doi: 10.1161/CIRCULATIONAHA.108.787630
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(Circulation. 2008;118:773-784.)
© 2008 American Heart Association, Inc.
New Drugs and Technologies |
Aliskiren
From the University of Cambridge, Cambridge, UK.
Correspondence to Morris J. Brown, FMedSci, FAHA, Clinical Pharmacology Unit, Box 110, Addenbrookes Hospital, Cambridge, CB3 9AA, UK. E-mail m.j.brown{at}cai.cam.ac.uk
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Abstract |
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Top
Abstract
IntroductionAliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg, there are dose-related falls in blood pressure comparable to those seen with other major classes of antihypertensive drugs and that these falls are associated with a placebo level of side effects. Aliskiren was found to be effective either as monotherapy or in combination with drugs from the other major classes. As expected, there was a greater benefit from adding aliskiren to natriuretic drugs than to other blockers of the renin system. However, there was also some consistent benefit from dual renin blockade. Aliskiren is likely to be of most value in patients uncontrolled by, or intolerant of, other classes. Rational understanding of the renin system will maximize its value, for instance, by encouraging greater use of natriuretic agents in patients with resistant hypertension to render their hypertension renin dependent. Whether there are cardiovascular benefits other than blood pressure control in blocking the renin system remains to be demonstrated. It is hoped that long-term outcome studies with aliskiren will finally allow this question to be answered.
Key Words: aliskiren • renin • renin inhibitor
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Introduction |
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The launch of aliskiren in 2007 brought the first new class of antihypertensive drugs for 13 years, dubbed direct renin inhibitors (DRIs). The advent of a new class is an exciting event for any disease because of the possibilities not only of improved treatment but also improved understanding of the disease pathogenesis and complications. For a decade or more, the view in the pharmaceutical industry had been that the leading role of hypertension as a cause of global morbidity was more than offset by the existing number of classes, most of which would be off patent by the time any new class was developed. Although most patients do not achieve internationally agreed blood pressure targets, especially the lower targets for patients with diabetes, it was unclear whether this failure would be remedied by development of novel classes.1
The gestation of a new drug is so long and tortuous that it would be wrong to look at developments in hypertension in the last 5 years as drivers to create DRIs. However, these developments may influence the success of DRIs and other new classes. There is a gulf between the current target for treatment, 140 mm Hg (130 mm Hg in diabetes), and the threshold above which the risk of stroke and myocardial infarction starts to rise, 115 mm Hg.2,3 The National Institutes of Health has therefore approved in principle a study, the Systolic Blood Pressure Intervention Trial (SPRINT), that will compare patients treated to targets of 140 or 120 mm Hg.4 When the results become available, it is an even bet that we will be looking for further, well-tolerated classes to achieve lower pressures in most patients.
Whether the DRI is a completely new class may be challenged, given the number of drugs already used to block the renin system, particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). However, β-blockers also lower blood pressure by blocking the renin system, yet their identity as a separate class would not be challenged.5,6 Indeed, they illustrate the point that classes with related mechanisms of action may differ in their long-term net benefits because of different off-target effects. Concerns about β-blockade have surfaced very late in their lifetime, triggered by the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), in which there was a substantial difference between arms in the incidence of stroke and new-onset diabetes.7–10 Not all hypertension guidelines have yet taken the direction of National Institute for Clinical Excellence (NICE) guidelines in the United Kingdom, in which β-blockade is no longer first-line therapy for hypertension.11 However, these developments illustrate how it is possible for a newer class to become validly preferred to an apparently similar older class and how the opinion on acceptable risks—asthma and angioneurotic edema—can change when a safer alternative becomes available and affordable.
The second recent development likely to influence thinking about new classes of antihypertensives is the genome-wide scans, showing that the inherited susceptibility of common complex disorders is due to multiple low-risk alleles.12 The implications (for therapeutics) are that drugs born of improved pathogenetic understanding are likely to achieve small incremental benefits and that most patients will require multiple drugs to target the multiple factors causing hypertension. Newer drugs are more likely to be block builders than blockbusters. Although molecules may be designed with multiple molecular targets, the omapatrilat experience illustrated how such molecules also can multiply the safety risk.13
It remains possible that there is an as-yet undiscovered vasoconstrictor system more important than the renin-angiotensin system (RAS) and that drugs can be effective antihypertensive agents without targeting the causes of hypertension. However, what singles RAS out as a drug target from other vasoconstrictor systems is that it uniquely compensates for Na+ depletion. Thus, although there may be continued debate about whether inappropriate levels of renin and Na+—relative to each other—are primary causes of hypertension, effective RAS blockade is undoubtedly necessary in most patients to achieve maximum benefit from diuretic treatment. All major classes of antihypertensive either work through RAS blockade, the "A,B" classes of ACE inhibitors/angiotensin blockers (A) and β-blockers (B), or potentiate the RAS blockers by causing reflex activation of RAS, the "C,D" classes of calcium-channel blockers (C) and diuretics (D) (Figure 1).6
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The Target for Direct Renin Inhibition |
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Renin was the first hormone to be discovered, by Tigerstedt in 1898, and is unique in being secreted into the arterial circulation. This reflects the importance of blood pressure sensing and regulation among the 4 factors that control renin (Figure 2). As the rate-limiting step in the pathway leading to angiotensin (ANG) II formation but downstream of the 4 stimulatory factors, direct inhibition of renin has long seemed an attractive therapeutic target. Proof of principle was established first by use of immunization against renin,14 followed by studies with a nonspecific inhibitor, pepstatin, and finally with peptide mimics of either prorenin or of the renin substrate angiotensinogen.15,16 Several of the peptide mimics were developed as possible drugs, and the invaluable knowledge gained has already been well described in the review of renin inhibitors by Staessen et al.17 Parenteral administration of peptide inhibitors to salt-depleted subjects confirmed proof of principle as an effective mechanism of blood pressure reduction,18 and the development of tetrapeptides led to clinical investigation of orally administered compounds (enalkiren, remikiren, zankiren).19 However, these compounds had predictably low bioavailability of <2% and short half-lives. Despite having a subnanomolar IC50, the drugs failed to achieve sustained renin inhibition sufficient to deliver the blood pressure reductions necessary to prolong their survival beyond phase 2 trials.19
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Aliskiren is a nonpeptide, piperidine (Figure 3), designed by molecular modeling of transition-state analogs of angiotensinogen.20 It binds with high affinity (IC50=0.6 nmol/L) to the active site of renin. Its high molecular weight still results in a low bioavailability (2.7%). However, the absorbed aliskiren is scarcely metabolized and slowly excreted, with a consequently long half-life of 24 to 40 hours (Figure 4).21,22 Therefore, its concentration in plasma accumulates over several doses to approximately twice that after a single dose23 and, at therapeutic doses, is reported to exceed the IC50 by 15- to 50-fold.24 However, this is difficult to reconcile with a clear dose response on blood pressure and renin levels; although spare aliskiren could explain why a 60% reduction in aliskiren absorption by food does not affect efficacy, it is likely that most aliskiren (estimates of 49% to 95%) in plasma is protein bound, with free aliskiren being closer to the IC50 value.25 Nevertheless, aliskiren was administered without respect to food intake during published clinical trials, and it is reasonable to assume that interindividual variation in response to aliskiren will have more to do with RAS status than with variable absorption or metabolism of the drug. At present, therefore, the low bioavailability of aliskiren does not seem to be a disadvantage. This prediction will be open to test as other Speedel DRIs (SPP1148, 635, and 676) with structures different from each other, some with reportedly higher bioavailabilities, become available for comparison.
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Metabolism |
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Top-line quotes that <1% of an oral load is renally excreted or metabolized need to be read in the context that <3% of the oral dose is absorbed in the first place.24 But studies of intravenously administered aliskiren confirm that <10% is recovered in the urine, and most of this (
70%) is unchanged aliskiren. The main route for elimination is biliary, where once again most of the aliskiren is unchanged. The small fraction of aliskiren metabolites in plasma or urine has been identified by 3H-nuclear magnetic resonance as mainly an O-demethylated product.24 Aliskiren is poorly metabolized by cytochrome P450 (predominantly the 3A4 isoenzyme), and there is no interaction with such drugs as cimetidine, warfarin, lovastatin, celecoxib, and atenolol, covering representative substrates of 3A4, 2D6, and other common isoforms. |
Mechanism of Action |
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Having been developed to inhibit renin, it might seem superfluous to discuss the mechanism of action of aliskiren. Indeed, a neat piece of evidence that its efficacy is closely correlated to the affinity for renin comes from the preclinical program of aliskiren in various species. Renin is a highly specific protease—there are no other substrates than angiotensinogen—and highly species specific. Therefore, studies of DRIs need to be performed either in primates or in transgenic animals expressing human renin.20,26 Because traditional development of an antihypertensive includes investigation in various rat models of hypertension, aliskiren was administered to rats at doses that were able to achieve the orders-of-magnitude-higher concentration necessary to inhibit the rat renin molecule. At these doses, aliskiren had the predicted effect on blood pressure.27
However, some discussion of the action of aliskiren is of interest, partly to understand the biochemical surrogates in clinical trials and partly to address the question of whether aliskiren might achieve any different net effect on RAS than other classes of RAS blocker. As predicted from Figure 1, a DRI would be expected to reduced plasma renin activity (PRA) and ANG I and ANG II levels, and exactly these changes were observed in phase 1 or 2 studies of aliskiren compared with either an ACE inhibitor (enalapril) or an ARB (valsartan) (Figure 5).21,28 Comparison of overall efficacy of different classes in blocking RAS is more problematic because most are expected to increase PRA and ANG I as a consequence of blocking the negative feedback of ANG II on renin secretion. Although it is possible to demonstrate some reduction in plasma or urine aldosterone consequent to RAS blockade, aldosterone is not as useful a "downstream" marker of RAS blockade as might be expected.28 The reason is that K+ is as least as important a secretagogue as ANG II, and a reduction in ANG II stimulation is offset by small rises in K+ when RAS is blocked. The best, and fortunately simplest, method for estimating efficacy of RAS blockade is the measurement of renin mass, which can be regarded as a downstream marker of RAS activity because of its sensitivity to suppression by ANG II. As will become apparent later in the discussion of phase 3 data, renin mass can rise by >100-fold when RAS is multiply targeted. Indeed, no intervention has yet saturated the increase in renin mass, explaining the potential for multiple targeting in patients with high RAS activity.
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Renin Measurement |
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Renin mass, being a large molecule, is amenable to measurement by robotic double-site immunoassay and enzymatic amplification of the signal by the revealing antibody. The assay is linear over the unusual (for a hormone) 1000-fold range between low- and high-renin patients and can easily detect the additive effects of increased RAS blockade. By contrast, renin activity assays rely on both endogenous substrate and enzyme activity.6,25 They therefore plateau as substrate runs out at high renin levels. They also lack sensitivity at the lower end of the range, where there is little generation of ANG I, and detection is by competition immunoassay. These observations explain the steep increase in renin mass over the dose range of aliskiren investigated in phase 2, 150 to 600 mg, with no apparent reduction in renin activity (Figure 6).29,30
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Is the increase in renin mass consequent to RAS blockade just a useful marker, or might it attenuate, or indeed amplify, any of the benefits of RAS blockade? Because of the difficulty of measuring low levels of ANG II in the presence of high levels of ANG I during ACE inhibition, we do not know whether the efficacy of ACE inhibitions is compromised by breakthrough or bypass production of ANG II, and this is an example of a long-standing question that could now be addressed by use of the renin inhibitor. Reversely, various speculative benefits have been assigned to increased stimulation of the AT2 receptor by the elevated levels of ANG II during ARB therapy.31 In recent years, evidence has accrued for an additional mechanism by which elevated renin levels may be harmful, namely stimulation of a renin receptor on heart, cardiac, and vascular tissue, followed by activation of the mitogen-activated protein kinase pathway.32,33 To date, there is only 1 published experiment using a decoy peptide to compete with prorenin that supports a possible role of receptor activation in the target organ damage of hypertension; the conclusions have recently been challenged by contradictory findings from a similar experiment in a different model of hypertension.34,35 The renin receptor is of potential scientific interest and is a reason for welcoming a clinical tool that has divergent actions on renin mass and activity. However, on the basis of current evidence, it is not a reason for using any 1 RAS blocker in preference to another.
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Clinical Investigation |
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Phase 2
The main objectives of a phase 2 program are to establish the dose range over which efficacy and tolerability appear sufficiently high to sustain a phase 3 program. Given that all previous renin inhibitors had failed to show sufficient efficacy because of their poor bioavailability, the phase 2 data were critical to establishing whether the subnanomolar affinity of aliskiren for the renin enzyme would compensate for the low bioavailability and plasma concentration. The phase 2 program examined aliskiren over a range of doses between 75 and 600 mg compared with placebo and a number of other comparators either alone or in combination with aliskiren (Table 1).29,36–39 Blood pressure showed inconsistent efficacy of the lowest dose, 75 mg, and little benefit from increasing the dose of aliskiren to >300 mg. Adverse events were no more frequent than with placebo for doses up to 300 mg, but diarrhea was significantly more frequent at 600 mg. Therefore, phase 3 concentrated on the 150- and 300-mg doses, with most studies force-titrating from the lower to higher doses. The program suggested that as monotherapy aliskiren would have an efficacy similar to angiotensin blockers and indeed that the dose range for aliskiren was similar to that for irbesartan and valsartan. A detailed permutation of aliskiren and hydrochlorothiazide doses showed, as might be expected, that a combination of diuretic and RAS blockade is more likely to be effective than a combination of 2 RAS blockers. However, the phase 2 study of combination RAS blockade, using aliskiren and valsartan, suggested sufficient additivity for this combination to be taken forward into phase 3. Because aliskiren lost its placebo-level tolerability at the 600-mg dose with no apparent gain in efficacy, the decision on maximum dose was straightforward. Whether a higher dose would be desirable in high-renin patients and whether it will be possible without a reduction in tolerability are questions that other DRIs are required to address.
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Phase 3
A phase 3 program needs to establish the efficacy and tolerability of a drug in those patients for whom an indication will be sought from the regulator (Table 2).40–48 The much larger phase 3 program for aliskiren than for the new classes introduced in the 1980s and 1990s reflects not only the larger number of possible individual alternatives but also the progress over the years from a trial-and-error cycling through monotherapies to recognizing that hypertension is a multifactorial disease requiring combination therapy. Because aliskiren is more likely, at least initially, to be added into existing therapy than to be used for newly diagnosed patients, much of the phase 3 program has investigated its use as add-on therapy to the major classes. Indeed, aliskiren has been studied both in comparison to and in combination with each of the RAS-blocking (A,B) and volume-blocking (C,D) classes of antihypertensive drugs. Consequently, an interesting bonus from the program is information gleaned about older drugs whose use in combination was less rigorously studied during their own development.
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The data in Tables 1 and 2
were accrued from published data from 13 000 patients, representing 75% of all patients who had participated in chronic dose studies with aliskiren. In some of these studies, patients were a selected rather than all-comers cohort of hypertensive patients. Selection was either by blood pressure (eg, above target despite a previous treatment) or for a demographic criterion such as age or obesity. The overall conclusion was that aliskiren is at least as effective as the other main monotherapies in hypertension. Table 3 illustrates some of the expected variation between studies, showing clearer dose responses in some than others. Because we can assume that a true dose response exists, the observation emphasizes how difficult it is to establish differences of 2 to 3 mm Hg between drugs or regimens. (This is why, for instance, it took many years to realize that 
-blockers are less effective than other classes and why it is rarely possible to demonstrate convincing differences in efficacy between drugs of the same class.49) Only when small differences are consistent and repeated in several studies does a case build for these being true differences.
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In light of such caution, what conclusions can be drawn about the efficacy of aliskiren compared with previously available drugs? Broadly, aliskiren appears to be as effective as drugs from the older classes, whether used as monotherapy or in combination with an older class. As can be seen in Tables 1 and 2, for each ACE inhibitor, ARB, and calcium channel blocker, either the better of aliskiren and the comparator varied between studies or there was no more than 1 to 2 mm Hg between classes in individual studies. Among ARBs, both valsartan and irbesartan were compared with aliskiren, and results were similar for both drugs. However, within the ACE inhibitor class, lisinopril had an efficacy similar to aliskiren, whereas ramipril was inferior to aliskiren by >2 mm Hg in each of 2 studies. This is consistent with just the sort of impression mentioned above, never formally tested, that ramipril is not the most effective of its class, supposedly reducing systolic blood pressure by only 3 mm Hg in the Heart Outcomes Prevention Evaluation (HOPE) study.50 Hydrochlorothiazide also was inferior to aliskiren 300 mg in 2 studies, leading the European Medicines Agency label for aliskiren to describe superiority over thiazide diuretics. Strictly, what was demonstrated was slight superiority in 2 studies of aliskiren 300 mg over hydrochlorothiazide 25 mg. However, it is less likely that aliskiren, unique among antihypertensives, is superior to thiazides than that in older patients, who cluster toward the lower, Na+-retaining end of the renin spectrum, hydrochlorothiazide 25 mg is not a maximal dose of thiazide.51,52
When added to D, aliskiren was at least as effective as A or C, each at maximum dose (Figure 7), confirming the more formal combination study of aliskiren plus hydrochlorothiazide in phase 2.43 A 4-way combination study with valsartan also confirmed the potential in phase 2 for dual RAS blockade using aliskiren plus valsartan (Figure 7).45 Given that adding aliskiren to amlodipine is likely to be a common clinical scenario, more data on this combination are desirable. The addition to amlodipine 5 mg was as effective as doubling the dose of amlodipine and avoided the increase in ankle edema.41
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90 mm Hg despite treatment with HCTZ 25 mg. |
Renin Measurements and Interpretation |
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Several of the studies measured plasma renin mass and activity (Figure 6). They confirm predictions that a renin inhibitor would cause divergent changes in these 2 parameters, with the mass rising because of reduced negative feedback by ANG II and activity falling because of the occupation of aliskiren of the active cleft of the secreted renin. The results from the combination studies appear to bear out the prediction from Figure 2 that there would be net inhibition of renin activity as a consequence of aliskiren acting downstream of all mechanisms controlling renin secretion. The results also provide an interesting demonstration of the large range over which renin secretion (reflected in renin mass) can fluctuate, which may in turn explain the need in some patients for dual blockade of the RAS.
The fact that every additional step to block RAS causes another large rise in renin mass tells us that the previous blockade had not maximally inhibited ANG II production or AT1 receptor activation. The renin activity measurements on aliskiren are probably an unreliable estimate of its efficacy because, as with β-blockade, PRA is likely to be reduced in many patients below the detection limit of the assay. This explains why there is no apparent dose response for the mean values shown in Figure 6 and why mean PRA appears scarcely to rise over 1 month after discontinuation of aliskiren. Inspection of individual patient data from the high-renin patients in whom aliskiren is most likely to be of value would give a better idea of the reduction in renin activity and whether the maximum dose of 300 mg overcomes the rise in renin mass. It is possible to answer this question by inspecting the mean data when aliskiren is added to other classes. As seen in Figure 6, there is a net fall in renin activity despite the increase in renin mass on combination therapy. For the addition of aliskiren to valsartan, data are available for renin activity, ANG I, and ANG II. Because they are all markedly increased during treatment with valsartan alone (as a consequence of blocking the ANG II negative feedback), it is likely that most of the individual renin activities remained measurable after addition of aliskiren. Extrapolating and approximating from the data in Figure 6 indicate that aliskiren causes a net fall in PRA of 75% despite the increase in renin mass of almost 10-fold.
This estimate of a 75% reduction in PRA is comparable to that achieved with β-blockade and compares with the need for reductions of >90% in ACE activity by ACE inhibitors. Because the sharp drop in ACE inhibitor efficacy, once ACE inhibition falls <90%, contributes to ACE inhibitor as a class being shorter-acting than ARBs, the less demanding need for PRA inhibition probably relates to renin being at the bottleneck of the RAS pathway. It would be interesting to test the duration of action of aliskiren using serial measurements of renin mass, rather than blood pressure, as the most accurate marker of RAS blockade.
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Tolerability |
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The frequency of adverse events during the phase 2 program is shown in Table 3. At licensed doses, aliskiren appears to have placebo-level tolerability. To date, no typical side effect has emerged at the licensed doses of 150 and 300 mg, with diarrhea being the only symptom that emerged as more frequent than the placebo rate when the dose was increased to 600 mg. Because, like the ankle edema on calcium channel blockers, the diarrhea is clearly dose related and doctors pay little attention to the concept of volume of distribution, there may emerge some cases of small patients in whom diarrhea occurs at 300 mg, but most small patients can probably receive near-maximal therapeutic benefit from the 150-mg dose.
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Safety |
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In addition to the routine reporting of more serious adverse events in the phase 3 program, one of the early surrogate end-point studies, Aliskiren Observation of Heart Failure Treatment (ALOFT), had a primary safety outcome.54 ALOFT randomized 302 patients with hypertension and New York Heart Association class 2 or 3 heart failure to aliskiren 150 mg or placebo in addition to conventional treatment for heart failure. There were no significant differences between these groups in the incidence of renal dysfunction (1.9% versus 1.4%), symptomatic hypotension (3.2% versus 1.4%), or hyperkalemia (6.4% versus 4.8%). Among the secondary efficacy end points, aliskiren reduced plasma B-type natriuretic peptide by 61 versus 12.2 pg/mL in the placebo group (P<0.05). Heart failure is not itself an indication for aliskiren, but 2 mortality studies are now planned in such patients.
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Other Surrogate End-Point Studies |
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Two studies have investigated the value of adding aliskiren to losartan and illustrate the plus and minus of hypothesizing non–blood pressure benefits of RAS blockade. The Evaluation of Proteinuria in Diabetes (AVOID) trial randomized 496 patients with hypertension, type 2 diabetes, and proteinuria to placebo or aliskiren 150 mg for 3 months and force-titrated to 300 mg for another 3 months.55 Patients in both groups received losartan 100 mg plus other antihypertensive therapy as required for at least 3 months before randomization throughout the trial. Mean urinary albumin to creatinine ratio was
87 mg/mmol. This fell by 18% in the aliskiren group compared with a 2% rise on placebo, with no significant difference in blood pressure between the groups. By contrast, in the Aliskiren Left Ventricular Assessment of Hypertrophy (ALLAY) study of 391 patients with hypertension and left ventricular hypertrophy, a similar fall in systolic blood pressure between aliskiren, losartan, and their combination (–6.5, –5.5, and –6.6 mm Hg, respectively) was associated with similar regression of left ventricular mass (–5.4%, –4.7%, and –6.4%). As in AVOID, investigators were permitted free use of antihypertensive treatment; a better design and aim might have been to demonstrate that the previously observed incremental fall in blood pressure when aliskiren was added to an ARB translates into incremental regression of left ventricular mass.56 Future ultrasound studies will test the effect of aliskiren on coronary and carotid atheroma. They follow the interesting demonstration that the entire RAS is expressed in macrophages and that deletion prevents their adherence to endothelium.57
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The Place of Aliskiren in Therapy |
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More than 15 000 patients in the preregistration trials and completion of 3 surrogate end-point trials within a year of registration paint a different picture from that accompanying the launch of new classes of antihypertensive in previous decades. As already remarked, the decision to study aliskiren almost as much in combination as in monotherapy reflects current practice in hypertension and paradoxically gives us better-quality data for the efficacy of combination than has ever been available for older drugs. There is no doubt that aliskiren is an effective antihypertensive agent and that at effective doses it is well tolerated. It appears to be safe, but this statement is made with the obvious qualification for any novel drug or class that rare or long-term adverse events may take time to become apparent. The questions at this stage are whether aliskiren has so far fulfilled the hopes from this new class, what its current and future places in therapy are likely to be, and how they may be influenced by longer-term studies.
Given the quest over several decades to develop an effective renin inhibitor and overcome the problems of low bioavailability, the launch of aliskiren and the substantial body of data available at this stage are grounds for satisfaction for the developers. As monotherapy, aliskiren appears as effective as an ACE inhibitor or ARB. If there were hopes that blocking RAS at its rate-limiting step would give it superiority, these hopes have not been confirmed in comparisons with ARBs, and the range of comparator ACE inhibitors is too small to conclude any more than that ramipril is not the most effective RAS blocker. The apparent superiority of aliskiren to hydrochlorothiazide is more likely to be seen as another nail in the coffin of recommending low-dose thiazides as first-line treatment for all patients than as an early reason for choosing aliskiren over other drugs for initial treatment.
Aliskiren also is effective in combination, especially with low-dose hydrochlorothiazide and amlodipine, but in patients able to tolerate older RAS blockers, there is no reason to prefer aliskiren. Although the proportion of patients who cannot tolerate either an ACE inhibitor or an ARB is small, this group may still provide one of the larger portals for the entry for aliskiren into clinical practice simply because dual combination therapy now makes up the largest section of the hypertension market.58
In most guidelines, more on the basis of theory than evidence, standard dual combination treatment comprises 1 drug that blocks RAS and 1 that vasodilates and stimulates Na+ excretion. Dual RAS blockade has been considered less effective, with few studies showing much benefit from adding ARB to ACE inhibitors or β-blockade to either of them. It is interesting, therefore, that the aliskiren program has once again shown greater benefits for adding a RAS blocker to a non-RAS blocker than for any of the other additions or combinations reported. On the other hand, there was clearly some benefit in every study that studied the addition of aliskiren to either an ACE inhibitor or ARB. The benefit of such dual blockade is likely to be increasingly helpful once RAS has been activated by other drugs and so may have been underestimated in the trials. Ideally, a pharmacologist would like to have seen the value of doubling the dose of individual drugs alongside the data from their combination. In practice, dose escalation is limited by the maximum tolerated or licensed dose. In most patients, the phase 2 studies showed no clear benefit from increasing the dose of aliskiren to >300 mg. However, greater degrees of renin inhibition might become valuable once RAS is activated by addition of other drugs.6
In markets in which β-blockade is still a first-line option, these drugs provide another option for RAS blockade. In the United Kingdom, β-blockade was demoted from a first-choice option because of the associated increase in new-onset diabetes in LIFE and ASCOT and the heart rate–related increase in arterial wave reflection that may be responsible for the lower efficacy of the class (than comparator drugs) at preventing strokes.8,10,11 Because β-blockers also inhibit RAS at its bottleneck, aliskiren could be seen as the alternative without the off-target effects on the heart. However, there is no published comparison that tests the prediction that patients can be directly swapped from β-blockade to aliskiren without loss of control. On the other hand, step 3 in an algorithm based on only 3 first-line classes has no degrees of freedom—it has to be A+C+D—and patients with resistant hypertension are definable as those uncontrolled on triple therapy. It is in these patients that the arrival of a new class may be most useful, inevitably lacking morbidity/mortality data but with evidence of achieving further blood pressure reduction when used in combination. The evidence is clearly imperfect, and the demonstration, for instance, that aliskiren is partially additive to A was not conducted in patients also receiving C+D. However, these classes both elevate plasma renin and should in theory amplify the need for dual RAS blockade. No company likes to conduct studies of its drug as fourth line—hence the evidence desert for such patients. Yet, in the more evidence- and cost-conscious world entered by aliskiren than its ancestors, with ARBs still limited in many markets to patients who cough on an ACE inhibitor, it is likely that aliskiren will and should find its initial niche as an additional agent in patients uncontrolled on or intolerant of conventional treatment. Our own practice at step 4 is to use plasma renin as a guide because one of the "bonuses" from the reduced use of β-blockade is the ease of interpreting a low plasma renin. Although the most common reason for a low renin used to be treatment with a β-blocker, all other drugs elevate renin secretion. Dual RAS blockade is most likely to be effective in patients at the high end of the renin spectrum. A low value despite receiving A+C+D is an almost infallible indicator of Na+ retention and thus the need for further diuretic.
The most effective way to convert low-renin patients to high-renin patients is the addition of a K+-sparing diuretic (Table 4), which may explain the apparent efficacy of spironolactone in resistant hypertension by presenting more of a "target" for RAS blockade.52,59 Although no efficacy data are available to confirm the utility of adding aliskiren fifth line, the surrogate end-point studies provide a large body of safety data to reassure that even in patients with comorbidities, aliskiren can be added to multiple therapies without causing hyperkalemia or impaired renal function.
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The Future |
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Whether aliskiren and the class of DRI become major players in hypertension will depend partly on the drive for lower targets and partly on the outcome of long-term studies investigating benefits on targets that are not related to blood pressure. Reinvestigation of renin as an independent predictor of cardiovascular risk in Framingham and the lack of difference in outcome among any permutation of single or combination RAS blockade in the recent Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) requires revaluation not only of the renin hypothesis but also of how, and how far, blood pressure should be lowered in high-risk patients.60–62 A number of current and planned morbidity/mortality studies give aliskiren the opportunity to demonstrate whether dual RAS blockade is effective when the compensatory increase in renin activity is inhibited. It will be imperative that study designs take into account the lower blood pressure–lowering efficacy of RAS blockade than calcium channel blocker or diuretics in older patients to avoid the difficult posthoc interpretations of studies like Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) and ASCOT.6,63,64
These add-on trials will not provide evidence to support initial therapy with DRI. However, the failure of the RAS-blocking arm in VALUE and ASCOT ever to catch up with blood pressure in the other arm, despite eventually receiving more add-on therapy, may reinforce the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Seventh Report recommendation to consider initial combination therapy1. Perhaps monotherapy sets up compensatory renin activation or Na+ retention. The British Hypertension Society is therefore collaborating in a randomized double-dummy study, ACCELERATE (Aliskiren and the Calcium Channel Blocker Amlodipine Combination as Initial Treatment Strategy in Stage I and II Hypertension), to investigate whether blood pressure reduction on amlodipine plus aliskiren remains indefinitely lower in the patients who start the 2 drugs simultaneously than in those treated sequentially.
So, do we need new drugs for hypertension? If they help us to answer old questions, to find out whether blocking renin improves outcome, to treat refractory hypertension, and to encourage combination therapy, then new is welcome, and their own place in therapy is likely to become defined.
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Acknowledgments |
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Disclosures
Dr Brown was president of the British Hypertension Society during discussions leading to ACCELERATE and has lectured on the renin system at Novartis-sponsored meetings.
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