Aliskiren Monotherapy Does Not Cause Paradoxical Blood Pressure Rises
Meta-Analysis of Data From 8 Clinical Trials
Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics all cause reactive rises in plasma renin concentration, but particularly high levels have been reported with aliskiren. This prompted speculation that blockade of plasma renin activity with aliskiren could be overwhelmed, leading to paradoxical increases in blood pressure. This meta-analysis of data from 4877 patients from 8 randomized, double-blind, placebo- and/or active-controlled trials examined this hypothesis. The analysis focused on the incidence of paradoxical blood pressure increases above predefined thresholds, after ≥4 weeks of treatment with 300 mg of aliskiren, angiotensin receptor blockers (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, 25 mg of hydrochlorothiazide, or placebo. There were no significant differences in the frequency of increases in systolic (>10 mm Hg; P=0.30) or diastolic (>5 mm Hg; P=0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%; P<0.001). None of the 536 patients with plasma renin activity data who received 300 mg of aliskiren exhibited an increase in systolic pressure >10 mm Hg that was associated with an increase in plasma renin activity >0.1 ng/mL per hour. In conclusion, the incidence of blood pressure increases with aliskiren was similar to that during treatment with other antihypertensive drugs. Blood pressure rises on aliskiren treatment were not associated with increases in plasma renin activity. This meta-analysis found no evidence that aliskiren uniquely causes paradoxical rises in blood pressure.
- ACE inhibitor
- angiotensin receptor blocker
- direct renin inhibitor
- plasma renin activity
Aliskiren, the first direct renin inhibitor approved for the treatment of hypertension, has been shown to provide effective blood pressure (BP) reduction and to be generally well tolerated as monotherapy or in combination with other antihypertensive agents.1 Aliskiren inhibits the renin-angiotensin (Ang) system at the rate-limiting step by reducing plasma renin activity (PRA) and thereby prevents the formation of Ang I and II.2 As with other agents that reduce the formation of Ang II (Ang-converting enzyme [ACE] inhibitors) or its effects on the Ang AT1 receptor (Ang receptor blockers [ARBs]), aliskiren disrupts the negative-feedback loop by which Ang II normally suppresses renin release from the kidney and thereby stimulates a reactive rise in plasma renin concentration (PRC).3
Biomarker data from clinical studies showed an apparently larger reactive rise in PRC with aliskiren than with ACE inhibitors2 or ARBs,4 prompting speculation that the increase in renin concentration might overwhelm the inhibitory effect of aliskiren and thereby lead to paradoxical increases in PRA and, consequently, BP.5–7 Available evidence suggests that these concerns are unfounded, however, because assay artifacts contribute to at least some of the apparent increase in PRC stimulated by aliskiren8,9 and stoichiometric calculations have shown that 20- to 100-fold increases in PRC (far higher than those observed during aliskiren treatment) would be required to overcome the levels of renin inhibition seen with aliskiren.10
We report here the results of a meta-analysis of the frequency of BP rises and associated changes in PRA in 8 randomized, double-blind clinical trials in patients with hypertension in which the BP-lowering efficacy of 300 mg of aliskiren (the maximum approved therapeutic dose) was compared with that of an ACE inhibitor, ARB, diuretic, and/or placebo. In addition to determining the absolute incidences of “paradoxical” increases in BP, the relationship between BP rises and changes in PRA was examined in the subset of patients with PRA data.
Patients and Methods
To be eligible for inclusion in the meta-analysis, aliskiren studies had to have a randomized, double-blind design; include aliskiren monotherapy and a placebo and/or active comparator (ARB, ACE inhibitor, or diuretic); enroll patients with mild-to-moderate hypertension; include measurement of seated office BP; and include measurement of PRA using a validated assay. In addition, study treatments had to have been taken for ≥4 weeks at the maximum commonly used dose. Only monotherapy treatment arms were included in the meta-analysis. Studies were excluded if they had a multifactorial or nonresponder design or if they only enrolled patients in a specific subgroup (eg, age, ethnicity, or diabetes mellitus). Of 27 aliskiren clinical trials that have assessed BP changes in patients with hypertension as a primary end point, 8 met the study inclusion criteria and were evaluated in the meta-analysis.11–18 Study details are shown in Table 1. PRA was measured in only a subset of patients in studies 3 to 8. All of the studies were conducted according to the ethical principles of the Declaration of Helsinki. The study protocols and any amendments were reviewed by the independent ethics committee or institutional review board for each study center, and patients provided written consent before participating in the studies.
Patient inclusion and exclusion criteria were broadly similar across the 8 studies. Briefly, eligible patients were men and women aged ≥18 years of age (except study 1, which included patients aged 21 to 70 years) with mild-to-moderate essential hypertension (average daytime ambulatory systolic BP [SBP] ≥140 mm Hg in study 1, mean sitting [ms] diastolic BP (DBP) ≥95 mm Hg and <110 mm Hg in studies 2 to 7, and mean 24-hour ambulatory DBP ≥85 mm Hg in study 8). Major exclusion criteria included severe hypertension, history or evidence of secondary hypertension, history or evidence of severe cardiovascular or cerebrovascular disease, and any condition that might affect the absorption, distribution, metabolism, or excretion of the study drugs.
BP and Plasma Renin Activity Measurements
In study 1, sitting BP was measured in the right arm using a calibrated automated sphygmomanometer (Omron HEM-705CP). In all of the other studies, sitting BP was measured using a calibrated mercury sphygmomanometer. BP was measured after 5 minutes resting in the sitting position. Three measurements were taken at 1- to 2-minute intervals in the arm that gave the highest reading at the first study visit, and the mean value was taken as the average BP for that visit.
In studies 1 and 2, PRA was measured by antibody trapping of generated Ang I and subsequent radioimmunoassay.19 In studies 3 to 8, PRA was measured by radioimmunoassay of generated Ang I using the DiaSorin kit (DiaSorin).
BP data from the week 4 end point (study 1), week 6 end point (study 8), week 8 end point (studies 2, 4, 6, and 7), and week 12 end point (studies 3 and 5) were assessed; these reflected the end of the monotherapy period in each study. For each study, the number (percentage) of patients with SBP increases (>10 or >20 mm Hg) or DBP increases (>5 or >10 mm Hg) from baseline was determined for each treatment group.
In the subset of patients with PRA measurements, the number of patients with BP increases and PRA increases >0.1 ng/mL per hour was determined. In addition to determining the changes in BP and PRA in each individual study, an analysis of BP changes was performed for the following pooled treatment groups: placebo, 300 mg of aliskiren, high-dose ARB (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, and 25 mg of hydrochlorothiazide (HCT). In the patients with PRA measurements, the changes in msSBP/msDBP and PRA were compared according to predefined categories. BP changes were categorized as less than −20 to more than +20 mm Hg in 10-mm Hg increments for msSBP and less than −10 to more than +10 mm Hg in 5-mm Hg increments for msDBP. Changes in PRA were categorized as follows: less than −1.0; −1.0 to less than −0.1; −0.1 to less than 0; 0 to less than +0.1; +0.1 to less than +1.0; or at or more than +1.0 ng/mL per hour (chosen on the basis of the assay coefficient of variation and consideration of a clinically relevant change in PRA).
P values for between-treatment differences in the incidence of SBP or DBP increases were determined using either a 4-sample test for equality of proportion without continuity correction (pooled aliskiren versus pooled ARBs, pooled ramipril, or pooled HCT) or a 2-sample test for equality of proportion with continuity correction (pooled aliskiren versus pooled placebo).
Patient baseline characteristics for the predefined treatment groups assessed in the 8 trials included in this meta-analysis are shown in Table 2. Baseline BP and PRA measurements were generally similar across treatment groups in all of the studies, although baseline msSBP was slightly higher and msDBP slightly lower in study 1 than in the other 7 studies, and baseline PRA levels showed some variability between treatment arms in study 5.
Incidence of Paradoxical BP Increases
The frequency of BP increases after antihypertensive therapy was similar across active treatment groups in the individual studies; the frequency of BP rises was higher in the placebo groups (Table S1, available in the online Data Supplement at http://hyper.ahajournals.org). Analysis of pooled treatment groups across the 8 studies also showed a low frequency of SBP increases >10 mm Hg or DBP increases >5 mm Hg in all active treatment groups. There were no statistically significant differences among the pooled 300 mg of aliskiren, high-dose ARBs, 10 mg of ramipril, or 25 mg of HCT groups in the incidence of msSBP increases >10 mm Hg (P=0.30) and >20 mm Hg (P=0.28) or msDBP increases >5 mm Hg (P=0.65) and >10 mm Hg (P=0.50; Figure 1). Increases in msSBP and msDBP occurred significantly more frequently in the pooled placebo group than in the pooled 300 mg of aliskiren group (P<0.001; Figure 1).
Association Between BP Rises and Increases in PRA
PRA was measured in 1164 of the 4877 patients included in the overall BP analysis. None of the 536 patients with PRA data on 300 mg of aliskiren exhibited a rise in either SBP >10 mm Hg or DBP >5 mm Hg that was associated with increases in PRA >0.1 ng/mL per hour (Figures 2A and 3⇓A). The few patients who did exhibit increases in PRA >0.1 ng/mL per hour on 300 mg of aliskiren treatment still experienced BP reductions from baseline and not BP rises. As expected, in the subset of patients with PRA data in the other active treatment groups, the greater the reactive rise in PRA, the greater the decrease in BP (Figures 2B through 2D and 3B through 3D). In patients receiving placebo, there was no discernible pattern relating changes in PRA with changes in BP (Figures 2E and 3⇓E).
Our meta-analysis of aliskiren clinical trials showed that the frequency of BP increases during treatment with aliskiren at the maximum approved therapeutic dose (300 mg) was not significantly different from that observed during treatment with high-dose ARBs (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), the ACE inhibitor ramipril (10 mg), or the diuretic HCT (25 mg). Moreover, analysis of the subset of patients with PRA measurements showed that none of the 536 patients with PRA data who were receiving 300 mg of aliskiren exhibited a marked increase in SBP (>10 mm Hg) or DBP (>5 mm Hg) that was associated with a rise in PRA >0.1 ng/mL per hour. We, therefore, found no evidence that aliskiren treatment is associated with paradoxical rises in BP and PRA.
Apparent increases in BP from baseline are observed in a small proportion of patients in all of the clinical trials in hypertension. These generally do not reflect a real effect of the drug concerned, but more likely reflect inherent variability in BP measurements that may result in artifactual BP fluctuations, and difficulties in establishing baseline BP because of incomplete washout of previous antihypertensive medication (and consequent regression to the mean of artifactually low baseline BP values).20 A proper assessment of the frequency of BP increases with a particular drug must, therefore, take into account this “background” rate. Our meta-analysis aimed to provide a systematic evaluation of the frequency of BP rises during 300 mg of aliskiren treatment relative to placebo and to treatment with comparator antihypertensive classes at therapeutically equivalent doses. To avoid selection bias, we included all of the randomized, double-blind, nonmultifactorial aliskiren trials that assessed the BP-lowering effect of aliskiren relative to placebo or active comparators in patients with uncomplicated hypertension and that included assessments of PRA. These trials included 1 ACE inhibitor (10 mg of ramipril), 1 diuretic (25 mg of HCT), and 3 different ARBs, for which data were pooled across the respective maximum approved therapeutic doses (300 mg of irbesartan, 100 mg of losartan, and 320 mg of valsartan). BP rises were defined as increases in msSBP >10 or >20 mm Hg or msDBP >5 or >10 mm Hg; these thresholds were selected with the aim of capturing any true treatment-induced paradoxical rises in BP while reducing the confounding influence of smaller chance fluctuations in BP.
Each of the studies, whether considered individually or in the meta-analysis, showed that treatment with 300 mg of aliskiren was not associated with a statistically significant difference in the frequency of BP rises from baseline compared with high-dose ARBs, 10 mg of ramipril, or 25 mg of HCT at all of the predefined SBP and DBP thresholds. Strikingly, in a total of 536 patients with PRA measurements on 300 mg of aliskiren, not a single case of an SBP rise >10 mm Hg or DBP rise >5 mm Hg was associated with a rise in PRA >0.1 ng/mL per hour. Moreover, the few patients who exhibited increases in PRA >0.1 ng/mL per hour still experienced BP reductions from baseline and not increases. These results strongly suggest that the reactive rise in PRC stimulated by aliskiren is not associated with paradoxical increases in PRA or BP.
This meta-analysis of data from 8 clinical trials found no evidence that aliskiren uniquely causes paradoxical rises in BP. The frequency of BP rises with aliskiren was similar to that observed after treatment with other antihypertensive drugs and was significantly less than that with placebo. There was no association between increased BP and increased PRA in patients treated with aliskiren. Our findings indicate that aliskiren is an effective treatment option for hypertension and should finally lay to rest concerns that aliskiren may cause paradoxical BP rises in patients with hypertension.
We thank Dr Jenny Handford (Oxford PharmaGenesis Ltd) for medical writing support, editorial assistance, and collation and incorporation of comments from all of the authors.
Sources of Funding
The 8 clinical trials included in this meta-analysis were funded by either Novartis Pharmaceuticals Corporation or Speedel Pharmaceuticals. This meta-analysis and the medical writing assistance for this article were funded by Novartis Pharmaceuticals Corporation.
A.V.S. has acted as a consultant to and has received honoraria and/or research support from Novartis and Speedel. A.H.G. has acted as a consultant to and received research support and speaker fees from Novartis. R.E.S. has received research grants and consulting and speaker fees from Novartis. J.N. has acted as a consultant to Novartis and Speedel and has received research support from Novartis. R.S. and M.F.P. are employees of Novartis Pharmaceuticals Corporation and are, thus, eligible for Novartis stock and stock options.
A.V.S., A.H.G., R.E.S., and J.N. proposed performing this meta-analysis of aliskiren clinical trials data to investigate the hypothesis that aliskiren treatment causes paradoxical BP increases. A.V.S., A.H.G., R.E.S., and J.N. liaised with M.F.P. (Novartis biomarkers lead) and R.S. (Novartis statistician [modeling and simulations group]) in developing the analysis. All of the authors participated in the development and writing of the article and approved the final article for publication. The authors take full responsibility for the contents of the article.
- Received May 12, 2009.
- Revision received May 20, 2009.
- Accepted October 19, 2009.
Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am J Hypertens. 2007; 20: 587–597.
Sealey JE, Laragh JH. Aliskiren fails to lower blood pressure in patients who have either low PRA levels or whose PRA falls insufficiently or reactively rises. Am J Hypertens. 2009; 22: 112–121.
Sealey JE, Laragh JH. It is the plasma renin activity level that counts, not stoichiometry. Hypertension. 2008; 52: e20.
Nussberger J, Aubert JF, Bouzourene K, Pellegrin M, Hayoz D, Mazzolai L. Renin inhibition by aliskiren prevents atherosclerosis progression: comparison with irbesartan, atenolol, and amlodipine. Hypertension. 2008; 51: 1306–1311.
Batenburg WW, de Bruin RJ, van Gool JM, Muller DN, Bader M, Nguyen G, Danser AH. Aliskiren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2008; 28: 1151–1157.
Danser AHJ, Charney A, Feldman DL, Nussberger J, Fisher ND, Hollenberg NK. The renin rise with aliskiren: it’s simply stoichiometry. Hypertension. 2008; 51: e27–e28.
Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005; 111: 1012–1018.
Palatini P, Jung W, Shlyakhto E, Botha J, Bush C, Keefe DL. Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study. J Hum Hypertens. In press.
Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003; 42: 1137–1143.
Puig JG, Schunkert H, Taylor AA, Boye S, Jin J, Keefe DL. Evaluation of the dose-response relationship of aliskiren, a direct renin inhibitor, in an 8-week, multicenter, double-blind, randomized, parallel-group, placebo-controlled study in adult patients with stage 1 or 2 hypertension. Clin Ther. In press.
Schmieder RE, Philipp T, Guerediaga J, Gorostidi M, Smith B, Weissbach N, Maboudian M, Botha J, van Ingen H. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide. Circulation. 2009; 119: 417–425.