Aliskiren and Antihypertensives in Elderly With Hypertension
Aliskiren and Antihypertensives in Elderly With Hypertension
This study was designed to clarify whether BP lowering in high-risk elderly individuals, with SBP in a range between 130 and 159 mm Hg, is safe and leads to reductions in major clinical outcomes. Our data show that in addition to other background BP lowering medications (mean of 1.5 drugs), up to two further antihypertensive drugs (for a mean of 3.5 drugs in the double active arm) could be safely administered and were well tolerated. While the effects on major clinical outcomes could not be definitively determined because of early study termination, the present results suggest that such a trial can be conducted safely, with effective BP lowering and high tolerability. After randomization, three levels of BP reductions were achieved, with aliskiren alone (BP reduction of 3.5/1.7 mm Hg), amlodipine or HCTZ alone (6.8/3.3 mm Hg), and the combination of aliskiren plus amlodipine or HCTZ (10.3/5.0 mm Hg) compared with their placebos. Such reductions were not routinely encountered when guidelines are followed in clinical practice. These levels of BP reductions from the single or combination therapies were anticipated in the design of the trial.
There was a trend towards a reduction in clinical events in each of the active arms, and an additive effect with their combination, against a background of 1.5 non-study BP lowering agents. The data suggest the potential for a clinically important benefit on major CVD outcomes from each component of the study medications with possibly an added benefit from the combination. Thus our data suggest that in the elderly with stage 1 and borderline hypertension up to four BP lowering agents at standard doses are often required to reduce BP to acceptable levels and that these can be safely combined. Further, such vigorous attempts at BP lowering with multiple agents have the potential for clinical outcome benefits. These findings are comparable with the results from the ASTRONAUT trial, which while the results did not achieve statistical significance, the trend in reduction of clinical outcomes is encouraging.
This trial had incorporated a run-in phase during which the active medications were up-titrated in steps to the trial target doses. During run-in, the incidence of serious adverse effects and clinical outcomes were low. None of the randomized treatment groups exhibited any excess adverse outcomes compared with their placeboes. By the final visit, ~10% of participants had discontinued the study medications permanently, similar to that observed in previous trials such as ONTARGET or the HOPE trial. This included those individuals who, even though they had tolerated the study drugs, decided to discontinue them because of concerns by participants or physicians about their safety when the decision was made to stop recruitment. The commonest reason was likely related primarily to individuals changing their minds about participating in a long-term trial and not because of adverse effects of the study drugs.
The APOLLO results on safety and tolerability appear to differ from those reported in the ALTITUDE trial which reported an excess of elevated serum potassium levels or renal dysfunction with aliskiren at similar doses. However, patients in ALTITUDE all had diabetes and impaired renal function and all also received an ACE inhibitor or ARB as background therapy whereas only ~40% of participants in our study had diabetes, and 43% were on an ACE inhibitor or an ARB.
While the BP reduction by aliskiren appears less than that from HCTZ or amlodipine, in the background of various background BP therapy, aliskiren is an effective BP lowering agent, and with a favourable tolerability profile, as also shown in the present study. Aliskiren reduces plasma renin activity and this effect had raised hopes that by effectively blocking the renin–angiotensin system it could produce cardiovascular benefits over and above those associated with its BP lowering effect. The hypothesis has also been advanced that with its proximal site of renin–angiotensin system blockade, it could oppose the adverse effects of angiotensin II production more completely than by ACE inhibition or angiotensin receptor antagonism. Unfortunately, the report from the ALTITUDE trial that the drug caused hypotension, hyperkalaemia and renal failure when used with another renin angiotensin blocking agent, such as an ACE inhibitor or an ARB, in individuals with diabetes and renal impairment may have precluded its use with these agents in individuals with, or even without, these pre-existing conditions. While the preliminary result of the APOLLO study shows that the drug appeared to be safe and well tolerated, the ALTITUDE trial results were extrapolated (perhaps unwarrantedly) to other populations. This extrapolation has precluded studies to explore whether clinical benefits could be observed in hypertensive individuals when aliskiren used alone or in combination with other drugs to lower BP. The APOLLO trial differed from the ALTITUDE trial in including those who had an elevated BP (and so the potential for benefits from BP lowering could be evaluated), the elderly (among whom BP lowering has a larger absolute benefit), utilizing a run-in phase where tolerability of all drug regimens were evaluated before randomization and where a strategy to achieve an important BP difference (by using combination therapies) was employed. These important differences in trial design and population between APOLLO and ALTITUDE make it possible that the clinical outcomes in the two trials would likely have differed.
In conclusion, the administration of the combination of aliskiren and HCTZ or amlodipine, and used in the background of an additional 1.5 antihypertensive drugs, was associated with an anticipated SBP reduction of ~10 mmHg and appeared to be safe. There were trends towards fewer clinical outcomes with the active and combination therapies. These findings also suggest that with the sample size and duration of follow-up in the original protocol of APOLLO, significant and substantial reductions in the clinical outcomes would likely to have been observed. However, whether or not these promising results on limited numbers of patients, who were followed for an average of only 0.6 years, would be associated with reductions in CV risk during long-term follow-up could not be determined given the decision to terminate the trial prematurely. Yet the trend towards beneficial reductions in the clinical outcome events supports use of multiple agents to lower BP in elderly individuals with a BP between 130 and 159 mm Hg while definitive trials on this important topic are urgently needed.
Discussion
This study was designed to clarify whether BP lowering in high-risk elderly individuals, with SBP in a range between 130 and 159 mm Hg, is safe and leads to reductions in major clinical outcomes. Our data show that in addition to other background BP lowering medications (mean of 1.5 drugs), up to two further antihypertensive drugs (for a mean of 3.5 drugs in the double active arm) could be safely administered and were well tolerated. While the effects on major clinical outcomes could not be definitively determined because of early study termination, the present results suggest that such a trial can be conducted safely, with effective BP lowering and high tolerability. After randomization, three levels of BP reductions were achieved, with aliskiren alone (BP reduction of 3.5/1.7 mm Hg), amlodipine or HCTZ alone (6.8/3.3 mm Hg), and the combination of aliskiren plus amlodipine or HCTZ (10.3/5.0 mm Hg) compared with their placebos. Such reductions were not routinely encountered when guidelines are followed in clinical practice. These levels of BP reductions from the single or combination therapies were anticipated in the design of the trial.
There was a trend towards a reduction in clinical events in each of the active arms, and an additive effect with their combination, against a background of 1.5 non-study BP lowering agents. The data suggest the potential for a clinically important benefit on major CVD outcomes from each component of the study medications with possibly an added benefit from the combination. Thus our data suggest that in the elderly with stage 1 and borderline hypertension up to four BP lowering agents at standard doses are often required to reduce BP to acceptable levels and that these can be safely combined. Further, such vigorous attempts at BP lowering with multiple agents have the potential for clinical outcome benefits. These findings are comparable with the results from the ASTRONAUT trial, which while the results did not achieve statistical significance, the trend in reduction of clinical outcomes is encouraging.
This trial had incorporated a run-in phase during which the active medications were up-titrated in steps to the trial target doses. During run-in, the incidence of serious adverse effects and clinical outcomes were low. None of the randomized treatment groups exhibited any excess adverse outcomes compared with their placeboes. By the final visit, ~10% of participants had discontinued the study medications permanently, similar to that observed in previous trials such as ONTARGET or the HOPE trial. This included those individuals who, even though they had tolerated the study drugs, decided to discontinue them because of concerns by participants or physicians about their safety when the decision was made to stop recruitment. The commonest reason was likely related primarily to individuals changing their minds about participating in a long-term trial and not because of adverse effects of the study drugs.
The APOLLO results on safety and tolerability appear to differ from those reported in the ALTITUDE trial which reported an excess of elevated serum potassium levels or renal dysfunction with aliskiren at similar doses. However, patients in ALTITUDE all had diabetes and impaired renal function and all also received an ACE inhibitor or ARB as background therapy whereas only ~40% of participants in our study had diabetes, and 43% were on an ACE inhibitor or an ARB.
While the BP reduction by aliskiren appears less than that from HCTZ or amlodipine, in the background of various background BP therapy, aliskiren is an effective BP lowering agent, and with a favourable tolerability profile, as also shown in the present study. Aliskiren reduces plasma renin activity and this effect had raised hopes that by effectively blocking the renin–angiotensin system it could produce cardiovascular benefits over and above those associated with its BP lowering effect. The hypothesis has also been advanced that with its proximal site of renin–angiotensin system blockade, it could oppose the adverse effects of angiotensin II production more completely than by ACE inhibition or angiotensin receptor antagonism. Unfortunately, the report from the ALTITUDE trial that the drug caused hypotension, hyperkalaemia and renal failure when used with another renin angiotensin blocking agent, such as an ACE inhibitor or an ARB, in individuals with diabetes and renal impairment may have precluded its use with these agents in individuals with, or even without, these pre-existing conditions. While the preliminary result of the APOLLO study shows that the drug appeared to be safe and well tolerated, the ALTITUDE trial results were extrapolated (perhaps unwarrantedly) to other populations. This extrapolation has precluded studies to explore whether clinical benefits could be observed in hypertensive individuals when aliskiren used alone or in combination with other drugs to lower BP. The APOLLO trial differed from the ALTITUDE trial in including those who had an elevated BP (and so the potential for benefits from BP lowering could be evaluated), the elderly (among whom BP lowering has a larger absolute benefit), utilizing a run-in phase where tolerability of all drug regimens were evaluated before randomization and where a strategy to achieve an important BP difference (by using combination therapies) was employed. These important differences in trial design and population between APOLLO and ALTITUDE make it possible that the clinical outcomes in the two trials would likely have differed.
In conclusion, the administration of the combination of aliskiren and HCTZ or amlodipine, and used in the background of an additional 1.5 antihypertensive drugs, was associated with an anticipated SBP reduction of ~10 mmHg and appeared to be safe. There were trends towards fewer clinical outcomes with the active and combination therapies. These findings also suggest that with the sample size and duration of follow-up in the original protocol of APOLLO, significant and substantial reductions in the clinical outcomes would likely to have been observed. However, whether or not these promising results on limited numbers of patients, who were followed for an average of only 0.6 years, would be associated with reductions in CV risk during long-term follow-up could not be determined given the decision to terminate the trial prematurely. Yet the trend towards beneficial reductions in the clinical outcome events supports use of multiple agents to lower BP in elderly individuals with a BP between 130 and 159 mm Hg while definitive trials on this important topic are urgently needed.
