Efficacy and Safety of LCZ696 According to Age
Efficacy and Safety of LCZ696 According to Age
A larger number of patients with a broader range of ages were included in PARADIGM-HF than in any previous trial in heart failure with reduced ejection fraction. We found that patient characteristics varied substantially by age, as in past trials. Although the rate of death and heart failure hospitalization increased with age, this gradient was not as pronounced in PARADIGM-HF as in prior trials. The benefit of LCZ696, over enalapril, was similar across the age categories examined.
Older patients, as expected, differed from their younger counterparts in many ways. As previously demonstrated, older individuals were more often women, although we did not find any interaction between treatment and sex or treatment and sex and age. Older patients had more comorbidities, higher average ejection fraction but worse NYHA functional class. They were also more likely to have an ischaemic aetiology. In addition to these differences we found older patients to have higher natriuretic peptide concentrations, presumably reflecting the higher prevalence of renal dysfunction and atrial fibrillation in these individuals (and despite their higher average ejection fraction).
The large number of countries which participated in PARADIGM-HF also meant that interactions between age, geographic region, and race/ethnicity were apparent. Non-white individuals and patients from Latin America, the Asia-Pacific region, and Central/Eastern Europe were more common in the younger age categories compared with the older ones. These findings are consistent with the global epidemiology of heart failure which shows heart failure often occurs at a younger age in countries outside Western Europe and North America where it is a condition that afflicts mainly the elderly.
A perhaps more surprising findings of the present analyses was the relatively shallow gradient in event rates, especially heart failure hospitalization, across the age categories studied. The gradient was most marked for death from any cause and steeper than for CV mortality, i.e. our findings showed, by inference, that the greatest age-related difference was in non-CV death. Furthermore, although the crude event rates were somewhat higher in the ≥75 year age group than in younger patients, the difference did not seem to be as large as in prior trials. These two observations suggest that in well-treated patients such as those in PARADIGM-HF, effective disease-modifying drugs may have attenuated the age-related gradient in CV events that was prominent in historical studies. Despite differences in baseline characteristics and crude mortality, there was no difference in the effect of LCZ696 vs. enalapril on outcomes across the range of age after adjusting for the baseline differences.
The median KCCQ clinical summary score was only notably lower in the oldest age group (compared with the younger age categories), showing that differences in health-related quality of life, like those for hospitalization and mortality, did not become marked until the age of 75 years or older.
From a treatment perspective, the most important finding was that the benefit of LCZ696 over enalapril was consistent across the age categories studied, although in the analysis of age as a continuous variable there was some uncertainty about fatal outcomes in the most elderly patients because of the modest number of patients age 85 years or older (n = 121). However, even in very elderly patients the effect of LCZ696 on heart failure hospitalization seemed qualitatively and quantitatively similar to its effect in younger patients. This finding is consistent with many but not all prior analyses of treatment effect by age, although some of these have been truncated by an upper inclusion age-limit or the enrolment few elderly patients in the trials concerned.
The effect of treatment on the KCCQ according to age has not been reported previously and in PARADIGM-HF, as with other outcomes, LCZ696 was superior to enalapril across the age-range examined in preventing deterioration in this measure of health-related quality of life, even in the most elderly group.
As anticipated from prior studies, treatment intolerance increased with increasing age (with the exception of angioedema), although the gradient was modest and the difference between LCZ696 and enalapril persisted across age categories. Overall, it is clear that the benefit–risk profile of LCZ696 compared with enalapril remained favourable across the broad spectrum of age studied. Despite this consistent finding with multiple drug treatments in heart failure, there is ample evidence that older patients with heart failure are often under-treated with therapies that reduce mortality and morbidity.
As with any study, this one has some limitations. This is a retrospective analysis and the age-categories are arbitrary (although commonly used and clinically meaningful). We enrolled a relatively small number of the most elderly patients. The number of African-American patients was also relatively small. The safety and adverse event data must be interpreted in the light of the trial design with an enalapril and LCZ696 active run-in period.
In summary, our analyses showed that LCZ696 was more beneficial than enalapril across the broad spectrum of age studied in PARADIGM-HF and that intolerance of LCZ696 leading to treatment withdrawal was uncommon, even in elderly individuals.
Discussion
A larger number of patients with a broader range of ages were included in PARADIGM-HF than in any previous trial in heart failure with reduced ejection fraction. We found that patient characteristics varied substantially by age, as in past trials. Although the rate of death and heart failure hospitalization increased with age, this gradient was not as pronounced in PARADIGM-HF as in prior trials. The benefit of LCZ696, over enalapril, was similar across the age categories examined.
Older patients, as expected, differed from their younger counterparts in many ways. As previously demonstrated, older individuals were more often women, although we did not find any interaction between treatment and sex or treatment and sex and age. Older patients had more comorbidities, higher average ejection fraction but worse NYHA functional class. They were also more likely to have an ischaemic aetiology. In addition to these differences we found older patients to have higher natriuretic peptide concentrations, presumably reflecting the higher prevalence of renal dysfunction and atrial fibrillation in these individuals (and despite their higher average ejection fraction).
The large number of countries which participated in PARADIGM-HF also meant that interactions between age, geographic region, and race/ethnicity were apparent. Non-white individuals and patients from Latin America, the Asia-Pacific region, and Central/Eastern Europe were more common in the younger age categories compared with the older ones. These findings are consistent with the global epidemiology of heart failure which shows heart failure often occurs at a younger age in countries outside Western Europe and North America where it is a condition that afflicts mainly the elderly.
A perhaps more surprising findings of the present analyses was the relatively shallow gradient in event rates, especially heart failure hospitalization, across the age categories studied. The gradient was most marked for death from any cause and steeper than for CV mortality, i.e. our findings showed, by inference, that the greatest age-related difference was in non-CV death. Furthermore, although the crude event rates were somewhat higher in the ≥75 year age group than in younger patients, the difference did not seem to be as large as in prior trials. These two observations suggest that in well-treated patients such as those in PARADIGM-HF, effective disease-modifying drugs may have attenuated the age-related gradient in CV events that was prominent in historical studies. Despite differences in baseline characteristics and crude mortality, there was no difference in the effect of LCZ696 vs. enalapril on outcomes across the range of age after adjusting for the baseline differences.
The median KCCQ clinical summary score was only notably lower in the oldest age group (compared with the younger age categories), showing that differences in health-related quality of life, like those for hospitalization and mortality, did not become marked until the age of 75 years or older.
From a treatment perspective, the most important finding was that the benefit of LCZ696 over enalapril was consistent across the age categories studied, although in the analysis of age as a continuous variable there was some uncertainty about fatal outcomes in the most elderly patients because of the modest number of patients age 85 years or older (n = 121). However, even in very elderly patients the effect of LCZ696 on heart failure hospitalization seemed qualitatively and quantitatively similar to its effect in younger patients. This finding is consistent with many but not all prior analyses of treatment effect by age, although some of these have been truncated by an upper inclusion age-limit or the enrolment few elderly patients in the trials concerned.
The effect of treatment on the KCCQ according to age has not been reported previously and in PARADIGM-HF, as with other outcomes, LCZ696 was superior to enalapril across the age-range examined in preventing deterioration in this measure of health-related quality of life, even in the most elderly group.
As anticipated from prior studies, treatment intolerance increased with increasing age (with the exception of angioedema), although the gradient was modest and the difference between LCZ696 and enalapril persisted across age categories. Overall, it is clear that the benefit–risk profile of LCZ696 compared with enalapril remained favourable across the broad spectrum of age studied. Despite this consistent finding with multiple drug treatments in heart failure, there is ample evidence that older patients with heart failure are often under-treated with therapies that reduce mortality and morbidity.
As with any study, this one has some limitations. This is a retrospective analysis and the age-categories are arbitrary (although commonly used and clinically meaningful). We enrolled a relatively small number of the most elderly patients. The number of African-American patients was also relatively small. The safety and adverse event data must be interpreted in the light of the trial design with an enalapril and LCZ696 active run-in period.
In summary, our analyses showed that LCZ696 was more beneficial than enalapril across the broad spectrum of age studied in PARADIGM-HF and that intolerance of LCZ696 leading to treatment withdrawal was uncommon, even in elderly individuals.
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