Author + information
- Received April 5, 2013
- Revision received September 22, 2013
- Accepted September 23, 2013
- Published online January 28, 2014.
- Robert J. Mentz, MD∗,†∗ (, )
- Samuel Broderick, MS‡,
- Linda K. Shaw, MS‡,
- Mona Fiuzat, PharmD∗,§ and
- Christopher M. O'Connor, MD∗,†
- ∗Department of Medicine, Duke University Medical Center, Durham, North Carolina
- †Division of Cardiology, Duke University Medical Center, Durham, North Carolina
- ‡Duke Clinical Research Institute, Durham, North Carolina
- §Division of Clinical Pharmacology, Duke University Medical Center, Durham, North Carolina
- ↵∗Reprint requests and correspondence:
Dr. Robert J. Mentz, Department of Medicine, Division of Cardiology, Duke University Medical Center, 2301 Erwin Road, Durham, North Carolina 27710.
Objectives This study investigated the characteristics and outcomes of patients with heart failure with preserved ejection fraction (HFpEF) and angina pectoris (AP).
Background AP is a predictor of adverse events in patients with heart failure with reduced EF. The implications of AP in HFpEF are unknown.
Methods We analyzed HFpEF patients (EF ≥50%) who underwent coronary angiography at Duke University Medical Center from 2000 through 2010 with and without AP in the previous 6 weeks. Time to first event was examined using Kaplan-Meier methods for the primary endpoint of death/myocardial infarction (MI)/revascularization/stroke (i.e., major adverse cardiac events [MACE]) and secondary endpoints of death/MI/revascularization, death/MI/stroke, death/MI, death, and cardiovascular death/cardiovascular hospitalization.
Results In the Duke Databank, 3,517 patients met criteria for inclusion and 1,402 (40%) had AP. Those with AP were older with more comorbidities and prior revascularization compared with non-AP patients. AP patients more often received beta-blockers, angiotensin-converting enzyme inhibitors, nitrates, and statins (all p < 0.05). In unadjusted analysis, AP patients had increased MACE and death/MI/revascularization (both p < 0.001), lower rates of death and death/MI (both p < 0.05), and similar rates of death/MI/stroke and cardiovascular death/cardiovascular hospitalization (both p > 0.1). After multivariable adjustment, those with AP remained at increased risk for MACE (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.17 to 1.45) and death/MI/revascularization (HR: 1.29, 95% CI: 1.15 to 1.43), but they were at similar risk for other endpoints (p > 0.06).
Conclusions AP in HFpEF patients with a history of coronary artery disease is common despite medical therapy and is independently associated with increased MACE due to revascularization with similar risk of death, MI, and hospitalization.
Angina pectoris (AP) is the symptomatic condition related to ischemia and has different prognostic implications in various patient populations (1). We have previously shown that the presence of AP in patients with heart failure (HF) with reduced ejection fraction (EF) is common despite medical therapy and previous revascularization, and is associated with increased cardiovascular death or rehospitalization (2). Heart failure with preserved ejection fraction (HFpEF) accounts for upward of 50% of all patients with HF (3), and the evidence for therapies to reduce adverse events in this population is limited (4). The implications of AP in HFpEF are not well defined because these patients have generally been excluded from AP studies (5). We compared the clinical characteristics and the outcomes of patients with and without AP in a cohort of HFpEF patients.
Patient data were obtained from the Duke Databank for Cardiovascular Disease (DDCD), an ongoing databank of all patients undergoing diagnostic cardiac catheterization at Duke University Medical Center. Patients were included in the study population if they underwent coronary angiography from January 2000 through December 2010, and if they had HFpEF and a history of ≥50% stenosis in at least 1 epicardial coronary vessel (only those patients with a history of significant coronary artery disease receive DDCD follow-up). Coronary stenoses were graded by visual consensus of at least 2 experienced observers. Patients were defined as having HFpEF if they had New York Heart Association (NYHA) functional class II to IV symptoms in the 2 weeks before index catheterization and EF ≥50% (6). Patients were excluded from analysis if they had EF <50%, unknown EF, unknown NYHA functional class, primary valvular heart disease (defined as moderate or severe aortic or mitral insufficiency, or severe stenosis of any heart valve), congenital heart disease, acquired immunodeficiency syndrome, or metastatic cancer.
Data from the index catheterization were prospectively collected as part of routine patient care. Baseline clinical variables for each patient were stored in the DDCD using methods previously described (7). Follow-up was obtained through self-administered questionnaires, with telephone follow-up to nonresponders. Patients not contacted through this mechanism had vital status determined through a search of the National Death Index (8).
AP classification was based on physician-obtained patient history just before cardiac catheterization and was defined as chest pain within the previous 6 weeks. Because many groups (e.g., women, elderly patients) present with atypical angina (9,10), we did not want to bias our results by using a classic angina definition alone. Given the prognostic value of angina characteristics, the severity, frequency, and pattern of occurrence were recorded at baseline. Revascularization was defined as treatment with percutaneous coronary intervention or coronary artery bypass graft. Death, myocardial infarction (MI), stroke, and cardiovascular rehospitalization were determined using methods previously described (7).
Baseline characteristics are described with medians and interquartile ranges (IQRs) for continuous variables and percentages for discrete variables in HFpEF patients with versus without AP. These characteristics were compared using the Wilcoxon rank sum test for continuous variables and chi-square tests for categorical variables unless otherwise noted. The primary endpoint was death/MI/revascularization/stroke (i.e., major adverse cardiac events [MACE]) and secondary endpoints were death/MI/revascularization, death/MI/stroke, death/MI, death, and cardiovascular death/cardiovascular hospitalization. Multivariable Cox proportional hazards regression analysis was used to adjust for baseline differences between groups. A comprehensive set of covariates was used for the adjustment analysis (see Table 3 footnote) based on clinical relevance and data from a previous investigation (2). With the large number of events in each analysis, there was no overfitting problem with adjustment variables. Adjusted time-to-event results were generated for the endpoints, and comparisons were made using the log-rank test. A p value of <0.05 was used to indicate statistical significance for all comparisons. Statistical analyses were performed by Duke Clinical Research Institute (Durham, North Carolina) using SAS (version 9.2, SAS Institute, Cary, North Carolina). The protocol was approved by the institutional review board at Duke University, and all patients voluntarily provided written informed consent.
A total of 3,517 patients met the criteria for the study (Fig. 1), and 1,402 (40%) had AP. In the AP cohort, 48% had typical angina and 49% had atypical angina in the previous 6 weeks. AP was described as stable, progressing, or unstable in 24%, 47%, and 27% of patients in the preceding 6 weeks, respectively. Using a modification of the Canadian Cardiovascular Society angina grade (11), the percentage of AP patients with Canadian Cardiovascular Society classes I (no symptoms with ordinary activity), II (symptoms with moderate exertion), III (symptoms with ordinary exertion), IV (symptoms with any exertion or at rest), and symptoms unrelated to exertion were 0.2%, 13.3%, 15.0%, 41.5%, and 30.1%, respectively. The median frequency per week of chest pain episodes was 4 (IQR: 3 to 7).
Baseline characteristics for the AP and non-AP groups are provided in Table 1. As expected, a number of baseline characteristics differed significantly between the cohorts, with AP patients tending to be older and more likely to have a prior history of hypertension, diabetes, hyperlipidemia, vascular disease, smoking, and coronary revascularization. Notably, those with AP tended to have less severe NYHA functional class symptoms and were less likely to have rales or an S3 gallop. Systolic blood pressure was significantly higher in the AP group. The basic laboratory parameters were similar between the 2 groups even though there were statistically significant differences in several of the laboratory parameters due to the large sample size. AP patients more often received beta-blockers, angiotensin-converting enzyme inhibitors, nitrates, and statins but were less likely to receive diuretics as compared with non-AP patients. In this HFpEF population, both groups had high baseline use of beta-blockers and angiotensin-converting enzyme inhibitors, but modest use of calcium channel blockers, nitrates, and hydralazine. In the AP group, 77% of patients received a beta-blocker, calcium channel blocker, or nitrate at baseline compared with 68% in the non-AP group.
The median follow-up time for all patients was 4.0 years (IQR: 1.6 to 7.6 years). Five-year unadjusted Kaplan-Meier (KM) survival for the study population was 66.3%. AP patients were observed to have a significantly increased event rate for the primary endpoint of MACE, as well as death/MI/revascularization (Table 2). Of note, many of the events for the MACE composite occurred early following the index catheterization (30-day and 6-month unadjusted KM event rates of 32.4% and 37.4% for the AP group, respectively). By contrast, the event rates were lower in the AP patients for the endpoints of death/MI and death compared with those in patients without AP (both p < 0.05). There were no significant differences between the event rates in those with and without AP for the endpoints of death/MI/stroke, and cardiovascular death/cardiovascular hospitalization (Table 2).
Following risk adjustment, AP was associated with a significantly higher risk of MACE and death/MI/revascularization than was no AP (both p < 0.0001) (Table 3). AP was an independent predictor of MACE (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.17 to 1.45) (Table 3). Patients with and without AP had similar risk for death/MI/stroke, death/MI, death, and cardiovascular death/cardiovascular hospitalization (all p > 0.06) (Table 3). Results for the composite endpoint of all-cause death/hospitalization in those with AP (adjusted HR: 0.91, 95% CI: 0.83 to 1.00; p = 0.056) were similar to the results for cardiovascular death/cardiovascular hospitalization. The adjusted time-to-event plots in patients with versus without AP are presented in Figures 2⇓ to 5⇓⇓.
There were several important findings from this study. First, AP was common in this HFpEF cohort despite medical therapy and previous revascularization. Most of these patients had angina that was progressive or unstable in the preceding weeks, with >50% experiencing Canadian Cardiovascular Society class III or IV symptoms. Second, HFpEF patients with AP had more comorbidities and more previous revascularization procedures than did non-AP patients. After multivariable risk adjustment, those with recent AP were at significantly increased risk for MACE. However, AP was not associated with increased risk for death/MI/stroke, death/MI, death, or cardiovascular death/hospitalization following adjustment for baseline characteristics. Thus, AP was an independent predictor of MACE driven by increased revascularization, but it was not associated with increased risk of death, MI, stroke, or rehospitalization.
Although the prevalence of AP in HFpEF patients is lower than in patients with HF with reduced EF (2,6), a significant percentage of HFpEF patients have AP. We found that 40% of HFpEF patients had AP despite previous revascularization (25% with coronary artery bypass grafting and 23% with percutaneous coronary intervention) and high usage of beta-blockers. The modest usage of calcium channel blockers, nitrates, and ranolazine in this cohort suggests that there is room for significant improvement in the use of medical therapies to reduce AP in these patients (1). These findings are particularly relevant in the context of the paucity of treatments for HFpEF patients. Potentially, by targeting angina symptoms with presently available medical therapies, the morbidity related to repeat revascularizations in HFpEF patients could be reduced. Despite the relative contraindication to calcium channel blockers in HF with reduced EF patients (12), further investigation is needed to define the use of calcium channel blockers as antianginals in HFpEF patients.
The AP patients in this cohort had a distinct phenotype from those without AP. Specifically, the AP patients were less likely to have rales, an S3 gallop, or baseline diuretic use, and they tended to have a lower NYHA functional class. Thus, these patients may have had more prominent anginal symptoms rather than volume overload with fatigue and dyspnea, which are used to characterize NYHA functional class.
The death/MI/revascularization/stroke event curves for the cohorts began to diverge early (i.e., within the first 6 months) with a persistent effect up to 10 years after the index catheterization. After adjusting for baseline comorbidities and medication use, AP remained a strong independent predictor of MACE. It was found that AP was associated with a 30% increased risk of long-term death/MI/revascularization/stroke. These findings, along with the lack of association between AP and other endpoints on adjusted analysis, suggest that the implications for AP are most strongly correlated with increased revascularization. These results support previous data that revascularization may be performed to relieve anginal symptoms, but it may not improve prognosis unless the patient demonstrates other high-risk features (1).
These results have important clinical applications, given the procedural costs and quality of life implications for revascularization procedures. Previous studies have also suggested that HFpEF patients with coronary artery disease who present with pulmonary edema tend to have recurrence of pulmonary edema despite revascularization (13). Thus, a reappraisal of the utility of revascularization in HFpEF patients may be warranted, given potential limitations in preventing HF decompensation. Future studies will need to explore whether improved management of AP may reduce revascularization rates.
Our findings that AP did not portend increased death or hospitalization following risk adjustment is concordant with previous studies of stable AP in the general (e.g., non-HF) population. Follow-up of the APSIS (Angina Prognosis Study in Stockholm) demonstrated that patients with stable AP had similar all-cause mortality when compared with patients without AP over a median follow-up of 9 years (14). We have previously shown that AP in the ischemic cardiomyopathy population with reduced EF was not associated with increased long-term death, death/MI, or death/all-cause hospitalization (2). The present study extends these results into the HFpEF population.
The observation that AP was associated with reduced death and death/MI on unadjusted analysis was unexpected. Potential reasons for reduced mortality associated with angina include increased use of prevention therapies (e.g., aspirin, statins), heightened physician follow-up, “ischemic pre-conditioning” protecting against subsequent adverse outcomes (15,16), and statistical chance. Interestingly, the between-group difference in outcomes narrowed over time. Our previous study in the reduced EF population demonstrated a trend toward reduced mortality associated with AP on unadjusted analysis (2). Similar to the present results, the association between AP and death in reduced EF patients was further attenuated with risk adjustment. Thus, these data present consistent evidence that AP is not associated with mortality across the spectrum of HF patients when baseline characteristics are accounted for.
The DDCD captures a subset of cardiac patients undergoing cardiac catheterization, which limits the population studied and may not reflect event rates in a broader population. For instance, the requirement to undergo cardiac catheterization likely reduced the age of the patients in the study cohort compared with other HFpEF datasets. On the other hand, the robust representation of both women and minorities in the DDCD provides important insights into patient characteristics and outcomes in frequently under-represented patient groups. A limitation related to this dataset is that only those patients with a history of significant coronary artery disease receive DDCD follow-up. Further empiric testing is required to explore outcomes in HFpEF patients without epicardial coronary disease, because underlying significant coronary artery disease likely influenced subsequent revascularization considerations. Given this study's long accrual time, the subjective AP classification was recorded by many investigators such that there was inherent variability in the databank. This is a recognized limitation of the databank, but it also represents the reality of clinical practice in which clinicians may categorize subjective symptoms differently. It is also possible that patients in both the AP and non-AP groups would be weighted toward those with a higher index of suspicion for intervenable coronary artery disease. Future studies should explore whether the degree of ischemia confounds the association between AP and outcomes because chest pain in HFpEF patients does not always represent underlying myocardial ischemia. Our use of AP classification at a single time point (index catheterization) is another potential limitation because we did not investigate persistent AP or the relation of a subsequent revascularization to AP. Given the multiple analyses conducted in the present study, these results should be viewed as exploratory, given the increased likelihood of a type I error. Our study provides the foundation for future studies of AP in HFpEF in an attempt to improve patients' symptoms and reduce revascularization rates.
AP in HFpEF patients with a history of coronary artery disease is common despite medical therapy and previous revascularization, and it is independently associated with increased MACE due to revascularization, with similar risk of death, MI, stroke, and hospitalization. Given the paucity of treatments for HFpEF patients, these data provide the foundation for pharmacological studies targeting anginal symptoms to reduce the morbidity associated with repeat revascularizations. Future prospective studies of angina in HFpEF patients are warranted.
Drs. Mentz, Fiuzat, and O'Connor have received research funding from Gilead Sciences, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Gregg C. Fonarow, MD, acted as Guest Editor for this paper.
- Abbreviations and Acronyms
- angina pectoris
- confidence interval
- Duke Databank for Cardiovascular Disease
- ejection fraction
- heart failure
- heart failure with preserved ejection fraction
- hazard ratio
- interquartile range
- major adverse cardiac events
- myocardial infarction
- New York Heart Association
- Received April 5, 2013.
- Revision received September 22, 2013.
- Accepted September 23, 2013.
- American College of Cardiology Foundation
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