New treament available for difficult to treat hypertension

Hypertension is a significant risk factor for both cardiovascular and renal disease in the general population. Results from the AusDiab study showed that one in three Australians aged over 25 years of age were hypertensive (BP≥140/90 mmHg) or taking antihypertensive medication.1

The five year follow-up AusDiab study had several key findings:¹

3.0% of adults develop hypertension every year
The incidence of hypertension increased with age, such that the risk of developing hypertension was 8.4% for those aged 65–74 years, compared to 1.0% for those aged 25–34 years
Those at greatest risk for developing hypertension included diabetics and those who were overweight or obese.
For smokers, the risk of hypertension was greater in males than in females.

New to the Pharmaceutical Benefits Scheme, as of 1 March 2009, is Micardis Plus 80/25mg (telmisartan 80 mg, plus hydrochlorothiazide 25 mg), indicated for hypertension. Micardis Plus provides an increased dose of hydrochlorothiazide compared to Micardis Plus 80/12.5mg.²

Associate Professor John Amerena, Cardiologist at Geelong Hospital Melbourne said that the listing of Micardis Plus onto the PBS, "means that there is a new medication available that can be used to improve blood pressure control using a compound that is safe and well tolerated and lowers blood pressure effectively."

Recent evidence has suggested that, in patients with hypertension not adequately managed with telmisartan 80 mg/hydrochlorothiazide 12.5 mg (T80/H12.5), an increased dose of thiazide in combination with telmisartan 80 mg (T80/H25) provides additional blood pressure reductions and is well tolerated.³

A/Prof Amerena said the "studies have shown additional blood pressure lowering by the increased dose of thiazide and this is not at the expense of increased side effects or a decrease in glycaemic control."

The study included adults with essential hypertension whose blood pressure was not satisfactorily controlled despite taking between one and three antihypertensives for at least four weeks. Patients then stopped their usual antihypertensive medication and instead received T80/H12.5 for a period of six weeks. After this period, those who had a trough seated diastolic blood pressure (DBP) > 90 mmHg were randomised to receive either T80/H25 or T80/H12.5 for 8 weeks. Both study arms showed a reduction in the primary endpoint of trough seated DBP; however, the reduction was greatest with T80/H25.³

The incidence of adverse events were similar between the two groups (29.6 vs 31.5% for T80/H12.5 vs T80/H25), as were serious adverse events (0.8 vs 1.4% for T80/H12.5 vs T80/H25) and discontinuations due to adverse events (3.0 vs 1.7% for T80/H12.5 vs T80/H25). Hypokaleamia was rare, affecting two in the T80/H12.5 group and one in the T80/H25 group.³

The long-term safety and efficacy of Micardis Plus (T80/H25), alone or with other antihypertensive medication, was assessed in an extension trial.⁴ Patients received T80/H25 for 24 weeks, during which the use of additional antihypertensive medication was permitted. Seated trough DBP was measured at several time points including weeks 0, 4, 12 and 24. The primary end point of seated trough DBP < 90 mmHg was attained in 71.4% of patients compared to only 52.4% at baseline (n = 639). This improvement was evident at week four and was sustained until study completion. For those patients who received additional antihypertensive medication (17.4%), DBP control was increased from 24.8% at baseline to 58.6% at study completion.⁴

During the study period, adverse events considered to be drug-related occurred in 29 (4.5%) patients, the most common including dizziness, hypertension, hypotension, palpitations and fatigue. Treatment was discontinued due to adverse events considered to be related to the trial treatment in eight patients (1.2%). The adverse events prompting discontinuation included palpitations, diarrhoea, nausea and dizziness, malaise and erythema, increased blood creatinine, diabetes mellitus, dizziness and hypotension. Serum potassium concentrations < 3.5 mEq/l occurred in eight patients.⁴

The authors concluded that "T80/H25 provides sustained and well-tolerated additive BP control, given alone or as part of a multi-antihypertensive therapy."⁴

High levels of compliance (>97%) were achieved in both studies. However, outside of clinical trials, long term compliance in patients with hypertension or dyslipidaemia is frequently unsatisfactory. Simons et al analysed claims for antihypertensive drugs from the Medicare Australia Pharmaceutical Benefits Scheme during the period 2004–2006, with a focus on angiotensin receptor antagonists (ARA), angiotensin converting enzyme inhibitors, and calcium channel blockers (CCB). While long term persistence was poor for all three classes of drugs, persistence was greatest for ARA.⁵

A/Prof Amerena said "most people who are on antihypertensives require at least two, and often three, blood pressure lowering agents to achieve the target level. So you could certainly use Micardis Plus with a calcium channel blocker and that would be a very efficacious, safe and well-tolerated combination."

Within the ARA class, telmisartan (Micardis) or candesartan (Atacand) had the best persistence by a 10–20% margin. It is possible that the ARAs may have performed slightly better due to increased tolerability. By acting on the receptor, they avoid some of the common side effects of ACE inhibitors associated with reduced bradykinin degradation, such as cough and angioedema.⁵ Some strategies to improve patient compliance include improved patient education, the use of drugs with fewer side effects, simple dosing schedules and combination products.⁶

References

Barr ELM, Magliano DJ, Zimmet PZ, Polkinhorne KR, Atkins RC, Dunstan DW, et al. AusDiab 2005: The Australian diabetes, obesity and lifestyle study. Tracking the accelerating epidemic: its causes and outcomes. Melbourne: International Diabetes Institute, 2006.
Micardis Plus Product Information. North Ryde, NSW: Boehringer Ingelheim Pty Ltd; 3 February 2009.
Neldam S, Edwards C. Results of increasing doses of hydrochlorothiazide in combination with an angiotensin receptor blocker in patients with uncontrolled hypertension. J Clin Hypertens (Greenwich). 2008; 10(8): 612-8.
Neldam S, Edwards C. Long-term, open-label evaluation of the safety and efficacy of telmisartan 80 mg/hydrochlorothiazide 25 mg fixed-dose combination alone or with other antihypertensive medication. Expert Opin Pharmacother. 2009; 10(3): 345-52.
Simons LA, Ortiz M, Calcino G. Persistence with antihypertensive medication: Australia-wide experience, 2004-2006. Med J Aust. 2008; 188(4): 224-7.
Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008; 358(15): 1547-59.