European Heart Journal Advance Access published online on June 11, 2007
European Heart Journal, doi:10.1093/eurheartj/ehm198
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Clinical course of isolated stable angina due to coronary heart disease
1 Cardiac Medicine, National Heart and Lung Institute, Imperial College London, London, UK
2 Department of Preventive Medicine, Faculty of Public Health, Medical and Health Sciences Centre, University of Debrecen, Debrecen, Hungary
3 SOCAR Research, Nyon, Switzerland
4 Amphia Ziekenhuis, Breda, The Netherlands
5 Department of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam, The Netherlands
Received 2 February 2007; accepted 26 April 2007.
* Corresponding author. Tel: +44 20 7351 8179; fax: +44 20 7351 8113. E-mail address: p.poole-wilson{at}imperial.ac.uk
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Abstract |
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Aims: To describe the clinical course of patients with stable angina due to coronary heart disease without a history of cardiovascular (CV) events or revascularization (isolated angina).
Methods and results: Of 7665 patients in a trial comparing long-acting nifedipine with placebo, 2170 (28%) had isolated angina. During a mean follow-up of 4.9 years, 147 of these died (1.4/100 patient-years), while 761 (8.7/100 patient-years) either died, or had a cardiac event or procedure. The first event was death in 82, myocardial infarction or heart failure in 112, coronary revascularization in 171, and chest pain requiring hospitalization in 396. Six hundred and twelve patients (6.8/100 patient-years) underwent coronary angiography (CAG), followed by revascularization in 371. Sixty-eight of 262 deaths or major cardiac events were preceded by chest pain requiring hospitalization or revascularization. Event-rates after CAG were higher than before. The stroke rate was 0.7/100 patient-years (75 patients).
Conclusion: Patients with stable isolated angina have low rates of death and major cardiac events, but relatively high rates of chest pain requiring hospitalization despite contemporary management. Since the majority of deaths and major CV clinical events are not preceded by clear warning symptoms, the main clinical implication is that measures to prevent such events must target all patients.
Key Words: Coronary heart disease • Angina • Natural history • Secondary prevention • Coronary angiography • Revascularization
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Introduction |
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Among patients who present with angina due to coronary heart disease (CHD), those with isolated stable angina, i.e. those who have not as yet undergone an interventional procedure or experienced a major cardiovascular (CV) event, are of special interest as future irreversible manifestations of CHD such as acute myocardial infarction (MI) can potentially still be prevented. The prognosis of isolated stable angina is unknown in a modern setting, but is a central health care issue both in patient management and in the provision of resources.
The available information on the prognosis of stable angina derives mainly from clinical studies1–4 prior to the use of modern medicines and interventional strategies. Trial reports focus on effects of treatment rather than on prognosis in general. Furthermore, trials in CHD5–8 usually include a broad spectrum of patients with and without symptoms or a history of major CV events. Hence, contemporary data that specifically documents the clinical course of patients with isolated angina is lacking.
ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine, GITS) was a randomized clinical trial comparing long-acting nifedipine, GITS (gastro-intestinal therapeutic system) with placebo in a wide range of patients with stable symptomatic angina.9 Seven thousand six hundred and sixty-five patients were included and the main results have been published.10 ACTION is the largest current database documenting the prognosis of stable angina. A general risk score for estimating the probability of death, MI, or debilitating stroke has been published.11 Here, we contrast the clinical history and outcome of the subgroup of ACTION patients who at baseline had isolated angina (n = 2170) with those who had a history of coronary revascularization only (n = 1478), and those who had a history of MI, heart failure (HF), or stroke (n = 4017). In addition, we consider the effects of nifedipine and the sequence of clinical events and utilization of coronary angiography (CAG) in patients with isolated angina in more detail.
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Methods |
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Design of ACTION
The design and main results of ACTION have been published.9,10 Briefly, ambulatory patients aged 35 years or older with stable symptomatic angina pectoris requiring treatment were randomly assigned to nifedipine GITS (maximally 60 mg once daily) or matching placebo. In addition to angina, patients had either a history of MI, CHD proven by CAG, or, in the absence of previous MI or CAG, a positive exercise or perfusion test. Patients with clinically significant HF, echocardiographic left ventricular (LV) ejection fraction (EF) below 40% or any condition that limited life expectancy were excluded. Physicians were encouraged to pursue risk factor modification and to treat symptomatic angina as appropriate. Standard baseline assessments were undertaken.12 Follow-up in outpatient clinics took place after randomization at 2 weeks, 6 weeks, and 6 months and then every 6 months. All patients who took at least one tablet of study medication were followed until death or until end of follow-up. Study medication was discontinued only when a clinical contraindication occurred.
Assessment of clinical events during follow-up
Clinical events and major diagnostic or intervention procedures were reported using standard serious adverse event report forms. As previously described,10 the Critical Events Committee (CEC) independently determined the occurrence of acute MI, refractory angina, new overt HF, debilitating stroke, and peripheral revascularization. Each patient could have several clinical events. The committee assessed the cause of death as CV, undetermined, or non-CV.
We defined chest pain requiring hospitalization as any chest pain or worsening angina reported by the investigator for which the patient was hospitalized, and included in the definition refractory angina as determined by the CEC. We defined any stroke as either debilitating stroke determined by the CEC or stroke diagnosed by the investigator.
Statistical analysis
We obtained descriptive statistics for three subgroups of ACTION participants: (i) those without a history of coronary revascularization, MI, HF, or stroke at baseline (isolated angina); (ii) those with a history of coronary revascularization only; and (iii) those with a history of MI, HF, or stroke.
All analyses of follow-up were done by assigned treatment (intention-to-treat). For events we report both the total occurrence and the number of patients who sustained the event considered, and took event-rates as the total number of patients who sustained the (combined) event concerned, divided by the total person-years ‘at risk’ of event. Percutaneous coronary intervention (PCI) was counted as CAG also.
For patients with isolated angina at baseline we estimated event-free survival probabilities for selected outcomes in both study treatment groups combined using the Kaplan–Meier method. We also determined the number of patients that evolved during follow-up from isolated angina to any of the following (ranked for severity): chest pain requiring hospitalization, coronary revascularization, major cardiac event (i.e. MI or HF), and death. We determined in addition how many patients progressed from any of these conditions or events to a more severe one. For each transition considered, we obtained the percentage of patients sustaining the transition concerned and the corresponding transition rate.
For patients with isolated angina at baseline who had CAG during follow-up, we determined the cardiac events that preceded CAG and those that occurred subsequently (based on the first CAG in patients who had more than one). In calculating event-rates up to CAG, we censored follow-up at the date of the first CAG (if any).
Using Cox proportional hazards models with treatment allocation as the only covariate, we derived hazard ratios (HRs) and their 95% confidence intervals (CIs) comparing event-rates between all patients assigned nifedipine and placebo, respectively. Treatment-subgroup interaction tests at the two-sided level of P < 0.05 were performed by adding two indicator variables and corresponding interaction terms.
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Results |
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ACTION was completed as planned and 7665 patients were included.10 Two thousand one hundred and seventy (28%) patients had isolated angina, 1478 (19%) a history of coronary revascularization only, and the remaining 4017 (52%) a history of MI, HF, or stroke.
Baseline patient profile
As shown in Table 1, patients with isolated angina tended to be older than those with a history of revascularization or CV events. Irrespective of history, <10% reported not having any anginal attacks. Forty-four per cent of patients with isolated angina had a pattern of coronary disease that had been documented by CAG prior to start of follow-up as opposed to 74% of patients with angina and a history of MI, HF, or stroke. Patients with a history of revascularization had the most extensive angiographic coronary disease. Risk factors and other findings were similar in each subgroup, with the exception of ECG signs of MI (present in 46% of patients with a history of MI, HF, or stroke).
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Details of CV medication at entry are shown in Table 2. Patients with isolated angina were least frequently treated with lipid-lowering and blood pressure-lowering drugs other than beta-blockers. The use of anti-platelet drugs was lowest among patients with isolated angina (85%) and highest among patients who had a history of revascularization only (92%).
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Occurrence of cardiovascular events and procedures during follow-up
Rates of CV events and procedures are given in Table 3. The shape of event-free survival curves (Kaplan–Meier method) shown in Figure 1 for both study treatment arms combined suggests that event-rates were essentially stable over time.
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Patients with isolated angina had an all-cause mortality rate of 1.37 per 100 patient-years. Those with a history of coronary revascularization had a similar mortality rate, but had generally higher rates of other events and procedures while those with a history of MI, HF, or stroke also had a higher mortality rate. The majority of deaths had a CV or undetermined cause.
As previously reported,10 nifedipine significantly reduced (95%CI of HR does not include unity) the rate of HF and the need for coronary bypass surgery in all patients assigned nifedipine GITS combined. Other significant reductions by nifedipine were observed for any chest pain requiring hospitalization; any coronary revascularization; any death or cardiac event; any stroke; the combination of any death, cardiac event, or stroke; and the combination of any death, MI, stroke, HF, CAG, or coronary revascularization. Effects of nifedipine were consistent across the three subgroups of history at baseline considered.
Sequence of events and procedures
There were in total 761 of 2170 patients with isolated angina who either died or had any cardiac event (8.66 per 100 patients years; Table 3). Figure 2 shows the order in which events occurred and the event-rates for the transitions indicated. Of the 82 deaths as first event, 40 were due to a non-CV cause. Of the 42 deaths as first event who had a CV or undetermined cause, death was not witnessed in 13 while in a further 13 the patient died within 1 h of onset of symptoms.
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Utilization of coronary angiography
During follow-up, CAG was performed at least once in 612 (28%) patients with isolated angina (Table 3). Of the remaining 1558 patients, 672 had a CAG before entry.
The events and the corresponding rates that occurred before and after CAG during follow-up, respectively, are shown in Table 4. In 87 of the 371 patients who had PCI or coronary artery bypass surgery (CABG) following CAG, revascularization was performed on the same day while in a further 132 this procedure was done within 1 week. For 14 of the 165 patients who had another CAG, the second one was done within 1 week. Of the 46 patients who sustained either MI or HF after the initial CAG, 11 did so within 1 week while of the 36 patients who died, two died within 1 week. In comparison to the rates up to CAG or end of follow-up, both the rates of death and of CV events were higher after CAG.
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Coronary revascularization
As shown in Table 3, 374 of 2170 (17%) of patients with isolated angina underwent either PCI or CABG during follow-up. This includes three patients who had CABG during follow-up although CAG had been done before entry into the trial. The first PCI in the 167 patients who underwent this procedure was followed by another PCI procedure in 31 patients (two within 1 week) and by CABG in 18 patients (one within 1 week). Within 1 week of any PCI (n = 204), one patient died while seven patients sustained an MI. No patient was diagnosed with HF or stroke. Similarly, the first CABG in the 234 patients who had this procedure was followed by PCI in 11 patients (one within 1 week) and by another CABG in one patient (none within 1 week). Within 1 week of any CABG (n = 235), five patients died while three patients sustained an MI and three patients sustained a stroke. No patient was diagnosed with HF within this time interval.
Stroke
As shown in Table 3, 75/2170 patients with isolated angina (0.71 per 100 patient-years) sustained any stroke (debilitating in 42). Of the 82 patients who died without a previous cardiac event (Figure 2), 15 sustained a stroke before death. Of the 1409 patients who neither died, nor had any cardiac event (Figure 2), 31 sustained a stroke. The remaining strokes occurred in 29 of the 679 patients who had any of the cardiac events shown in Figure 1.
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Discussion |
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Based on this study, three in 10 patients with stable angina seen in clinical practice have isolated angina, two have angina despite previous revascularization, while the remaining five have angina after previous MI, HF, or stroke. Other than the history, the present study suggests that these three subgroups have essentially similar clinical features and no major differences in event-rates during follow-up. Similarly, the effects of nifedipine on outcomes, such as the significant reduction by 13% in any of the events listed in Table 3, were consistent across the subgroups considered.
Profile of patients with stable isolated angina
Our findings confirm that isolated angina is not just a disease of the elderly (median age 65 years), and it is predominantly a disease of men. That patients with isolated angina were older than those with a history of coronary revascularization or CV events suggests that their CHD progresses more slowly. Less than half of patients with isolated angina had undergone CAG before entry (Table 1). Apparently, CAG is often deferred until mandated by the need to consider revascularization. Less than 10% of patients did not have any anginal attacks at baseline, which suggests that anti-anginal treatment with beta-blockers and nitrates but without calcium antagonists (which were not allowed in ACTION at baseline) is frequently unable to prevent anginal attacks completely. As expected, risk factors were frequently present.
‘Natural history’ of isolated angina and scope for prevention
The current treatment of stable angina rests on four pillars: life style modification, drugs that prevent anginal attacks, drugs that act on risk factors or have a preventive effect because of other mechanisms, and coronary revascularization. Hence, ‘natural history’ is a moving target because it reflects disease progression modulated by the effects of treatment.
The use of drugs known to have a preventive effect in patients with CHD by substantial proportion of patients with isolated angina in this study (Table 2) will have contributed to their relatively good prognosis, as has been observed before.5,7 Had the use of preventive drugs been even more widespread, the prognosis might conceivably have been even better. After a mean follow-up of almost 5 years, 60% of patients with isolated angina were alive and free of any cardiac event, including worsening chest pain that required hospitalization (Figure 1). The rates of all-cause death and of myocardial infarction were low (1.37 and 1.24 per 100 patient-years, respectively) while the rate of any stroke (0.71 per 100 patient-years) was substantially lower than that of myocardial infarction. The proportion of deaths due to non-CV causes (61 of 147; Table 3) was perhaps higher than expected, which may be due to cause-of-death competition in the context of a low CV death rate.
Additional measures to improve prognosis further are particularly relevant in patients with isolated angina as their CHD has as yet not resulted in irreversible damage to the myocardium. Among the 2170 patients with isolated angina in this study, there were a total of 262 deaths or major cardiac events (147 + 153 – 38; Figure 2). One preventive strategy would be to administer treatment to all 2170 patients from the beginning. This could theoretically prevent or postpone all deaths or major cardiac events occurring during the course of the study. The ACTION trial evaluated this strategy for the addition of nifedipine GITS to the basic treatment of the 2170 patients with isolated angina. As reported elsewhere, nifedipine GITS significantly reduced the incidence of HF, the need for coronary interventions, and stroke, but had no effect on death or MI in all 7665 ACTION patients combined. Effects of nifedipine were similar in each of the three subgroups shown in Table 3.
An alternative strategy would be to limit preventive measures to patients who present with chest pain requiring hospitalization, or who require coronary revascularization. In this strategy, only 567 patients (396 + 171; Figure 2), or 26% of the total number of patients, would become candidates for prevention during the course of the study. But by that time 194 (82 + 112, Figure 2) of the 262 deaths or major cardiac events would have occurred already, leaving only 68 or 26% of the total number of events that could possibly be prevented or postponed. Because the risks of future events are higher in the second strategy than in the first, the second strategy will be more cost-effective in the patients treated. Other alternative strategies based on risk stratification, or on targeted management of risk factor such as hypertension, would face the same limitations.
The decision to perform CAG depends on a variety of considerations. Of the 612 patients who underwent CAG during follow-up, 299 had either chest pain requiring hospitalization or a major cardiac event before the procedure (233 + 66; Table 4) and a further 199 had chest pain that did not require hospitalization. This suggests that worsening or recurrent symptoms was among the reasons to perform CAG in 81% [(299 + 199)/612] of cases. We have no information on the reasons why CAG was not performed in 134 patients who also had chest pain requiring hospitalization during follow-up (Table 4).
Of the patients who had CAG, 61% had revascularization during the remainder of follow-up. The aim of CAG and revascularization is to reduce anginal symptoms. It is therefore disappointing that 612 patients who had CAG had such high subsequent rates of chest pain requiring hospitalization. The rate of the latter subsequent to CAG of 8.79 per 100 patient-years (Table 4) suggests that revascularization has limited efficacy even in reducing anginal symptoms.
Limitations of the present study
The ACTION trial focussed on a broad spectrum of patients with stable symptomatic angina but was not specifically designed to document the profile and prognosis of patients with this condition. Furthermore, the ACTION selection criteria may have impacted on the present findings in several ways.
Patients on a calcium antagonist that could not be stopped were excluded because this interfered with the purpose of the trial. To what extent this has affected the profile of patients included is a matter of conjecture.
Patients who had revascularization or a major CV event during the last 3 months were excluded. This should not have impacted the event-rates observed in this study for patients with isolated angina as follow-up of a stable condition to assess event-rates can theoretically be started at any time during the chronic phase of the condition concerned. The same argument does not apply to patients who have a history of revascularization or CV events. Such patients initially have a high risk of (recurrent) events. Due to the exclusion mentioned earlier, this initial high-risk period is not represented in our data. It follows that the event-rates as shown in Table 3 for patients with a history of revascularization or CV events only apply to the chronic phase, and furthermore only to patients who also have symptomatic angina as patients without symptoms were not considered for inclusion in ACTION.
Finally, that ACTION did not require a baseline CAG raises the question of how certain CHD is as cause of angina. Patients without a history of MI in whom CAG had not been performed (patients known to have no significant angiographic abnormalities were not considered) could only be included if an exercise or perfusion test suggested CHD. Men and women over 50 years of age with definite angina have a prior probability of angiographic coronary disease in excess of 80%.13 As the probability of angiographic CHD given a positive exercise or perfusion test is even higher, the number of patients without CHD in the present cohort must have been very few indeed.
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Conclusions |
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Patients with stable symptomatic CHD without a history of any major CV event or coronary revascularization (‘isolated angina’) have an excellent prognosis with regard to death,MI, HF, and stroke. Chest pain requiring hospitalization is a relatively common occurrence even in patients who undergo coronary revascularization.
Since the majority of deaths and major CV clinical events are not preceded by clear warning symptoms such as chest pain requiring hospitalization, the key clinical implication is that measures to prevent such events must target all patients with isolated angina.
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Acknowledgements |
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The ACTION study was carried out by an independent Steering Committee and Research Group with the support Bayer Healthcare AG. P.A.P-W chaired the study. B.-A.K. was project director, P.H.J.M.D. was a member of the Critical Events Committee and J.L. was the responsible biostatistician. The data analysis for this manuscript was performed by S.d.B. and Z.V. Z.V. and J.L. drafted the manuscript, which was approved by all authors.
Conflict of interest: P.A.P.-W., Z.V., P.H.J.M.D., and J.L. have served as consultants to or received travel expenses, or funding for research from the sponsor and other pharmaceutical companies. S.d.B. and B.-A.K. are full-time employees of SOCAR Research SA, which was responsible for study management, data collection, and analysis.
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References |
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