Anales de Hipertensión Arterial
Número 106, 14 de Enero de 2010
Noticia adicional
FULLTEXT: -HYPERTENSION: -Aliskiren fails to lower blood pressure in patients who have either low PRA levels or whose pra falls insufficiently or reactively rises
Background
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.
Methods
To investigate their prevalence we reanalyzed data from three published clinical trials of the renin inhibitor aliskiren.
Results
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.
Conclusions
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
INTRODUCTION
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
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.8,9,10
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 active12,13,14 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.15,16,17,18,19,20
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,25,26,27 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.
American Journal of Hypertension (2009); 22, 1, 112–121. doi:10.1038/ajh.2008.275
Jean E. Sealey1 and John H. Laragh2
1Department of Medicine, Cardiovascular Center, Weill Cornell Medical College, New York, New York, USA
2Department of Cardiothoracic Surgery, Cardiovascular Center, NewYork-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA
Corresp: Jean E. Sealey, (jsealey@med.cornell.edu)
SEE FULLTEXT
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.
Methods
To investigate their prevalence we reanalyzed data from three published clinical trials of the renin inhibitor aliskiren.
Results
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.
Conclusions
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
INTRODUCTION
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.4,5,6,7
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.8,9,10
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 active12,13,14 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.15,16,17,18,19,20
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,25,26,27 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.
American Journal of Hypertension (2009); 22, 1, 112–121. doi:10.1038/ajh.2008.275
Jean E. Sealey1 and John H. Laragh2
1Department of Medicine, Cardiovascular Center, Weill Cornell Medical College, New York, New York, USA
2Department of Cardiothoracic Surgery, Cardiovascular Center, NewYork-Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA
Corresp: Jean E. Sealey, (jsealey@med.cornell.edu)
SEE FULLTEXT
http://www.nature.com/ajh/journal/v22/n1/full/ajh2008275a.
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