Abstract
Suppressed baseline plasma renin activity (PRA) levels or large reactive increases in renin secretion are two possible reasons for treatment failure with antirenin system drugs.
To investigate their prevalence we reanalyzed data from three published clinical trials of the renin inhibitor aliskiren.
Aliskiren failed to lower systolic blood pressure (SBP) by at least 10 mm Hg in half of all patients. It was very effective in two-thirds of medium- to high-renin patients (‐19 mm Hg). But BP did not fall in most low-renin patients, or in 30% of medium- to high-renin patients. BP actually rose by >10 mm Hg in 5% of patients taking aliskiren and in >10% of patients when aliskiren was added to an angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEI). PRA changed in parallel with BP. Although PRA fell in most patients, it actually rose in 5% and in up to 30% when aliskiren was added to an ARB or ACEI.
There are two reasons for treatment failure with aliskiren. Many hypertensive patients have large BP falls. But, BP does not fall in most low-renin patients or in medium- to high-renin patients whose PRA levels do not fall sufficiently. If the concept of that treatment resistance is caused by excessive reactive increases in renin secretion is confirmed, then a PRA determination during treatment could be used to guide subsequent addition or subtraction of either natriuretic or antirenin drug types, to thereby correct BP and reduce cardiovascular risk.
American Journal of Hypertension (2009). doi:10.1038/ajh.2008.275
Over the years US hypertension treatment guidelines for controlling blood pressure (BP) have consistently advocated adding one drug type on top of another and never stopping any antihypertensive drug, even when it might be ineffective.1 With this strategy, BP remains uncontrolled in half of all treated patients,2 and a worrisome increase has been reported in the prevalence of treatment-resistant hypertension.3
An alternative approach to drug type selection is based on the differences in underlying pathophysiology that can be detected by the baseline ambulatory plasma renin activity (PRA) test.4–7 Using this approach we have observed that low-renin hypertensive patients respond best to sodium-volume-depleting natriuretic drugs and do not respond to drugs that block the renin system, whereas the medium- to high-renin patients respond best to antirenin system drugs. But, some medium- to high-renin-patients react to the fall in BP with large increases in renin secretion; the consequent rise in circulating renin diminishes the BP fall and is a potential cause of treatment resistance.8–10 Hypertensive patients differ in the magnitude of these reactive increases in renin8 (perhaps because of differences in nephron heterogeneity)11 and this accounts, at least in part, for the rather large range of BP responses to antirenin system drugs among patients with similar baseline renin levels.6 In fact, reactive increases in renin can be so large that they completely overcome the antihypertensive effect of antirenin system drugs. This could not occur if these drugs completely blocked renin activity, but they all leave ≥10% of circulating renin fully active12–14 and therefore become ineffective when renin secretion increases more than tenfold.
Large reactive increases in renin secretion have been associated with BP increases during diuretic-, or diet-, or dialysis-induced sodium depletion.15–20 It therefore seemed possible that antirenin drugs might also raise BP when they induce large reactive increases in renin secretion. In our first analysis of aliskiren trials,13 we proposed that patients might be particularly susceptible to a BP rise with aliskiren because it induces greater reactive increases in renal renin secretion than do angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), particularly when given in combination with an ACEI or ARB or a diuretic.21 Several investigators flatly rejected the possibility that pressor responses can be induced by aliskiren22,23 or claimed that the larger increases in renin were assay artifacts.14,24
Since these contradictory opinions22,23 did not provide any documentation, we decided to review the aliskiren literature once more to determine (i) whether the BP of low-renin patients falls with aliskiren and (ii) whether the BP or PRA levels ever increase when patients are given aliskiren alone or in combination with other antirenin system drugs. We limited this analysis to trials in which Nussberger's group had measured PRA levels,25–27 because their assay is not artifactually suppressed by the presence of a renin inhibitor.14,23,28 The published data did not allow us to determine whether the patients who had a rise in PRA also had a rise in BP; so we investigated instead whether the BP response patterns were consistent with their PRA response patterns. Because the secondary forms of hypertension that are known to have highly reactive renal renin secretory responses8 (advanced, renovascular and malignant) were excluded from all three of the trials, we anticipated finding very few instances of increases in PRA or BP. This, however, did not prove to be the case.
Methods
BP definitions. Significant changes in BP (up or down), measured by 24-h ambulatory BP monitoring, were defined as: systolic ≥10 mm Hg or diastolic ≥5 mm Hg. Figures were enlarged to the largest size that enabled the clearest definition of the individual points. Where logarithmic data were reported, the antilog of the scale was superimposed. Each data point was transcribed to an Excel file for subsequent analysis.
Protocols. All three trials25–27 enrolled only patients with mild-to-moderate hypertension. The individual BP and PRA data used in this report were all transcribed from figures published in these reports.
Stanton et al.25 reported data from a randomized, double blind, parallel group study of 226 patients who received either 37.5, 75, 150, or 300 mg of aliskiren or 100 mg losartan daily for 4 weeks. (150 mg is the lowest recommended starting dose for aliskiren.) Baseline measurements were made after a 2–4 week washout period. At the beginning and end of the study period, 24-h ambulatory BPs were recorded every half hour and mean daytime (9 AM to 9 PM) systolic BP (SBP) readings were reported for individual patients. Stanton et al.25 related baseline to treatment (24 h after the last dose) PRA levels and baseline PRA to changes in daytime ambulatory SBP. There was no figure provided that related induced changes in PRA to changes in BP.
Nussberger et al.26 reported trough (24 h after the last dose) clinic BPs and trough PRA levels from patients enrolled in a multi-center, randomized, double blind, placebo-controlled parallel group trial. Baseline BP was derived from the average of three BPs in seated patients after a 4–6 week washout period.29 Nussberger et al.26 showed individual BP data in relation to baseline renin only for patients who were treated for 8 weeks with either 600 mg of aliskiren (N = 113) or placebo (N = 111) and baseline PRA in relation to treatment PRA levels only for those given either 150 mg aliskiren (N = 112) or placebo or 150 mg irbesartan.
O'Brien et al.27 carried out three open label studies in which BP was assessed by ambulatory monitoring. We did not analyze data from the patients given aliskiren monotherapy because results were reported only for those whose BP was deemed to be controlled. Data of the relationship between the change in PRA and the change in BP were from Figures II and III reported only on the journal website (http://hyper.ahajournals.org). The protocol was as follows: after 3 weeks of treatment with either 150 mg of irbesartan (N = 23) or 5 mg of ramipril (N = 21), 75 mg aliskiren was force titrated for 3 weeks and then the aliskiren dose was increased from 75 to 150 mg for another 3 weeks. The incremental changes in day and nighttime systolic and diastolic pressures were reported for each change in drug regimen. However, we were unable to track consecutive BP changes in individual patients when the regimen was changed. As the directional and proportional changes in systolic and diastolic pressure were similar, only changes in systolic pressures are presented herein.
PRA measurements. All three reports measured PRA using an enzyme kinetic assay in which high-affinity antibodies were used to trap the Ang I generated at 37 °C and pH 7.4. Ang I was then measured by radioimmunoassay.30 This may be the only accurate way to measure PRA during aliskiren as the binding of Ang I to antibodies protects it from degradation and eliminates the need for adding phenylmethylsulfonyl fluoride that reportedly alters the binding equilibrium between renin and renin inhibitors.24,28,31 A 13% change in PRA is considered to be significant, based on the between-assay coefficient of variation in the low-renin range.30
As the rate of Ang I generation at pH 7.4 used in this assay is close to half of that at pH 6.0 (the pH we use in our laboratory),32 we defined low renin as ≤0.3 ng/ml/h, instead of 0.65 ng/ml/h.4
Estimation of renin secretion. None of the reports actually reported changes in plasma renin concentration in individual patients, a parameter that has been used together with PRA measurements to assess reactive changes in renin secretion.13 Nonetheless, changes in PRA during aliskiren can be used for this purpose. Given that aliskiren blocks close to 90% of circulating renin13,14 it ought to lower PRA values to 10% of baseline. If PRA is higher than that, renin secretion must have increased. For example, if PRA levels are 20% of baseline during aliskiren, renin secretion must have increased twofold, if they are at 50% of baseline renin secretion must have increased fivefold, and if PRA remains unchanged during aliskiren renin secretion must have increased tenfold. Thus, a rise in PRA during aliskiren means that renin secretion has most likely increased more than tenfold.
Statistical analyses
BP response of low-renin patients: For analyzing data from Stanton et al.,25 we dichotomized change in SBP as response (≥10 mm Hg) or no response and tested with χ2 the proportion with responses between the low-renin and the medium- to high-renin patients. Mean SBP decline for all drug regimens combined was compared between PRA defined groups with an independent samples t-test after confirming that assumptions for the t-test were sufficiently met. We repeated this analysis separately for those randomized to losartan and those randomized to any dose of aliskiren, as well as specifically for 300 mg aliskiren. For analyzing data from Nussberger et al.,26 we used an independent samples t-test to compare mean SBP decline between those on placebo to those on 600 mg aliskiren, within the low-renin and medium-/high-renin groups separately
All statistical tests used a two-tailed α of 0.05 for significance.
Results
The BP responses to aliskiren and to losartan in low-renin hypertensive patients
Based on transcribed data from figures reported by Stanton et al.,25 the daytime SBP of most low-renin patients did not fall during treatment with any dose of aliskiren or losartan 100 mg (Figure 1a, left side). For all antirenin system regimens combined, the overall SBP response rate of 14% for low-renin patients was significantly lower than the 43% response rate for medium-/high-renin patients (P = 0.001). Similarly, the mean change in SBP (±s.d.) was +1.8 ± 9.8 mm Hg for low-renin and –7.4 ± 12.7 for medium- to high-renin patients (P = 0.01). Among the 35 patients given losartan 100 mg, low-renin patients (n = 5) had a mean SBP gain of +2.0 ± 5.4 mm Hg compared to a –12.6 ± 13.7 decline for the medium-/high-renin group (P = 0.03). For those taking any dose of aliskiren, the fall in SBP in low-renin patients was not significantly different (P = 0.12) (mean –2.4 ± 10.3 mm Hg) from the fall of –6.1 ± 12.1 mm Hg in the medium- to high-renin group. Among those taking 300 mg aliskiren, the highest approved dose, the seven low-renin patients had a substantially lesser decline (–2.1 ± 7.9) compared to the 29 medium- to high-renin patients (–12.6 ± 13.0) (P = 0.05).
Data redrawn from ref. 25. Patients were divided into low renin (left side, open symbols: plasma renin activity (PRA) ≤0.3 ng/ml/h) and medium/high renin (right side, solid symbols: PRA >0.3 ng/ml/h). Changes in systolic blood pressure (SBP) and PRA were measured after 4 weeks in patients with mild to moderate hypertension given 37.5 (diamonds), 75 (squares), 150 (triangles), or 300 mg (circles) aliskiren or 100 mg losartan (short lines). (a) Change in individual patients in the average daytime SBP (9 AM to 9 PM) measured by ambulatory BP monitoring. Data above and below the solid lines indicate ≥10 mm Hg changes in BP. (b) Change in absolute levels of PRA. (c) Treatment PRA as % of baseline: 100% = no change. Line at 10% indicates the expected change in PRA if aliskiren blocks 90% of renin activity without any increase in renin secretion. A, aliskiren; LOS, losartan.
Figure 2, derived from Nussberger et al.,26 shows individual clinic SBP changes during treatment with either placebo or 600 mg aliskiren. The placebo control data are important in this analysis because SBP fell by an average of –10.9 ± 15.1 mm Hg in the 17 low-renin patients taking only placebo (center group, diamonds), virtually the same as in the 17 low-renin patients taking 600 mg aliskiren (–10.7 ± 15.1 mm Hg, P = 0.96). In contrast, the 84 medium- to high-renin patients had only a –2.9 ± 14.0 mm Hg SBP fall during placebo whereas the 90 medium- to high-renin patients had a –14.0 ± 13.5 mm Hg fall during 600 mg aliskiren (P < 0.001). Thus, there was no net fall in SBP compared to placebo in the low-renin group, whereas the net fall in the medium- to high-renin group was a statistically significant. (A possible explanation for the greater BP fall in the low-renin placebo group is that, before entering the trial they were more likely to have been corrected with natriuretic than with antirenin system drugs.4,5,7 As persistent rebound sodium retention often occurs after stopping natriuretic drugs33 their BP might have been more prone to transiently overshoot beyond the washout period to inappropriately elevate their “baseline” BP level.)
Changes in clinic systolic blood pressure (SBP) after 8 weeks of treatment with either placebo (diamonds) or 600 mg aliskiren (triangles) in patients with mild-to-moderate hypertension. Patients were divided into low renin (middle group, plasma renin activity (PRA) ≤0.3 ng/ml/h) and medium/high renin (right side, PRA >0.3 ng/ml/h). Horizontal lines = mean SBP. Vertical lines = ±1 s.d. (Redrawn from ref. 26.)
The inclusion of low-renin patients underestimates the efficacy of antirenin system drugs
We next investigated whether the magnitude of the BP fall with aliskiren or losartan was being underestimated by including low-renin patients in the analysis25 (Table 1). When the low-renin patients were excluded, the median fall in BP with 300 mg aliskiren changed from –10.5 to –15 mm Hg, and from –11 to –15 mm Hg with 100 mg losartan. Thus, by failing to separate out low-renin patients the efficacy of antirenin system drugs in medium- to high-renin patients was underestimated.
Median changes in the average daytime (9 AM to 9 PM) systolic blood pressure in patients given either aliskiren or losartan (LOS) for 8 weeks
Median changes in the average daytime (9 AM to 9 PM) systolic blood pressure in patients given either aliskiren or losartan (LOS) for 8 weeks
PRA responses to antirenin system drugs
PRA changes during monotherapy with aliskiren or losartan, irbesartan or ramipril. Absolute levels of PRA were essentially unchanged in low-renin patients during both aliskiren and losartan (Figure 1b, left side).25 The % changes in PRA were widely scattered (Figure 1c, left side), most likely a reflection of the inaccuracy of this parameter when PRA levels are low.
PRA increased in most medium-/high-renin patients given 100 mg losartan25 (Figure 1b,c, right side) and was >300% baseline in 45% of them (Figure 3c, dotted bar). In most patients taking aliskiren, PRA fell as expected (Figure 1b,c, right side); nonetheless, >20% of medium-/high-renin patients taking aliskiren 300 mg had PRA levels >30% baseline (Figure 3b,c, open bars) and PRA actually increased in close to 1 in 20 (Figure 3b, open bars).
Percentages of medium- to high-renin patients whose daytime systolic BP (closed bar) (a) fell by at least 10 mm Hg, (b) rose by at least 10 mm Hg, or (c) was unchanged (less than ±10 mm Hg) during 37.5, 75, 150, or 300 mg aliskiren or 100 mg losartan. Open bars = % whose plasma renin activity (PRA) (a) fell by at least 70%, (b) was unchanged or rose, or (c) whose PRA fell by 1–69%. BP, blood pressure; LOS, losartan. (Redrawn from ref. 25.)
As O'Brien et al.27 did not report baseline PRA levels, it was only possible to assess whether PRA rose or fell. One hundred percent of patients had an increase in PRA with irbesartan 150 mg and 85% with ramipril 5 mg (data not shown).
Although there was a positive relationship between the baseline renin and the reactive rise in renin during losartan, large reactive increases in renin secretion occurred across the spectrum of medium- to high-renin patients (Figure 4).
Relationship between baseline plasma renin activity (PRA) and treatment PRA (24 h after the last dose) in mild to moderate hypertensive patients who had been given 100 mg losartan for 4 weeks. (Redrawn from ref. 25.)
PRA changes when aliskiren was added to irbesartan or ramipril. When 75 mg aliskiren was added to 150 mg irbesartan or to 5 mg ramipril,27 PRA levels fell in most patients (Figure 5) but it rose in 10 and 16%, respectively (Figure 6e, open bars). When the dose of aliskiren was increased from 75 to 150 mg during irbesartan, PRA levels rose in a third of all patients (Figure 6e, open bars). Similarly, when the dose of aliskiren was increased during ramipril, PRA levels rose in 39% (Figure 6e, open bars). Thus, there was more than a one in three chance of PRA rising when the dose of aliskiren was increased while taking an ACEI or ARB.
Percentages of patients whose systolic blood pressure (SBP) fell by at least 10 mm Hg, rose by at least 10 mm Hg, or was unchanged. (a–c) daytime SBP (9 AM to 9 PM); (d–f) nighttime SBP (1 AM to 6 AM). Open bars in e indicate percentages whose plasma renin activity levels rose at each stage. Protocol is described in legend to Figure 7. (Redrawn from ref. 27.)
Change in trough plasma renin activity (PRA) (24 h after the last dose) in patients with mild-to-moderate hypertension when 75 mg aliskiren was added to either 150 mg irbesartan (triangles) or 5 mg ramipril (squares) for 3 weeks, and when the dose of aliskiren was increased from 75 to 150 mg in patients taking irbesartan (diamonds) or ramipril (circles). Open symbols indicate patients whose average nighttime ambulatory systolic pressure rose during the same time period. Horizontal lines and values in boxes indicate median PRA values. (Redrawn from ref. 27.)
BP responses to antirenin system drugs
BP changes during monotherapy with 150 or 300 mg aliskiren or losartan, irbesartan or ramipril. Daytime SBP fell by –17 mm Hg in those medium-/high-renin patients given aliskiren 150 mg who had a daytime SBP fall of at least 10 mm Hg (Figures 1a and 3a, solid bars).25 No patient taking 150 mg had a SBP rise, but 59% had no change in daytime SBP (Figure 3c, solid bars). With aliskiren 300 mg, SBP fell even more (–19 mm Hg) in the 69% of patients that had a fall in SBP, but it also rose as much (+23 mm Hg) in 6% of patients (Figure 3b) while 24% had no SBP change (Figure 3c). Similarly, with 100 mg losartan, SBP fell by –22 mm Hg in the 60% that had a BP fall but it increased in one patient by +17 mm Hg while there was no change in SBP in 37% (Figure 3a–c). Thus, BP fell in more than half of the medium- to high-renin patients taking the highest dose of aliskiren (300 mg) or losartan 100 mg, but it failed to fall in almost 30% and actually rose in about 1 in 20.
SBP fell by –16 mm Hg in the 48% taking 150 mg irbesartan that had a daytime SBP fall of at least 10 mm Hg (Figures 6a and 7);27 none had a BP rise (Figure 6b) but 52% had no BP change (Figure 6c). Similarly, with ramipril 5 mg SBP fell by –17 mm Hg in the 35% that had a BP fall, but one patient had a 15 mm Hg BP rise and 68% of patients had no change in daytime SBP. The lower proportion of BP responders most likely reflects the inclusion of low-renin patients and the use of a relatively low dose of ramipril.
Change in the average (a) daytime systolic pressure (9 AM to 9 PM) and (b) nighttime systolic pressure (1 AM to 6 AM) measured by ambulatory blood pressure (BP) monitoring in patients with mild-to-moderate hypertension during either 150 mg irbesartan (diamonds) or 5 mg ramipril (circles) for 3 weeks. Also shown are the further BP changes that occurred when 75 mg of aliskiren was added for 3 weeks and then when the aliskiren dose was increased to 150 mg for 3 weeks. Open symbols identify patients whose trough plasma renin activity (PRA) levels did not fall (δPRA ≥0 ng/ml/h) when aliskiren was added or when the dose of aliskiren was increased. The short horizontal lines indicate the median change in BP. (Redrawn from ref. 27.)
BP changes when aliskiren was added to irbesartan or ramipril. These changes in BP are illustrated in Figures 6 and 7 redrawn from O'Brien et al.27 When aliskiren 75 mg was added to irbesartan or ramipril, half as many patients had a rise in daytime BP (+15 and +12 mm Hg) as had a fall (–14 and –15 mm Hg) (compare Figure 6a,b) and BP either rose or was unchanged in 80% of patients (Figure 6c).
When the dose of aliskiren added to either irbesartan or ramipril was increased from 75 to 150 mg, daytime SBP rose (+13 and + 12 mm Hg) in almost as many patients as it fell (–14 and –16 mm Hg) (compare Figure 6a,b). Approximately 80% of patients derived no benefit from increasing the aliskiren dose (Figure 6b,c). The data on the right side of Figure 6 show that the proportions of patients whose nighttime SBP fell, rose, or was unchanged were almost identical to the proportions whose daytime SBP fell, rose, or was unchanged.
The relationship of BP to PRA changes
We next tried to investigate whether the same patients who had a rise in PRA during aliskiren had an increase in BP. Unfortunately, Stanton et al.25 did not report the data in a way that allowed this analysis. O'Brien et al.27 reported absolute changes but not % changes in PRA in relation to changes in SBP. We therefore analyzed the data in broad terms. Nighttime BP was used here because it was measured closer to the time when PRA was measured since PRA was measured 24 h after the last dose.
Figure 5 shows absolute changes in PRA and identifies with open symbols patients in whom nighttime SBP rose. When aliskiren was added or the dose was increased in patients already taking irbesartan or ramipril, nighttime SBP rose in 33% of the patients in whom PRA levels also rose and in only 9% of the patients in whom PRA was suppressed. Reciprocally, Figure 7 shows changes in BP and identifies with open symbols patients whose PRA rose when aliskiren was added to either irbesartan or ramipril or when the dose was increased. PRA increased in 44% (4 of 9) of patients whose nighttime SBP rose, and in only 15% (3 of 20) of those whose nighttime SBP fell.
Another way of investigating this question was to determine whether similar proportions of patients had increases or falls or no change in SBP and PRA levels. During treatment with four different doses of aliskiren25 (Figure 3), almost identical proportions of patients had a >10 mm Hg fall in SBP and a >70% fall in PRA, and almost identical proportions of patients had a >10 mm Hg rise in SBP and a rise in PRA, and almost identical proportions of patients had no change in SBP and a <70% fall in PRA. Moreover, when aliskiren was added to irbesartan or ramipril or the dose was increased, similar proportions of patients had increases in PRA (Figure 6e, open bars) and increases in SBP (Figure 6e, closed bars).
PRA and BP increases in patients taking 37.5 mg aliskiren for 4 weeks
Among medium-/high-renin patients taking 37.5 mg aliskiren,25 daytime SBP rose in 16% (Figures 1a and 3b left hand bars) by an average of +26 mm Hg. Moreover, 13% had elevated PRA levels 24 h after the last dose.
Discussion
The present analysis of three clinical trials of aliskiren25–27 found that only half of all hypertensive patients had a fall in BP with aliskiren, or with the comparator ACEIs or ARBs. Moreover, when aliskiren was added to an ACEI or an ARB, or when the dose of aliskiren was increased while taking an ACEI or ARB, a mere 20% of patients had a fall in BP. Furthermore, among these resistant patients ~5% had an actual rise in BP with aliskiren alone, and ≥10% had a rise in BP when the dose of aliskiren was increased while taking an ACEI or ARB.
By understanding the reasons for treatment resistance, it might be possible to develop more rationale antihypertensive treatment strategies. There appeared to be two reasons for BP resistance to aliskiren: (i) no renin to block in low-renin patients or (ii) an insufficient reduction or even a reactive rise in PRA levels.
The absence of a BP fall in most low-renin patients confirms many previous results with various antirenin system drugs.4,5,6,7,34–36 This also adds weight to our conceptual model in which low-renin patients have a putative body salt excess rather than a renin excess as the pathophysiological basis for sustaining their hypertension and therefore are more appropriately treated with natriuretic drugs.4,5 This lack of a BP response also indicates that if such low-renin patients were to have an intrinsic intrarenal renin system that is blocked by antirenin system drugs, as has been proposed,23,37,38 its role appears to have little relevance to BP control. Moreover, because more than half of all African American hypertensives do not have low-renin levels39 it seems more rationale to use a plasma renin test, rather than ethnicity, as a basis for identifying patients who are unlikely to respond to antirenin system drugs.
The second reason that aliskiren fails to lower BP is the failure to cause a large enough fall in PRA. Since therapeutic doses of aliskiren leave close to 10% of plasma renin in the active state,13,14 PRA levels would always fall to 10% of baseline if aliskiren never caused a reactive increase in renin secretion. Figure 1c shows that the PRA level of almost every medium- to high-renin patient taking a therapeutic dose of aliskiren was >10% of baseline. Thus, almost every patient had a reactive increase in renin secretion and in some patients the increases exceeded tenfold. Reactive increases in renin secretion are also induced by ACEIs and ARBs but with these other antirenin system drug types PRA levels actually increase. Nonetheless, they are at best only 10% active12 because ACEIs block ~90% of the conversion of Ang I to Ang II and ARBs block Ang II receptor binding by ~90%. The magnitude of reactive increases in renal renin secretion differs among individual hypertensive patients8 (Figure 4) and most likely influence whether or not BP falls.
Increases in PRA and BP occurred more frequently when aliskiren was added to an ACEI or an ARB and when the aliskiren dose was increased while taking an ACEI or ARB. If large reactive increases in renin secretion also occur when ACEIs and ARBs are combined, it might explain the failure of such combination therapy to reduce cardiovascular events in clinical trials despite reducing the average fall in BP.40,41 Moreover, the practice of initiating antihypertensive treatment with such combination drugs could cause synergistic reactive increases in renin secretion in susceptible patients thereby causing treatment resistance and putting patients at increased risk because of a rise in both PRA and BP levels.42,43
ACEIs and ARBs and aliskiren appear to be more alike than different in the BP response patterns they induce. Nonetheless, there may be one key difference. Aliskiren binds avidly to the kidneys44 and causes prolonged increases in renin secretion that may outlast the blockade of renin in the circulation.45 If so, this could cause an overshoot of BP during withdrawal periods. These different rates of clearance may explain why a few patients taking a suboptimal dose of aliskiren (37.5 mg) had large (+26 mm Hg) increases in their average daytime systolic pressure, and in PRA levels 24 h after the last dose (Figures 1 and 3b).25 Although BP measurements during withdrawal from aliskiren have not revealed an overshoot of BP27,46,47 data were only reported for groups as a whole, and transient BP increases in individual patients could have been missed. Thus the casual denial of the real possibility that aliskiren sometimes increases BP22,23 hides potential problems with its clinical use in pathophysiological subsets of patients who are readily identifiable by ambulatory renin testing.
Perspective
If further studies confirm (i) that antirenin system drugs lower BP in only half of all hypertensive patients; (ii) that BP fails to fall in low-renin patients and in patients who have large reactive increases in renin secretion; (iii) that these large reactive increases in renin secretion occur more frequently when antirenin system drugs are given in combination; and (iv) that increases in reactive renin can sometimes be so great that BP rises instead of falls, then it calls into question the treatment strategy of adding one drug on top of another without stopping those that fail to lower BP,1 because that strategy may cause treatment-resistant hypertension. If instead, failure to respond to any first drug (after a suitable time and dose) were followed by an ambulatory PRA determination, the PRA result could be used to guide subsequent therapy.4 Then, a low PRA level would identify the patient who has no renin to block and who needs instead volume depletion with a natriuretic drug. A high PRA level would identify a patient with a hyper-reactive renin system and indicate the need for further renin system blockade, perhaps with a drug that suppresses renin secretion such as a beta adrenergic blocker4,48 or a centrally acting α-adrenergic agonist.49 A medium-renin level would indicate the need for an antirenin drug, perhaps aided by a natriuretic drug. Taken altogether, and because the hyper-reactive renin form of drug resistance increases cardiovascular risk by raising both circulating renin levels and BP,42,43 discovering its cause and promptly correcting the problem is likely to improve BP control and reduce cardiovascular morbidity.
Some may disagree with this pathophysiological basis for drug selection based on plasma renin testing. Notwithstanding, we recently successfully tested this conceptual model in a proof of concept trial50 in which three physicians applied our treatment algorithm to 39 patients whose BP remained uncontrolled despite taking an average of three antihypertensive drugs. BP was reduced from 157/87 (±2.6/2.0) to 128/73 (±2.3/1.8) without requiring any increase in the number of drugs.
This study was supported by May and Samuel Rudin Family Foundation, Trust of Frederick Schwartz, and Lawrence M. Gelb Foundation.
Disclosure
J.E.S.: Consultant, Diasorin Inc., Stillwater, MN. J.H.L.: Consultant, Diasorin Inc., Stillwater, MN; Licensed Patent #09/657,027 “Method for Evaluating and Treating Hypertension” to Diasorin Inc., Stillwater, MN.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
