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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:M716-M721 (2004)
© 2004 The Gerontological Society of America

Use of Angiotensin-Converting Enzyme Inhibitors in Elderly People With Heart Failure: Prevalence and Outcomes

Claudio Pedone1,, Marco Pahor2, Luciana Carosella1, Roberto Bernabei1, Pierugo Carbonin1 and for the GIFA Investigators

1 Centro di Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Roma, Italy.
2 Sticht Center on Aging, Wake Forest University Baptist Medical Center, North Carolina.

Address correspondence to Claudio Pedone, MD, MPH, Centro di Medicina dell'Invecchiamento, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy. E-mail: claudio_pedone{at}rm.unicatt.it


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. There is a lack of information on the effects of angiotensin-converting enzyme (ACE) inhibitors in very old people with heart failure (HF). The objective of this study is to estimate the prevalence of prescriptions of ACE inhibitors in elderly people with HF discharged from acute care hospitals, and to evaluate the effect of these drugs on 1-year mortality rates.

Methods. We used data from the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA). In 1998, we undertook a 1-year longitudinal study on elderly people (aged 65+ years) discharged with a diagnosis of HF. We compared the demographic and clinical characteristics associated with a prescription at discharge of ACE inhibitors, and used a Cox proportional hazard regression model to calculate the relative hazard of dying associated with the use of ACE inhibitors.

Results. We enrolled 818 patients in the study with a mean age of 79 years (range: 65–101 years). One fourth of the participants were aged 85 years or older. ACE inhibitors were prescribed to 550 patients (67.2%) at discharge. Older age and physical disability were negatively correlated with the use of ACE inhibitors. People using ACE inhibitors had a 40% reduction of mortality (HR [hazard ratio]: 0.60; 95% CI [confidence intervals]: 0.42–0.88). The reduction in mortality was much stronger among disabled people (HR: 0.35; 95% CI: 0.19–0.64).

Conclusion. ACE inhibitors are still underprescribed among elderly people with HF discharged from acute care hospitals. Even in this frail, elderly population, we found a beneficial effect of ACE inhibitors. There is room to further improve the quality of care for elderly people with HF.

THE positive effects of angiotensin-converting enyme (ACE) inhibitors in people with heart failure (HF) of any severity are well documented (1,2). There are few randomized trial on ACE inhibitors, however, that include people with advanced age. A meta-analysis of five large trials on the effects of ACE inhibitors in HF showed a pooled mean age lower than 65 years (3). Information on the effects of ACE inhibitors in older people comes from observational studies, but little data are on community-dwelling people and, for the most part, are obtained from people with myocardial infarction. The objective of this study is to estimate the prevalence of prescriptions of ACE inhibitors in elderly people with HF discharged from acute care hospitals, and to compare 1-year mortality rates in people taking or not taking these drugs.


   METHODS
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 Abstract
 Methods
Results
 Discussion
 References
 
Study Design
The Gruppo Italiano di Farmacoepidemiologia nell'Anziano (GIFA) ("Italian Group of Pharmacoepidemiology in the Elderly") is a collaborative group collecting data on inpatients admitted to geriatric and internal medicine wards of teaching and nonteaching hospitals in Italy.

In 1998, we started a follow-up study of patients discharged with a diagnosis of HF with the objective of evaluating the relationships between indicators of quality of care and health-related outcomes. We included in this study people aged 65 years or older with a diagnosis of HF. Exclusion criteria were explicit terminal prognosis (<6 months), thyroid diseases, living more than 20 miles from the hospital where the patient was enrolled, anemia (Hb [hemoglobin] < 9 g/dL), and chronic dialytic treatment. In-person follow-up visits were performed 3, 6, and 12 months after discharge.

We used the standard GIFA questionnaire for the baseline assessment (4). We collected information on sociodemographic and clinical characteristics. We evaluated cognitive status using the Italian version of the Abbreviated Mental Test (5,6), and physical function using the Basic and Instrumental Activities of Daily Living (ADL and IADL). We used the New York Heart Association (NYHA) scale to classify the severity of HF. To avoid the confounding effect of acute illness, we performed the measurements at discharge.

The questionnaire included a detailed section on the drugs taken just before hospital admission, during the hospital stay, and prescribed at discharge. All coexisting diseases were listed. To obtain more detailed information on comorbidity, we used the Cumulative Illness Rating Scale (CIRS) (7). This scale assigns a score to the total burden of illness relative to each body system, ranging from no disease (score = 0) to life-threatening disease (score = 4). The CIRS showed excellent concordance with data coming from autopsy (8).

In-person follow-up visits were performed at 3, 6, and 12 months. On each follow-up, the interviewer completed a subset of the baseline questionnaire. For participants who died, the interviewer recorded the date and cause of death by a telephone interview with the next of kin.

All participants gave informed consent, and this study was approved by the Ethical Committee of each participating center.

Analytic Approach
We evaluated the proportion of people with a prescription of ACE inhibitors at discharge, and compared the sociodemographic, functional, and clinical characteristics of people prescribed and not prescribed this drug, using the odds ratios (OR) along with 95% confidence intervals (CI) to express the strength of the association between the variable taken into account and the prescription of ACE inhibitors. Age was categorized into three groups (<75 years, 75–84 years, ≥85 years), and we considered as physically impaired those who needed help in at least 1 ADL. Cognitive impairment was defined as having a score on the Abbreviated Mental Test of 7 or lower. The prevalence of selected diseases (ischemic heart disease, atrial fibrillation, diabetes, renal failure, chronic obstructive pulmonary disease) in the two groups was analyzed. We used the item from the CIRS for this analysis when possible, with the score dichotomized as disease absent (CIRS score = 0) or present (CIRS score > 0). For diseases not specifically reported in the CIRS (coronary artery disease, atrial fibrillation), we used a list of diagnoses. We also compared the two groups with respect to laboratory findings (sodium, potassium, and cholesterol), presence of obesity (body mass index ≥ 30) (9), NYHA class, and drugs prescribed at discharge beside ACE inhibitors. Adverse drug reactions to ACE inhibitors during the hospital stay were also taken into account.

We estimated the mortality rate in the two groups using the product limit method. We used a multiple Cox regression model to obtain a deconfounded estimate of the hazard ratio (HR) associated with the use of an ACE inhibitors. To account for people who switched from one group to the other, we treated ACE inhibitor use as a time-dependent covariate. All the analyses were performed using SAS V8 software (SAS Institute, Cary, NC).


   RESULTS
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 Abstract
 Methods
 Results
Discussion
 References
 
Overall, we enrolled 818 persons. The mean age was 79.0 years (SD [standard deviation]: 7; range 65–101), and 24.2% were aged 85 years or older. Women comprised 49.9%. People discharged with a prescription of ACE inhibitors equaled 550 (67.2%). Angiotensin receptor blockers (ARBs) were prescribed at baseline only to 43 persons (7.8%). The prevalence of use of ARBs in subsequent follow-up visits was similar.

Table 1 compares the demographic and functional characteristics of people discharged with or without a prescription of ACE inhibitors, along with the correspondent OR of being prescribed an ACE inhibitor in people having or not having the selected characteristic. Those discharged with a prescription of ACE inhibitors were younger (22.7% of patients aged 85 years or more vs 27.2%), and had fewer physical impairments.


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  		Table 1. Baseline Sociodemographic and Functional Characteristics of Participants.

 
Table 2 shows the comparison of the prevalence of selected diseases in the two groups. The prevalence of coronary artery disease and atrial fibrillation was similar, while vascular diseases were slightly more prevalent among those being prescribed ACE inhibitors (73.5% vs 68.1%). Hypertension was positively correlated with a prescription of ACE inhibitors (OR: 2.40, 95% CI: 1.68–3.41), as was a diagnosis of diabetes mellitus (OR: 1.43, 95% CI: 1.01–2.03). As expected, low blood pressure (either diastolic or systolic) was less prevalent among those with a prescription of ACE inhibitors. In this group, we also found a lower prevalence of low sodium levels at discharge. The severity of congestive HF, as measured by NYHA classifications, was similar in the two groups.


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  		Table 2. Clinical Characteristics of Participants at Baseline.

 
In Table 3, we report the prevalence of prescription at discharge of cardiovascular drugs beside ACE inhibitors. People with a prescription of ACE inhibitors at discharge were more likely to also use digoxin (68.5% vs 60.4%; OR 1.42, 95% CI 1.05–1.93) and diuretics (86.7% vs 76.9%; OR: 1.97, 95% CI: 1.35–2.86). The prevalence of use of potassium-sparing diuretics, calcium-channel blockers, and antiarrhythmic drugs was lower among those discharged in therapy with ACE inhibitors, while we found no association between use of ACE inhibitors at discharge and prescription of antiplatelet agents, anticoagulants, HMG-CoA (hepatic hydroxymethyl glutaryl coenzyme A) reductase inhibitors, and occurrence of adverse reactions to ACE inhibitors during hospital stay.


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  		Table 3. Drugs Prescribed at Discharge.

 
Of the 818 patients enrolled, we had no follow-up information for 71, leaving 747 persons with at least 1 follow-up interview. An additional 54 patients were lost to follow-up after the first visit. There were no differences between the number of patients lost to follow-up in the group discharged with or without a prescription of ACE inhibitors (14.7% vs 16.4%, respectively). The mean follow-up time was 10.0 (SD: 3.7) months, and 50% of patients were followed for at least 12 months. At each follow-up visit, we found that approximately 5% of those previously treated with ACE inhibitors had discontinued the drug, while approximately 10% were new users. Overall, 155 patients died (18.9%), 90 patients (16.4%) were among those taking ACE inhibitors at baseline, and 65 patients (24.2%) were in the counterpart group. The different survival between those discharged with or without a prescription of ACE inhibitors is showed in Figure 1. The reduction of mortality associated with a prescription of ACE inhibitors was 44% (HR: 0.56, 95% CI: 0.41–0.78), the benefit being already evident at the beginning of follow-up. The correction for potential confounder changed this estimate only marginally (see Table 4). We found comparable results among people aged 75–85 years (HR: 0.55; 95% CI: 0.31–0.97) and aged 85 years or older (HR: 0.51; 95% CI: 0.27–0.95); while in the group aged 65–74 years, the HR was 1.92 (95% CI 0.63–5.83). We checked for effect modification on the multiplicative scale across gender and disability levels (Figure 2), calculating the ratio of the hazard ratios (RHR) along with their 95% CIs (10). We found that disability was a strong effect modifier, with a risk reduction of 65% associated with ACE inhibitor use (HR: 0.35; 95% CI: 0.19–0.64) among disabled people (n = 153), and 12% (HR: 0.88; 95% CI: 0.51–1.52) among nondisabled people (n = 595); the RHR was 2.53 (95% CI: 1.12–3.11). The effect modification across gender strata was less evident: The HR was 0.53 (95% CI: 0.31–0.89) in women (n = 375) and 0.69 (95% CI: 0.39–1.22) in men. The RHR was 0.76 (95% CI: 0.35–0.74).



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  		Figure 1. Kaplan-Meier estimate of survival in people discharged with (dashed line) or without (solid line) angiotensin-converting enzyme inhibitors (ACE-I)

 

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  		Table 4. Cox Regression Model Estimating the Adjusted Hazard Ratio and 95% Confidence Intervals for Mortality*.

 


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  		Figure 2. Stratified analysis of the risk of dying in people taking or not taking angiotensin-converting enzyme inhibitors (ACE-I) (estimates were obtained from Cox regression models adjusted for all the variables in Table 4). RHR = relative hazard ratio; CI = confidence intervals

 

   DISCUSSION
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Our findings confirm the relatively low prevalence of use of ACE inhibitors in people with congestive HF, and are consistent with data reported in other studies (11,12). Even in a very old population with a potentially less favorable risk/benefit ratio, the lack of a prescription in 30% of cases may not be justifiable, given the relatively low incidence of adverse drug reactions to these drugs (13) and the small number of contraindication. Older age and physical disability were negatively associated with the use of ACE inhibitors, and this finding is in accordance with other studies (14–16). The available evidence suggests that older people can benefit from ACE inhibitors therapy (17,18), and denying treatment only on the basis of age does not seem to be reasonable. The presence of potential contraindications, such as hypotension, renal dysfunction, and hyperkalemia is not a likely explanation for this finding, since none of these factors were associated with an ACE inhibitor prescription at discharge.

As expected, low systolic or diastolic blood pressure and concomitant use of calcium-channel blockers are associated with nonprescription of ACE inhibitors, as is the use of potassium-sparing diuretics. This latter finding is explained by the fact that ACE inhibitors can cause hyperkalemia, and their potassium-sparing effects are comparable to those of spironolactone in magnitude (19). This is also the likely explanation for the slightly lower use of ACE inhibitors among people with a potassium level ≥ 5 mEq/L.

The prevalence of prescriptions for diuretics and digoxin was high, and both of these drugs were associated with the use of ACE inhibitors in accordance with the current guidelines for the management of HF (20).

We found that the use of ACE inhibitors was associated with a 42% reduction of mortality, independent of age, disability, concomitant diseases, or drug therapy, and severity of congestive HF. This reduction is similar to the one observed in another observational study carried over in a similar setting (21), but is remarkably larger, for example, than the one observed in a meta-analysis on five clinical trials (20%) (22). In the context of an observational study, the overestimation of a beneficial effect of an intervention is predictable, and therefore this discrepancy is not surprising (23).

The finding that ACE inhibitors also have a protective role in people of advanced age and with a significant burden of comorbid diseases and disability is of value, because the generalization of the evidence from randomized clinical trials to patients with such characteristics, who are rarely involved in this type of studies (24), is not always straightforward (25,26).

In contrast with other studies (27), we did not find potassium-sparing diuretics to have an effect on mortality. However, differences in the characteristics of the population, HF severity, and concomitant medication use are likely to explain this difference.

The finding of a protective effect of diuretics on mortality was not expected. These drugs are known to relieve HF symptoms, and to improve ventricular function and resistance to exercise (28,29), but there is no conclusive evidence that they can lower mortality. Further information from randomized studies is needed to better explore this issue.

We could show no effect of ACE inhibitors in people aged younger than 75 years. However, the low number of events in this group (30) makes our estimate imprecise and does not permit the ruling out of either a beneficial or harmful effect.

In our study population, we found an interaction between the effect on mortality of ACE inhibitors and gender, with the protective effect of ACE inhibitors being more evident among women. We can only speculate on this finding on the basis of the data we have available. The different baseline risk of dying between men and women with HF may be implicated (30), as well as a different response to the drug in men and women. For example, studies on animal models have shown a differential effect of ACE inhibitors in male and female rats (31).

We also found that the effect of ACE inhibitors on mortality was much stronger among disabled people. A possible explanation is that noncardiac factors such as reduction of skeletal muscle mass may be implicated in the pathogenesis of HF (32). ACE inhibitors can act on skeletal muscle, reversing these changes in part and improving exercise tolerance (33,34). Disability is directly correlated with skeletal muscle mass (35), and it is plausible that the effect on skeletal muscle is more evident in disabled people, in whom muscle abnormalities are likely to be more important. This action could at least partially explain the higher protection observed among disabled people, although it is not possible to automatically translate the benefit on exercise tolerance to the benefit on survival.

This study has some limitations. We did not perform a chart review, and we were unable to analyze the reasons for the lack of prescriptions at the individual level. For the same reason, we could not differentiate between systolic versus diastolic heart failure. We had no survival information for 15% of the people in this sample. Although the percentage of people lost to follow-up was not differential between those discharged with or without ACE inhibitors, we do not know to what extent that our findings have been biased by this loss of information. Being an observational study, we cannot establish a direct cause–effect correlation between ACE inhibitors and reduction in mortality. However, our results are consistent with the evidence coming from other sources, and in particular from randomized clinical trials. The study design makes it impossible to avoid the bias due to confounding by indication (meaning that those receiving the drug will most likely benefit from the treatment).

Conclusion
The findings presented here lend support to the hypothesis that it is safe to extend the results of randomized clinical trials on ACE inhibitors in heart failure as well as the guideline's recommendations on the use of these drugs to very old, frail people. The lack of prescription of these drugs to a substantial proportion of people in this group does not seem to be justified on the basis of current knowledge. In particular, the lower rate of prescriptions among disabled people is of concern in consideration of the beneficial effect observed in this group. Although the rate of prescriptions of ACE inhibitors in elderly people with HF is rising (36), efforts should be made to further improve the quality of care for HF in this population.


   Acknowledgments
 
This research was funded by a grant from the Regione Toscana Health Agency and from the Italian National Research Council. The GIFA (Gruppo Italiano di Farmacovigilanza nell'Anziano) study group received financial support from Merck, Sharp & Dohme, Rome, Italy.

The GIFA Study Group Steering Committee: P. U. Carbonin, L. Carosella, M. Pahor, C. Pedone.

Participating Centers: Unità di Geriatria, INRCA, Ancona (A. Paciaroni, L. Gigli); Ospedale S. Donato, Arezzo (C. Pedace, P. Corsi); Cattedra di Geriatria, Policlinico Universitario, Università di Bari (A. Capurso, V. Solfrizzi, F. Panza, R. Noya, N. Marella); Dipartimento di Epidemiologia e Clinica Geriatrica, Università di Chieti (G. Abate, A. Di Iorio, T. Palmerio, N. Morelli, B. Paganelli, L. Fracassi, E. Sparvieri); Reparto Medicina Geriatrica, INRCA, Cosenza (A. Corsonello, B. Mazzei, C. Zottola, G. Gaudio); Istituto di Medicina Interna II, Università di Ferrara (R. Fellin, S. Volpato, R. Zanca, A. Blè, E. Calmieri, G. Zuliani); Istituto di Clinica Medica e Cardiologia, Università di Firenze (G. Gensini, E. Cecchi, L. Reali); Istituto di Gerontologia, Università di Firenze (G. Masotti, S. Fumagalli); Istituto di Farmacologia Clinica, Firenze (A. Mugelli, R. Matucci); Dipartimento di Medicina Interna, Università di Messina (V. Nicita Mauro, G. Basile); Istituto di Medicina Interna, Università di Milano (D. Mari, P. Ferrazzi, C. Lodigiani, I. Quaglia); Divisione di Geriatria, Policlinico Universitario, Università di Modena (G. Salvioli, C. Mussi); Cattedra di Geriatria, Università di Napoli (F. Rengo, P. Abete, G. Lucchetti); Istituto di Medicina Interna e Geriatria, Università di Palermo (M. Barbagallo, A. Di Sciacca, L. Dominguez); Istituto di Clinica Medica, Università di Palermo (G. Licata, B. Tuttolomondo); Cattedra di Geriatria, Università di Parma (G. Valenti); Sezione di Gerontologia e Geriatria, Università di Perugia (U. Senin, A. Cherubini); Centro di Medicina dell'Invecchiamento, Università Cattolica del S. Cuore, Roma (G. Onder, F. Pellicciotti, S. Urgese); II Divisione Bassi, Ospedale S. Camillo, Roma (G. Di Lascio, S. Pedace); Cattedra di Gerontologia e Geriatria, Università "La Sapienza," Roma (V. Marigliano, L. Tafaro, P. Cicconetti, E. Ettorre, I. Trani, M. T. Tombolillo); Istituto di Semeiotica Medica e Geriatria, Policlinico "Le Scotte," Siena (S. Forconi, M. Guerrini, S. Rosati); Istituto di Clinica Medica, Università di Trieste (L. Cattin, E. Buratti, M. Fonda, I. Buda, E. Manca); I Divisione Geriatrica, Ospedale Civile Maggiore, Verona (G. Zavateri, A. Alberto, C. Bellamoli, M. P. Conti, P. N. Garzoli, P. Peroli, M. Scodellari, M. Confetti).

Received August 4, 2003

Accepted January 23, 2004


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