The renin inhibitor aliskiren (Tekturna

AJH 2007; 20:587 597 Aliskiren, the First Renin Inhibitor for Treating Hypertension: Reactive Renin Secretion May Limit Its Effectiveness Jean E. Sealey and John H. Laragh A review of six clinical trials of aliskiren involving 5,000 patients with mild to moderate hypertension indicated that this first of a new class of orally active antihypertensive drugs is no more effective than angiotensin-converting enzyme inhibitors (CEIs), angiotensin receptor blockers (ARBs), or diuretics for lowering blood pressure. The starting dose is 150 mg; 300 mg is usually more effective, but 600 mg is no better than 300 mg. Aliskiren in combination with a diuretic appeared to lower blood pressure more than an aliskiren-arb combination, but still failed to control blood pressure ( 140/ 90) in 50% of the patients. Although aliskiren suppresses plasma renin activity, it causes much greater reactive rises in plasma renin concentration than does any other antihypertensive class tested. Because aliskiren, like CEIs and ARBs, only blocks 90% to 95% of plasma renin, the pressor consequences of its greater reactive increases in plasma renin concentration appear to offset its net ability to lower blood pressure, especially with higher doses. Patients with hyperreactive renin systems (renovascular, advanced, and malignant hypertension) were excluded from all of the trials. Until the possibility is eliminated of inducing increases in blood pressure with aliskiren in patients with highly reactive renin levels, it seems safe and simple to stick to the less expensive, equally effective and widely available generic CEI drugs for treating the renin factor in hypertension. Am J Hypertens 2007;20:587 597 2007 American Journal of Hypertension, Ltd. Key Words: Aliskiren, renin inhibitor, renin, reninangiotensin, clinical trial, hypertension, renovascular hypertension, malignant hypertension, angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker, diuretic. The renin inhibitor aliskiren (Tekturna, Rasilez ) is the first of a new class of orally active antihypertensive drugs that joins at least seven other antihypertensive drug classes, most of which have lost patent protection and are available as generic drugs. The other classes include diuretics, aldosterone receptor antagonists, calcium channel blockers, alpha blockers, beta blockers, converting enzyme inhibitors (CEIs), and angiotensin receptor blockers (ARBs). Many antihypertensive drugs are also available in extended-release form or in combination with other agents, so that prescribing healthcare professionals must choose from over a hundred different formulations. Given the growing abundance of effective, generic antihypertensive drugs, it seems reasonable to ask if there is anything unique about aliskiren that could justify its use. Renin inhibitors, for which aliskiren is a prototype, comprise the fourth class of drugs to lower blood pressure by blocking the renin-angiotensin system. These four classes reduce the renal secretion of renin, interfere with the generation of angiotensin (Ang) I, reduce the rate of formation of Ang II, or interfere with the action of Ang II. 1,2 Thus, beta blockers lower the secretion rate of the enzyme renin from the kidneys by suppressing -adrenergic receptor activation of the renin secretory mechanism, causing a fall in the levels of plasma renin activity (PRA). Renin inhibitors also reduce PRA levels, but do so by binding to the renin molecule to block its catalytic activity, thereby interfering with its ability to cleave Ang I from plasma angiotensinogen. Although converting enzyme inhibitors (CEIs) increase PRA levels, they reduce renin-system activity by preventing the conversion of inactive Ang I to the active hormone, Ang II. Although angiotensin receptor blockers (ARBs) increase both PRA and plasma Ang II levels, they prevent Ang II from Received February 21, 2007. First decision March 30, 2007. Accepted April 1, 2007. From the Department of Cardiothoracic Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York. Supported by grants from the Gelb Foundation, New York, NY, the Commonwealth Foundation, New York, NY, and the Rudin Foundation, New York, NY. Potential conflicts of interest: J.E.S. and J.H.L. are consultants for Diasorin, Inc., Stillwater, MN; J.H.L. has licensed US patent 09/657,027, Method for Evaluating and Treating Hypertension, to Diasorin, Inc., Stillwater, MN; and J.E.S. is a consultant to Daiichi Sankyo, Inc., Parsippany, NJ. Address correspondence and reprint requests to Dr. Jean E. Sealey, now at 5 Sandpiper Drive, Village of Golf, FL 33436; e-mail: jsealey@med.cornell.edu 2007 by the American Journal of Hypertension, Ltd. Downloaded from Published https://academic.oup.com/ajh/article-abstract/20/5/587/139429 by Elsevier Inc. 0895-7061/07/$32.00 doi:10.1016/j.amjhyper.2007.04.001

588 REVIEW OF ALISKIREN CLINICAL TRIALS AJH May 2007 VOL. 20, NO. 5 binding to Angiotensin II (AT 1 ) receptors in the vascular walls, thereby blocking its vasoconstrictor effect on the arterioles and reducing blood pressure. Only beta blockers lower the secretion rate of renin from the kidneys to reduce its plasma concentration (PRC). In contrast, renin inhibitors, CEIs, and ARBs all induce reactive increases in renin secretion and in PRC levels because they release the renin secretory mechanism from tonic feedback suppression by the higher blood pressure and higher Ang II levels. Thus their drug-induced hypotension and the falling Ang II levels (or effect) induce the reactive rises in renin. Because these anti-renin system drugs are not 100% effective, their efficacy can be limited by reactive increases in PRC. The greater the stimulation of PRC, the more likely that Ang II formation or activity will occur. Thus, the potency of renin inhibitors, CEIs, and ARBs are all limited by the reactive rise in renin secretion. In fact, aliskiren increases the PRC more than does any other anti-renin system drug class, and this may limit its effectiveness, especially at higher doses when PRA and blood pressure fall no further as PRC levels continue to rise. In this setting, it is possible to begin to understand and assess the antihypertensive effectiveness of aliskiren compared to the other antihypertensive drug classes. In the present report, we analyzed the results of several published trials in 5,000 mildly-to-moderately hypertensive patients (diastolic pressures, 95 to 109 mm Hg) (Table 1). Three were randomized, multicenter, double-blind, -controlled, active-comparator, 8-week trials 3 5 in which trough (24 h after last dose) clinic blood pressures were analyzed. A fourth trial 6 had no comparator drug, and performed 24-h ambulatory blood pressure monitoring (ABPM) in a subset of patients. A fifth single-center comparator trial 7 used ABPM. A sixth and much smaller trial also used ABPM, and dealt largely with combination therapy. 8 The most striking and uniform finding in the multicenter trials 3 6 was a large fall in blood pressure (BP) in the groups (Table 1), especially in diastolic pressure. After subtracting this effect, the average baseline diastolic blood pressure of multicenter trial patients (147/93, 3 145/92, 4 143/90, 5 and 147/94 6 ) was below the entry criterion. This may account in part for the relatively modest net effects of aliskiren on blood pressure. This effect was blamed on regression to the mean, on the limitations of cuff BP measurements, and on carry-over effects of previous drugs, but the possible effects of cash payments to enroll patients were not considered. In the following analyses of the antihypertensive efficacy of aliskiren, the effect was subtracted from the total falls in blood pressure. Effect of Aliskiren Monotherapy on Blood Pressure Three multicenter protocols differed primarily in the doses of aliskiren and in the comparator drugs used. 3 5 Gradman et al 3 compared 150 mg of irbesartan with 150 mg, 300 mg, and 600 mg of aliskiren in 652 patients (Table 1 and Fig. 1). This trial was the only one in which aliskiren (300 and 600 mg only) caused a statistically significant greater fall in BP (diastolic only) than the comparator drug, irbesartan, that was given only at the starting dose recommended for hypertension. 9 Thus, 150 mg of aliskiren was equivalent to 150 mg of irbesartan, and 300 mg and 600 mg of aliskiren were more effective. Interestingly, there was no additional fall in BP between 300 and 600 mg, a finding similar to that of Oh et al, 6 who found no significant dose response to the same three aliskiren doses (Table 1). Villamil et al 4 compared aliskiren with the sulfonamide diuretic hydrochlorothiazide (HCTZ) in 2776 patients. Systolic and diastolic pressure fell more than with for 150 and 300 mg aliskiren and with 6.25, 12.5, and 25 mg HCTZ; 75 mg of aliskiren lowered diastolic BP (DBP) but not systolic BP (SBP) more than did a (Table 1, Fig. 1). Aliskiren was not more efficacious than the diuretic. Although the differences were not significant, the absolute falls in SBP and DBP exhibited a dose response with aliskiren. Forty-six percent of the group were responders (DBP, 90 mm Hg, or a 10 mm Hg fall). After the subtraction of this effect, only a third of the patients treated with the highest dose of aliskiren (300 mg), at best, could be considered as responders (Table 1). Thus, Villamil et al 4 showed that aliskiren is an active antihypertensive agent, no better than an inexpensive diuretic. Pool et al 5 compared the BP response to 75, 150, and 300 of mg aliskiren with that of 80, 160, and 320 mg of valsartan, another ARB, in 1123 patients (Table 1 and Fig. 1). A statistical analysis was performed after correction. Only the 300-mg dose of aliskiren caused significant falls in trough clinic BPs (systolic and diastolic), and the BP response to valsartan was not significantly different from that of aliskiren. After correction, 38% responded to the highest aliskiren dose, and 19% had their BP controlled. The authors reported a statistically significant dose relationship for the effect of aliskiren on mean seated SBPs and DBPs, although the absolute changes in BP were small (Fig. 1). The results of this trial showed that 300 mg of aliskiren lowered BP better than, and that aliskiren was not a more efficacious antihypertensive agent than the ARB valsartan. The 4-week, single-center trial of aliskiren monotherapy by Stanton et al 7 used ABPM, and compared 37.5, 75, 150, and 300 mg aliskiren with 100 mg of a third ARB, losartan (Table 1, Fig. 2). Although there was no control, the lack of any BP response to 37.5 mg suggests that there was no effect. The three higher doses of aliskiren were effective, but even the highest dose (300 mg) was no better than 100 mg of losartan in lowering daytime BP. There was a significant dose-dependent decrease in the primary endpoint, ie, the change in daytime ambulatory SBP. In a much smaller trial, O Brien et al 8 used ABPM to evaluate the effect of 150 mg of aliskiren in

Table 1. Reference Gradman et al 3 Summary of blood pressure data (mm Hg) from five trials of aliskiren monotherapy* Treatment (mg) Trough clinic BP Pre Post (est) SBP trough clinic DBP trough clinic SBP DBP Responders Responders BP controlled 8 weeks Placebo 152/99 147/93 5.3 6.3 21% Aliskiren 150 151/99 140/90 11.4 9.3 6.1 3.0 38% Aliskiren 300 152/99 136/87 15.8 11.8 10.5 5.5 50% Aliskiren 600 153/99 137/87 15.7 11.5 10.4 5.2 46% Irbesartan 150 153/99 140/90 12.5 8.9 7.2 2.6 34% BP controlled Villamil 8 weeks (est) et al 4 Placebo 153/99 145/92 7.5 6.9 46% 28% Aliskiren 75 153/99 145/90 9.4 8.7 1.9 1.8 52% 11% Aliskiren 150 153/99 141/90 12.2 8.9 4.7 2.0 52% 11% Aliskiren 300 154/99 138/89 15.7 10.3 8.2 3.4 64% 33% 47% 26% HCTZ 6.25 153/99 142/90 11.0 9.1 3.5 2.2 54% 15% HCTZ 12.5 153/99 139/89 13.9 10.1 6.4 3.2 61% 28% HCTZ 25 155/99 141/90 14.3 9.4 6.8 2.5 59% 24% Pool et al 5 8 weeks (est) Placebo 153/99 143/90 10.0 8.6 48% 28% Aliskiren 75 153/99 141/69 12.1 10.3 2.1 1.7 60% 23% 36% 11% Aliskiren 150 154/99 142/69 12.1 10.3 2.1 1.7 59% 21% 31% 4% Aliskiren 300 153/99 138/87 15.0 12.3 5.0 3.7 68% 38% 42% 19% Valsartan 80 152/99 141/88 11.2 10.5 1.2 1.9 55% 13% 38% 14% Valsartan 160 155/99 139/88 15.5 11.0 5.5 2.4 66% 35% 47% 26% Valsartan 320 153/99 136/88 16.5 11.3 6.5 2.7 63% 29% 42% 19% Oh et al 6 Stanton et al 7 8 weeks Placebo 151/99 147/94 3.8 4.9 Aliskiren 150 152/100 139/90 13.0 10.3 9.2 5.4 Aliskiren 300 153/100 138/89 14.7 11.1 10.9 6.2 Aliskiren 600 152/99 136/86 15.8 12.5 12.0 7.6 4 Weeks Ambulatory Blood Pressure Monitoring (ABPM) Pre day Post day (est) SBP day (est) DBP day (est) No Aliskiren 37.5 154/93 154/92 0.5 0.5 Aliskiren 75 154/95 149/92 5.5 3.0 Aliskiren 150 156/97 148/92 8.0 4.5 Aliskiren 300 153/94 142/87 11.0 7.0 Losartan 100 153/91 142/95 11.0 5.5 ABPM ambulatory blood pressure monitoring; Bold statistically significant v ; BP blood pressure; DBP diastolic blood pressure; HCTZ hydrochlorothiazide; Italics significant v comparator drug; SBP systolic blood pressure. * Estimated (est) data were extracted from figures or were derived from other data in the report. AJH May 2007 VOL. 20, NO. 5 REVIEW OF ALISKIREN CLINICAL TRIALS 589

590 REVIEW OF ALISKIREN CLINICAL TRIALS AJH May 2007 VOL. 20, NO. 5 FIG. 1. Changes ( ) in trough clinic systolic blood pressure (stippled bars) and diastolic blood pressure (hatched bars) during monotherapy. Data from the group are all relative to baseline; other data are presented after subtraction of change in blood pressure in the group. Redrawn from the reports of Gradman et al, 3 Villamil et al, 4 and Pool et al. 5 A aliskiren; Irb irbesartan; H hydrochlorothiazide; V valsartan. See Table 1 for statistical significances. 23 patients with mild-to-moderate systolic hypertension (140 to 180 mm Hg). Only 6 of 23 (26%) of patients had their BP controlled to 135/85. When considered as a group, these monotherapy trials showed that 150, 300, and 600 mg of aliskiren lower trough BP, that 600 mg is not better than 300 mg, that the FIG. 2. Changes in daytime (9 AM to 9 PM) systolic blood pressure (stippled bars) and diastolic blood pressure (hatched bars) measured by ambulatory blood pressure monitoring during monotherapy. Redrawn from Stanton et al. 7 A aliskiren; L losartan.

AJH May 2007 VOL. 20, NO. 5 REVIEW OF ALISKIREN CLINICAL TRIALS 591 dose response to aliskiren is quite variable, and that aliskiren per se is not a more effective antihypertensive drug than an ARB or a diuretic. Aliskiren in Combination With a Diuretic, an ARB, or a CEI Three trials 4,5,8 investigated the BP-lowering effects of aliskiren in combination with a diuretic, an ARB, or a CEI (Table 2). Villamil et al 4 added three different doses of HCTZ to either 75 or 150 mg of aliskiren (Fig. 3), and found that adding a diuretic to aliskiren improved the BP response in a dose-dependent manner, and increased the proportion of responders. Nonetheless, 43% of patients remained unresponsive to the highest dose combination of aliskiren/hctz (300/25 mg) (Table 2). Pool et al 5 tested three combinations of aliskiren and valsartan (75/80 mg, 150/160 mg, and 300/320 mg), as well as HCTZ with valsartan (12.5/160 mg) (Table 2 and Fig. 3). The BP reductions were numerically greater than for the respective component monotherapies, but the differences were small and generally not statistically significant. The highest dose aliskiren-and-arb combination was no more effective than an intermediate-dose diureticand-arb combination. Again, almost 50% remained unresponsive, and only 31% were controlled with the highest dose combination of aliskiren/valsartan (300/320 mg). O Brien et al 8 used ABPM to compare the effects of adding 75 mg and then 150 mg aliskiren to a CEI (5 mg of ramipril) or an ARB (150 mg of irbesartan) (Table 2 and Fig. 4). Patients were force-titrated every 3 weeks. They found added benefit in daytime and nighttime BP when aliskiren was added to the CEI, but only in nighttime BP with the ARB, perhaps because the ARB lowered BP more when given alone (Fig. 4). When O Brien et al 8 analyzed the combination of aliskiren with a diuretic in 23 patients, they used a different protocol. They found that 150 mg of aliskiren monotherapy for 3 weeks normalized daytime ambulatory BP ( 135/85) in six patients (Table 2 and Fig. 4). When 25 mg of HCTZ were added in the remaining 17 patients, the fall in BP was significantly greater. They did not report on the number of patients who were controlled or who responded to the combination. The authors concluded that BP control is improved when aliskiren is combined with an ACE, an ARB, or a diuretic. However, the combination with a diuretic appeared to produce the greatest falls in blood pressure (Fig. 4). In conclusion, when combined with an ACE, an ARB, or a diuretic, aliskiren usually lowered BP more than with monotherapy. Although direct comparisons were not made, aliskiren appeared to be more efficacious in combination with a diuretic than with an ACE or an ARB. But even with combination therapy, BP rarely fell to 140/90 in more than a third of the patients, and 50% of patients could be considered responders after the effect was taken into account. Effects of Aliskiren on Plasma Renin The plasma renin data provide clues as to why aliskiren given alone may be no better than CEIs or ARBs, why 600 mg were no more effective than 300 mg in controlling BP, and why only 50% of hypertensive patients, at best, responded with a significant fall in BP even when aliskiren was given in combination with other drug classes. Before reviewing the renin data, various renin terms need some clarification: Plasma renin concentration (PRC) 4 (reported as either U/mL 4 or pg/ml 10,11 ) measures the actual concentration of renin in plasma, and not its activity. In the presence of a renin inhibitor, PRC measures both unbound renin and renin bound to aliskiren. Thus, PRC quantifies the reactive rise in plasma renin induced by aliskiren, or by CEIs or ARBs (Table 3). In two reports, PRC was referred to as active renin concentration (ARC 10,11 ), but that term is misleading because PRC is mostly inactive in the presence of a renin inhibitor. Plasma renin activity (PRA) 4,5,8,10,11 (reported as ng Ang I/mL/h) measures the actual activity of the renin-angiotensin system in the circulation, because it integrates the effects of changes in renin concentration and plasma angiotensinogen levels. Because the modifying effect of angiotensinogen is rarely important, this assay usually reflects changes in PRC. However, during aliskiren treatment, PRA assays measure only the active renin moiety, and not its concentration. Moreover, PRA quantifies the degree of suppression of renin activity by aliskiren, integrating the suppressive effect of enzyme blockade and the reactive rise in renin. PRA:PRC ratio: Unlike PRA, the PRA:PRC ratio measures the in vivo inhibitory effect of aliskiren on renin. The PRA:PRC ratio is not affected by the reactive rise in renin and that explains why the degree of renin inhibition (i.e. the fall in the PRA:PRC ratio) is greater than the fall in PRA (Table 3). Thus, the ratio indicated that 600 mg aliskiren blocked more than 90% of circulating renin, yet PRA fell by only 75%. The PRA/PRC relationship is very stable. Thus, although the PRA and PRC both increased with the ARB irbesartan, they increased proportionally so that the PRA/PRC ratio was unchanged (Table 3). During treatment with ARBs, BP does not increase as PRA and PRC rise, because the Ang II that is formed is blocked at the level of the receptor. PRA or PRC: During renin inhibition, PRC can be used to monitor the time course and evaluate the dose response curve to the drug. With either CEIs or ARBs, PRA can also be used for the same purpose. These three types of renin system blockers all induce reactive increases in PRC, and such changes in renin are a more accurate way of assessing the drugs activity than is BP. For example, in the trial by Gradman et al 3 (Table 3), BP failed to fall further when aliskiren was increased from 300 to 600 mg, yet PRC increased from 21 to 34.9

Table 2. Summary of blood pressure data (mm Hg) from three trials of aliskiren combination therapy* SBP clinic trough DBP clinic trough SBP DBP Responders Treatment (mg) Responders Villamil et al 4 8 weeks Placebo 46% A75 HCTZ 6.25 14.3 10.8 6.8 3.9 62% 29% A75 HCTZ 12.5 15.6 11.1 8.1 4.2 64% 33% A75 HCTZ 25 17.3 11.5 9.8 4.6 70% 44% A 150 HCTZ 6.25 15.3 10.4 7.8 3.5 58% 22% A 150 HCTZ 12.5 17.6 11.9 10.1 5.0 70% 44% A 150 HCTZ 25 19.5 12.7 12 5.8 71% 46% A 300 HCTZ 12.5 19.8 13.9 12.3 7.0 81% 65% A 300 HCTZ 25 21.2 14.3 13.7 7.4 77% 57% BP controlled BP controlled Pool et al 5 8 weeks Placebo 48% 28% A75V80 15.0 12.0 4.0 3.0 75% 52% 43% 21% A 150 V 160 17.0 12.0 7.0 3.0 67% 37% 37% 13% A 300 V 320 18.0 13.0 8.0 4.0 75% 52% 50% 31% V160/HCTZ 19.0 14.0 9.0 5.0 79% 60% 55% 38% OʼBrien et al 8 Cumulative SBP (est) day Ambulatory blood pressure monitoring Cumulative DBP (est) day Cumulative SBP (est) night Cumulative DBP (est) night A 150 6 wk then 10 6 8 5 A 150 HCTZ 25 3 wk 18 10 15 7 Ramipril5 3 wk then 7 6 2 1 R75 A75 3 wk then 11 8 8 5 R75 A1503wk 14 9 9 5 Irbesartan 150 3 wk then 12 7 9 4 I 150 A 75 3 wk then 14 8 16 8 I 150 A1503wk 13 7 13 7 Bold statistically significant v ; Italics significant v aliskiren monotherapy (Table 1); BP blood pressure; DBP diastolic blood pressure; HCTZ hydrochlorothiazide; I irbesartan; R ramipril; SBP systolic blood pressure; V valsartan. Numerals next to drug name mg/day. * Estimated (est) data were extracted from figures or were derived from other data in the report. In this limb of the trial, only nonresponders were given HCTZ. 592 REVIEW OF ALISKIREN CLINICAL TRIALS AJH May 2007 VOL. 20, NO. 5

AJH May 2007 VOL. 20, NO. 5 REVIEW OF ALISKIREN CLINICAL TRIALS 593 FIG. 3. Changes ( ) in trough clinic systolic blood pressure (SBP) (stippled bars) and diastolic blood pressure (DBP) (hatched bars) during combination therapy. Data from the group are all relative to baseline; other data are presented after subtraction of change in blood pressure in the group. Redrawn from the reports of Villamil et al 4 and Pool et al. 5 A aliskiren; ARB angiotensin receptor blocker; H and HCTZ hydrochlorothiazide; V valsartan. pg/ml (PRC data reported by Nussberger et al 10 ), showing that the degree of renin system blockade had increased with the higher dose, even though BP did not fall further. The reason that BP is not a good way of assessing whether an anti-renin system drug is actually blocking renin is that the reactive rise in renin always counteracts FIG. 4. Changes in daytime (9 AM to 9 PM) systolic blood pressure (SBP) (stippled bars) and diastolic blood pressure (DBP) (hatched bars) measured by ambulatory blood pressure monitoring during combination monotherapy. Redrawn from OʼBrien et al. 8 A aliskiren; H and HCTZ hydrochlorothiazide; R ramipril; I irbesartan; CEI converting enzyme inhibitor; ARB angiotensin receptor blocker.

594 REVIEW OF ALISKIREN CLINICAL TRIALS AJH May 2007 VOL. 20, NO. 5 Table 3. Reactive renin increases counteract falls in plasma renin activity and blood pressure PRC pg/ml PRA (ng/ml/h) SBP* (mm Hg) PRA PRC PRA/PRC** Oh et al 6 Placebo n.a. n.a. 0.0 0% 0% 100% A 150 n.a. n.a. 11.4 80% 52% 13% A 300 n.a. n.a. 10.5 79% 102% 10% A 600 n.a. n.a. 11.7 75% 239% 8% Gradman et al 3 and Nussberger et al 10 Placebo 5.6 0.64 0.0 11% 10% 100% A 150 15.3 0.2 6.1 70% 155% 11% A 300 21 0.17 10.5 71% 244% 7% A 600 34.9 0.16 10.4 75% 503% 4% Irb 150 11.3 1.33 7.2 108% 105% 103% A aliskiren (in mg); Irb irbesartan (in mg); n.a. raw data not available in report; PRA plasma renin activity; PRC plasma renin concentration; SBP systolic blood pressure. *Ohetal 6 studied ambulatory blood pressure. Gradman et al 3 and Nussberger et al 10 studied trough clinic blood pressure. ** PRA/PRC ratio during treatment. Data were normalized relative to. the fall in BP to some degree. A quick calculation shows that if plasma renin is blocked by 90%, the effective PRA of a patient with a baseline renin of 10 ng/ml/h would fall to 1 ng/ml/h. However, if the PRC increased to 50 ng/ml/h at the same time, the PRA level would only fall to 5 ng/ml/h, and if PRC increased to 100 ng/ml/h, the PRA level would not change at all, and BP would not fall. The consequences of a reactive rise in renin on BP can be seen in Fig. 1 of O Brien et al 8 (in supplemental online figures). Although adding a diuretic to aliskiren augmented the BP fall in 12 of 14 patients, BP fell least in those with the greatest reactive rise in renin (r 0.49, P.06). Effect of Aliskiren on PRC Aliskiren induced greater increases in renin secretion than did ARBs or a diuretic (Fig. 5 and Table 3). Nussberger et al 10 (their patients were part of the study of Gradman et al 3 ) reported 155%, 244%, and 501% increases in PRC with 150, 300, and 600 mg of aliskiren, respectively, compared to only a 105% increase with 150 mg of irbesartan (Fig. 5). FIG. 5. Delta percent changes in plasma renin concentration during aliskiren monotherapy, or aliskiren in combination with a diuretic or an ARB. HCTZ hydrochlorothiazide. Redrawn from the reports of Nussberger et al, 10 Villamil et al, 4 and Azizi et al. 11 Numerals next to drug name mg/day.

AJH May 2007 VOL. 20, NO. 5 REVIEW OF ALISKIREN CLINICAL TRIALS 595 4 Similarly, Villamil et alreported a 348% increase in PRC Aliskiren dramatically suppresses PRA (and thus with 300 mg of aliskiren, compared with only a 108% plasma Ang II levels) by about 75% 6,7,10 (Table 3). In increase with 25 mg of HCTZ. contrast, ARBs increase PRA by about 100%. Despite this The combination of aliskiren with a diuretic, or with anrise, ARBs were just as efficacious on BP as aliskiren (Fig. 2), ARB during dietary sodium depletion, induced even greaterbecause the ARB interferes with the effect of Ang II at the reactive rises in renin. Thus, the PRC increased by 1211% level of its vascular wall receptor. 4 when aliskiren was combined with HCTZ, which was much Diuretics and sodium depletion increase PRA levels, greater than the sum of the increases when aliskiren or HCTZ but less so in the presence of aliskiren. Villamil et al 4 were given alone Fig. ( 5). Moreover, in 12 mildly sodiumdepleted normal subjects, Azizi et al(fig. 5) measured a neutralized the compensatory rise in PRA induced by a made much of the fact that renin inhibition with aliskiren 11 huge 1308% increase in plasma renin concentration 24 hdiuretic. For reasons discussed above, the PRA data of after a single 300-mg dose of aliskiren, compared to Villamil a et al 4 need to be confirmed using a different 466% increase with 160 mg of valsartan. In combination, method that is clearly not rendered inaccurate by the lower doses of aliskiren and valsartan increased PRC bypresence of the inhibitor. O Brien et al 8 found that 150 mg 1077%. Altogether, these data consistently show that of aliskiren alone suppressed PRA by 65%, and by 43% in aliskiren increases renin secretion considerably more than combination with a diuretic. During mild sodium depletion do any other types of renin system-blocking drugs, andin normal subjects, Azizi et al 11 measured only a 39% fall that extraordinarily high increases occur when aliskiren isin PRA with aliskiren, whereas 160 mg of valsartan increased PRA by 214%. When aliskiren and valsartan were combined with dietary or drug-induced sodium depletion. Moreover, all of these increases were measured 24 h after combined, the PRA was 50% above baseline. Thus, the drug was given. The greatest increases in renin occurred about 4 h after administration of the drug. aliskiren does not prevent PRA from increasing under all 11 circumstances. This increase depends on the degree of the These larger rises in PRC induced by aliskiren were reactive rise in renin. quite unexpected. Clearly it is not because aliskiren is a more effective antihypertensive agent. It is possible thatconsequences of the Reactive Rise aliskiren interfered with the clearance of renin, but that in PRC would normally cause renin secretion to feed back to appropriate levels. Alternatively, aliskiren may have induced a greater blockade of Ang II feedback. In an ab- 300, and 600 mg of aliskiren suggest that the greater The PRA, PRC, and BP data from trials 3,6,10 that used 150, 12 stract, Feldman et al reported extensive autoradiographic reactive rise in renin induced by 600 mg of aliskiren may localization of aliskiren in the kidneys, ie, in renal glomeruli, renal arteries, and capillaries, but not in renalnor BP fell more with 600 mg than with 300 mg of limit its antihypertensive efficacy (Table 3). Neither PRA tubules. Prorenin is synthesized in approximately two mil-aliskirenlion juxtaglomerular apparatuses (JGAs) in the two kid-creases in the blockade of circulating renin. The yet the PRA:PRC ratios indicated further in- PRA neys, where it is processed to renin and then secreted into failed to fall because the PRC increased too much. It the circulation. 13 It is possible that this widespread renal seems reasonable to assume that BP failed to fall for the distribution of aliskiren might have caused greater feedback inhibition of renin secretion, and thereby induced designed to block the activity of the renin system. same reason, considering that the drug in question was excessive renin secretion. Further studies are needed to address this question. Effect of Aliskiren on PRA The PRA assay is not always accurate in the presence of a renin inhibitor. 14 The antibody-trapping method measures PRA accurately, 7,8,10 but the assay used by Villamil et al 4 and Oh et al 6 may be suspect in the presence of aliskiren, because certain reagents used in the assay may change the equilibrium between renin and aliskiren. Also, the assay may not have had sufficient sensitivity to measure accurately the very low PRA levels during treatment with aliskiren, especially if the assay was not modified to extend the Ang I generation time to 18 h. 15 This may explain in part why Villamil et al, 4 in contrast to O Brien et al, 8 observed no stimulatory effect of HCTZ on PRA during treatment with aliskiren. Can Certain Anti-Renin System Drugs Actually Increase BP When Given to Patients Who Have Hyperreactive Renin Systems? It may seem reasonable to assume that there is no risk from the aliskiren-induced larger increases in renin secretion and resulting higher plasma renin levels, because PRA levels fall as renin is blocked in the circulation. The lack of important adverse events during trials seems to support this contention. But we do not know what happened in individual patients. In some of them, BP may have actually increased. In the only study of aliskiren that reported the number of patients with poor BP control, 5 there were five unsatisfactory therapeutic effects in the group, 10 with 75 mg of aliskiren, four with 150 mg of aliskiren, four with 300 mg of aliskiren, and two with 80

596 REVIEW OF ALISKIREN CLINICAL TRIALS AJH May 2007 VOL. 20, NO. 5 mg of valsartan. However, we were not told if BP actually increased in some patients. This is an important question. Various antihypertensive agents are known to increase BP in particular susceptible situations. Propranolol can be pressor in patients with low renin, 16 most likely because the unopposed alpha tone cannot be offset by a concurrent fall in already drug-suppressed PRA. Diuretics or a low salt diet can increase BP in patients with renovascular 17 or even essential hypertension, 18 because sodium chloride depletion drives up renin secretion. To our knowledge, a rise in BP has never been reported for patients taking CEIs or orally active ARBs, but it is clear that reactive increases in renin secretion do offset the induced fall in BP. Thus, the captopril test 19 for identifying patients with renovascular hypertension is based on the fact that captopril induces greater increases in plasma renin in patients with renovascular hypertension than in patients with essential hypertension, but BP responses cannot be used as a surrogate for changes in plasma renin in the captopril test, because BP falls only transiently in those with the greatest reactive rise in plasma renin. 19 Patients with renovascular hypertension are not alone in having a hyperreactive renin secretory response to renin system blockade. Patients with advanced or malignant hypertension also exhibit hyperreactivity. 19 Thus the very patients who were excluded from the aliskiren trials are the ones most likely to have the largest increases in renin secretion. Because aliskiren induces even larger reactive increases in renin than do CEIs and ARBs, the possibility that BP might actually increase above baseline with aliskiren in certain susceptible patients cannot be ruled out, especially when aliskiren is combined with a diuretic, and especially during the hours immediately after taking the drug, when blood levels of aliskiren and PRC peak. To define the values or risks of aliskiren under controlled conditions, patients with renovascular, advanced, and malignant hypertension should be studied carefully with aliskiren monotherapy and in combination with other drugs. Such studies could lead to a new level of understanding for applying the anti-renin system and other antihypertensive drugs, alone and in combination, across the spectrum of hypertensive disorders. Upon review of these initial studies, it seems reasonable to assume that the relatively weak antihypertensive effects of aliskiren probably result from its inducing prompt and large reactive rises in renin secretion, far greater in degree than we have observed with any other antihypertensive drugs. The agenda for the immediate future is to define the nature of the reactive renal renin release, and develop means for its control, exploitation, or elimination. Conclusion Based on our review of clinical trials involving 5,000 patients with hypertension, aliskiren, the first renin-inhibitor drug to be given orally to hypertensive patients, was shown to be no more effective as an antihypertensive agent than are CEIs, ARBs, or diuretics, and aliskiren has a limited antihypertensive dose response curve. Although aliskiren lowered BP more in combination with a CEI, an ARB, or a diuretic, BP was never controlled in 50% of patients. The reasons for the limited potency of aliskiren, for its aborted dose response curve, and for its limited effectiveness in combination with a CEI or an ARB can all be ascribed to aliskiren s unexpectedly strong stimulation of kidney renin secretion. Thus, PRCs increased twice as much with aliskiren as they did with a CEI or an ARB. Since none of these anti-renin system drugs block 100% of the circulating renin, their potency is always counteracted to some degree by concurrent reactive rises in renin. This renin reactivity was proportionally increased by higher doses of aliskiren, by adding another anti-renin system drug, or by adding a diuretic. In fact, in combination with a diuretic, the renin rise was greater than the sum of the individual responses. Nonetheless, the aliskiren-and-diuretic combination reduced BP more than did the aliskiren-and-cei or aliskiren-and-arb combinations, because the diuretics at the same time reduced the sodium-volume support of BP, rather than attacking the same renin-mediated support of BP as do CEIs or ARBs. Still, it appears that these greater reactive renin responses took their toll across the board, so that less than half of the patients had their BP controlled ( 140/90), even by the aliskiren-and-diuretic combination. While aliskiren may be a clinically useful anti-renin system drug in patients who have side effects to converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers, aliskiren s pervasive stimulation of varying degrees of reactive renin secretion could be a problem in particular for those hypertensive patients who already have hyperreactive renin systems, such as patients with renovascular, advanced, or malignant hypertension. Their reactive renin responses could be so great as to induce a rise in BP. However, to date, all of the reported trials were performed only in patients with mild-to-moderate hypertension. Before aliskiren is used in the general hypertensive population, patients with hyperreactive renin systems should be evaluated systematically to ensure that their BP does not increase, instead of falling, when taking the drug. Is there a place for aliskiren among the drugs that are already available for the treatment of hypertension? It is still hard to tell. 20 The results of these trials are very disappointing. It was certainly not anticipated that aliskiren would stimulate kidney renin secretion more than the other anti-renin system drugs. Given this reaction, its best partner in combination therapy may be a beta blocker, 21 23 because beta blockers were already shown to reduce the reactive rise in renin induced by captopril. 24 On the other hand, it seems odd that the first trials of a new drug that specifically blocks the renin system were performed without excluding patients with suppressed plasma renin levels. No doubt the poor or absent responses of patients with low renin contributed to making the drug

AJH May 2007 VOL. 20, NO. 5 REVIEW OF ALISKIREN CLINICAL TRIALS 597 look weak. It would have been more appropriate and more informative to test aliskiren first, and carefully, in those patients in whom plasma renin was known to be contributing to hypertension. But on a larger stage, the primary strategy of designing studies which fail to acknowledge the existence of two different forms of long-term hypertension, one salt volume-mediated (V) and the other renin-mediated (R), and the fact that patients with low renin do not respond to anti-renin system drugs, surely work against the goals of the pharmaceutical industry to develop more effective new drugs for hypertension. Thus, little or no progress can be expected without recognizing that two types of hypertension exist and must be targeted differently for primary drug therapy, giving natriuretic antivolume drugs to low renin hypertension, and antirenin drugs to patients with the renin types of hypertension, because this strategy corrects 60% to 85% of hypertensive patients using only one drug. 2 However, it seems that until the possibility is eliminated of inducing adverse increases in BP with aliskiren in certain individual patients, it would be safest and simplest to stick to the less expensive generic drugs that are widely available and broadly effective, especially when properly targeted for the salt-volume or the renin dependent patients. References 1. 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