European Journal of Heart Failure

European Journal of Heart Failure 2004 6(5):663-668; doi:10.1016/j.ejheart.2004.03.011

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© 2004 European Society of Cardiology

Relation of sex, age and concomitant diseases to drug prescription for heart failure in primary care in Europe^*

Jorg Muntwyler^a,*, Alain Cohen-Solal^b, Nick Freemantle^c, Joanne Eastaugh^c, John G. Cleland^d and Ferenc Follath^a

^a Department of Internal Medicine, University Hospital Zurich, Switzerland
^b L'Hôpital Beaujon Clichy, France
^c Department of Primary Care and General Practice, University of Birmingham Birmingham, UK
^d Department of Cardiology, University of Hull Kingston upon Hull, UK

^* Corresponding author. Present address: Cardiovascular center, University Hospital, 8091 Zurich, Switzerland. Tel.: +41-1-255-85-83; Fax: +41-1-255-45-54. E-mail address: joerg.muntwyler{at}dim.usz.ch

	Abstract

Top Notes Abstract 1. Background 2. Study population and... 3. Results 4. Discussion References

 
Aim: To study the role of sex, age and concomitant diseases for prescription of cardiovascular drugs among patients with heart failure cared for in the community.

Methods and Results: In 15 European countries, a survey was conducted during 1999 and 2000 among 1363 primary care physicians who included 8256 patients with symptoms of heart failure. Predictors of drug prescription were assessed with multivariate logistic regression. Overall prescription rates for ACE-inhibitors/angiotensin receptor blockers (ACE-I/ARB), beta-blockers, digitalis, diuretics and oral anticoagulants were 69%, 30%, 41%, 75% and 18%. Women had no reduced likelihood to receive ACE-I/ARB and beta-blockers (odds ratio [OR]=0.96 [95% CI 0.87–1.06] and 1.02 [0.92–1.13], respectively), but prescription of oral anticoagulants was decreased (OR=0.74, 95% CI 0.65–0.84). Compared to patients <65 years of age, ACE-I/ARB prescription did not materially decline up to 75–85 years (R=0.91, 95% CI 0.81–1.04), whereas beta-blocker prescription was already significantly decreased in this age category (OR=0.49, 95% CI 0.43–0.56). There was no general under-prescription of evidence-based cardiovascular drugs in patients with concomitant diseases.

Conclusions: Among heart failure patients cared for in the community advanced age strongly predicts decreased prescription of beta-blockers. Female sex and comorbidity is not associated with a consistent underutilization of evidence-based cardiovascular drugs.

Key Words: Heart failure • Drug utilization • Quality of care • ACE-inhibitors • Beta-blockers • Oral anticoagulants

Received July 14, 2003; Revised February 19, 2004; Accepted March 10, 2004

	1. Background

Top Notes Abstract 1. Background 2. Study population and... 3. Results 4. Discussion References

 
Heart failure is associated with a poor prognosis. Patients hospitalized for heart failure have a 1-year mortality of up to 40% [1], and in patients cared for in the community 1-year mortality is three-fold increased compared to controls [2] and to the general population [3]. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACE-I and ARB) [4–6] as well as beta-blockers [7–9] are highly effective in the reduction of cardiovascular endpoints. Despite the marked benefit, there is evidence that drug therapy of patients with heart failure is less than optimal. In patients with other heart diseases, advanced age [10], concomitant diseases [10] and female sex [11] were associated with reduced prescription rates of evidence-based cardiovascular medications. As for heart failure, data on predictors affecting current drug utilization are limited. In previous studies, the association between sex and ACE-I prescription was inconsistent [12–18] and that with beta-blockers is unknown. There was a strong decline in ACE-I prescription with increasing age in most studies [12–14] but data on the relationship between age and beta-blocker prescription in current heart failure patients are sparse [18]. With respect to concomitant diseases, the influence on drug prescription in heart failure patients is also not clear [19]. Furthermore, most of the assessments of drug therapy refer to patients under the care of a hospital physician [12,13,16,18,19]. Since patients with chronic heart failure are mostly cared for by the primary care physicians, it is important to know the factors which affects the current drug therapy in this setting.

We therefore studied the role of sex, age and concomitant diseases on prescription of cardiovascular drugs in a large heart failure population representing treatment patterns in primary care in 15 European countries.

	2. Study population and methods

Top Notes Abstract 1. Background 2. Study population and... 3. Results 4. Discussion References

 
The enrollment procedure and main results of the IMPROVEMENT of HF survey have been published in detail elsewhere [20]. The survey was conducted during 1999 and 2000 in 15 European countries. In each country, 10 regions were selected. From a list of physicians, a random sample of approximately 10 primary care physicians per region was included. Participating physicians recorded in a log file over a 6-week period, the patients they saw with heart failure or who had a myocardial infarction. Health care professionals visited the participating physicians and completed a perception and actual practice survey. For the actual practice survey, from the log file 6 patients with heart failure and 3 patients with history of myocardial infarction (with or without heart failure) were randomly chosen. Data regarding personal history of heart disease, concomitant diseases, diagnosis, advice to the patients, and therapy were collected. Of 11 062 enrolled subjects, we selected all patients (n=8256) who had New York Heart Association class II–IV heart failure symptoms.

In the primary analyses of the IMPROVEMENT data set, we presented results on the extent to which patients with an established diagnosis of heart failure and evidence of left ventricular systolic dysfunction (3796 patients) are prescribed appropriate medication [20]. In the current study, we assess in more detail drug prescription in the broader, less selected group of patients with symptoms of heart failure.

2.1. Statistical analysis
Age was arbitrarily categorized into <65, 65–74, 75–84, and 85 years. Means and proportions were calculated overall, according to age classifications and sex. The independent effects of age, sex and co-morbid conditions on the treatment likelihood with different cardiovascular drugs were assessed with multivariate logistic regression. Outcome variables were prescription of ACE-inhibitors or angiotensin receptor blockers (ACE-I/ARB); beta-blockers; digitalis; loop diuretics or thiazides; spironolactone; and oral anticoagulants. Predictor variables were sex, age, coronary, peripheral arterial and cerebrovascular disease, diabetes mellitus, pulmonary disease, renal dysfunction (reported as pathological BUN and/or creatinine), atrial fibrillation and NYHA functional class. All analyses were performed with SAS 8.1. All P-values are two-sided, and P<0.05 was taken to be statistically significant.

	3. Results

Top Notes Abstract 1. Background 2. Study population and... 3. Results 4. Discussion References

 
A total of 8256 patients fulfilled the selection criteria. Patient's characteristics overall and according to age classification are given in Table 1. Mean age was over 70 years. About two-thirds of the patients <65 years of age were male, whereas among those >85 years two-thirds were female. Among younger patients coronary heart disease and idiopathic dilated cardiomyopathy were more frequently observed as the underlying cause of heart failure than in older subjects, whereas unknown etiology of heart failure was more common in older patients. In all age categories, there was a high level of comorbidity (Table 1). Among older subjects, prevalence of cerebrovascular disease, renal dysfunction and atrial fibrillation was higher compared to younger subjects.

View this table: [in this window] [in a new window]   Table 1 Characteristics of the study population according to age

 
In Table 2, prescription frequencies of cardiovascular drugs according to sex and age are given. There was no difference in prescription of ACE-I/ARB between men and women (women vs. men, 69% vs. 69%, P=0.73). Up to an age of 85 years, there was no notable decline in prescription of ACE-I/ARBs, but among male patients of 85 years of age, prescription was moderately reduced. The proportion of women who received beta-blockers was lower compared to men (27% vs. 33%, P<0.001). In the different age subgroups, however, there was evidence for a difference in beta-blocker prescription between men and women only among patients <65 years of age. Beta-blocker prescription markedly declined with increasing age in men and women. Despite the fact that atrial fibrillation was reported in a higher proportion of women (29% vs. 24%, P<0.001), oral anticoagulants were less frequently prescribed to women (15% vs. 21%, respectively, P<0.001).

View this table: [in this window] [in a new window]   Table 2 Prescription of cardiovascular drugs according to sex and age

 
In Table 3, we present the multivariate predictors of drug prescription. For ACE-I/ARB and beta-blockers, there was no evidence that female sex was associated with reduced likelihood of prescription. In contrast, there was a markedly reduced likelihood for prescription of oral anticoagulants.

View this table: [in this window] [in a new window]   Table 3 Multivariatea predictors of drug prescription expressed as odds ratios (95% confidence intervals)

 
With regard to age, the multivariate models confirmed a relatively stable likelihood of ACE-I/ARB prescription, up to the category of patients aged 75–84 years, whereas for beta-blockers, already in the age category 65–74 years, the prescription probability significantly declined. A significant decrease in prescription likelihood was observed for oral anticoagulants in patients over 75 years of age.

Concomitant diseases were strongly associated with the drug prescription patterns. Diabetes mellitus and hypertension predicted increased utilization of ACE-I/ARBs. Definite coronary artery disease was associated with a markedly increased use of beta-blockers whereas pulmonary disease predicted reduced utilization of beta-blockers. For oral anticoagulants there was an increased use in subjects with atrial fibrillation and also in those with coronary, peripheral or cerebrovascular disease.

	4. Discussion

Top Notes Abstract 1. Background 2. Study population and... 3. Results 4. Discussion References

 
This large study among patients with symptoms of heart failure cared for by primary care physicians provides an insight into important factors potentially determining drug therapy in primary care across Europe. Overall, there was no indication for a sex bias in drug therapy of heart failure. There was also only limited evidence for inadequate drug utilization due to concomitant diseases. However, there was evidence for reduced prescription of certain cardiovascular medications above drug-specific age cut offs.

4.1. Sex and drug prescription
In several studies, prescription of ACE-I has been shown to be lower among women compared to men [12–14], but other studies have not found differences between the sexes [15,16]. In our study, for the mainstays of heart failure therapy – ACE-I/ARBs and beta-blockers – there was no evidence for a difference between men and women despite the high power to detect small treatment deviations. For beta-blockers, the crude proportion of treatment frequency might have suggested that women are undertreated. However, this difference was mostly explained by the different age distribution of men and women, and therefore, in the multivariate model, there was no significant reduced treatment likelihood among females. These findings do not suggest that there was a sex-bias in favour of treating men with beta-blockers. However, since among the elderly there is a high proportion of female, women are more strongly affected by the reduced beta-blocker prescription at advanced age. The only cardiovascular drug class for which in women there was an independent lower treatment probability was oral anticoagulants. This difference could not be explained by differences in the age distribution, prevalence of coronary artery disease, atrial fibrillation and other stroke risk factors since this finding persisted in the multivariate adjusted model. Although the reason remains unknown, this observation is consistent with studies among patients with atrial fibrillation that also found an unexplained lower probability of anticoagulation among women [11,21].

4.2. Age and drug prescription
There is a large body of evidence that advanced age is one of the most important predictors of reduced drug utilization. Specifically, in patients with heart diseases it has been shown that treatment with ACE-inhibitors [12–14], beta-blockers [10] and anticoagulants [11,21] decreases with advancing age. The large sample size of the current study allowed us not only to test the overall association of age with drug utilization, but also to receive precise estimates for different age groups. Unlike former studies, we found only a modest decline in prescription of ACE-I/ARB with advancing age; indeed, up to age of 85 years, prescription remained stable. Clinical guidelines, training and experience had made agents that block the renin-angiotensin system part of the standard therapy of heart failure even among elderly patients.

In sharp contrast to this finding, beta-blocker prescription as a relatively novel drug in heart failure therapy [7–9] was limited overall and declined steeply with age. This was already true for patients aged 65–74 years, for which clinical trials have demonstrated an important risk reduction [8,9]. With increasing age, poor beta-blocker tolerance may account for part of the decrease in prescription. Nevertheless, the large between-country variability [20] and the steep drop in beta-blocker prescription with increasing age makes it unlikely that this is the principal cause of reduced treatment likelihood. Our results indicate a clear need for physician education to improve beta-blocker utilization in heart failure patients in general, and among older heart failure patients in particular.

Use of oral anticoagulation was relatively similar in different age categories up to 75 years of age, and then declined. There is no evidence for the use of anticoagulants in all patients with heart failure, but there is a sizable proportion of subjects with atrial fibrillation and other indications for oral anticoagulants in this population. The proportion of subjects with atrial fibrillation exceeded the fraction of patients using anticoagulants in all age categories, but the gap increased with advancing age. Since bleeding risk was not systematically assessed in our study, we cannot determine the proportion of patients who were not anticoagulated for this reason. Our data, however, raise the possibility that there is a substantial underuse of oral anticoagulants particularly among elderly heart failure patients. Further studies are needed to more clearly define the probable underuse of oral anticoagulants in heart failure patients.

4.3. Concomitant diseases and drug prescription
Concomitant diseases have been found to be associated with decreased prescription rates of important cardiovascular drugs [10,19]. Since the number of concomitant diseases is high among heart failure patients [22], underuse associated with comorbidity could markedly affect drug prescription. However, in the current study, the impact of comorbidity on underuse of cardiovascular drugs appeared to be limited. In previous studies of patients with acute heart failure, there was evidence that renal dysfunction is associated with lower prescription of ACE-I [19]. In the current study of patients in primary care, those with renal dysfunction were not less likely to receive ACE-I/ARBs. Beta-blockers were formerly considered to be contraindicated in patients with diabetes mellitus and obstructive pulmonary diseases. Because it has been shown that beta-blockers decrease the cardiovascular risk as much or even more in patients with comorbidity compared to those without [10,23], it is now recommended to prescribe beta-blockers to most patients with comorbid conditions if tolerated. In our heart failure population, only those with pulmonary disease had a moderately reduced probability of beta-blocker prescription. Non-prescription in a fraction of those with obstructive pulmonary disease may be due to poor drug tolerance and moreover might be justified among patients with severe pulmonary obstruction [24]. There was, however, no reduced treatment likelihood among patients with peripheral vascular disease and diabetes as observed in earlier studies of patients after myocardial infarction [10]. Thus, the former misconception of restricting the use of beta-blockers to patients without important comorbidities appears no longer to affect beta-blocker prescription in general.

While there was only limited evidence for an underuse of drugs due to comorbidity there were concomitant diseases associated with a marked increase in prescription of ACE-I/ARB and beta-blockers. Patients with diabetes mellitus and those with hypertension were more likely to receive ACE-I/ARB, and as expected patients with coronary disease were more likely to receive beta-blockers. Thus, in contrast to the perception that comorbidity is mainly associated with underuse of drugs, our data indicate that absence of certain concomitant diseases for which specific drugs are indicated may be associated with lower drug prescription rates.

4.4. Study limitations
It is important to note that that the current study does not assess the initial treatment of patients with suspected heart failure treated by primary care physicians, but does show treatment rates and factors affecting therapy cross-sectionally, which will also be influenced, among other factors, by duration of the disease, previous hospital stays and assessment by other physicians. Participation in this survey was voluntary, and participating physicians might have had a special interest in heart failure. Moreover, it is possible that physicians tended to include patients with a clear heart failure diagnosis. Therefore, we cannot exclude the possibility that drug therapy in our study population was somewhat superior compared to the general outpatient heart failure population in Europe. If so, this would indicate that even in a population with above-average quality of care, some drugs are underprescribed and more so in older patients. The patient selection for the current study was based on heart failure symptoms, and left ventricular ejection fraction was not considered for the sample selection. With these wide inclusion criteria, patients with systolic heart failure, but also those with less precisely defined diastolic heart failure and patients without assessed ventricular function were included. It is therefore likely that heart failure was misdiagnosed in a portion of the study population. Our results therefore represent an overall picture of predictors of drug prescription among subjects with heart failure symptoms in Europe, but predictors of drug utilization may vary between specific subgroups or countries. For example, among patients with heart failure symptoms and known reduced left-ventricular systolic function, ACE-inhibitor prescription (not including angiotensin receptor blockers) was slightly, but significantly lower among women compared to men (odds ratio 0.80, 95% CI 0.70–0.92) [20]. Finally, at the time when the current study was undertaken, evidence for the benefit of beta-blockers was new [7–9], and the most recent ESC guidelines [25] regarding the use of beta-blockers had not yet been published. Drug prescription as well as the respective predictors may change relatively rapidly over time, and therefore, periodical re-assessment of quality of care of heart failure therapy will be necessary.

In summary, this study provides an insight into the current role of sex, age and concomitant diseases on the utilization of cardiovascular drugs among patients with symptoms of heart failure cared for in the community in Europe. Overall, female sex and comorbidity were not major predictors of drug underuse as suggested in some former studies. However, in agreement with previous studies, increasing age was still associated with reduced likelihood of treatment, particularly for beta-blockers. There is a need to improve physician education about beta-blocker prescribing for patients with heart failure. With increasing confidence in beta-blocker use in this setting, it is likely that prescription will also be extended to the older segment of the heart failure population.

	Notes

Top Notes Abstract 1. Background 2. Study population and... 3. Results 4. Discussion References

 
Funding: Unrestricted educational grant by SERVIER SA, Paris, France and the respective country braches.

	References

Top Notes Abstract 1. Background 2. Study population and... 3. Results 4. Discussion References

 

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