharmS

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Three decades have passed since the discovery of the first angiotensin-receptor blocker (ARB). That initial research bore fruit in 1995, when Merck Sharp & Dohme launched losartan. Now, with Takeda’s candesartan becoming the third ARB to join the generics price war, the company has launched a second ARB — azilsartan medoxomil (Edarbi tablets). The question is, with UK prescribers already having seven ARBs to choose from, why.

“Less than half of patients treated for hypertension are controlled to target,” claims Emma Roffe, Takeda’s cardiovascular medical manager. “In clinical trials, treatment with azilsartan medoxomil reduced blood pressure significantly more than maximum doses of valsartan, olmesartan and ramipril,” she says.

Essentially, Takeda reckons it has created an ARB with a bit more potency than the others. The hope is that it will become an option for patients whose hypertension is not controlled despite reaching stage 3 of the hypertension treatment algorithm (see Panel), used in place of an angiotensin-converting enzyme inhibitor or another ARB.

NICE hypertension treatment algorithm

Step 1 Angiotensin-converting enzyme (ACE) inhibitor* for patients under 55 years, calcium-channel blocker (CCB) for patients over 55 years or of African-Caribbean origin
Step 2 ACE* + CCB
Step 3 ACE* + CCB + thiazide diuretic
Step 4 Add a further diuretic, alpha-blocker or beta-blocker

*Where patients experience side effects with ACE inhibitors, an angiotensin-II receptor blocker can be used.

 

How it works

The pharmacodynamics of ARBs is well documented. Renin from the kidneys promotes the conversion of angiotensinogen to angiotensin I, which is subsequently transformed into angiotensin II by enzymes. Angiotensin II has several effects, including stimulating AT1 receptors in blood vessel endothelial cells, causing vasconstriction. By blocking this receptor, ARBs promote vasodilation and blood pressure reduction. “Differences in binding characteristics may account for the differences in efficacy of the various ARBs,” explains Dr Roffe.

 

Research

Azilsartan has been compared with ramipril in a double blind, industry-sponsored trial.1 In total, 884 people with a clinic-measured systolic blood pressure (SBP) of 150–180mmHg were randomly assigned to azilsartan 40mg or 80mg od, or ramipril 10mg od. After 24 weeks, the average reduction in SBP was 20.6, 21.2 and 12.2mmHg, respectively — a difference of statistical significance (P<0.001).

Diastolic blood pressure, also monitored in clinic, was also lowered significantly more by azilsartan.

Azilsartan has also been compared with olmesartan for its effect on 24-hour mean ambulatory SBP — a study that, again, was industry sponsored.2 Over 1,200 patients with hypertension were assigned placebo, azilsartan (20mg, 40mg or 80mg od) or olmesartan 40mg od. After six weeks, azilsartan 80mg was found to reduce mean SBP by 14.6mmHg compared with 12.6mmHg for olmesartan (P=0.038). The lower strengths of azilsartan were shown to be non-inferior to olmesartan.

Similar results were shown when azilsartan 40mg and 80mg od were compared with valsartan 320mg od (reductions in 24-hour mean SBP of 14.9mmHg, 15.3mmHg and 11.3mmHg, respectively; P<0.001).3

Administration

Azilsartan is taken once daily at a starting dose of 40mg (20mg can be considered for those over 75 years of age and at risk of hypotension, and for those with mild to moderate hepatic impairment). It can be taken with or without food. Near maximal antihypertensive effect is achieved after a fortnight; if a patient’s blood pressure is still not controlled, an 80mg dose may be used.

No dose adjustment is required for patients with mild to moderate renal impairment, but caution should be exercised in severe renal impairment. Azilsartan is not recommended for patients with severe hepatic impairment.

Safety

“ARBs are the best tolerated drugs in the management of hypertension,” says Terry McCormack, GP and executive committee member of the British Hypertension Society. According to its summary of product characteristics, the most common side effects associated with azilsartan are dizziness, diarrhoea and increases in blood creatine phosphokinase. [High levels of creatine phosphokinase usually indicate injury or stress to the heart, the brain, or muscles.]

Cost

According to the electronic Drug Tariff (accessed 4 June 2012), costs of 28 days supply of ARB treatment in primary care are:


•    Candesartan — £9.78 to £16.13 (4mg to 32mg daily)

•    Eprosartan — £7.31 to £15.77 (300mg to 800mg daily)

•    Irbesartan — £9.69 to £15.93 (75mg to 300mg daily)

•    Losartan — £1.09 to £1.44 (25mg to 100mg daily)

•    Olmesartan — £10.95 to £17.50 (10mg to 40mg daily)

•    Telmisartan — £11.10 to £17.00 (20mg to 80mg daily)

•    Valsartan — £4.08 to £10.54 (40mg to 320mg daily — using generic capsules)


Azilsartan will cost primary care trusts £16.80 for the 20mg or 40mg strengths, while 80mg will set them back £19.95.

Place in therapy

“Azilsartan is a very potent ARB,” confirms Dr McCormack. “For patients who can only take ARBs, many of them will need one that is very potent.” Nonetheless, convincing formulary committees to spend £400 a year on azilsartan rather than £20 a year on a generic such as losartan is likely to require more than a reduction of a few millimetres of mercury. “It’s difficult to see where azilsartan will fit given that there are several generic ARBs available already,” predicts Alison Warren, lead cardiac pharmacist for Brighton and Sussex University Hospitals NHS Trust. “The data are unlikely to be sufficient at present for inclusion in local formularies. While they show good blood pressure lowering effects in the short term, there are no longer-term data. Ideally, I would like to see outcome data comparing it against other antihypertensives."

 

DECLARATION OF INTEREST Dr McCormack received honararia from Takeda for attending advisory boards and giving lectures.
 

References

  1. Bonner G, Bakris GL, Sica D et al. Comparison of antihypertensive efficacy of the new angiotensin receptor blocker azilsartan medoxomil with ramipril. Presented at the 20th European meeting on hypertension of the European Society of Hypertension (ESH): 18–21 June 2010; Oslo, Norway.
  2. Bakris GL, Sica D, Weber M et al. The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure. Journal of Clinical Hypertension 2011;13:81–8.
  3. Sica D, White WB, Weber MA et al. Comparison of the novel angiotensin II receptor blocker azilsartan medoxomil vs valsartan by ambulatory blood pressure monitoring. Journal of Clinical Hypertension 2011;13:467–72.

Citation: Electronicjuice URI: 11103522

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