Regional differences in the characteristics and treatment of patients participating in an international heart failure trial

Journal of Cardiac Failure Vol. 4 No. 1 1998

Clinical Investigations Regional Differences in the Characteristics and Treatment of Patients Participating in an International Heart Failure Trial BARRY M. MASSIE, MD, FACC,* JOHN G.E CLELAND, MD, FRCR FESC, FACC,* PAUL W. ARMSTRONG, MD, FACC,~ MILTON PACKER, MD, FACC,~ PHILIP A. POOLE-WILSON, MD, FRCR FESC, FACC,* RYDEN LARS, # FOR THE ASSESSMENT OF TREATMENT WITH LISINOPRIL AND SURVIVAL (ATLAS) TRIAL INVESTIGATORS San Francisco, California; Glasgow, United Kingdom; Edmonton, Canada; New York, New York; London, United Kingdom; Stockholm, Sweden

ABSTRACT Aims: This study was designed to determine regional differences in patient characteristics and medication use among patients entered into an international heart failure trial. Methods and Results: Data for this analysis were derived from the Assessment of Treatment with Lisinopril and Survival Study (ATLAS), a prospective randomized comparison of high- and low-dose therapy with lisinopril in patients with New York Heart Association class II, III, or IV chronic heart failure, which enrolled 3164 patients in 291 centers in 19 countries on 3 continents. Information was collected at baseline concerning patient demographics, etiology of heart failure, accompanying conditions, prior revascularization procedures, and medication use. The primary findings were a lower incidence of ischemic cardiomyopathy in southern and western Europe, more frequent diabetes in North America, and a greater use of coronary revascularization in the United States and Canada. There was substantial variation in medication use, particularly with regard to digoxin, anticoagulants, and amiodarone. Conclusions: Although there is considerable overlap in guidelines concerning the treatmerit of heart failure issued by authorities in Europe and North America, there are significant regional variations in medication use. Some, but not all, of these differences can be explained by differences in patient characteristics. Key words: heart failure, angiotensin-converting enzyme inhibitors, clinical trial, practice patterns, drug therapy.

From the *Department of Medicine, University of California, San Francisco, California; *University of Glasgow, Glasgow, United Kingdom; .~Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom; ~Department of Medicine, University of Alberta, Edmonton, Canada; ~Columbia University College of Physicians and Surgeons, New York, New York; and Karolinska Hospital, Stockholm, Sweden. Manuscript received October 9,1997; manuscript accepted December 12,1997. Reprint requests: Barry M. MassJe, MD, FACC, University of California, Veterans Affairs Medical Center (111C), 4150 Clement Street, San Francisco, CA 94121. e-mail: massie'barry@sanfrancisc°'va'g°v Copyright © 1998 by Churchill Livingstone ® 1071-9164/98/0401-000258.00/0

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Journal of Cardiac Failure Vol. 4 No. 1 March 1998

Chronic heart failure (CHF) is a growing health problem worldwide, resulting in considerable mortality, morbidity, and health care resource utilization (1-3). In the developed world, the etiology and management of patients with CHF are often regarded as homogeneous. Guidelines developed by expert committees in the United States, Canada, and Europe are remarkably similar in their recommendations concerning the evaluation and treatment of CHF patients (4-8). However, there are few data available comparing the characteristics and treatment of these patients. Therefore, we have analyzed the baseline data from the ongoing Assessment of Treatment with Lisinopril and Survival trial (ATLAS), the first large trial to enroll CHF patients in Australia, North America, and throughout Europe.

Methods The ATLAS trial was designed to test the hypothesis that patients treated with high doses of an angiotensinconverting enzyme (ACE) inhibitor (lisinopri132.5 or 35 mg daily) would have a better survival rate than those treated with low doses (lisinopril 2.5 or 5 mg daily) (9). Enrolled patients could have New York Heart Association II, III, or IV symptoms, but class II subjects were required to have been hospitalized or received emergency treatment for CHF within 6 months of entry. All participants were required to have had a left ventricular ejection fraction --30% within the prior 3 months and to have received diuretics for 60 days or longer. Treatment with ACE inhibitors before entry was permitted but not required. No other drugs were required or restricted in the treatment of CHE Other exclusion criteria that influenced the characteristics and treatment of the participants included age -<18 years, premenopausal women who were not surgically sterilized, myocardial infarction or cardiac surgery within 2 months of entry, percutaneous coronary revascularization within 2 weeks of entry, ongoing therapy with class I antiarrhythmic or nonsteroidal anti-inflammatory agents (except aspirin), serum creatinine concentration >221 txmol/L (2.5 mg/dL), contraindications to the use of ACE inhibitors, or other conditions that might limit survival. Altogether, 3164 patients entered the study and were randomized to low- or high-dose lisinopril between October 1992 and June 1994, and these form the population for the present analysis. This population was recruited from 291 centers in 19 countries on 3 continents: Australia, North America (United States [US] and Canada), and Europe. To provide adequate-sized groups for analysis (a minimum of 200 patients), Europe was subdivided into blocs according to geographic proximity: the

United Kingdom and the Republic of Ireland (UK/Ire), Netherlands and Belgium (Neth/Belg), the Nordic countries (Denmark, Finland, Norway, and Sweden), Central Europe (Cent-Eur) (Czech Republic, Hungary, Slovakia, and Switzerland [which contributed only 2 patients]), and southwest Europe (SW-Eur) (France, Portugal, and Spain). Before undertaking this consolidation, it was determined that there were no significant differences between the countries that were grouped together. To identify regional differences in patient characteristics or treatment, data were analyzed by one-way analysis of variance (ANOVA) for parametric variables, such as age, or contingency table analyses for all other data. With regard to the latter, the chi-square statistic was used to identify variables in which significant regional differences were present. If these were found, each region was compared to the remainder of the study population. Since eight regions were compared for each variable, a Bonferroni correction was used, establishing the threshold for statistical significance at P < .006 (.05/8).

Results Characteristics of the Overall Patient Population The mean age of the overall group was 64 _+ 10 (SD) years, 79% were men, 91% were white, and approximately 80% had CHF for more than i year (mean, 3.4 _+ 3.6 years). The etiology of heart failure (primary or contributing factor) recorded by the investigator was ischemic heart disease in 64 % of patients, idiopathic dilated cardiomyopathy in 28%, hypertension in 20%, valvular heart disease in 6%, and other or unknown cause in 7%. The medical histories disclosed that 55 % had prior myocardial infarctions, 15% had a history of unstable or severe angina pectoris, 24% had undergone coronary artery bypass surgery, and 6% had prior percutaneous coronary angioplasty. At the time of entry, 20% of patients were receiving medication for diabetes mellitis (7% insulin, 13% oral hypoglycemic agents). At the beginning of the study, 77% of participants were classified as New York Heart Association class III, with 16% and 7% as class II and class IV, respectively. The mean ejection fraction was 23%.

Regional Differences in Patient Characteristics Table i shows the regional differences in patient characteristics. The differences in patient age by region were generally small, although those from Cent-Eur were 3 to 7 years younger than elsewhere. Fewer women were enrolled from UK/Ire centers, and a significantly higher percentage of the patients from the US were women. There were more nonwhites in US centers.

International Differences in CHF Patients

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Table 1. Regional Differences in CHF Patient Characteristics Region/Country All Patients n Age (yr) Women (%) Nonwhite (%) Ischemic CM (%) Idiopathic CM (%) Hypertension (%) Diabetes Rx (%) Atrial fibrillation (%) Prior CABG (%) Prior PTCA (%)

3164 64 +- 10 21 9 64 21 20 20 18 24 6

US

Canada

Australia

UK/Ireland

1198 64 +_ 11 23 20 61 19

290 64 +- 10 21 7 69 19

362 64 -+ 10

17 26

91 66 -+ 8 19 4 68 20 15 19 14 32

8

4

28 26 14 34 10

13 31

Nordic Netherlands/ Countries* Belgium

1

460 65 -+10 18 0

72

74

17 I2

18 17

6 23

11

Central Europe*

SW Europe*

259

255

66 ~- 9

59 +- 10

249 62 -+ 10 18 5

19

22 23

26 0 67 16 16 15 19 19

3

2

5

14

18 0 65 26 20 19 18 5 1

43 41

12 15 21 6 3

Values in bold italic print are significantly different from remainder of patient population at P < .01. CM, cardiomyopathy; Diabetes Rx, therapy with insulin or oral hypoglycemia; CABG, coronary artery bypass surgery; PTCA, percutaneous transluminal coronary angioplasty or other procedure; SW Europe, southern and western Europe. * See the Methods section for specific countries.

T h e r e w e r e s t r i k i n g l y f e w e r p a t i e n t s w h o s e C H F was

H y p e r t e n s i o n w a s listed as t h e c a u s e o r a c o n t r i b u t i n g

a t t r i b u t e d t o i s c h e m i c h e a r t d i s e a s e in S W - E u r , w i t h cor-

f a c t o r in t h e e t i o l o g y o f h e a r t f a i l u r e m o r e f r e q u e n t l y in

r e s p o n d i n g l y f e w e r p a t i e n t s giving a h i s t o r y o f m y o c a r -

t h e US, a n d less o f t e n in U K / I r e , S E - E u r , a n d C a n a d a .

dial i n f a r c t i o n o r u n s t a b l e a n g i n a p e c t o r i s . I s c h e m i c

T h e r e w e r e s u b s t a n t i a l l y m o r e t r e a t e d d i a b e t i c s in C a n -

h e a r t d i s e a s e was c i t e d as t h e e t i o l o g y m o r e f r e q u e n t l y

a d a a n d t h e US.

in N o r d i c a n d U K / I r e p a t i e n t s . C o n v e r s e l y , n o n i s c h e m i c

The n u m b e r of patients with a history of prior revas-

d i l a t e d c a r d i o m y o p a t h y w a s m o r e c o m m o n in S W - E u r

c u l a r i z a t i o n p r o c e d u r e s also v a r i e d widely, a n d this vari-

a n d less so in N o r d i c a n d U K / I r e c o h o r t s . T h e slightly

ability c a n n o t fully b e e x p l a i n e d b y t h e p r e v a l e n c e o f

h i g h e r p r o p o r t i o n o f n o n i s c h e m i c c a r d i o m y o p a t h y in

ischemic cardiomyopathy. The n u m b e r of patients w h o

t h e U S p a t i e n t s also a c h i e v e d s t a t i s t i c a l significance.

had undergone coronary bypass surgery ranged from

Table 2. Regional Differences in Baseline Medication Usage Region/Country All Patients n Prior ACE inhibitors Diuretics Digitalis Atrial fibrillation Sinus rhythm Nitrates Ischemic CM Nonischemic CM Beta-blockers Ca2+ blockers Aspirin Ischemic CM Nonischemic CM Anticoagulants Ischemic CM Nonischemic CM Atrial fibrillation Sinus rhythm Amiodarone

US

Canada

Australia

UK/Ireland

Nordic Countries*

Netherlands/ Belgium

Central Europe*

SW Europe*

3164 88 91 67 88 62 43 51 25

1198

290

460

95

76

81

99

100

255 90 99

249 88 98

76

82

57

80

92

74 38

80

46 26

37 44 22

91 93 100 55 69 53 39 52 10

362

91

11

9

8

11

12 41 51 21 37 35 40 65 31

13 41 52 24 36 36 36 71 30

10 42 50 25 36 32 45 72 29

9 51 66 17 36 24 41 77 22

9

6

9

13

99

99

259 90 99

36

61

57

81

80 23 42 53 15

92 52 42 50 21

88

89

78

50

79 64 81

52 55 75

6 18 48 60

25

32 5 9 42 56 18 33 34

27 4 9

17 25 24 29 42 20 9

10 44

54 16 33 30 43 64 24 4

Values in bold italic print are significantly different from remainder of patient population at P < .01. CM, cardiomyopathy; SW Europe, southern and western Europe. * See the Methods section for specific countries.

43 41

27 15 9 27 24

14 54 56 49 84

32 49

46

30

19

6

27

43 24 54 53 55

67 51 24

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Journal of Cardiac Failure Vol. 4 No. 1 March 1998

5% in Cent-Eur to 34% in the US, with all three nonEuropean countries having substantially higher rates than the European centers. Prior percutaneous coronary revascularization procedures were also more frequent in the US patients.

Regional Differences in Medication Use The considerable regional variation in medication use is shown in Table 2. Approximately 80% of patients in Canada, Cent-Eur, and US used digitalis preparations, but only 36% used this medication in UK/Ire; this variation was reflected in the use of digoxin by patients who were in sinus rhythm because it was used in a large proportion of patients with atrial fibrillation in all regions. In the Nordic countries, 25% of patients used betablockers, and in Neth/Belg, 15% used these drugs, which was a significantly higher rate than elsewhere in Europe; percentages in Australia, US, and Canada were in the middle of these two regions. The use of calcium channel blockers was greater in UK/Ire, and the trend in Australia was toward a higher rate of use. The disparity in use of coumarin anticoagulants was noted. The majority of patients enrolled in SE-Eur and Neth/Belg received anticoagulant therapy, compared to only 25% of those in UK/Ire. Anticoagulation was used more frequently in patients with atrial fibrillation in all regions, but the regional variation was apparent regardless of rhythm. There was no significant difference in the proportion of patients with and without eschemic heart disease treated with anticoagulants, but aspirin was used much more frequently in patients with ischemic cardiomyopathy. Not surprisingly, the use of aspirin was inversely related to the use of anticoagulants. A final striking observation was the very high number of patients receiving amiodarone therapy in SW-Eur and Neth/Belg, and the relatively low number in the Nordic countries, US, and Cent-Eur. Again, this difference cannot be explained by specific indications because a history of symptomatic ventricular arrhythmia was an exclusion criterion. Overall, 88% of patients entering the ATLAS trial were taking an ACE inhibitor before entry. This number was significantly lower in UK/Ire patients (76 %) and the Nordic countries (81%) and somewhat higher in Canada and the US. However, these figures must be viewed with particular caution because recruiting may have focused on untreated patients in some centers and patients in a long-term follow-up program (and probably receiving ACE inhibitors) in other centers.

Discussion Heart failure is the most rapidly growing cardiovascular condition in developed countries, affecting approximately 1-2% of the adult population (1-3). It is associ-

ated with a high mortality rate and is responsible for an increasing proportion of health care resources. Recognition of the magnitude of this problem has led health authorities to designate heart failure as an important area for research initiatives and for improving clinical practices. There have been important advances in both the pharmacological and surgical treatment of heart failure. During the past couple of decades, the efficacy of vasodilators, ACE inhibitors, and beta-blockers has been proved in the management of this syndrome, and at the same time the potential adverse effects of many calcium channel blockers and a number of positive inotropic drugs have been observed (4-8,10). Apparently improving results with surgical coronary artery revascularization, although not as yet subjected to a randomized controlled trial, has made this approach an option for appropriate patients (11). One notable phenomenon during this period has been the extent to which clinical trials of heart failure treatments have contributed to the evolution of clinical practices (10,12). Perhaps even more remarkable is the general reproducibility and global influence of the major findings of these trial results, whether they are conducted in Europe, North America, or Australia-New Zealand. For example, the first study demonstrating a survival benefit of an ACE inhibitor, CONSENSUS (13), had a profound influence far beyond Scandinavia, and was subsequently confirmed and extended by trials conducted in North America, such as SOLVD and VHeFT-II (14,15). The use of this class of drugs in the setting of left ventricular dysfunction after myocardial infarction has also resulted in comparable experiences in a number of regions (16-19). Beta-blocker studies in Europe, the US, and Australia-New Zealand, showed similar evidence of benefit, although with different endpoints and degrees of certainty (20-23). Adverse survival effects with positive inotropic drugs have also been observed across national and continental boundaries (24-27). Perhaps not surprisingly, given this commonality of experience and the rapid global dissemination of trial results, practice guidelines from the US, Canada, and Europe have incorporated very similar recommendations (4-8), which differ more in relation to the time of completion than the nation of origin. However, despite this appearance and implicit assumption of the global (in developed countries) similarity of the magnitude of the problem of heart failure, the characteristics of the patients with heart failure and their treatment, there is, in fact, little information to support this assumption of homogeneity. Indeed, if there are important regional differences in the types of patients presenting with heart failure and their usual treatment, these may limit the applicability of clinical trial information. Perhaps the most salient example of this is the discordance between two trials evaluating amio-

International Differences in CHF Patients

darone therapy in patients with heart failure. In the G E S I C A study (28), amiodarone therapy was associated with a substantial survival benefit, whereas in CHFSTAT (29), a neutral result was obtained, with the most likely explanation being differences in the etiology and severity of the underlying disease (30). The present study was undertaken to determine whether the characteristics and treatment of patients with heart failure in a number of regions of the developed world are similar. The baseline information from the ATLAS trial provides a unique database for accomplishing this analysis because this is a large international heart failure study enrolling patients from North America, Australia, and diverse parts of Europe. The results of these analyses appear to belie the assumption that heart failure patients and their treatment are homogeneous throughout these far-flung areas. Among the patient characteristics, the most salient differences are greater racial diversity among the US patients, the much lower proportion of patients with a coronary heart disease as the etiology of heart failure in southwestern Europe than in other parts of Europe, and the higher incidence of diabetes among patients in Canada and the US. Both surgical and percutaneous revascularization procedures were much more frequent in the US. The differences in medication usage are, perhaps, more striking. Some of these differences, such as the low frequency of digitalis use in UK/Ire (especially in relation to North America and other parts of Europe), the higher frequency of beta-blocker use in Scandinavia, and the more frequent use of amiodarone in several countries in Europe, are probably explained by longstanding local practice patterns in the absence of definitive trial data (in the 1992-1994 time period when these data were collected). The higher frequency of aspirin prescription in Australia, North America, UK/Ire, and the Nordic countries may reflect the higher incidence of ischemic heart disease in patients from these countries. Other differences, such as the relatively low rate of anticoagulant use in UK/Ire despite the higher rate of atrial fibrillation there, and the higher usage of calcium channel blockers in Australia and UK/Ire, are difficult to explain in terms of available evidence. The lower use of ACE inhibitors on entry in UK/Ire and the Nordic countries is difficult to interpret because this may reflect different approaches to patient enrollment for a trial using these agents rather than different practice patterns. This use of baseline data from a clinical trial population to evaluate regional differences in patients with heart failure and their treatment has several advantages, but also important limitations. The common entry and exclusion criteria ensure certain uniform characteristics in the patients, such as the presence of symptoms, the absence of new-onset heart failure, and the universal presence of moderate to severe systolic function. The

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Massie et al.

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participating centers were selected by virtue of their expertise in managing heart failure and/or their record of participation in clinical trials and may not be representative of physicians in their countries. Obviously, these results cannot be extrapolated to other types of patients and treating physicians. Indeed, the fact that these patients were considered candidates for a clinical trial distinguishes them from the larger population of patients with heart failure, in that such participants tend to be younger, more frequently men, and to have fewer comorbid conditions and barriers to compliance. In the case of ATLAS, no known contraindications to longterm therapy with medium to high doses of ACE inhibitors were permitted, which may, together with the nature of the enrolling centers, explain the high rate of use of these agents at entry. On the other hand, there were relatively few exclusions to participation in this large, relatively simple trial, such as requirements for exercise testing, frequent visits, invasive procedures, or exclusion of concomitant medications (none other than certain antiarrhythmic agents and investigational drugs). It is, therefore, likely that, although the absolute percentages may not reflect the broader populations of patients with heart failure in the participating countries, the larger differences between regions observed in this study probably reflect true differences in patient characteristics and treatment practices. In summary, this study suggests that there appear to be important differences in patient characteristics and the use of medications and coronary revascularization between different geographic regions of the developed world. These may influence the results and applicability of clinical trials: If such results are to be widely applied, the nature of the patients and background medications must be examined closely to determine if they apply to the practice of each physician and the characteristics of the individual patients. These results also provide a strong rationale for conducting truly international trials.

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