Relationship Between Angina Pectoris and Outcomes in Patients With Heart Failure and Reduced Ejection Fraction

An Analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)

Athar A. Badar; Ana Cristina Perez-Moreno; Pardeep S. Jhund; Chih M. Wong; Nathaniel M. Hawkins; John G.F. Cleland; Dirk J. van Veldhuisen; John Wikstrand; John Kjekshus; Hans Wedel; Stuart Watkins; Roy S. Gardner; Mark C. Petrie; John J.V. McMurray

Disclosures

Eur Heart J. 2015;35(48):3426-3433. 

In This Article

Discussion

In the ~5000 patients with HF-REF of ischaemic aetiology in CORONA, we found that 47% had current chest pain, presumed to be angina. This proportion is consistent with the few prior reports of ongoing angina in other studies, assuming that most or all of patients with angina (20–25% of patients overall) in those studies were among the patients with an ischaemic aetiology (50–70% of patients).[3,4]

There were some notable differences between patients with chest pain at baseline and those without. In the former (Group C), 71% of patients were in NYHA functional class III or IV, compared with 58% of those in Group B (no current chest pain but history of angina) and 54% of patients in Group A (neither current chest pain nor history of angina). This worse functional status probably reflected myocardial ischaemia rather than severity of HF per se. Patients in Group C had the highest LVEF and blood pressure and lowest creatinine and NT-proBNP, in keeping with better overall haemodynamic status, despite their worse functional status. This finding highlights the potential of anti-ischaemic treatment to improve functional status in these patients.

Comparing the two groups of patients with a history of angina (Groups B and C), those without current chest pain (Group B) were more likely to have previously experienced an MI and much more likely to have undergone CABG (especially) or PCI. Lack of chest pain may therefore reflect the absence of viable ischaemic myocardium (because of infarction) or effective revascularization and suggests that this group was probably a heterogeneous mixture of patients.

Patients with current chest pain (Group C) were more than twice as likely to experience an acute coronary syndrome (ACS), or an ACS plus revascularization, as patients without a history of angina and without current chest pain (Group A). Patients with a history of angina but without current chest pain (Group B) were also more likely than those in Group A to experience an ACS but their risk was not as high as that of patients in Group C. This finding suggests that anti-ischaemic/anti-infarction treatment has the potential to reduce coronary events, as discussed below.

The risk of the expanded 'coronary' composite, including sudden-death, defibrillation by an ICD and resuscitated cardiac arrest was not increased as much as the risk of an ACS (or an acute ACS plus revascularization) in patients in Group C, compared with those in Group A (and not increased at all in Group B), suggesting that many or even most arrhythmic events in HF are not related to active ischaemia but rather to myocardial scars.

Similarly, the risk of death from any cause (and CV causes) was not increased in patients with chest pain (or in those with a history of angina but no chest pain), compared with patients with neither of these. This observation appears puzzling as it implies that the increased risk of ACS in patients in Group C did not lead to an increased risk of death due to pump failure or arrhythmia, as might be expected. However, even in patients with ischaemic HF and ongoing chest pain, MI and UA are relatively infrequent events. In our study, a first event of this type occurred in only ~10% of patients, compared with death in nearly 30%, meaning that ACS are likely to have only a small effect on mortality. This does not preclude the possibility of a modest mortality benefit from revascularization, a conclusion consistent with the Surgical Treatment for Ischaemic Heart Failure trial (STICH), which showed that CABG did not reduce all-cause mortality in patients with HF-REF, although there was a borderline-significant reduction in CV death.[9]

In contrast, patients in Group C had a modestly increased risk of HF hospitalization compared with those in Group A; there was a numerically smaller and non-significant trend in the same direction when Group B was compared with Group A. This finding is of interest given that patients in Group C had a better overall HF risk-profile and is consistent with the view that myocardial ischaemia may precipitate some HF hospitalizations and the results of STICH.[10] Although the STICH investigators did not report HF hospitalization as an individual outcome, CABG did reduce the composite of all-cause death or HF hospitalization [HR: 0.84 (0.71–0.98); P = 0.03].[9]

The potential to reduce morbidity appears greatest in patients with chest pain (presumed angina), as patients in Group C had the highest rate of coronary and HF events. However, we cannot preclude benefit in patients without ongoing chest pain as patients in our Group B, as discussed above, were heterogeneous (and more than half had undergone coronary revascularization) and we did not have a non-ischaemic comparator group for Group A (patients with neither a history of angina or current chest pain but all of ischaemic aetiology). We know that patients with an ischaemic aetiology have worse outcomes than those with non-ischaemic HF and coronary revascularization might still improve outcomes in the former.[11,12]

We know of only two other studies to examine the relationship between angina and outcomes in HF-REF. Mentz et al. examined outcomes in 2376 patients with CAD and a LVEF <40%, either with (n = 1412) or without (n = 964) angina over a median follow-up of 4.5 years. In an adjusted analysis, patients with angina were less likely to experience the composite of death, MI or revascularization than those without angina (5-year risk 85 vs. 87%; P = 0.01) but not death from any cause (41% in both groups), the latter finding consistent with the present study.[5] This US cohort had a very high revascularization rate compared with CORONA where only 3.3% of patients underwent PCI and 1.2% CABG, i.e. CORONA better reflects the unaltered 'natural history' of CAD in HF-REF.

Of the 3029 patients in COMET, 53% of patients had an ischaemic aetiology and 22% had current angina at baseline. Angina was not associated with worse clinical outcomes in adjusted analyses, possibly because of lack of power. COMET included fewer patients with an ischaemic aetiology (~1600 vs. 5011 in CORONA), angina (~670 vs. 2285) and did not examine coronary events, which were the outcomes which showed the clearest increase in patients with chest pain in CORONA.[3,13]

The most obvious implication of our study is the potential for therapeutic benefit from relief of myocardial ischaemia and prevention of coronary events, which might include improvement in functional capacity and reduction in hospitalization for ACS and, importantly, HF. While this has been demonstrated to some extent with CABG, the possible benefit of PCI is unknown but is under investigation.[14] Pharmacological interventions should also be considered, including anti-ischaemic therapy (e.g. nicorandil which has been shown to reduce hospitalization for angina) and anti-thrombotic therapy.[15]

Our study has a number of limitations. We assumed chest pain at baseline represented angina pectoris which may not always be correct; conversely myocardial ischaemia may be present in HF even in the absence of epicardial CAD.[16] The subgroups examined in our analysis were not pre-specified and our findings have the inherent limitations of all post hoc analyses. We did not have the results of coronary angiography and the severity of CAD may be independently related to prognosis.[11] Our results cannot be generalized to all patients with HF, particularly those with preserved LVEF.

In summary, angina is a common symptom in patients with HF-REF and is associated with worse functional status, increased risk of acute coronary events, and HF hospitalization. These findings highlight the potential for anti-ischaemic and anti-infarction strategies to improve symptoms and outcomes in HF, but these need to be tested in randomized controlled-trials.

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