Differences in management and outcome of ischemic and non-ischemic cardiomyopathy

International Journal of Cardiology 129 (2008) 198 – 204 www.elsevier.com/locate/ijcard

Differences in management and outcome of ischemic and non-ischemic cardiomyopathy Austin Chin Chwan Ng a,b,1 , Andrew Paul Sindone a,b,1 , Helen Siu Ping Wong a,1 , Saul Benedict Freedman a,b,c,⁎ a

Concord RG Hospital, Department of Cardiology, Hospital Road, Concord 2139 NSW Australia b The University of Sydney, Hospital Road, Concord 2139 NSW Australia c Anzac Research Institute, Hospital Road, Concord 2139 NSW Australia Received 28 May 2007; accepted 1 July 2007 Available online 15 August 2007

Abstract Background: Ischemic and non-ischemic cardiomyopathy (ICM and NICM) both cause heart failure, but the different etiologies may result in differences in management and outcome, which were explored in this study. Methods: Cohort study of 168 consecutive patients (90 ICM, 78 NICM) recruited from a tertiary referral heart failure clinic followed for 40 ± 19 months. Results: Patients with ICM were older than NICM with worse NYHA functional state but similar left ventricular ejection fraction (LVEF) and dimensions at baseline. Similar proportions (N80%) in both groups were on a beta-blocker and angiotensin-converting-enzyme inhibitor and/ or angiotensin-II-receptor blocker (ACE inhibitor ± ARB) by end of study. Mean LVEF improved in both groups over time (27.3 ± 11.9% vs. 33.1 ± 12.6%, p b 0.05). Overall 40-month mortality was 17%. In univariate analysis of patients b80 years old, ICM, NYHA class, serum creatinine, ACE inhibitor ± ARB, and amiodarone use were predictors of mortality, but only serum creatinine was significant in multivariate analysis, with a 2.9-fold relative risk of death (95%CI, 1.34–6.42, p b 0.01) for creatinine ≥ 120 μmol/L compared to b 120 μmol/L. Conclusions: Mortality of patients with cardiomyopathy remains high and is strongly related to serum creatinine. NICM patients were younger and showed greater improvement in symptoms and left ventricular function in long-term follow-up. Crown Copyright © 2007 Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Ischemic cardiomyopathy; Non-ischemic cardiomyopathy; Treatment; Prognosis; Heart failure

1. Introduction Over the last 50 years there has been an improvement in survival after the onset of heart failure of 12% per decade [1]. These improvements have been attributed in part to the availability of disease modifying medications of proven ⁎ Corresponding author. Tel.: +61 2 9767 7358; fax: +61 2 9767 6780. E-mail addresses: [email protected] (A.C.C. Ng), [email protected] (A.P. Sindone), [email protected] (H.S.P. Wong), [email protected] (S.B. Freedman). 1 Tel.: +61 2 9767 5215; fax: +61 2 9767 6994.

efficacy [1–4], particularly angiotensin-converting-enzymes (ACE) inhibitors and beta-blockers [5]. Despite the favorable trend in survival, the prognosis of heart failure in community studies remains poor with five-year mortality rate approximating 50% [1]. It is estimated that 2.3% of Americans aged over 20 years (∼ 4.9 million), have congestive heart failure, with 550,000 new cases diagnosed each year [6]. According to the US National Health and Nutritional surveys, heart failure prevalence rate rises with increasing age, affecting 2% of people aged 40–59 years and 10% of people aged above 70 years [7]. In 2002, there were 970,000 hospital discharges for heart failure. The estimated direct and indirect cost of

0167-5273/$ - see front matter. Crown Copyright © 2007 Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.07.014

A.C.C. Ng et al. / International Journal of Cardiology 129 (2008) 198–204

congestive heart failure for the United States in 2005 was $27.9 billion. In the United Kingdom, 3% of people aged over 45 years have heart failure [8]. Ischemic heart disease is the most common etiology of heart failure [2], but management guidelines do not significantly differentiate ischemic cardiomyopathy (ICM) from non-ischemic cardiomyopathy (NICM) [2,9,10]. In clinical studies, the proportion of heart failure caused by ICM as assessed by perfusion study, coronary angiography or history of myocardial infarction varies from 52% to 67% [11–13], and is lower in younger age groups [11]. In assessing the impact of treatment of heart failure in clinical trials, the magnitude of improvement has not been identical in the two etiologies [12–15]. In the CIBIS II study of bisoprolol, there was no difference in absolute mortality for the NICM subgroup [15], with most of the survival benefit confined to ICM. Similarly, in the MERIT-HF study of metoprolol CR/XL, most of the survival benefit was attributed to ICM, though the authors acknowledged the study was not designed nor powered to separately analyze survival in NICM [12]. The absolute mortality for NICM in these trials was usually lower than ICM, but differences in management of these two etiologies were not systematically analyzed. We conducted a longitudinal observational study in a teaching hospital heart failure clinic to assess whether the previously described differences in outcome between ICM and NICM persist with contemporary medical management. 2. Methods 2.1. Study population We enrolled 168 patients: 90 with ICM and 78 with NICM. Patients were defined as having ICM if one of the following was present: previous myocardial infarction (documented clinical history, increases in serial cardiac biomarkers and presence of electrocardiograph findings consistent with myocardial infarction); previous history of coronary revascularization; flow limiting stenosis on coronary angiography (luminal diameter stenosis ≥ 50% in ≥ one epicardial artery) [15]; reversible ischemia or myocardial infarction identified on stress nuclear perfusion imaging or stress echocardiogram. Patients with none of the above criteria were considered to have NICM. Of the 78 patients classified as having NICM, 27 did not have a prior angiogram or stress nuclear perfusion study. These patients were considered to have NICM as there had been no documented history or electrocardiograph change indicating previous myocardial infarction or chest pain potentially due to coronary artery disease. Diagnosis of heart failure was based on clinical criteria [2,10] including shortness of breath, fatigue, or fluid retention in the presence of abnormal cardiac contractility (left ventricular ejection fraction ≤ 50%). A review of the diagnosis was made on the initial clinic visit by two

199

cardiologists to ensure conformity with the study definition. 2.2. Setting Study patients were recruited consecutively at the time of their first visit to a hospital-based specialist heart failure clinic between November 1997 and November 2002, and reviewed at 3 to 6 month intervals for a mean of 40± 19 months (median 38, range 3–87 months). Referrals to the clinic came from a variety of sources including general practitioners, specialist general physicians, geriatricians and cardiologists, or via hospital admission. We excluded patients with New York Heart Association (NYHA) functional class IV symptoms at baseline clinic assessment. 2.3. Data collection A detailed medical history and physical examination was obtained at entry for each patient. All patients had an electrocardiogram and transthoracic echocardiogram to measure left ventricular ejection fraction and dimensions. Blood samples were drawn for full blood count, serum electrolytes and creatinine. During each clinic visit, patients were seen by at least two cardiologists, one of whom was a specialist in heart failure. Echocardiograms were performed on a yearly basis to monitor cardiac dimensions and function. A dose equivalence algorithm was used to calculate comparative dose in each class of medications used most commonly for heart failure patients [2,10]. For example, ramipril was used to represent the class of ACE inhibitor; doses of other ACE inhibitors were expressed as an equivalent dose of ramipril to allow comparisons between patients. Similarly, carvedilol was to be the comparator for beta-blockers, candesartan for angiotensin-II-receptor blockers (ARB), isosorbide mononitrate sustained released for long acting nitrates, frusemide for diuretics and simvastatin for statins. 2.4. Statistical analysis All continuous variables are expressed as mean ± SD (standard deviation). To convert serum creatinine from μmol/L to mg/dL, divide the serum creatinine value by 88.4. Comparison between groups used unpaired t test for continuous variables and χ2 tests or Fisher's exact test for dichotomous variables. Kaplan–Meier survival methods were used to compare unadjusted survival rates between ICM and NICM. Univariate and multivariate Cox proportional hazards models were used to evaluate variables predictive of survival. As a survival difference between ICM and NICM was noted in patients ≤ 80 years of age followed up to 80 months, univariate and multivariate analyses were performed on this group. Analysis was performed using SPSS version 13.0 (SPSS Inc., Chicago,

200

A.C.C. Ng et al. / International Journal of Cardiology 129 (2008) 198–204

Illinois). A two-tailed probability value b 0.05 was considered statistically significant. 2.5. Ethical considerations The study was approved by the institutional Human Research Ethics Committee. 3. Results Table 1 outlines the baseline characteristics of the study cohort. The ICM group was on average 10 years older than the NICM group (p b 0.0001). Mean left ventricular ejection fraction (LVEF) was low (27%) at baseline but did not differ between the two groups. ICM patients had a higher mean NYHA functional class at baseline than NICM patients, and significantly fewer were class I. Mean diastolic blood pressure was higher in NICM but systolic blood pressure was similar in both groups. Both left ventricular enddiastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were elevated at baseline and did not differ significantly between ICM and NICM. Serum urea and creatinine levels were similar in the two groups. There was a greater proportion with peripheral vascular disease and hyperlipidemia in ICM.

Table 1 Baseline characteristics Characteristic

All patients ICM (N = 168) (N = 90)

NICM (N = 78)

p value

Males — no. (%) Mean age (years) Mean LVEF (%) Mean LVEDD (mm) Mean LVESD (mm) Mean NYHA NYHA 4 (%) NYHA 3 (%) NYHA 2 (%) NYHA 1 (%) Mean SBP (mm Hg) Mean DBP (mm Hg) Mean Urea (mmol/L) Mean Creatinine (ìmol/L) Co-morbidities (%) Hypertension Diabetes Mellitus Peripheral Vascular Disease Hyperlipidemia Atrial Fibrillation Chronic lung disease

116 (69) 68 ± 12 27.3 ± 11.9 60.5 ± 10.1 46.8 ± 12.2 2.24 ± 0.73 0 38 41 21 130 ± 21 75 ± 12 10.7 ± 5.9 119 ± 61

61 (68) 73 ± 8 26.9 ± 11.5 59.1 ± 10.1 46.3 ± 11.8 2.40 ± 0.65 0 45 42 13 130 ± 21 73 ± 12 11.2 ± 6.0 123 ± 63

55 (71) 63 ± 14 27.9 ± 12.5 62.0 ± 9.9 47.4 ± 12.8 2.06 ± 0.78 0 31 40 29 130 ± 21 78 ± 13 10.1 ± 5.7 114 ± 59

NS b0.0001 NS NS NS 0.007 0.03

64 27 18

71 30 31

56 24 4

NS NS b0.0001

56 41 32

73 36 31

37 47 32

b0.0001 NS NS

NS 0.006 NS NS

Values are shown as mean ± SD. p values for comparison of ICM vs. NICM; NS, not significant; ICM, ischemic cardiomyopathy; NICM, non-ischemic dilated cardiomyopathy; LVEF, left ventricular ejection fraction; LVEDD, left ventricle end-diastolic dimension; LVESD, left ventricle end-systolic dimension; NYHA, New York Heart Association functional classification; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Fig. 1. a. Cumulative Kaplan–Meier survival curves (unadjusted) of the two study cohorts involving patients ≤80 years old, followed up to 80 months. –▴– represents the survival curve of ICM patients while –▵– represents the survival curve of NICM patients. b. Kaplan–Meier survival curves (unadjusted) of study cohort over 6-years, stratified by serum creatinine: –▵– CreatGp1, Group 1 with baseline serum creatinine b120 μmol/L; –▴– CreatGp2, Group 2 with baseline serum creatinine ≥120 μmol/L.

The overall mortality of the study cohort was 17% at a mean follow-up period of 40 months. Age was a predictor of survival for the whole group in univariate analysis, but was no longer significant when the very elderly (N 80 years old, n = 20) were excluded from the analysis. In patients ≤ 80 years old followed up to 80 months (n = 143; mean follow-up 40 ± 17 months), the survival rate for ICM was significantly worse (Fig. 1a) with a hazard ratio (HR) of 2.5 compared to NICM patients (95% CI, 1.01–5.64). In the univariate Cox-regression analysis, variables predictive of survival included baseline NYHA functional class, serum creatinine, use of ACE inhibitor and/or ARB, and amiodarone use (Table 2), while ICM was only of borderline significance (p = 0.056). In the multivariate Cox-regression analysis, serum creatinine was the only variable that remained a significant predictor of mortality. After adjusting for creatinine, the difference in survival between the ICM and NICM was not significant (HR 2.06, 95% CI, 0.79–5.37, p = 0.14). The mortality of patients with baseline serum creatinine ≥ 120 μmol/L (the mean value for the study cohort) was significantly worse than for patients with a serum creatinine b 120 μmol/L (HR 2.93, 95% CI, 1.34–6.42, p b 0.01) (Fig. 1b). Although differences in serum creatinine

A.C.C. Ng et al. / International Journal of Cardiology 129 (2008) 198–204 Table 2 Predictors of outcome a Variables

Univariate analysis, p value

Multivariate analysis, p value

Baseline NYHA functional class Baseline serum creatinine ICM ACE inhibitor ± ARB Amiodarone

0.02 b0.001 0.06 0.01 0.03

0.17 0.02 0.17 0.81 0.28

The variables, ACE inhibitor ± ARB and amiodarone, represented proportions of patients who were on these medication classes at study end. ACE inhibitor ± ARB, indicates patients either on an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin-II-receptor blocker (ARB) or on both. a The univariate and multivariate Cox-regression analysis was performed on patients who were ≤80 years old followed up to 80 months.

can be due to differences in body mass, this was not the case in our cohort: the body mass index was 27.7 ± 4.1 kg/m2 in the group with creatinine ≥ 120 μmol/L, and 28.6 ± 5.9 kg/m2 in the group with creatinine b120 μmol/L (p = 0.39). Changes in left ventricular size and function over the study period are shown in Table 3. There was a significant improvement in mean LVEF for the entire cohort during follow-up (27.3 ± 11.9% to 33.1 ± 12.6%, p b 0.0001). This improvement was similar in both ICM and NICM. Mean LVEDD for the entire cohort improved (60.5 ± 10.1 mm to 57.3 ± 10.7 mm, p b 0.0001), but the magnitude of the reduction was significantly greater in NICM. Mean left ventricular end-systolic diameter (LVESD) also improved significantly, but similarly, in both groups.

201

For the entire cohort, there was a significant reduction in mean NYHA functional class over the study period (from 2.24 ± 0.7 to 2.05 ± 0.7, p b 0.0001), with fewer in class III and more in class I or II. Fig. 2 shows the change in NYHA functional class in ICM and NICM. Although there was a trend towards an improvement in mean NYHA functional class for ICM (2.4 ± 0.7 to 2.3 ± 0.7), this was not significant (p = 0.11). The improvement was significant in the NICM group (2.1 ± 0.8 to 1.8 ± 0.7, p = 0.0003). At the end of the study, mean NYHA class remained significantly worse in ICM than NICM (2.3 ± 0.7 vs. 1.8 ± 0.7, p b 0.0001), and significantly fewer were in class I (12% vs. 42%, p = 0.03). Table 4 shows the pattern of medication use in the two groups. The trend in the use of beta-blockers, ACE inhibitor and/or ARB, and spironolactone over time was similar in both study groups with no statistically significant differences in use based on etiology. As might be expected, more ICM patients were on nitrates, statins, antiplatelet and/or anticoagulation than NICM patients at baseline and at end of the study. Amiodarone was more frequently used in NICM patients at baseline, but use equalized between the groups by the end of the study. Approximately 60% were on beta-blockers at study commencement and this rose to over 80% during followup with no difference between groups. ACE inhibitor use fell in both groups over time and was associated with a concomitant increase in ARB use, while spironolactone use decreased significantly in both groups. There was an increase in statin use in both groups, significant only in ICM. The mean dosage change for each class of medications is presented in Table 5. There was no significant change in the

Table 3 Changes in left ventricular size, function and blood pressure during study Parameter

Mean LVEF (%) All patients ICM NICM Mean LVEDD (mm) All patients ICM NICM Mean LVESD (mm) All patients ICM NICM Mean SBP (mm Hg) All patients ICM NICM Mean DBP (mm Hg) All patients ICM NICM

Baseline

Study end

27.3 ± 11.9 26.9 ± 11.5 27.9 ± 12.5

33.1 ± 12.6 ⁎ 31.7 ± 11.8 ⁎ 34.7 ± 13.3 ⁎

60.5 ± 10.1 59.1 ± 10.1 62.0 ± 9.9

57.3 ± 10.7 ⁎ 57.4 ± 10.4 ⁎ 57.1 ± 11.2 ⁎

46.8 ± 12.2 46.3 ± 11.8 47.4 ± 12.8

42.2 ± 12.9 ⁎ 43.1 ± 12.1 ⁎ 41.1 ± 13.7 ⁎

130.3 ± 21.0 130.4 ± 21.2 130.2 ± 20.9

123.3 ± 18.7 ⁎ 123.7 ± 19.9 ⁎ 122.8 ± 17.5 ⁎

75.0 ± 12.5 72.6 ± 11.6 77.9 ± 12.7

71.6 ± 10.2 ⁎ 70.5 ± 10.1 72.9 ± 10.2 ⁎

Changes over study period All patients

ICM

NICM

+6.3 ± 12.0

+5.5 ± 10.1

+7.2 ± 13.9 (p = NS)

− 3.4 ± 8.3

− 1.8 ± 8.2

− 5.2 ± 8.0 (p = 0.009)

− 4.8 ± 10.4

− 3.5 ± 10.3

− 6.3 ± 10.4 (p = NS)

− 7.0 ± 22.8

− 6.7 ± 25.4

− 7.3 ± 19.5 (p = NS)

− 3.4 ± 13.8

Values are shown as mean ± SD. p values for comparison of change over study period for ICM vs. NICM; NS, not significant. ⁎ p b 0.05 for comparison of value at end of study to baseline.

− 2.0 ± 14.2

− 5.0 ± 13.1 (p = NS)

202

A.C.C. Ng et al. / International Journal of Cardiology 129 (2008) 198–204

arms of recent beta-blocker trials than that seen in the Olmsted County population study (Table 6). There was a high use of beta-blocker and ACE inhibitor (or ARB) in our non-trial based patients who derived similar survival benefits to that seen in the trials of beta-blockers. The better functional state at entry could possibly explain the lower mortality in the present study, as survival appears related to the proportion with NYHA class III or greater (Table 6). In the recent trials of beta-blocker therapy for heart failure, both ICM and NICM were included, but none of the trials were designed or powered to detect a difference in mortality benefit between the groups. CIBIS II found a greater effect on mortality of bisoprolol in ICM than NICM, but the differences were not significant [15]. In COPERNICUS, both ICM and NICM subgroups benefited from carvedilol [13]. Mortality on beta-blockers was higher in the ICM subgroups of the COMET trial (40% for carvedilol and 47% for metoprolol) compared to NICM (27% and 31% respectively) [17]. A similar but non-significant trend to improved survival in NICM was seen in the MERIT-HF trial [12]. Other studies using strict angiographic inclusion criteria have shown reduced survival in ICM compared to NICM, but details of medical therapy were not available, and such studies have been largely performed before the widespread use of beta-blockers [18]. In the present study, there was comparable and consistent use of beta-blockers and ACE inhibitors (or ARBs) in both ICM and NICM: while mortality was greater in the ICM, this difference was Fig. 2. a. Proportions of ICM patients in each NYHA functional class expressed as percentage of all ICM patients, at baseline (baseline) and at end of the study (study end). ICM indicates ischemic cardiomyopathy. b. Proportions of NICM patients in each NYHA functional class expressed as percentage of all NICM patients, at baseline (baseline) and at end of the study (study end). NICM indicates non-ischemic cardiomyopathy.

mean dose of ACE inhibitor or ARB over the study period for either group. Mean beta-blocker dose increased significantly by the end of the study period, while mean spironolactone dose decreased in both groups. Mean dose for nitrates increased significantly in the ICM patients. At study end, the dose of beta-blocker, ACE inhibitor, diuretic, hydralazine and digoxin was higher in NICM than ICM. Amiodarone and statin doses were comparable between the two groups. 4. Discussion 4.1. Survival The overall mortality of our study cohort was 17% at a mean follow-up of just over 3 years. In contrast, the population-based cohort study from Olmsted County Minnesota showed a 5-year age-adjusted mortality of 48% for the time-period 1996–2000 (non-age adjusted mortality was 46% with a mean follow-up of 4.2 years) following a diagnosis of heart failure [16]. The mortality in our study was therefore closer to the mortality observed in the treatment

Table 4 Percentage of patients on medications and changes during study Medication

ICM patients (%)

NICM patients (%)

Comparison between ICM and NICM medication use (p value) Baseline Study Baseline Study Baseline Study end end end

Beta-blocker ACE inhibitor ARB ACE inhibitor ± ARB Spironolactone Isosorbide mononitrate Hydralazine Frusemide Digoxin Amiodarone Simvastatin Antiplatelet or anticoagulation

63.3 71.1 18.9 87.8

81.1 ⁎ 56.7 48.9 ⁎ 88.9

34.4 57.8

20.0 ⁎ 42.3 65.6 38.5

17.9 ⁎ NS 38.5 .01

NS .0001

6.6 67.8 36.3 12.2 77.8 86.7

14.4 57.8 35.2 21.1 90.0 ⁎ 90.0

20.5 43.6 38.5 19.2 39.7 64.1

NS NS NS NS b0.0001 b0.0001

61.5 67.9 25.6 88.5

14.1 52.6 26.9 29.5 23.1 64.1

84.6 ⁎ 53.8 48.7 ⁎ 89.7

NS NS NS NS

NS NS NS 0.007 b0.0001 0.0009

NS NS NS NS

p values for comparison of medication use between ICM vs. NICM groups at baseline and end of study. NS, not significant; ACE inhibitor, angiotensin-converting-enzyme inhibitor; ARB, angiotensin-II-receptor blocker; ACE inhibitor ± ARB, indicates percentage of patients either on an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin-II-receptor blocker (ARB) or on both. ⁎ p b 0.05 for comparison of proportional changes of patients on various medications between baseline vs. end of study.

A.C.C. Ng et al. / International Journal of Cardiology 129 (2008) 198–204 Table 5 Mean dose changes over study period Equivalent medication (mg)

ICM patients Baseline Study end

Carvedilol 31.6 Ramipril 4.6 Candesartan 17.9 Spironolactone 17.3 Isosorbide 87.7 mononitrate Hydralazine 110.0 Frusemide 61.6 Digoxin (mcg) 100.2 Amiodarone 154.5 Simvastatin 25.6

NICM patients p value

Baseline Study end

p value

42.9 6.0 16.3 11.7 105.3

0.01 NS NS 0.006 0.02

41.0 6.1 13.0 19.7 91.0

63.5 7.6 13.7 14.3 97.0

0.0002 NS NS 0.03 NS

117.3 75.4 75.6 126.3 32.7

NS NS 0.03 NS NS

67.1 54.2 159.2 143.5 30.6

178.1 81.6 107.3 133.3 38.7

0.0005 NS 0.05 NS NS

p values for comparison between baseline vs. study end changes; NS, not significant.

not significant when other variables were taken into account in multivariate analysis. 4.2. Predictors of mortality Baseline NYHA class, serum creatinine, use of an ACE inhibitor and/or ARB, and amiodarone use were all found to be significant univariate predictors of mortality in patients b 80 years of age followed up to 80 months. Multivariate analysis revealed baseline serum creatinine as the most powerful and only significant predictor of increased mortality. These results are similar to findings in previous studies showing that renal function is an important predictor of survival [19]. In a meta-analysis of 16 studies, involving more than 80,000 patients, Smith et al found a 15% increased mortality risk for every 44.2 μmol/L (0.5 mg/dL) increase in serum creatinine [19]. In our study, patients with a serum creatinine ≥120 μmol/ L had a near 3-fold increased risk of death compared to those with creatinine b 120 μmol/L, and the addition of age as a covariable in patients b80 years old did not alter the predictive power of serum creatinine. A higher serum creatinine may reflect worse cardiac function through chronic renal hypoperfusion, or the influence of age on multiple organ function.

Patients with NICM had a greater and significant improvement in functional status during follow-up than those with ICM, who had no significant improvement in functional class, despite similar use of beta-blockers, ACE inhibitors, ARBs and spironolactone. In addition, there was a greater reduction in mean LVEDD in NICM than ICM despite similar improvement in LVEF. It is possible that current optimal medical therapy produces more favorable ventricular remodeling in NICM than ICM. 4.4. Medication use An interesting observation in the present study was the increase in both beta-blocker use and beta-blocker dose during the follow-up period, as well as the increase in use of ARB, while spironolactone dose decreased. This may be a reflection of greater certainty in the benefits of beta-blockade and greater familiarity with dose titration to achieve maximum dosage. The major difference in medications between ICM and NICM was a greater use of nitrates, statins and antiplatelet agents in ICM. Recent observational studies suggested statin therapy is associated with improved survival in patients with both ICM and NICM, independent of age, gender, and NYHA functional class [22,23]. Randomized trials are currently ongoing to determine if statins improve survival particularly in NICM patients [24]. Amiodarone use also differed significantly in our study, with more NICM patients on amiodarone at baseline but usage equalized during the study period. While amiodarone use was a univariate predictor of survival in the present study (Table 2), this was not significant in multivariate analysis, in keeping with the neutral effect of amiodarone on survival in clinical trials [25]. 4.5. Limitations Our study may have misclassified some patients as either ICM or NICM because angiographic confirmation was not universal (54% of NICM and 80% of ICM had undergone Table 6 Estimated 40-month mortality in beta-blocker heart failure trials Heart failure studies

4.3. Baseline characteristics We found patients with ICM to be significantly older, with a worse functional status, and more peripheral vascular disease and hyperlipidemia, than those with NICM. The incidence and prevalence of coronary artery disease increases in the older age groups [6], and risk factors such as diabetes mellitus, hyperlipidemia and peripheral vascular disease are more prevalent in older populations [20], leading to an increased risk of myocardial infarction. Thus it was not unexpected that ICM patients had a greater burden of vascular disease and a higher prevalence of hypertension, diabetes and hyperlipidemia. Importantly, these co-morbidities also contribute to morbidity and mortality in heart failure [21].

203

Beta-blocker trials MERIT-HF[12] CIBIS-II[15] COPERNICUS [13]

Mean ICM mLVEF NYHA Estimated 40age, yrs mth mortality 64 61 63

Olmsted County, 74 Minnesota study [16] Current study 68

65% 28% 50% 28% 69% 20% NA

NA

54% 27%

56% III 23% a 83% III 29% b 100% III, 37% c IV NA 37% d 38% III 17%

ICM, ischemic cardiomyopathy; mLVEF, mean left ventricular ejection fraction; NYHA, New York Heart Association; yrs, years; mth, month; NA, not available. a Based on a 7.8% mortality rate per patient-year of follow-up. b Based on an estimated annual mortality rate of 8.8%. c Based on a 11.4% cumulative risk of death at one year. d Based on a 46% mortality rate (non age-adjusted) over 4.2 years (mean).

204

A.C.C. Ng et al. / International Journal of Cardiology 129 (2008) 198–204

coronary angiography). Physicians rely on clinical presentation and non-invasive investigations to classify patients, and angiography may not be indicated in many patients on clinical grounds. Nevertheless, the proportion ascribed to ICM in the present study is similar to previous studies using angiography [11] and to other heart failure trials [26]. Our patients were recruited from a single institution and may not truly represent the heart failure community in general. In addition, the patients were managed by a specialised heart failure clinic and were receiving optimum medical care for their condition. Patients with worsening symptoms were followed up more closely (with a dedicated community heart failure nurse) and in the event of decompensation were admitted to the hospital promptly to receive necessary medical attention. The difference in mortality between the current study cohort and that of the general heart failure population highlights the potential for improvement. Although our study did not detect a significant difference in mortality between ICM and NICM, there was a suggestion that ICM may have a worse prognosis, which could be explained by covariates, as ICM was not significant in multivariate analysis. A much larger sample size would be required to determine if ICM carried independent prognostic information. 5. Conclusions Recent evidence suggests that patients with heart failure are not a homogenous group with respect to survival or response to therapy [27]. We observed that patients with NICM had greater improvement in symptoms and left ventricular function and remodeling on contemporary treatment. Although mortality of patients with heart failure remains high, a better survival rate was noted in this cohort of heart failure patients attending a specialized tertiary clinic than in a recent population study, and similar to survival in the treatment groups of recent major heart failure clinical trials, possibly related to the high use of beta-blockers and ACE inhibitors (or ARBs). In our patients, serum creatinine was the most important predictor of outcome. References [1] Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397–402. [2] Krum H. Guidelines for management of patients with chronic heart failure in Australia. Med J Aust 2001;174:459–66. [3] Lowery SL, Massaro R, Yancy Jr CW. Advances in the management of acute and chronic decompensated heart failure. Lippincotts Case Manag 2004;9:S1–S15 quiz S16–17. [4] Field B. Heart failure...what of the future? Australian Institute of Health and Welfare AIHW; 2003. Bulletin no.6. [5] Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensinconverting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol 2003;41:1529–38.

[6] American Heart Association. Heart disease and Stroke Statistics — 2005 Update. Dallas, Texas: American Heart Association; 2005. [7] NHLBI:(National Heart, Lung and Blood Institute). Congestive heart failure in the United States: A new epidemic. National Heart, Lung and Blood Institute; 1996. www.nhlbinih.gov/health/public/heart/other/ CHF.htm. [8] Davies M, Hobbs F, Davis R, et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet 2001;358:439–44. [9] Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–60. [10] Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:1115–40. [11] Fox KF, Cowie MR, Wood DA, et al. Coronary artery disease as the cause of incident heart failure in the population. Eur Heart J 2001;22:228–36. [12] Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/ XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7. [13] Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–8. [14] A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation 1994;90:1765–73. [15] The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. [16] Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. Jama 2004;292:344–50. [17] Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7–13. [18] Bart BA, Shaw LK, McCants Jr CB, et al. Clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. J Am Coll Cardiol 1997;30:1002–8. [19] Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006;47:1987–96. [20] Fair JM. Cardiovascular risk factor modification: is it effective in older adults? J Cardiovasc Nurs 2003;18:161–8. [21] Bonow RO, Smaha LA, Smith Jr SC, Mensah GA, Lenfant C. World Heart Day 2002: the international burden of cardiovascular disease: responding to the emerging global epidemic. Circulation 2002;106:1602–5. [22] Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol 2004;43:642–8. [23] Anker SD, Clark AL, Winkler R, et al. Statin use and survival in patients with chronic heart failure—results from two observational studies with 5200 patients. Int J Cardiol 2006;112:234–42. [24] Krum H, Tonkin A. The rosuvastatin impact on ventricular remodeling cytokines and neurohormones (UNIVERSE) study. J Am Coll Cardiol 2006;47:61A–2A. [25] Naccarelli GV, Wolbrette DL, Patel HM, Luck JC. Amiodarone: clinical trials. Curr Opin Cardiol 2000;15:64–72. [26] Krum H, Gilbert RE. Demographics and concomitant disorders in heart failure. Lancet 2003;362:147–58. [27] Hampton JR. Different causes of heart failure need different treatment strategies. J Cardiovasc Pharmacol 1999;33(Suppl 3):S37–41.