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Heart Failure Complicating Non–ST-Segment Elevation Acute Coronary Syndrome
JACC: Heart Failure 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 1, No. 3, 2013 ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2013.02.007
Heart Failure Complicating Non–ST-Segment Elevation Acute Coronary Syndrome Timing, Predictors, and Clinical Outcomes Maria Cecilia Bahit, MD,* Renato D. Lopes, MD, PHD,y Robert M. Clare, MS,y L. Kristin Newby, MD, MHS,y Karen S. Pieper, MS,y Frans Van de Werf, MD, PHD,z Paul W. Armstrong, MD,x Kenneth W. Mahaffey, MD,y Robert A. Harrington, MD,k Rafael Diaz, MD,{ E. Magnus Ohman, MD,y Harvey D. White, DSC,# Stefan James, MD, PHD,** Christopher B. Granger, MDy Rosario, Argentina; Durham, North Carolina; Leuven, Belgium; Edmonton, Alberta, Canada; Stanford, California; Auckland, New Zealand; and Uppsala, Sweden Objectives
This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS).
Background
Little is known about HF-complicating NSTE-ACS.
Methods
Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality.
Results
Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.
Conclusions
In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed. (J Am Coll Cardiol HF 2013;1:223–9) ª 2013 by the American College of Cardiology Foundation
Heart failure (HF) is a frequent complication of acute coronary syndrome (ACS) and is associated with poor prognosis (1,2). However, most previous studies have
included only patients with ST-segment elevation myocardial infarction (STEMI) (3–5). Less is known about the incidence of or prognosis associated with the occurrence of
From the *Estudios Clínicos Latino América, Rosario, Argentina; yDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; zUniversity Hospitals Leuven, Leuven, Belgium; xUniversity of Alberta, Edmonton, Alberta, Canada; kStanford University, Stanford, California; {Estudios Clínicos Latino América, Rosario, Argentina; #Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand; and the **Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden. This work was supported internally by the Duke Clinical Research Institute. Dr. Lopes has a financial relationship with Bristol-Myers Squibb. Dr. Newby is a consultant to AstraZeneca, Biosite Inc., Biosite Diagnostics, CV Therapeutics, Daiichi Sankyo, Mosby, Novartis Pharmaceutical Company, Proctor and Gamble, Roche Diagnostic Corp., and Scios; and has received grant support from Adolor Corporation, AstraZeneca, BG Medicine, Bisoite Inc., Biosite Diagnostics, BristolMyers Squibb, Medicure, Sanofi-Aventis, and Schering Plough Corporation. Dr. Mahaffey has financial relationships with Amylin, AstraZeneca, Baxter, Cordis, Eli Lilly, GlaxoSmithKline, Ikaria, Johnson & Johnson, Luipold, Medtronic, Merck, Novartis, Pozen, Regado, Roche Diagnostic, Schering-Plough, Abbott Vascular, Amgen, Boehringer Ingleheim, Cubist PharmaCeuticals, Daiichi Sankyo, Edwards Lifesciences,
Guidant, Portola, Novartis, Sanofi, The Medicines Company, Adolor, Bayer Healthcare, Bristol-Myers Squibb, Exeter Group, Genentech, Orexigen, Ortho McNeill, WebMD, Elsevier, Biotronik, Forest, Gilead Science, Pfizer, Polymedix, St. Jude Medical, Dialouges, Haemonetics, Johns Hopkins University, South East Area Health Education Center, and Sun Pharma. Dr. Ohman is a consultant for AstraZeneca, BoehringerIngelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Liposcience, Merck, Pozen Inc., Roche, Sanofi-Aventis, The Medicines Co., and WebMD; and has received research grants from Daiichi Sankyo, Eli Lilly & Co., and Gilead Sciences. Dr. White has financial relationships with Aventis, Eli Lilly, The Medicines Company, U.S. National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Schering-Plough, Merck Sharpe & Dohme, Astra Zeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb. Dr. Granger has financial relationships with Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Lilly, Pfizer, Sanofi-Aventis, Takeda, The Medicines Company, and AstraZeneca. Anthony N. DeMaria, MD, acted as Guest Editor for this article. Manuscript received December 18, 2012; revised manuscript received January 29, 2013, accepted February 12, 2013.
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HF as a complication in non–STsegment elevation (NSTE)-ACS. A report from the GRACE ACS = acute coronary (Global Registry of Acute Corosyndrome nary Events) study showed that CI = confidence interval among >14,000 ACS patients, HF = heart failure the incidence of HF was similar MI = myocardial infarction in STEMI (15.6%) and nonNSTE = non–ST-segment STEMI (14.7%) patients but elevation was 50% lower among patients OR = odds ratio with unstable angina (6). STEMI = ST-segment Because the incidence of nonelevation myocardial STEMI as a proportion of all infarction MIs is increasing (7), the relevance of assessing determinants and the impact of HF in NSTE-ACS are important. In the present study, we used a pooled dataset from 7 randomized clinical trials that enrolled patients with NSTE-ACS to describe the occurrence and timing of HF complicating NSTE-ACS, to identify factors associated with HF at different times during the index ACS hospitalization, and to evaluate the association of HF with 30-day clinical outcomes. Abbreviations and Acronyms
Methods We analyzed information pooled at the patient level from the databases of 7 large clinical trials that enrolled patients with NSTE-ACS. These trials included GUSTO IIb (Global Use of Strategies to Open Occluded Coronary Arteries IIb) (8), PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) (9), PARAGON A (Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network-A) (10), PARAGON B (11), ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) (12), SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) (13), and EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) (14). A synopsis of the characteristics of these trials is provided in Table 1. All patients gave written Table 1 Study
informed consent to participate in the trials, and the protocol for each trial was approved by the ethics committees or institutional review boards of participating hospitals. The current analysis was approved and declared exempt by the institutional review board of Duke University Medical Center. Heart failure definition. HF was defined at 2 time points. HF at presentation included patients who presented with Killip classes II to III. HF during hospitalization included patients without HF at presentation and an in-hospital complication of HF or pulmonary edema noted on the study case report form. In-hospital complications of HF or of pulmonary edema were collected as prespecified events in the case report forms. HF classification was used as recorded on the case report form; no attempt was made to adjudicate these classifications. Patients with cardiogenic shock were excluded from this analysis because this group of patients has a wellknown high rate of 90-day death (approximately 50%) and could potentially have driven our results (2). Myocardial infarction definition. Myocardial infarction (MI) was defined by the presence of symptoms suggestive of ischemia and new electrocardiographic changes or elevation of creatine kinase (CK) or creatine kinase-myocardial band (CK-MB) levels to 2 times the upper limit of normal. Statistical analysis. Baseline characteristics and medications are described using medians with 25th and 75th percentiles for continuous variables and frequencies and proportions for categorical variables. Multivariable logistic regression modeling with a stepwise selection procedure was used to identify variables associated with HF at presentation and during hospitalization, death from hospital discharge to 30 days postdischarge, and death or MI from hospital discharge to 30 days postdischarge. Candidate variables for these models were selected based on clinical importance, previously developed models, and a review of related literature. The linearity assumption for continuous variables was evaluated using restricted cubic spline transformations. If the nonlinear transformation significantly improved the model chi-square, then a plot of the logit of the outcome versus the factor of interest was used to determine the most appropriate transformation for modeling. In those cases, a linear spline was used as the final transformation for modeling.
Overview of Trials Included in the Pooled Data Year of Enrollment
N
GUSTO IIb
1994–1995
12,142
PURSUIT
1995–1997
PARAGON A
1995–1996
PARAGON B
1998–1999
Patient Population
Treatment and Comparator Drugs
NSTE-ACS
Hirudin versus UFH
10,948
NSTE-ACS
Eptifibatide versus placebo
2,282
NSTE-ACS
Lamifiban versus placebo
5,225
NSTE-ACS
Lamifiban versus placebo
NSTE-ACS
Enoxaparin versus UFH
ESSENCE
1994–1996
3,171
SYNERGY
2001–2003
10,027
EARLY ACS
2004–2008
9,492
NSTE-ACS treated with an intended early invasive strategy
Enoxaparin versus UFH
NSTE-ACS assigned to an invasive strategy
Early eptifibatide versus delayed eptifibatide
ACS ¼ acute coronary syndrome; EARLY ACS, Early Glycoprotein IIb/IIIa Inhibition in Patients with Non–ST-Segment Elevation Acute Coronary Syndrome; ESSENCE ¼ Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; GUSTO IIb ¼ Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes; NSTE ¼ non–ST-segment elevation; PARAGON A and B ¼ Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; SYNERGY ¼ Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitor; UFH ¼ unfractionated heparin.
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Clinical trial was included as a stratification factor in presenting the association between covariates and HF in the two HF models. We ran an alternate version of each model with trial included as a covariate (rather than as a stratifying factor) to calculate the corresponding C index, recognizing that this would conservatively estimate the statistic. In the postdischarge efficacy models, HF experience through hospital discharge (defined as none, baseline, or new onset) as well as trial were considered among other candidate variables for stepwise selection. Results A total of 53,287 patients were enrolled in the 7 trials. After we excluded patients with cardiogenic shock or Killip class IV at presentation (n ¼ 1,120) and patients with missing HF information on admission (n ¼ 5,648), 46,519 remained for examination in the present study. Among these patients, 4,910 (10.6%) had HF (Killip class II/III or pulmonary edema) at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization (Fig. 1). Patient population. Patients with HF were older and less often male or current smokers (Table 2) than those without HF. Multiple comorbidities and cardiac risk factors were more common among patients with HF. In particular, prior HF was 4 times more common among patients who had HF at presentation or developed HF during hospitalization. More patients with HF had an enrolling MI and STsegment changes on electrocardiography (ECG) than those with no HF. Presenting heart rate was higher and
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blood pressure was lower in patients with HF than in those without HF. Concomitant medications and in-hospital procedures. Treatment with aspirin was similar among patients both with and without HF. Beta-blockers were more commonly prescribed for patients without HF at presentation. Use of angiotensin-converting enzyme inhibitors was more common among patients with HF (Table 3). Patients with HF were less likely to undergo cardiac catheterization (62.3% vs. 70.3%, respectively) and percutaneous coronary interventions (23.4% vs. 33.1%, respectively) than patients without HF. Predictors of HF at presentation and in-hospital HF. In multivariable logistic regression modeling, older age, female sex, race, current smoker status, higher heart rate, diabetes, prior MI, hypertension, peripheral vascular disease, enrolling MI, and ST-segment changes on the presenting ECG were significantly associated with HF at presentation (Table 4). Among patients with no HF at presentation, the baseline factors associated with HF during hospitalization are shown in Table 5 and were similar to those observed for patients with HF at presentation. Clinical outcomes. Patients who presented with HF had an approximately 4-fold higher 30-day mortality rate (5.2% vs. 1.3%, p < 0.001, respectively) and were also more likely to suffer an MI (11.1% vs. 8.4%, p < 0.001, respectively) than patients without HF at presentation. The increased risk in patients with HF is seen in-hospital and also between discharge and 30 days. Patients with HF at presentation or during hospitalization had a higher risk of death at 30 days than patients without HF (adjusted odds ratios [ORs]: 1.74 [95% confidence interval (CI): 1.35 to 2.26] and 2.34 [95% CI: 1.58 to 3.49], respectively). Patients with HF at presentation or in-hospital had a significantly higher risk of death or MI at 30 days than those patients without HF (adjusted OR: 1.76 [95% CI: 1.47 to 2.11] vs. 1.46 [95% CI: 1.04 to 2.05], respectively). There were no differences in prognostic impact between HF at presentation and HF during hospitalization (Fig. 2). Of the overall population, 32.9% (n ¼ 15,320) had quantitative ejection fraction. The median (25th, 75th quartiles) ejection fraction was lower in patients with baseline HF (49% [35%, 60%]) than in patients without baseline HF (55% [45%, 65%]). Likewise, ejection fraction was lower among patients with in-hospital HF (45% [32%, 55%]) than among those without in-hospital HF (55% [45%, 65%]). Discussion
Figure 1
Patient Population
Flow diagram. *Outcome data available for patients with no HF at presentation (n ¼ 41,609): 30-day death (n ¼ 41,563); for 30-day death/MI (n ¼ 41,458). *Outcome data available for patients with HF at presentation (n ¼ 4910): 30-day death (n ¼ 4907); 30-day death/MI (n ¼ 4882). HF ¼ heart failure; MI ¼ myocardial infarction; NSTE-ACS ¼ non–ST-segment elevation-acute coronary syndrome.
In this study of more than 46,000 patients with NSTE-ACS, we found that patients with HF at presentation or occurring during hospitalization were older and had more comorbidities than patients who did not have HF complicating their NSTE-ACS presentation. Furthermore, patients with HF either at presentation or during hospitalization had substantially worse 30-day outcomes than patients with no HF. This study highlights the fact that even in patients with unstable
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Table 2
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Baseline Characteristics for Patients With ACS According to the Presence of HF at Presentation or During Hospitalization No HF (n ¼ 40,415)
Any HF (n ¼ 6,104)
HF at Presentation (n ¼ 4,910)
GUSTO IIb
85.4
14.6
12.0
2.5
PURSUIT
88.6
11.4
8.8
2.6
PARAGON A
86.7
13.3
9.4
4.0
PARAGON B
86.9
13.1
12.0
1.1
ESSENCE
90.4
9.6
8.8
0.8
SYNERGY
84.0
16.0
11.7
4.3
EARLY ACS
87.9
12.1
10.3
Trial
Age (yrs)
65.0 (56.0, 72.0)
Female
32.8
71 (63.4, 77.0)
HF During Hospitalization (n ¼ 1,194)
1.8
71.0 (63.1, 77.0)
38.6
71.0 (64.0, 77.0)
38.8
37.8
Medical history Current smoker
27.4
22.3
23.1
19.1
Prior diabetes
22.4
35.4
35.3
35.9
Prior HF
6.6
28.7
31.0
19.3
Prior MI
29.7
40.5
40.9
39.1
Prior CABG
13.2
16.3
16.2
16.9
Prior PCI
16.7
17.2
18.0
13.9
Hypertension
58.0
66.1
66.1
66.2
7.9
14.3
14.1
14.8
PVD Baseline characteristics Heart rate (beats/min)
72.0 (63.0, 83.0)
79.0 (68.0, 91.0)
80.0 (68.0, 92.0)
76.0 (66.0, 88.0)
Systolic BP (mm Hg)
136.0 (120.0, 151.0)
135.0 (120.0, 151.0)
135.0 (120.0, 152.0)
133.0 (118.0, 150.0)
Diastolic BP (mm Hg)
80.0 (70.0, 88.0)
76.0 (66.0, 85.0)
77.0 (66.0, 86.0)
75.0 (65.0, 83.0)
1.0 (0.9, 1.2)
1.1 (0.9, 1.3)
1.1 (0.9, 1.3)
1.1 (0.9, 1.3)
Creatinine concentration (mg/dl) Killip class 1
100
19.6
0
2
0
69.8
86.8
100 0
3
0
10.6
13.2
0
No. of diseased vessels 0
11.2
7.7
8.7
4.2
1
31.2
18.8
20.9
11.6
2
26.3
24.7
25.0
23.5
3
32.1
48.8
45.4
60.6
Enrolled with MI
61.3
70.1
69.2
73.8
ST-segment changes
53.1
64.2
62.9
69.6
Values are % or median (25th, 75th percentile). CABG ¼ coronary artery bypass grafting; HF ¼ heart failure; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; PVD ¼ peripheral vascular disease. Other abbreviations are shown in Table 1.
angina or non-STEMI, HF at any time during hospitalization is independently associated with poor outcomes. Our study raises the issue of the generalizability of data from clinical trial databases. Even from large multicenter trials, patients who can provide consent and have fewer comorbidities are more often selected for participation. Balancing the shortcomings of patient selection is the much Table 3
higher quality of data collected in clinical trials, in particular claims data. As we analyzed HF as a postrandomization variable, there is little selection based on the occurrence of HF. Our study draws from several trials that were conducted more than 10 years ago, and it is possible that the occurrence of HF and the association with other outcomes is changing, although this seems unlikely.
Baseline Medications According to the Presence of HF at Presentation or During Hospitalization
Medication
No HF (n ¼ 40,415)
Any HF (n ¼ 6,104)
HF at Presentation (n ¼ 4,910)
HF During Hospitalization (n ¼ 1,194)
Aspirin
97.5
97.6
97.4
98.4
Beta-blockers
76.1
71.9
69.3
82.5
Lipid lowering
46.6
45.8
44.6
50.8
Ticlopidine/clopidogrel/dipyridamole
49.2
48.0
47.2
51.4
ACE inhibitors
47.1
64.9
62.0
76.5
Values are %. ACE ¼ angiotensin-converting enzyme; HF ¼ heart failure.
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Bahit et al. HF in NSTE-ACS: Timing, Predictors, and Outcomes
Multivariate Predictors of HF at Presentation in Patients Admitted With ACS
Table 4
Multivariable Predictors of HF During Hospitalization in Patients Admitted With ACS
Table 5
Chi-Square Test
OR
95% CI
p Value
Age (per 5-yr increase)
716.24
1.3
1.28–1.33
<0.0001
Age (per 5-yr increase)
Heart rate (beats/min)
464.47
<0.0001
Heart rate <50 beats/min (per 10 beats/min increase)*
0.7
0.50–0.90
Heart rate >50 beats/min (per 10 beats/min increase)*
1.2
1.21–1.26
1.5
1.37–1.58
Factor
Prior MI
118.28
Chi-Square Test
OR
95% CI
p Value
230.36
1.3
1.23–1.31
<0.0001
MI at enrollment
73.26
1.9
1.63–2.18
<0.0001
Heart rate
69.17
Heart rate 50 beats/min (per 10-beats/min increase)*
0.7
0.45–1.09
Heart rate >50 beats/min (per 10-beats/min increase)*
1.2
1.12–1.20
<0.0001
Factor
<0.0001
White race
99.08
0.6
0.54–0.67
<0.0001
Diabetes
50.26
1.6
1.41–1.84
Diabetes
88.76
1.4
1.33–1.54
<0.0001
ST-segment changes
43.26
1.6
1.38–1.81
MI at enrollment
87.38
1.4
1.33–1.54
<0.0001
Systolic BP
43.07
Creatinine concentration
80.81
<0.0001
0.80–0.91
1.8
1.31–2.55
Systolic BP <130 mm Hg (per 10-mm Hg increase)*
0.9
Creatinine <1 mg/dl* Creatinine >1 mg/dl*
1.4
1.25–1.47
Systolic BP 130 mm Hg (per 10-mm Hg increase)*
1.0
0.93–1.01
1.5
1.27–1.66
Current smoker
52.88
1.4
1.26–1.50
<0.0001
ST-segment changes
43.84
1.3
1.19–1.37
<0.0001
Prior MI
29.86
<0.0001
Creatinine
27.55
Weight
36.70
Weight <70 kg (per 10-kg increase)*
1.0
Weight >70 kg (per 10-kg increase)*
1.1
PVD
31.06
Systolic BP
24.65
1.3
0.95–1.09 1.05–1.11 1.20–1.47
Systolic BP <130 mm Hg (per 10-mm Hg increase)*
0.9
0.89–0.96
Systolic BP >130 mm Hg (per 10-mm Hg increase)*
1.0
0.95–1.00
1.2
1.12–1.31
Female
22.60
Diastolic BP
22.53 0.9
0.88–0.95
Diastolic BP >85 mm Hg (per 10-mm Hg increase)*
1.1
1.00–1.15
1.1
1.02–1.18
Hypertension
5.81
<0.0001 <0.0001 <0.0001
<0.0001 <0.0001
Creatinine <1 mg/dl*
1.8
1.01–3.35
Creatinine >1 mg/dl*
1.3
1.17–1.53
Prior PCI
18.04
0.7
0.55–0.80
<0.0001
PVD
17.63
1.5
1.23–1.75
<0.0001
<0.0001
North America
9.18
1.2
1.08–1.41
0.0024
<0.0001
Hypertension
6.42
1.2
1.04–1.36
0.0113
*Where necessary, spline transformations were used to account for changes in the linear aspect of relationships between continuous covariates and the model endpoint. In these cases, separate odds ratio (OR) estimates are presented above and below the point identified as the location of this change. PCI ¼ percutaneous coronary intervention; other abbreviations as in Table 4.
<0.0001 <0.0001
Diastolic BP <85 mm Hg (per 10-mm Hg increase)*
227
0.0159
*Where necessary, spline transformations were used to account for changes in the linear aspect of relationships between continuous covariates and the model endpoint. In these cases, separate odds ratio (OR) estimates are presented above and below the point identified as the location of this change. C statistic ¼ 0.725. BP ¼ blood pressure; beats/min ¼ beats per minute; CI ¼ confidence interval; MI ¼ myocardial infarction; PVD ¼ peripheral vascular disease.
HF in ACS. Previous research of HF complicating ACS has been conducted in cases of STEMI (4,5,15–18). Killip classification has been extensively studied in this setting and has been associated with high-risk baseline characteristics including older age, diabetes, prior MI, and prior HF (16,19,20). There are only 2 published studies that assessed prognosis of HF in NSTE-ACS. Mehta et al. (21) examined the incidence, predictors, and clinical outcomes of patients who developed HF after ACS in the OASIS-2 (Organization to Assess Strategies for Ischemic Syndromes) trial (21). The cumulative incidence rates of HF were reported as 2.7% at 24 h, 4.9% at day 7, and 6.3% at 6 months, rates substantially lower than those reported in the GRACE registry (22). Patients with HF in the OASIS-2 trial had a significantly higher risk of death or MI than those with no HF. Patients with HF in that study share similar high-risk characteristics with patients with HF in our study and with STEMI patients with HF (i.e., they were
older, more likely female, and more frequently had diabetes, hypertension, and prior MI). A report from the GRACE registry (6) evaluated the factors associated with HF in the setting of NSTE-ACS and its relationship with outcomes. It is important to mention that the patient population also included patients with STEMI. The authors reported that the overall incidence of HF was 13% and was similar in patients with STEMI (15.6%) and non-STEMI (14.7%) but half as frequent in patients with unstable angina (8.2%). As in our study, patients with HF were older than patients with no HF and were more often women and less likely to smoke. History of diabetes and hypertension, prior MI or TIA/stroke, and prior HF were more common in patients with HF than in those without HF. The high-risk baseline features of the HF population were similar to those of our HF patients. While we found in the subset of patients from whom ejection fraction was collected that ejection fraction was lower in the HF population, a large proportion had ejection fraction in the normal or mildly reduced range. Treatment of patients with HF. In our study, consistent with the studies by Mehta et al. (21) and the GRACE registry (6), patients with HF were less likely to undergo cardiac catheterization and percutaneous coronary interventions than patients without HF. These findings are consistent with the results of another report from the GRACE registry (23) describing the use of revascularization in NSTE-ACS patients with HF. In that study, only one-
228
Figure 2
Bahit et al. HF in NSTE-ACS: Timing, Predictors, and Outcomes
JACC: Heart Failure Vol. 1, No. 3, 2013 June 2013:223–9
Model Effect of 3-Level Baseline/In-Hospital HF (No HF/HF at Presentation/HF During Hospitalization)
30-day outcomes in HF. CABG ¼ coronary artery bypass grafting; HF ¼ heart failure; HR ¼ heart rate; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; PVD ¼ peripheral vascular disease.
fifth of the patients with HF were revascularized compared with 35% of the patients without HF. In addition, among patients with HF, revascularized patients had lower-risk baseline clinical features than those who were not revascularized. Steg and colleagues (23) also showed a consistent reduction in postdischarge death in patients with HF who underwent revascularization, suggesting that a broader application of revascularization in this high-risk group may be beneficial. It is important to mention that among the 7 studies included in our analysis, there were only 2 that by inclusion criteria, required that patients be assigned an early invasive strategy (13,14). Predictors of HF complicating ACS. Predictors of HF were consistent between our study and the Mehta and GRACE analyses (6,21). In OASIS-2 (21), independent predictors of HF included older age, history of diabetes, prior MI, and admission diagnosis of non-STEMI. In the GRACE registry (6), older age, history of diabetes and hypertension, prior MI, higher pulse rate, STEMI and nonSTEMI on admission, and prior use of diuretic agents were among the strongest independent predictors of HF. Similarly, we found that older age, history of diabetes and hypertension, and prior MI were key factors associated with
HF at presentation as were MI at enrollment and ST segment changes. Interestingly, some of these factors associated with higher risk of HF following non-STEMI vary over the course of treatment, such as elevated heart rate and lower blood pressure. Thus, close attention to patients with those baseline characteristics in this setting might prompt treatment, such as earlier inhibitors of the renin angiotensin aldosterone system, which might help prevent the development of HF and improve patient outcomes as a result. Strengths and limitations. This is one of the largest studies to examine the relationship between HF at presentation or during hospitalization and subsequent clinical outcomes in patients with NSTE-ACS. However, this is an observational study and cause and effect relationships between HF and clinical outcomes cannot be concluded. Furthermore, as this was a population of patients enrolled in clinical trials, the results may not be generalizable to the broader population of patients with ACS treated in clinical practice. Additionally, the definition of HF was not standardized or consistently adjudicated. Even though there is no standard definition for HF outside clinical trials (24), we believe the physician-reported data reflect classification in typical clinical practice; thus, our results should be relevant. Second, the time period for patient
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inclusion in the trials whose databases were included in this analysis dated from 1994 and extended to 2008. As a result, there is wide variation in the treatment of NSTE-ACS in this patient population. Finally, we lack specific data regarding timing of HF prior to hospitalization and timing of HF occurrence during hospitalization. Therefore, we are uncertain whether HF during hospitalization is new onset HF or a consequence of a previous condition or whether other inhospital complications may have occurred before or after the development of in-hospital HF. Conclusions In this large database, HF at presentation was a frequent complication of NSTE-ACS and was associated with higherrisk baseline features and more adverse outcomes. Readily available baseline characteristics identified patients with increased risk of developing HF, which was associated with subsequent mortality. Patients with NSTE-ACS and HF were also undertreated with evidence-based therapies and interventions, suggesting an opportunity to reduce adverse outcomes through adherence to guidelines recommendations. Further prospective studies are needed to assess the best treatment strategies for this high-risk group of patients. Reprint requests and correspondence: Dr. Renato D. Lopes, Duke Clinical Research Institute, Duke University Medical Center, Box 3850, 2400 Pratt Street, Room 0311 Terrace Level, Durham, North Carolina 27705. E-mail: [email protected].
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1. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 1998;97: 282–9. 2. French JK, Armstrong PW, Cohen E, et al. Cardiogenic shock and heart failure post-percutaneous coronary intervention in ST-elevation myocardial infarction: observations from “Assessment of Pexelizumab in Acute Myocardial Infarction”. Am Heart J 2011;162:89–97. 3. Spencer FA, Meyer TE, Gore JM, Goldberg RJ. Heterogeneity in the management and outcomes of patients with acute myocardial infarction complicated by heart failure: the National Registry of Myocardial Infarction. Circulation 2002;105:2605–10. 4. Wu AH, Parsons L, Every NR, Bates ER. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 2002;40: 1389–94. 5. McManus DD, Chinali M, Saczynski JS, et al. 30-year trends in heart failure in patients hospitalized with acute myocardial infarction. Am J Cardiol 2011;107:353–9. 6. Steg PG, Dabbous OH, Feldman LJ, et al. Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004;109:494–9. 7. McManus DD, Gore J, Yarzebski J, Spencer F, Lessard D, Goldberg RJ. Recent trends in the incidence, treatment, and outcomes of patients with STEMI and NSTEMI. Am J Med 2011;124:40–7.
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8. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775–82. 9. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998;339:436–43. 10. The PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina. Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network. Circulation 1998;97:2386–95. 11. Randomized, placebo-controlled trial of titrated intravenous lamifiban for acute coronary syndromes. Circulation 2002;105:316–21. 12. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of lowmolecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337:447–52. 13. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45–54. 14. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009; 360:2176–90. 15. Werns SW, Bates ER. The enduring value of Killip classification. Am Heart J 1999;137:213–5. 16. Neskovic AN, Otasevic P, Bojic M, Popovic AD. Association of Killip class on admission and left ventricular dilatation after myocardial infarction: a closer look into an old clinical classification. Am Heart J 1999;137:361–7. 17. Rocha S, Nabais S, Magalhaes S, et al. Heart failure after acute coronary syndrome: identify to treat better! Rev Port Cardiol 2007;26: 349–59. 18. Henriques JP, Zijlstra F, de Boer MJ, et al. The prognostic importance of heart failure and age in patients treated with primary angioplasty. Eur J Heart Fail 2003;5:291–4. 19. DeGeare VS, Boura JA, Grines LL, O’Neill WW, Grines CL. Predictive value of the Killip classification in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 2001;87:1035–8. 20. Rott D, Behar S, Gottlieb S, Boyko V, Hod H. Usefulness of the Killip classification for early risk stratification of patients with acute myocardial infarction in the 1990s compared with those treated in the 1980s. Israeli Thrombolytic Survey Group and the Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT) Study Group. Am J Cardiol 1997;80:859–64. 21. Mehta SR, Eikelboom JW, Demers C, Maggioni AP, Commerford PJ, Yusuf S. Congestive heart failure complicating non-ST segment elevation acute coronary syndrome: incidence, predictors, and clinical outcomes. Can J Physiol Pharmacol 2005;83:98–103. 22. Steg PG, Goldberg RJ, Gore JM, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 2002;90:358–63. 23. Steg PG, Kerner A, Van de Werf F, et al. Impact of in-hospital revascularization on survival in patients with non-ST-elevation acute coronary syndrome and congestive heart failure. Circulation 2008;118: 1163–71. 24. Zannad F, Stough WG, Pitt B, et al. Heart failure as an endpoint in heart failure and non-heart failure cardiovascular clinical trials: the need for a consensus definition. Eur Heart J 2008;29:413–21.
Key Words: acute coronary syndromes elevation - outcomes - timing.
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heart failure
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non–ST-segment
Vol. 1, No. 3, 2013 ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2013.02.007
Heart Failure Complicating Non–ST-Segment Elevation Acute Coronary Syndrome Timing, Predictors, and Clinical Outcomes Maria Cecilia Bahit, MD,* Renato D. Lopes, MD, PHD,y Robert M. Clare, MS,y L. Kristin Newby, MD, MHS,y Karen S. Pieper, MS,y Frans Van de Werf, MD, PHD,z Paul W. Armstrong, MD,x Kenneth W. Mahaffey, MD,y Robert A. Harrington, MD,k Rafael Diaz, MD,{ E. Magnus Ohman, MD,y Harvey D. White, DSC,# Stefan James, MD, PHD,** Christopher B. Granger, MDy Rosario, Argentina; Durham, North Carolina; Leuven, Belgium; Edmonton, Alberta, Canada; Stanford, California; Auckland, New Zealand; and Uppsala, Sweden Objectives
This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS).
Background
Little is known about HF-complicating NSTE-ACS.
Methods
Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality.
Results
Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.
Conclusions
In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed. (J Am Coll Cardiol HF 2013;1:223–9) ª 2013 by the American College of Cardiology Foundation
Heart failure (HF) is a frequent complication of acute coronary syndrome (ACS) and is associated with poor prognosis (1,2). However, most previous studies have
included only patients with ST-segment elevation myocardial infarction (STEMI) (3–5). Less is known about the incidence of or prognosis associated with the occurrence of
From the *Estudios Clínicos Latino América, Rosario, Argentina; yDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; zUniversity Hospitals Leuven, Leuven, Belgium; xUniversity of Alberta, Edmonton, Alberta, Canada; kStanford University, Stanford, California; {Estudios Clínicos Latino América, Rosario, Argentina; #Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand; and the **Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden. This work was supported internally by the Duke Clinical Research Institute. Dr. Lopes has a financial relationship with Bristol-Myers Squibb. Dr. Newby is a consultant to AstraZeneca, Biosite Inc., Biosite Diagnostics, CV Therapeutics, Daiichi Sankyo, Mosby, Novartis Pharmaceutical Company, Proctor and Gamble, Roche Diagnostic Corp., and Scios; and has received grant support from Adolor Corporation, AstraZeneca, BG Medicine, Bisoite Inc., Biosite Diagnostics, BristolMyers Squibb, Medicure, Sanofi-Aventis, and Schering Plough Corporation. Dr. Mahaffey has financial relationships with Amylin, AstraZeneca, Baxter, Cordis, Eli Lilly, GlaxoSmithKline, Ikaria, Johnson & Johnson, Luipold, Medtronic, Merck, Novartis, Pozen, Regado, Roche Diagnostic, Schering-Plough, Abbott Vascular, Amgen, Boehringer Ingleheim, Cubist PharmaCeuticals, Daiichi Sankyo, Edwards Lifesciences,
Guidant, Portola, Novartis, Sanofi, The Medicines Company, Adolor, Bayer Healthcare, Bristol-Myers Squibb, Exeter Group, Genentech, Orexigen, Ortho McNeill, WebMD, Elsevier, Biotronik, Forest, Gilead Science, Pfizer, Polymedix, St. Jude Medical, Dialouges, Haemonetics, Johns Hopkins University, South East Area Health Education Center, and Sun Pharma. Dr. Ohman is a consultant for AstraZeneca, BoehringerIngelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Liposcience, Merck, Pozen Inc., Roche, Sanofi-Aventis, The Medicines Co., and WebMD; and has received research grants from Daiichi Sankyo, Eli Lilly & Co., and Gilead Sciences. Dr. White has financial relationships with Aventis, Eli Lilly, The Medicines Company, U.S. National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Schering-Plough, Merck Sharpe & Dohme, Astra Zeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb. Dr. Granger has financial relationships with Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Lilly, Pfizer, Sanofi-Aventis, Takeda, The Medicines Company, and AstraZeneca. Anthony N. DeMaria, MD, acted as Guest Editor for this article. Manuscript received December 18, 2012; revised manuscript received January 29, 2013, accepted February 12, 2013.
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HF as a complication in non–STsegment elevation (NSTE)-ACS. A report from the GRACE ACS = acute coronary (Global Registry of Acute Corosyndrome nary Events) study showed that CI = confidence interval among >14,000 ACS patients, HF = heart failure the incidence of HF was similar MI = myocardial infarction in STEMI (15.6%) and nonNSTE = non–ST-segment STEMI (14.7%) patients but elevation was 50% lower among patients OR = odds ratio with unstable angina (6). STEMI = ST-segment Because the incidence of nonelevation myocardial STEMI as a proportion of all infarction MIs is increasing (7), the relevance of assessing determinants and the impact of HF in NSTE-ACS are important. In the present study, we used a pooled dataset from 7 randomized clinical trials that enrolled patients with NSTE-ACS to describe the occurrence and timing of HF complicating NSTE-ACS, to identify factors associated with HF at different times during the index ACS hospitalization, and to evaluate the association of HF with 30-day clinical outcomes. Abbreviations and Acronyms
Methods We analyzed information pooled at the patient level from the databases of 7 large clinical trials that enrolled patients with NSTE-ACS. These trials included GUSTO IIb (Global Use of Strategies to Open Occluded Coronary Arteries IIb) (8), PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) (9), PARAGON A (Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network-A) (10), PARAGON B (11), ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) (12), SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) (13), and EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) (14). A synopsis of the characteristics of these trials is provided in Table 1. All patients gave written Table 1 Study
informed consent to participate in the trials, and the protocol for each trial was approved by the ethics committees or institutional review boards of participating hospitals. The current analysis was approved and declared exempt by the institutional review board of Duke University Medical Center. Heart failure definition. HF was defined at 2 time points. HF at presentation included patients who presented with Killip classes II to III. HF during hospitalization included patients without HF at presentation and an in-hospital complication of HF or pulmonary edema noted on the study case report form. In-hospital complications of HF or of pulmonary edema were collected as prespecified events in the case report forms. HF classification was used as recorded on the case report form; no attempt was made to adjudicate these classifications. Patients with cardiogenic shock were excluded from this analysis because this group of patients has a wellknown high rate of 90-day death (approximately 50%) and could potentially have driven our results (2). Myocardial infarction definition. Myocardial infarction (MI) was defined by the presence of symptoms suggestive of ischemia and new electrocardiographic changes or elevation of creatine kinase (CK) or creatine kinase-myocardial band (CK-MB) levels to 2 times the upper limit of normal. Statistical analysis. Baseline characteristics and medications are described using medians with 25th and 75th percentiles for continuous variables and frequencies and proportions for categorical variables. Multivariable logistic regression modeling with a stepwise selection procedure was used to identify variables associated with HF at presentation and during hospitalization, death from hospital discharge to 30 days postdischarge, and death or MI from hospital discharge to 30 days postdischarge. Candidate variables for these models were selected based on clinical importance, previously developed models, and a review of related literature. The linearity assumption for continuous variables was evaluated using restricted cubic spline transformations. If the nonlinear transformation significantly improved the model chi-square, then a plot of the logit of the outcome versus the factor of interest was used to determine the most appropriate transformation for modeling. In those cases, a linear spline was used as the final transformation for modeling.
Overview of Trials Included in the Pooled Data Year of Enrollment
N
GUSTO IIb
1994–1995
12,142
PURSUIT
1995–1997
PARAGON A
1995–1996
PARAGON B
1998–1999
Patient Population
Treatment and Comparator Drugs
NSTE-ACS
Hirudin versus UFH
10,948
NSTE-ACS
Eptifibatide versus placebo
2,282
NSTE-ACS
Lamifiban versus placebo
5,225
NSTE-ACS
Lamifiban versus placebo
NSTE-ACS
Enoxaparin versus UFH
ESSENCE
1994–1996
3,171
SYNERGY
2001–2003
10,027
EARLY ACS
2004–2008
9,492
NSTE-ACS treated with an intended early invasive strategy
Enoxaparin versus UFH
NSTE-ACS assigned to an invasive strategy
Early eptifibatide versus delayed eptifibatide
ACS ¼ acute coronary syndrome; EARLY ACS, Early Glycoprotein IIb/IIIa Inhibition in Patients with Non–ST-Segment Elevation Acute Coronary Syndrome; ESSENCE ¼ Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; GUSTO IIb ¼ Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes; NSTE ¼ non–ST-segment elevation; PARAGON A and B ¼ Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; SYNERGY ¼ Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitor; UFH ¼ unfractionated heparin.
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Clinical trial was included as a stratification factor in presenting the association between covariates and HF in the two HF models. We ran an alternate version of each model with trial included as a covariate (rather than as a stratifying factor) to calculate the corresponding C index, recognizing that this would conservatively estimate the statistic. In the postdischarge efficacy models, HF experience through hospital discharge (defined as none, baseline, or new onset) as well as trial were considered among other candidate variables for stepwise selection. Results A total of 53,287 patients were enrolled in the 7 trials. After we excluded patients with cardiogenic shock or Killip class IV at presentation (n ¼ 1,120) and patients with missing HF information on admission (n ¼ 5,648), 46,519 remained for examination in the present study. Among these patients, 4,910 (10.6%) had HF (Killip class II/III or pulmonary edema) at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization (Fig. 1). Patient population. Patients with HF were older and less often male or current smokers (Table 2) than those without HF. Multiple comorbidities and cardiac risk factors were more common among patients with HF. In particular, prior HF was 4 times more common among patients who had HF at presentation or developed HF during hospitalization. More patients with HF had an enrolling MI and STsegment changes on electrocardiography (ECG) than those with no HF. Presenting heart rate was higher and
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blood pressure was lower in patients with HF than in those without HF. Concomitant medications and in-hospital procedures. Treatment with aspirin was similar among patients both with and without HF. Beta-blockers were more commonly prescribed for patients without HF at presentation. Use of angiotensin-converting enzyme inhibitors was more common among patients with HF (Table 3). Patients with HF were less likely to undergo cardiac catheterization (62.3% vs. 70.3%, respectively) and percutaneous coronary interventions (23.4% vs. 33.1%, respectively) than patients without HF. Predictors of HF at presentation and in-hospital HF. In multivariable logistic regression modeling, older age, female sex, race, current smoker status, higher heart rate, diabetes, prior MI, hypertension, peripheral vascular disease, enrolling MI, and ST-segment changes on the presenting ECG were significantly associated with HF at presentation (Table 4). Among patients with no HF at presentation, the baseline factors associated with HF during hospitalization are shown in Table 5 and were similar to those observed for patients with HF at presentation. Clinical outcomes. Patients who presented with HF had an approximately 4-fold higher 30-day mortality rate (5.2% vs. 1.3%, p < 0.001, respectively) and were also more likely to suffer an MI (11.1% vs. 8.4%, p < 0.001, respectively) than patients without HF at presentation. The increased risk in patients with HF is seen in-hospital and also between discharge and 30 days. Patients with HF at presentation or during hospitalization had a higher risk of death at 30 days than patients without HF (adjusted odds ratios [ORs]: 1.74 [95% confidence interval (CI): 1.35 to 2.26] and 2.34 [95% CI: 1.58 to 3.49], respectively). Patients with HF at presentation or in-hospital had a significantly higher risk of death or MI at 30 days than those patients without HF (adjusted OR: 1.76 [95% CI: 1.47 to 2.11] vs. 1.46 [95% CI: 1.04 to 2.05], respectively). There were no differences in prognostic impact between HF at presentation and HF during hospitalization (Fig. 2). Of the overall population, 32.9% (n ¼ 15,320) had quantitative ejection fraction. The median (25th, 75th quartiles) ejection fraction was lower in patients with baseline HF (49% [35%, 60%]) than in patients without baseline HF (55% [45%, 65%]). Likewise, ejection fraction was lower among patients with in-hospital HF (45% [32%, 55%]) than among those without in-hospital HF (55% [45%, 65%]). Discussion
Figure 1
Patient Population
Flow diagram. *Outcome data available for patients with no HF at presentation (n ¼ 41,609): 30-day death (n ¼ 41,563); for 30-day death/MI (n ¼ 41,458). *Outcome data available for patients with HF at presentation (n ¼ 4910): 30-day death (n ¼ 4907); 30-day death/MI (n ¼ 4882). HF ¼ heart failure; MI ¼ myocardial infarction; NSTE-ACS ¼ non–ST-segment elevation-acute coronary syndrome.
In this study of more than 46,000 patients with NSTE-ACS, we found that patients with HF at presentation or occurring during hospitalization were older and had more comorbidities than patients who did not have HF complicating their NSTE-ACS presentation. Furthermore, patients with HF either at presentation or during hospitalization had substantially worse 30-day outcomes than patients with no HF. This study highlights the fact that even in patients with unstable
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Table 2
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Baseline Characteristics for Patients With ACS According to the Presence of HF at Presentation or During Hospitalization No HF (n ¼ 40,415)
Any HF (n ¼ 6,104)
HF at Presentation (n ¼ 4,910)
GUSTO IIb
85.4
14.6
12.0
2.5
PURSUIT
88.6
11.4
8.8
2.6
PARAGON A
86.7
13.3
9.4
4.0
PARAGON B
86.9
13.1
12.0
1.1
ESSENCE
90.4
9.6
8.8
0.8
SYNERGY
84.0
16.0
11.7
4.3
EARLY ACS
87.9
12.1
10.3
Trial
Age (yrs)
65.0 (56.0, 72.0)
Female
32.8
71 (63.4, 77.0)
HF During Hospitalization (n ¼ 1,194)
1.8
71.0 (63.1, 77.0)
38.6
71.0 (64.0, 77.0)
38.8
37.8
Medical history Current smoker
27.4
22.3
23.1
19.1
Prior diabetes
22.4
35.4
35.3
35.9
Prior HF
6.6
28.7
31.0
19.3
Prior MI
29.7
40.5
40.9
39.1
Prior CABG
13.2
16.3
16.2
16.9
Prior PCI
16.7
17.2
18.0
13.9
Hypertension
58.0
66.1
66.1
66.2
7.9
14.3
14.1
14.8
PVD Baseline characteristics Heart rate (beats/min)
72.0 (63.0, 83.0)
79.0 (68.0, 91.0)
80.0 (68.0, 92.0)
76.0 (66.0, 88.0)
Systolic BP (mm Hg)
136.0 (120.0, 151.0)
135.0 (120.0, 151.0)
135.0 (120.0, 152.0)
133.0 (118.0, 150.0)
Diastolic BP (mm Hg)
80.0 (70.0, 88.0)
76.0 (66.0, 85.0)
77.0 (66.0, 86.0)
75.0 (65.0, 83.0)
1.0 (0.9, 1.2)
1.1 (0.9, 1.3)
1.1 (0.9, 1.3)
1.1 (0.9, 1.3)
Creatinine concentration (mg/dl) Killip class 1
100
19.6
0
2
0
69.8
86.8
100 0
3
0
10.6
13.2
0
No. of diseased vessels 0
11.2
7.7
8.7
4.2
1
31.2
18.8
20.9
11.6
2
26.3
24.7
25.0
23.5
3
32.1
48.8
45.4
60.6
Enrolled with MI
61.3
70.1
69.2
73.8
ST-segment changes
53.1
64.2
62.9
69.6
Values are % or median (25th, 75th percentile). CABG ¼ coronary artery bypass grafting; HF ¼ heart failure; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; PVD ¼ peripheral vascular disease. Other abbreviations are shown in Table 1.
angina or non-STEMI, HF at any time during hospitalization is independently associated with poor outcomes. Our study raises the issue of the generalizability of data from clinical trial databases. Even from large multicenter trials, patients who can provide consent and have fewer comorbidities are more often selected for participation. Balancing the shortcomings of patient selection is the much Table 3
higher quality of data collected in clinical trials, in particular claims data. As we analyzed HF as a postrandomization variable, there is little selection based on the occurrence of HF. Our study draws from several trials that were conducted more than 10 years ago, and it is possible that the occurrence of HF and the association with other outcomes is changing, although this seems unlikely.
Baseline Medications According to the Presence of HF at Presentation or During Hospitalization
Medication
No HF (n ¼ 40,415)
Any HF (n ¼ 6,104)
HF at Presentation (n ¼ 4,910)
HF During Hospitalization (n ¼ 1,194)
Aspirin
97.5
97.6
97.4
98.4
Beta-blockers
76.1
71.9
69.3
82.5
Lipid lowering
46.6
45.8
44.6
50.8
Ticlopidine/clopidogrel/dipyridamole
49.2
48.0
47.2
51.4
ACE inhibitors
47.1
64.9
62.0
76.5
Values are %. ACE ¼ angiotensin-converting enzyme; HF ¼ heart failure.
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Bahit et al. HF in NSTE-ACS: Timing, Predictors, and Outcomes
Multivariate Predictors of HF at Presentation in Patients Admitted With ACS
Table 4
Multivariable Predictors of HF During Hospitalization in Patients Admitted With ACS
Table 5
Chi-Square Test
OR
95% CI
p Value
Age (per 5-yr increase)
716.24
1.3
1.28–1.33
<0.0001
Age (per 5-yr increase)
Heart rate (beats/min)
464.47
<0.0001
Heart rate <50 beats/min (per 10 beats/min increase)*
0.7
0.50–0.90
Heart rate >50 beats/min (per 10 beats/min increase)*
1.2
1.21–1.26
1.5
1.37–1.58
Factor
Prior MI
118.28
Chi-Square Test
OR
95% CI
p Value
230.36
1.3
1.23–1.31
<0.0001
MI at enrollment
73.26
1.9
1.63–2.18
<0.0001
Heart rate
69.17
Heart rate 50 beats/min (per 10-beats/min increase)*
0.7
0.45–1.09
Heart rate >50 beats/min (per 10-beats/min increase)*
1.2
1.12–1.20
<0.0001
Factor
<0.0001
White race
99.08
0.6
0.54–0.67
<0.0001
Diabetes
50.26
1.6
1.41–1.84
Diabetes
88.76
1.4
1.33–1.54
<0.0001
ST-segment changes
43.26
1.6
1.38–1.81
MI at enrollment
87.38
1.4
1.33–1.54
<0.0001
Systolic BP
43.07
Creatinine concentration
80.81
<0.0001
0.80–0.91
1.8
1.31–2.55
Systolic BP <130 mm Hg (per 10-mm Hg increase)*
0.9
Creatinine <1 mg/dl* Creatinine >1 mg/dl*
1.4
1.25–1.47
Systolic BP 130 mm Hg (per 10-mm Hg increase)*
1.0
0.93–1.01
1.5
1.27–1.66
Current smoker
52.88
1.4
1.26–1.50
<0.0001
ST-segment changes
43.84
1.3
1.19–1.37
<0.0001
Prior MI
29.86
<0.0001
Creatinine
27.55
Weight
36.70
Weight <70 kg (per 10-kg increase)*
1.0
Weight >70 kg (per 10-kg increase)*
1.1
PVD
31.06
Systolic BP
24.65
1.3
0.95–1.09 1.05–1.11 1.20–1.47
Systolic BP <130 mm Hg (per 10-mm Hg increase)*
0.9
0.89–0.96
Systolic BP >130 mm Hg (per 10-mm Hg increase)*
1.0
0.95–1.00
1.2
1.12–1.31
Female
22.60
Diastolic BP
22.53 0.9
0.88–0.95
Diastolic BP >85 mm Hg (per 10-mm Hg increase)*
1.1
1.00–1.15
1.1
1.02–1.18
Hypertension
5.81
<0.0001 <0.0001 <0.0001
<0.0001 <0.0001
Creatinine <1 mg/dl*
1.8
1.01–3.35
Creatinine >1 mg/dl*
1.3
1.17–1.53
Prior PCI
18.04
0.7
0.55–0.80
<0.0001
PVD
17.63
1.5
1.23–1.75
<0.0001
<0.0001
North America
9.18
1.2
1.08–1.41
0.0024
<0.0001
Hypertension
6.42
1.2
1.04–1.36
0.0113
*Where necessary, spline transformations were used to account for changes in the linear aspect of relationships between continuous covariates and the model endpoint. In these cases, separate odds ratio (OR) estimates are presented above and below the point identified as the location of this change. PCI ¼ percutaneous coronary intervention; other abbreviations as in Table 4.
<0.0001 <0.0001
Diastolic BP <85 mm Hg (per 10-mm Hg increase)*
227
0.0159
*Where necessary, spline transformations were used to account for changes in the linear aspect of relationships between continuous covariates and the model endpoint. In these cases, separate odds ratio (OR) estimates are presented above and below the point identified as the location of this change. C statistic ¼ 0.725. BP ¼ blood pressure; beats/min ¼ beats per minute; CI ¼ confidence interval; MI ¼ myocardial infarction; PVD ¼ peripheral vascular disease.
HF in ACS. Previous research of HF complicating ACS has been conducted in cases of STEMI (4,5,15–18). Killip classification has been extensively studied in this setting and has been associated with high-risk baseline characteristics including older age, diabetes, prior MI, and prior HF (16,19,20). There are only 2 published studies that assessed prognosis of HF in NSTE-ACS. Mehta et al. (21) examined the incidence, predictors, and clinical outcomes of patients who developed HF after ACS in the OASIS-2 (Organization to Assess Strategies for Ischemic Syndromes) trial (21). The cumulative incidence rates of HF were reported as 2.7% at 24 h, 4.9% at day 7, and 6.3% at 6 months, rates substantially lower than those reported in the GRACE registry (22). Patients with HF in the OASIS-2 trial had a significantly higher risk of death or MI than those with no HF. Patients with HF in that study share similar high-risk characteristics with patients with HF in our study and with STEMI patients with HF (i.e., they were
older, more likely female, and more frequently had diabetes, hypertension, and prior MI). A report from the GRACE registry (6) evaluated the factors associated with HF in the setting of NSTE-ACS and its relationship with outcomes. It is important to mention that the patient population also included patients with STEMI. The authors reported that the overall incidence of HF was 13% and was similar in patients with STEMI (15.6%) and non-STEMI (14.7%) but half as frequent in patients with unstable angina (8.2%). As in our study, patients with HF were older than patients with no HF and were more often women and less likely to smoke. History of diabetes and hypertension, prior MI or TIA/stroke, and prior HF were more common in patients with HF than in those without HF. The high-risk baseline features of the HF population were similar to those of our HF patients. While we found in the subset of patients from whom ejection fraction was collected that ejection fraction was lower in the HF population, a large proportion had ejection fraction in the normal or mildly reduced range. Treatment of patients with HF. In our study, consistent with the studies by Mehta et al. (21) and the GRACE registry (6), patients with HF were less likely to undergo cardiac catheterization and percutaneous coronary interventions than patients without HF. These findings are consistent with the results of another report from the GRACE registry (23) describing the use of revascularization in NSTE-ACS patients with HF. In that study, only one-
228
Figure 2
Bahit et al. HF in NSTE-ACS: Timing, Predictors, and Outcomes
JACC: Heart Failure Vol. 1, No. 3, 2013 June 2013:223–9
Model Effect of 3-Level Baseline/In-Hospital HF (No HF/HF at Presentation/HF During Hospitalization)
30-day outcomes in HF. CABG ¼ coronary artery bypass grafting; HF ¼ heart failure; HR ¼ heart rate; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; PVD ¼ peripheral vascular disease.
fifth of the patients with HF were revascularized compared with 35% of the patients without HF. In addition, among patients with HF, revascularized patients had lower-risk baseline clinical features than those who were not revascularized. Steg and colleagues (23) also showed a consistent reduction in postdischarge death in patients with HF who underwent revascularization, suggesting that a broader application of revascularization in this high-risk group may be beneficial. It is important to mention that among the 7 studies included in our analysis, there were only 2 that by inclusion criteria, required that patients be assigned an early invasive strategy (13,14). Predictors of HF complicating ACS. Predictors of HF were consistent between our study and the Mehta and GRACE analyses (6,21). In OASIS-2 (21), independent predictors of HF included older age, history of diabetes, prior MI, and admission diagnosis of non-STEMI. In the GRACE registry (6), older age, history of diabetes and hypertension, prior MI, higher pulse rate, STEMI and nonSTEMI on admission, and prior use of diuretic agents were among the strongest independent predictors of HF. Similarly, we found that older age, history of diabetes and hypertension, and prior MI were key factors associated with
HF at presentation as were MI at enrollment and ST segment changes. Interestingly, some of these factors associated with higher risk of HF following non-STEMI vary over the course of treatment, such as elevated heart rate and lower blood pressure. Thus, close attention to patients with those baseline characteristics in this setting might prompt treatment, such as earlier inhibitors of the renin angiotensin aldosterone system, which might help prevent the development of HF and improve patient outcomes as a result. Strengths and limitations. This is one of the largest studies to examine the relationship between HF at presentation or during hospitalization and subsequent clinical outcomes in patients with NSTE-ACS. However, this is an observational study and cause and effect relationships between HF and clinical outcomes cannot be concluded. Furthermore, as this was a population of patients enrolled in clinical trials, the results may not be generalizable to the broader population of patients with ACS treated in clinical practice. Additionally, the definition of HF was not standardized or consistently adjudicated. Even though there is no standard definition for HF outside clinical trials (24), we believe the physician-reported data reflect classification in typical clinical practice; thus, our results should be relevant. Second, the time period for patient
JACC: Heart Failure Vol. 1, No. 3, 2013 June 2013:223–9
inclusion in the trials whose databases were included in this analysis dated from 1994 and extended to 2008. As a result, there is wide variation in the treatment of NSTE-ACS in this patient population. Finally, we lack specific data regarding timing of HF prior to hospitalization and timing of HF occurrence during hospitalization. Therefore, we are uncertain whether HF during hospitalization is new onset HF or a consequence of a previous condition or whether other inhospital complications may have occurred before or after the development of in-hospital HF. Conclusions In this large database, HF at presentation was a frequent complication of NSTE-ACS and was associated with higherrisk baseline features and more adverse outcomes. Readily available baseline characteristics identified patients with increased risk of developing HF, which was associated with subsequent mortality. Patients with NSTE-ACS and HF were also undertreated with evidence-based therapies and interventions, suggesting an opportunity to reduce adverse outcomes through adherence to guidelines recommendations. Further prospective studies are needed to assess the best treatment strategies for this high-risk group of patients. Reprint requests and correspondence: Dr. Renato D. Lopes, Duke Clinical Research Institute, Duke University Medical Center, Box 3850, 2400 Pratt Street, Room 0311 Terrace Level, Durham, North Carolina 27705. E-mail: [email protected].
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Key Words: acute coronary syndromes elevation - outcomes - timing.
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heart failure
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non–ST-segment