The Scottish Medicines Consortium issued on 5th December 2008 an advice on aliskiren (Rasilez, Tekturna in the US):
Aliskiren (Rasilez) is not recommended for use within NHS Scotland for the treatment of
Aliskiren has shown comparable efficacy to other antihypertensive agents in terms of blood
pressure reduction, though its effects on mortality and long-term morbidity are currently
unknown. The manufacturer did not present a sufficiently robust clinical or economic
analysis to gain acceptance by SMC for the position sought.
This is an excerpt of the detailed advice on aliskiren (Rasilez):
The recommended dose of aliskiren is 150mg once daily. In patients whose blood pressure is not adequately controlled, the dose may be increased to 300mg once daily. Aliskiren may be used alone or in combination with other antihypertensive agents.
Product availability date
3rd September 2007.
Summary of evidence on comparative efficacy
Aliskiren inhibits the activity of renin, thereby inhibiting activation of the renin-angiotensin system at an earlier stage than angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor antagonists (ARA).
The submitting company has requested that the Scottish Medicines Consortium consider the use of this product in a sub-set of patients being treated for essential hypertension: patients reaching step 4 of the joint guidelines from the National Institute for Health and Clinical Excellence and the British Hypertension Society (NICE/BHS) and who are unresponsive to other agents and/or for whom there are no suitable alternatives. The clinical data for this proposed niche will be presented later, but the following paragraphs give an overview of the antihypertensive efficacy of aliskiren based on clinical evidence from 15 clinical trials presented for European registration of this product.
All studies recruited patients with mild to moderate essential hypertension (except one small study in patients with uncomplicated severe hypertension) and exclusion criteria in all studies included the presence of a renal disorder, a secondary form of hypertension and conditions altering the pharmacokinetics of any medicinal product.
All studies were randomised and double-blind, parallel-group design and included a placebo run-in phase preceded by a washout period for patients who had been taking previous antihypertensive therapy. Some studies were dose-finding in the range 75mg to 600mg once daily, and all included at least one of the licensed doses of 150mg and 300mg aliskiren daily.
The duration of active treatment was up to 26 weeks but was 8 weeks in eight studies.
Studies investigating aliskiren in special groups involved patients with diabetes mellitus, obesity and patients ≥65 years of age.
All studies recorded the change from baseline to endpoint in mean sitting diastolic and systolic blood pressures (msDBP and msSBP) and the primary end-point was diastolic BP in 13 studies, ambulatory SBP in one study, and safety in another. These were analysed in the intention to treat (ITT) populations. Secondary endpoints included msSBP or msDBP (when each was not a primary endpoint), the proportion of patients with successful BP response and control and effects on plasma renin concentration and activity.
Aliskiren at doses of 150mg and 300mg provided dose-dependent reductions in both systolic and diastolic BP that were maintained over the entire 24-hour dose interval, with 85-90% of the maximal BP lowering effect being observed after 2 weeks. For example, statistically significant placebo-controlled reductions in msDBP over 8 weeks were in the range 2.0 to 5.4mmHg for 150mg aliskiren and 3.3 to 7.5mgHg for 300mg. The equivalent ranges for msSBP were 4.8 to 9.3mmHg and 5.0 to 11.2mmHg respectively. The BP reductions were sustained during long-term treatment. The antihypertensive effect was independent of age, gender, body mass index and ethnicity. Aliskiren monotherapy in five studies has shown BP lowering effects comparable to other classes of antihypertensive agents including ACEi, ARAs and the diuretic hydrochlorothiazide. For example, in the only study to show a significant difference between aliskiren and comparator for both msDBP and msSBP reduction, the difference between aliskiren 300mg and hydrochlorothiazide 25mg at 12 weeks was 2.0mmHg for msDBP and 2.8mmHg for msSBP.
Aliskiren was studied in combination with hydrochlorothiazide, ARA, ACEi, calcium channel blocking drugs (CCB) and beta-adrenergic blocking drugs. Combination therapy studies have shown additive BP-lowering effects of aliskiren compared to the corresponding monotherapies, although the difference was not consistently significant. For example, aliskiren in combination with valsartan showed an additive antihypertensive effect at 8 weeks, which was significant in one study comparing the combination with aliskiren monotherapy but not in another study comparing it with valsartan monotherapy. In the first study the difference in BP reduction between aliskiren 300mg/valsartan 320mg and aliskiren alone was 2.7mmHg for msDBP and 4.4mmHg for msSBP. In the second study the non- significant difference in msDBP reduction was 1.1mmHg comparing aliskiren 150mg/valsartan 160mg with valsartan alone and 1.7mmHg for aliskiren 300mg/valsartan 320mg versus valsartan. The equivalent differences for msSBP reduction were 1.1mmHg and 1.5mmHg respectively. In one study in diabetic hypertensive patients, aliskiren 300mg provided significant additive BP reductions when added to ramipril 10mg (2.1mmHg for msDBP and 4.6mmHg for msSBP). Combination studies have also demonstrated comparable efficacy for aliskiren compared with a second agent when both were combined with a third agent. Effects of aliskiren on mortality, cardiovascular morbidity, and target organ damage are currently unknown.
Evidence to support the proposed niche for aliskiren at step 4 of NICE/BHS guidelines comes from two observational studies, one of which surveyed GPs who had prescribed
aliskiren while the other surveyed hospitals experienced in its use. Both asked for details of patients whose records indicated that they had been prescribed aliskiren for at least four weeks, had been tried on a representative drug from all classes of therapy recommended in steps 1 to 3 of the NICE/BHS guidelines and, despite this, required addition of or substitution with a fourth-line agent. The authors concluded that, over four weeks, aliskiren 150mg achieved a mean reduction in systolic blood pressure of 17.25mmHg in 90 patients in primary care and 27mmHg in three hospital patients. The corresponding reductions with 300mg aliskiren were 15.7mmHg (n=26) and 11mmHg (n=19) respectively.
Summary of evidence on comparative safety
The European Medicines Agency’s (EMEA) European Public Assessment Report (EPAR)describes a pooled analysis of safety data obtained in a total of 11,566 treated patients
including 7,896 who received at least one dose of aliskiren, 2,367 who were exposed to aliskiren for 6 months and 1,270 exposed for 12 months. The safety population consisted of adults with mild to moderate essential hypertension with exception of one study (severe essential hypertension). Common adverse events (AEs) included diarrhoea, cough, peripheral oedema, fatigue, rash, and influenza. Diarrhoea was the most common AE though the incidence was low at doses up to 300mg. Cough was the second most common AE but was substantially less frequent in patients treated with aliskiren than in patients treated with ACEi (1.0% versus 3.8%). Peripheral oedema was substantially less frequent in patients treated with aliskiren than in patients treated with amlodipine (0.9% versus 7.3%).
The incidence of serious AEs was similar for aliskiren and placebo. Increases in serum potassium were minor and infrequent in patients with essential hypertension treated with aliskiren alone. However, in one study where aliskiren was used in combination with an ACEi in a diabetic population, increases in serum potassium were more frequent. Therefore as with any agent acting on the renin-angiotensin system, routine monitoring of electrolytes and renal function is indicated in patients with diabetes mellitus, kidney disease or heart failure.
Summary of clinical effectiveness issues
Change in blood pressure was investigated in line with EMEA guidance during the aliskiren clinical programme, but it is recognised that change in blood pressure is a surrogate
endpoint in such studies. In none of the aliskiren studies were mortality or morbidity data analysed or target organ damage assessed. The EMEA guidance notes that, even if an
antihypertensive effect has been proven, a significant concern about a detrimental effect on mortality and/or cardiovascular morbidity might lead to a need for outcome studies.
The main clinical programme supports the antihypertensive efficacy of aliskiren as monotherapy and in combination with other antihypertensive agents, predominantly in
patients with mild to moderate hypertension. In general, efficacy was comparable to the alternative treatment regimens studied.
The submitting company has requested that aliskiren be considered for use in a sub-set of patients at step 4 of NICE/BHS guidelines i.e. for patients who have failed to respond to at least three other agents, who require additional therapy and for whom existing alternatives are ineffective and/or unsuitable. The main clinical trial programme provides no specific data for patients at this stage of treatment. Furthermore, because all trials involved placebo wash-out and run-in periods, none are representative of the proposed niche where aliskiren would be added to the existing therapy of heavily pre-treated patients. Also patients at step 4 are more likely to have severe, treatment resistant hypertension and are unlikely to reflect the patient population studied in the clinical trial programme in which all but one study recruited patients with mild to moderate hypertension.
The company has therefore presented the results of two observational studies in which prescribers in primary and secondary care were asked for data on patients who had been prescribed aliskiren for four weeks or more and whose prescribing history indicated that the patient had been treated with three classes of drug.
Expert opinion suggests that the niche proposed for aliskiren at step 4 represents an area of unmet clinical need, however there are concerns about the robustness of the observational data presented for this population and its applicability to clinical practice at this stage of therapy. These are related to:
• How prescribers were selected from within the sample of those prescribing aliskiren and whether such ‘early adopters’ and their patients are representative of clinical
• Whether methods of BP measurement were as rigorous and consistent as would be expected in controlled trials.
• The definition of a non-responder in these studies, which implies that any SBP reduction would be treated as a response – much less rigorous than the targets for BP response and control identified in controlled trials.
• The fact that patients could be included if they had received three classes of antihypertensive in the past and may not have been receiving these at the time of initiation of aliskiren: only about half of the patients who had been prescribed aliskiren fell into the above category and were included in the analyses.
Update 20 february 2009: EMEA recommends new contraindication for aliskiren (Rasilez): angioedema