Aliskiren as Add-On Therapy in the Treatment of Hypertensive Diabetic Patients Inadequately Controlled with Valsartan/HCT Combination

Background

Hypertension frequently coexists with diabetes mellitus, resulting in increased cardiovascular risk. Thus, BP control is crucial in decreasing morbidity and mortality in this difficult-to-treat patient population.

Objective

The objective of this study was to evaluate the efficacy and safety of aliskiren in hypertensive patients with diabetes not adequately responsive to the combination of valsartan and hydrochlorothiazide (HCT).

Methods

After a 1-to 4-week washout period, patients with a mean sitting diastolic BP (msDBP) ≥95mmHg were treated with valsartan 160mg for 2 weeks followed by valsartan/HCT 160mg/25mg for an additional 4 weeks (single-blind active run-in period). Patients whose msDBP remained ≥85mmHg after the active run-in period were randomized (1 : 1) to receive aliskiren 150mg (n = 184) or placebo (n = 179) as add-on therapy for 6 weeks. Aliskiren was then force-titrated to 300mg once daily for another 6 weeks. Efficacy variables were: the change in msDBP and mean sitting systolic BP (msSBP) from baseline to week 12 endpoint, diastolic response (msDBP < 80mmHg or reduction of at least 10mmHg), and BP control rate (<130/80mmHg).

Results

Of the 363 patients randomized, 328 (90.4%) completed the study (aliskiren and placebo groups: 89.7% and 91.1%, respectively). At week 12 endpoint, the least squares mean (LSM) changes in msDBP (aliskiren vs placebo: ?5.8 vs ?4.8mmHg; p = 0.2767) and msSBP (aliskiren vs placebo: ?7.3 vs ?4.8 mmHg; p = 0.0725) were numerically greater in patients treated with aliskiren compared with those treated with placebo; however, this difference was not statistically significant. The proportion of diastolic responders (aliskiren and placebo: 68.5% and 72.9%, respectively; p = 0.8482) and patients achieving BP control (aliskiren and placebo: 16.0% and 16.4%, respectively; p = 0.7511) were similar for both groups. Overall, 63 (34%) and 59 (33%) patients in the aliskiren and placebo groups, respectively, experienced adverse events (AEs). The most commonly reported AEs were headache (placebo group: 6.1%) and dizziness (aliskiren group: 4.4%). Aliskiren was well tolerated.

Conclusion

The reductions in BP with aliskiren added to valsartan/HCT in this study were numerically greater compared with placebo added to valsartan/HCT, although not statistically significant. Trial Registration: ClinicalTrials.gov identifier NCT00219102.     

Antihypertensive efficacy and tolerability of aliskiren/hydrochlorothiazide (HCT) single-pill combinations in patients who are non-responsive to HCT 25 mg alone*

ABSTRACT

Objective: Thiazide diuretics such as hydrochlorothiazide (HCT) are a widely used first-line treatment for hypertension, but most patients will not achieve blood pressure (BP) control with HCT alone and so will require combination therapy. In this study the efficacy, safety and tolerability of a single-pill combination (SPC) of the direct renin inhibitor aliskiren with HCT were investigated in patients non-responsive to HCT 25?mg therapy.

Methods: In this study, 722 patients with hypertension and an inadequate response to 4?weeks of HCT 25?mg (mean sitting diastolic BP ≥90 and <110?mmHg) were randomized to once-daily, double-blind treatment for 8?weeks with an SPC of aliskiren/HCT 300/25?mg or 150/25?mg, or continued HCT 25?mg monotherapy. Least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from double-blind baseline were analyzed for the ITT population at week?8 endpoint.

Results: Aliskiren/HCT 300/25?mg and 150/25?mg SPCs lowered msSBP/DBP from baseline by 16.7/10.7 and 12.9/8.5?mmHg, respectively, both significantly greater reductions than HCT 25?mg alone (7.1/4.8?mmHg; both p?<?0.001). Rates of BP control (<140/90?mmHg) were also significantly higher with aliskiren/HCT 300/25?mg (58%) and 150/25?mg (49%) than with HCT (26%; both p?<?0.001). Aliskiren/HCT 300/25?mg provided significantly greater msSBP/DBP reductions and rates of BP control than the 150/25?mg SPC dose (all p?<?0.05). Aliskiren/HCT SPC treatment showed similar tolerability to HCT alone and a numerically lower incidence of hypokalemia (serum potassium <3.5?mmol/L; aliskiren/HCT, 1.3–2.2%: HCT alone, 3.4%).

Conclusion: Aliskiren/HCT SPCs provide clinically significant BP reductions and improved BP control rates in patients who are non-responsive to HCT 25?mg monotherapy. Limitations of the study were the mainly Caucasian patient population and the non-responder design.     

Current concepts: renin inhibition in the treatment of hypertension

The development of aliskiren, the first orally effective renin inhibitor, utilized molecular modeling based upon X-ray crystallographic analysis of renin's active site to design a potent, low molecular weight renin inhibitor with improved bioavailability (approximately 2.6%). In patients with hypertension, dose-dependent BP reduction occurs with aliskiren 75-300 mg once daily; at these doses, the safety and tolerability profile is comparable to placebo. In direct comparison studies, BP reduction with aliskiren is equivalent to commonly used antihypertensive agents including diuretics, ACE inhibitors, and ARBs. Persistent BP reduction and prolonged suppression of plasma renin activity (PRA) is observed after aliskiren withdrawal. Aliskiren suppresses PRA when given either as monotherapy or in combination with other agents. When added to an ARB, aliskiren blocks compensatory RAS activation and produces significant additional BP reduction. In patients with diabetic nephropathy, addition of aliskiren to losartan, 100 mg resulted in a 20% greater reduction in proteinuria. Ongoing studies evaluating the long-term renal protective effects of aliskiren and its effects on ventricular remodeling are currently planned or underway.     

Aliskiren: a review of its use as monotherapy and as combination therapy in the management of hypertension

Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300?mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2 (mild to moderate) hypertension, alone or in combination with other antihypertensives, including HCTZ, valsartan or amlodipine.     

Clinical pharmacokinetics and pharmacodynamics of aliskiren

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1-3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47-51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7-8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion. No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability. Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12,000 patients with hypertension have demonstrated that aliskiren provides effective long-term blood pressure (BP) lowering with a good safety and tolerability profile at these doses. Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics (hydrochlorothiazide, furosemide [frusemide]), ACE inhibitors (ramipril) and angiotensin receptor blockers (valsartan), despite greater increases in the plasma renin concentration. Moreover, PRA inhibition and BP reductions persist for 2-4 weeks after stopping treatment, which is likely to be of benefit in patients with hypertension who occasionally miss a dose of medication. Preliminary data on the antiproteinuric effects of aliskiren in type 2 diabetes mellitus suggest that renoprotective effects beyond BP lowering may be possible. Further studies to evaluate the effects of aliskiren on cardiovascular outcomes and target organ protection are ongoing and will provide important new data on the role of direct renin inhibition in the management of hypertension and other cardiovascular disease.     

Safety and efficacy of aliskiren in the treatment of hypertension and associated clinical conditions

Aliskiren is the first known representative of a new class of non-peptide orally active renin inhibitors that blocks the renin-angiotensin-aldosterone-system (RAAS) at its rate-limiting step. It induces a net reduction in plasma renin activity (PRA), angiotensin II and aldosterone levels. Aliskiren is effective in reducing blood pressure (BP) and is well tolerated. The incidence of adverse events and the number of study discontinuations as a result of adverse events during aliskiren treatment were relatively low and generally not dissimilar from placebo. In placebo-controlled studies, aliskiren showed a dose-related systolic/diastolic BP lowering effect at doses between 75 and 300 mg/day. When compared to active treatments, aliskiren was generally as effective as hydrochlorothiazide, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers, in reducing BP. Aliskiren exhibits synergistic effects when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE inhibitors or ARBs. Although in clinical studies aliskiren proved to reduce proteinuria, the early termination of the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) confirms previous concerns about the full suppression of the RAAS, in this case with aliskiren combined with ACE-inhibitors or ARBs, in patients with diabetes and concomitant renal impairment. This review summarizes the available data on its safety profile and its clinical development for treatment of arterial hypertension, diabetes and nephropathy.     

Aliskiren, a novel orally effective renin inhibitor, exhibits similar pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects

AIMS: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study compared the pharmacokinetic and pharmacodynamic properties of aliskiren in Japanese and Caucasian subjects. METHODS: In this open-label, single-centre, parallel-group, single- and multiple-dose study, 19 Japanese and 19 Caucasian healthy young male subjects received a single 300-mg oral dose of aliskiren on day 1 and then aliskiren 300 mg once daily on days 4-10. Blood samples were collected for the measurement of plasma aliskiren concentration, plasma renin concentration (PRC) and plasma renin activity (PRA). RESULTS: Pharmacokinetic parameters were comparable in Japanese and Caucasian subjects following administration of a single dose of aliskiren {ratio of geometric means: C(max) 1.12 [90% confidence interval (CI) 0.88, 1.43]; AUC(0-72 h) 1.19 [90% CI 1.02, 1.39]} and at steady state [mean ratio: C(max) 1.30 (90% CI 1.00, 1.70); AUC(0-tau) 1.16 (90% CI 0.95, 1.41)]. There was no notable difference in the plasma half-life of aliskiren between Japanese and Caucasian groups (29.7 +/- 10.2 h and 32.0 +/- 6.6 h, respectively). At steady state, peak PRC level and AUC for the concentration-time plot were not significantly different between Japanese and Caucasian subjects (P = 0.64 and P = 0.80, respectively). A single oral dose of aliskiren significantly reduced PRA to a similar extent in Japanese and Caucasian subjects (by 87.5% and 85.7%, respectively, compared with baseline; P < 0.01). Aliskiren was well tolerated by both ethnic groups. CONCLUSIONS: The oral renin inhibitor aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects.     

Effect of aliskiren addition to amlodipine on ankle edema in hypertensive patients: a three-way crossover study

Objective: The aim of this study was to assess the effect of aliskiren and amlopidine on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP).

Research design and methods: After 4-week placebo, 120 outpatients with grade 1 – 2 hypertension were randomized to amlodipine 10 mg or aliskiren 300 mg or their combination for 8 weeks in three crossover periods. At the end of each treatment, blood pressure, AFV, PSTP, plasma renin activity (PRA) and norepinephrine were assessed.

Results: Both monotherapies similarly reduced systolic blood pressure (SBP; p < 0.001) and diastolic blood pressure (DBP; p < 0.001), but the reduction was greater with amlodipine/aliskiren combination (SBP: - 24.6 mmHg, p < 0.001 vs monotherapy; DBP: -20.9 mmHg, p < 0.01 vs monotherapy). Amlodipine increased both AFV (+ 28.4%, p < 0.01) and PSTP (+ 80.4%, p < 0.01), while the combination produced a less marked increase in AFV (+ 6.6%, p < 0.01 vs amlodipine) and PSTP (+ 20.1%, p < 0.01 vs amlodipine). Plasma norepinephrine increased with amlodipine (+ 53.5%, p < 0.01) and this increase was not reduced by aliskiren addition. PRA was unaffected by amlodipine, while it was reduced by both aliskiren monotherapy (- 77.7%, p < 0.01) and aliskiren/amlodipine combination (- 75.7%, p < 0.01).

Conclusions: Direct renin inhibition by aliskiren partially counteracts the microcirculatory changes responsible for calcium-channel-induced edema formation, possibly through preferential vasodilation of venous capacitance vessels.     

Aliskiren in patients with diabetes: a systematic review

Objective: Diabetic patients are at risk of macro- and micro-vascular complications, including diabetic nephropathy, and have difficulties in achieving blood pressure (BP) goals. Aliskiren, a direct renin inhibitor, inhibits the first step of the renin angiotensin aldosterone system. We aimed to systematically address the relevant evidence on the effects of aliskiren in diabetic individuals. Methods: We considered randomized controlled trials (RCTs) evaluating aliskiren in diabetic patients. Information was recorded independently by 2 investigators. We were limited to trials published in English. Results: PubMed search retrieved 16 items. After excluding 12, we ended with 4 eligible studies with 1488 participants. Mean baseline BP levels were 143/82 mmHg and median follow up was 2 months. Aliskiren was compared against angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) or aliskiren plus ACE inhibitor/ARB in 2 studies and against placebo in the other 2. The most frequent indication for aliskiren therapy was diabetes plus hypertension and albuminuria. Aliskiren seems to be effective in reducing BP levels, albuminuria in diabetics, either as monotherapy (compared with placebo), or in addition to ACE inhibitors/ARB (compared with monotherapy), without any major safety considerations. Conclusions: There are promising results on the effect of aliskiren in diabetic patients, but the available evidence is limited so far. This is a poorly investigated field with few RCTs and new studies focusing on "hard" outcomes are needed.     

Aliskiren: a review of its use in the management of hypertension

Aliskiren (Tekturna) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents.Monotherapy with aliskiren 150-300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was generally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1-3 months), the BP-lowering effect of aliskiren 150-300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5-25mg once daily and noninferior to, or significantly greater than, that of ramipril 5-10mg once daily. It was similar to that of valsartan 160-320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowering effects when combined with HCTZ 12.5-25 mg/day, ramipril 5-10 mg/day, amlodipine 5mg once daily or valsartan 160-320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-based therapies in lowering BP after 6 months, and was similarly well tolerated.The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension.     

Antihypertensive efficacy and safety of benidipine and its effects on cardiac structure and function in elderly Chinese patients with mild to moderate hypertension: an open-label, long-term study

Benidipine (CAS 91599-74-5) has been reported as an effective antihypertensive treatment and its cardioprotective effects have been shown in several basic and clinical studies. However, the long-term efficacy and safety of benidipine remain unknown in elderly Chinese patient with hypertension. In this prospective, multicenter, open-label clinical trial, 152 eligible patients aged 60 to 75 years with mild to moderate essential hypertension (sitting systolic blood pressure (BP) > or = 140 mmHg and/or sitting diastolic BP > or = 90 mmHg) entered a 52-week study. All patients initially received benidipine 2-4 mg once a day, followed by titration to benidipine 8 mg/day to achieve the target BP (< 140/90 mmHg in non-diabetics and <130/80 mmHg in diabetics). Add-on hydrochlorothiazide (CAS 58-93-5) and/or metoprolol tartaric acid (CAS 3750-58-6) were permitted during the study. Overall, 132 patients completed the 52-week treatment with benidipine as monotherapy or combination therapy. It showed that the regimen based on benidipine provided an obvious mean trough BP reduction of 13.8 +/- 12.4/8.3 +/- 9.2 mmHg (p < 0.001), and 62.5% of patients reached the target BP. In patients with left ventricular hypertrophy, the left ventricular mass index significantly decreased from 147.1 +/- 27.6 g/m2 at baseline to 136.0 +/- 17.5 g/m2 at 52 weeks (p = 0.036). Clinical adverse events (AEs) were found in 15.1% of all patients, and six patients discontinued the treatment due to drug-related AEs during the entire trial. Patients' compliance was an average of 98.7%. Benidipine, with a favorable tolerability profile, provides a long-term antihypertensive effect and potential benefit for the heart in elderly patients with mild to moderate hypertensive, suggesting that it is suitable for elderly patients with hypertension.     

新型口服抗高血压药阿利克伦的临床药理学研究进展

肾素直接抑制剂阿利克伦是一种新型、安全、有效的口服抗高血压药物,并且具有肾脏保护、减少左心窒肥厚等作用,可以单用或者与ACE抑制剂(如雷米普利)、Aug Ⅱ受体阻滞剂(如缬沙坦)和噻嗪类利尿剂等降压药物联合使用,降压作用具有剂量依赖性,病人耐受性良好.     

Efficacy and tolerability of candesartan cilexetil/hydrochlorothiazide and amlodipine in patients with poorly controlled mild-to-moderate essential hypertension.

The antihypertensive efficacy and tolerability of combination therapy with candesartan cilexetil, 16 mg plus hydrochlorothiazide (CC/HCTZ), 12.5 mg was compared with that of amlodipine, in a multicentre, double-blind, randomised, parallel-group study in patients with mild-to-moderate essential hypertension inadequately controlled by monotherapy. After a two week run-in period on existing therapy, patients with a sitting diastolic blood pressure (DBP) of 90-110 mmHg and a sitting systolic blood pressure (SBP) 相似文献   

Time course of antiproteinuric effect of aliskiren in arterial hypertension associated with type 2 diabetes and microalbuminuria

Objective: The aim was to compare the antiproteinuric effect of aliskiren and ramipril in hypertensive patients with type 2 diabetes and microalbuminuria.

Research design and methods: A total of 138 patients were treated with aliskiren 300 mg/day or ramipril 10 mg/day for 12 weeks and checked after 1, 2, 4, 8 and 12 weeks and 2 and 4 weeks after treatment withdrawal.

Main outcome measures: Clinic and ambulatory BP, urinary albumin excretion rate (UAER) and plasma aldosterone were measured.

Results: Both aliskiren and ramipril induced a similar lowering in clinic and ambulatory BP (p < 0.001 vs baseline). However, such a lowering persisted longer after stopping aliskiren than after stopping ramipril regimen. Both treatments reduced UAER, but the decrease in UAER associated with aliskiren was more pronounced, the difference vs ramipril being maximal at week 12 (?42 vs ?15%, p < 0.01). Two weeks after stopping therapy, UAER remained below baseline values with aliskiren, but not in the ramipril group. Plasma aldosterone decreased in the aliskiren group, whereas in the ramipril group it decreased until week 8 and thereafter increased toward baseline values.

Conclusions: Aliskiren has a greater and more prolonged antiproteinuric effect than R; it might partly be related to a higher degree of intrarenal renin–angiotensin–aldosterone system blockade.     

Safety and efficacy of aliskiren in the treatment of hypertension: a systematic overview

INTRODUCTION: Aliskiren is the first orally active direct renin inhibitor approved for the treatment of hypertension. Aliskiren's inhibitory effect on angiotensin I generation, through renin blockade, is highly specific and long-lasting (24 hours). This feature differentiates aliskiren from traditional antihypertensive drugs. AREAS COVERED: This paper reviews the results of various clinical trials which investigate the safety and efficacy of aliskiren on blood pressure (BP) reduction and clinical end points. EXPERT OPINION: Aliskiren is suitable for once-daily administration. Its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses. The tolerability profile of aliskiren is placebo-like at the licensed doses of 150 and 300 mg. In particular, the discontinuation of therapy due to clinical adverse events occurs similarly among patients treated with either aliskiren or placebo. Aliskiren is not recommended in association with ACE-inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and renal impairment. Pending disclosure of full results, the early termination of the ALTITUDE seems to confirm previous concerns about the safety of the dual pharmacological blockade of the renin-angiotensin system in these patients. Aliskiren is a well-tolerated antihypertensive drug that may help to achieve the recommended targets of BP control.     

Long-term safety,tolerability and efficacy of aliskiren in combination with valsartan in patients with hypertension: a 6-month interim analysis

ABSTRACT

Background: Renin–angiotensin system (RAS) blockade with ACE inhibitor and/or angiotensin receptor blocker therapy can lead to increased potassium levels, hence the need to assess dual blockade involving a direct renin inhibitor. Here we report the results of a pre-planned 6-month interim analysis of a long-term, open-label study examining the safety, tolerability and efficacy of the aliskiren/valsartan 300/320-mg combination in patients with hyper­tension.

Methods: A total of 601 patients with hyper­tension (msDBP ≥?90 and <?110?mmHg) received a combination of aliskiren/valsartan 150/160?mg for 2 weeks followed by forced titration to aliskiren/valsartan 300/320?mg once daily for a targeted duration of 52 weeks. Optional hydrochlorothiazide (HCTZ) addition was allowed from week 8 for inadequate BP control (≥?140/90?mmHg). The primary objective was to assess the safety of combination therapy; potassium elevations were a pre-defined safety outcome. BP was measured at regular intervals during the study.

Results: At the 6-month cut-off date, 512 patients (85.2%) were still ongoing with study treatment, and 192 patients had received at least one dose of HCTZ add-on during this period. Combination therapy was generally well-tolerated; the most commonly reported adverse events were headache (7.5%), dizziness (7.3%) and nasopharyngitis (7.2%). Ten patients (2.5%) receiving aliskiren/valsartan and two patients (1.0%) receiving aliskiren/valsartan/HCTZ had serum potassium elevations >?5.5?mmol/L. Only one patient (0.2%) exhibited potassium levels ≥?6.0?mmol/L during this period and the patient was treated with aliskiren/valsartan. Mean msSBP/DBP reductions of 22.3/14.4?mmHg were observed at 6-month endpoint (LOCF analysis) and 73.4% of patients achieved BP control (<?140/90?mmHg; LOCF).

Conclusions: Although lack of an active comparator group is a limitation of the study, our findings show that long-term treatment with the aliskiren/valsartan 300/320-mg combin­ation provided clinically significant BP lowering, was well-tolerated and was associated with a very low rate of potassium elevations in patients with hyper­tension.     

Pharmacokinetics and pharmacodynamics of aliskiren/hydrochlorothiazide single-pill combination tablets and free combination of aliskiren and hydrochlorothiazide

Single-pill combinations (SPCs) of complementary antihypertensive agents provide patients with a simple and effective treatment regimen. To ensure that the efficacy and safety of an SPC is the same as that for the individual drugs administered together (free combination), SPC and free-combination formulations must be shown to be bioequivalent. Three open-label, randomized studies compared the pharmacokinetics of SPC tablets of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT), at doses of 150/25, 300/12.5, and 300/25 mg, with the corresponding free combinations in healthy volunteers. Data from 2 randomized, double-blinded studies of patients with hypertension were used to assess inhibition of plasma renin activity (PRA) by the aliskiren/HCT 300/25 mg SPC and the free combination. At all dose combinations, aliskiren and HCT systemic drug exposure was similar when administered as an SPC or free combination, indicating bioequivalence. Aliskiren/HCT 300/25 mg SPC inhibited PRA to the same extent as the free combination. HCT alone increased PRA through activation of the renin-angiotensin system; aliskiren prevented this diuretic-induced increase to the same extent when administered as the free combination or as the SPC. In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination.     

Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with type 2 diabetes mellitus

BACKGROUND: The renin system is an attractive target for antihypertensive therapy in patients with diabetes mellitus. However, diabetes is associated with changes in gastrointestinal, renal and hepatic function that may affect the absorption and disposition of oral drugs. This study compared the pharmacokinetics and pharmacodynamics of the orally active direct renin inhibitor, aliskiren, in healthy volunteers and patients with type 2 diabetes. METHODS: This was an open-label study conducted in 30 patients with type 2 diabetes and 30 healthy volunteers matched for age, bodyweight and race. Following a 10-hour fast, all participants received a single oral dose of aliskiren 300mg. Blood samples were taken at frequent intervals for 96 hours post-dose for determination of plasma concentrations of aliskiren (using a high-performance liquid chromatography-tandem mass spectroscopy method). Plasma renin activity (PRA) and renin concentration (RC) were also measured for 24 hours after dosing. RESULTS: Aliskiren exhibited similar pharmacokinetics in patients with type 2 diabetes and healthy volunteers. Exposure to aliskiren was slightly higher in patients with type 2 diabetes compared with healthy volunteers (mean area under the plasma concentration-time curve from 0 to 24 hours 1859 vs 1642 ng . h/mL; maximum observed plasma drug concentration 394 vs 348 ng/mL), while apparent clearance corrected for bioavailability was slightly lower (205 vs 234 L/h) and elimination half-life slightly longer (44 vs 39.9 hours), but there were no statistically significant differences for any pharmacokinetic parameters. There was no significant correlation between glycaemic control (% glycosylated haemoglobin) and any of the measured pharmacokinetic parameters in patients with type 2 diabetes. Aliskiren caused sustained suppression of PRA for at least 24 hours after dosing despite increasing RC; there were no major differences in the pharmacodynamic effects of aliskiren between patients with type 2 diabetes and healthy volunteers. Aliskiren was well tolerated in both patient groups, with no clinically significant changes in laboratory values and a low risk of adverse events. CONCLUSION: Aliskiren showed a similar pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes, and administration of a single oral 300 mg dose of aliskiren was well tolerated by both patients and healthy volunteers. The pharmacodynamic effects of aliskiren were also similar in healthy volunteers and diabetic patients, with sustained inhibition of renin system activity observed for at least 24 hours after dosing.     

Renin inhibition with aliskiren

1. Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. 2. Aliskiren has a low bioavailability (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23-36 h), which makes it suitable for once-daily dosing. 3. The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 (AT1) receptor blockers (losartan, valsartan, irbesartan), hydrochlorothiazide, angiotensin converting enzyme inhibitors (ramipril and lisinopril) or long acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, irbesartan or ramipril. 4. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme (ACE) inhibition and Ang II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor. 5. Blockade of the renin angiotensin system (RAS) with ACE inhibitors, AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize RAS blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the RAS fully quiescent is a new possibility requiring further study.     

The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension

1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomised, crossover study in 20 patients (mean age 55.4 years; range 46-69) with uncomplicated mild to moderate hypertension (supine diastolic > 90 mmHg < 115 mmHg after 4 weeks of single-blind wash-out on placebo). The four randomised, double-blind, crossover study phases evaluated the response to 4 weeks of once daily treatment with placebo, monotherapy with each drug and the combination. Noninvasive ambulatory blood pressure monitoring (Spacelabs 90207) was performed for 24 h at the end of each phase. 2. The mean 24 h ambulatory blood pressure (mmHg) was 147.9/92.0 following placebo, 141.3/87.8 following monotherapy with ramipril 2.5 mg, 136.8/85.8 following monotherapy with felodipine ER 5 mg and 131.1/82.6 following the combination of ramipril 2.5 mg and felodipine ER 5 mg. All active treatment phases significantly reduced mean 24 h ambulatory diastolic pressure by comparison with placebo. The antihypertensive efficacy of the combination was additive. 3. The coadministration of ramipril did not attenuate the incidence of headache attributable to felodipine ER.