a Department of Cardiology, University Hospitals Basel, Petersgraben 4, 4031 Basel, Switzerland
b Kantonsspital, Lucern, Switzerland
c University Hospital, Zürich, Switzerland
d Triemli Spital, Zürich, Switzerland
e Kantonsspital, Biel, Switzerland
f Institute of Social and Preventive Medicine, University of Basel, Switzerland
* Corresponding author. Tel.: +41-61-265-52-13/14; fax: +41-61-265-45-98
E-mail address: pfisterer{at}email.ch
Received 3 December 2003; accepted 4 February 2004
Abstract
Aim To assess treatment effects of optimised medical therapy and PCI or CABG surgery on one-year outcome in patients 75 years old with chronic angina.
Methods and Results On-treatment analysis of the TIME data: all re-vascularised patients (REVASC : 112 randomised to revascularisation and 62 to drugs with late revascularisation) were compared to all patients on continued drug therapy (MED
: 86 randomised to drugs and 41 to revascularisation only). Baseline characteristics of both groups were similar (age 80±4 years). Risk of death at one year (adjusted hazard ratio (HR)=1.31; 95%-CI: 0.582.99;
) and of death/infarction (adjusted hazard ratio=1.77; 95%-CI 0.913.41;
) were comparable between REVASC and MED patients. Furthermore, the risk of death within 30 days was even slightly lower among REVASC patients (unadjusted hazard ratio=0.73; 95%-CI: 0.212.53;
. Overall, REVASC patients had greater improvements in symptoms and well-being than MED patients
. Surgical patients had similar mortality rates as angioplasty patients, but they also had greater symptomatic improvements
.
Conclusion Treated medically, elderly patients with chronic angina have a similarly high 30-day and one-year mortality as patients of the same age being re-vascularised; however, they can expect lower improvements in symptoms and well being.
Key Words: Aging Angina Coronary disease Mortality Quality of life Revascularisation
Introduction
Mortality and complications of coronary artery bypass grafting (CABG) surgery and percutaneous coronary interventions (PCI) are increased in elderly patients with chronic coronary artery disease (CAD) as compared to those in younger patients.16 However, little is known about risks and complications of optimised drug therapy in patients of the same advanced age which may also be increased. In general, there is a marked lack of data on the management of elderly patients with chronic CAD since they have mostly been excluded from randomised clinical trials.7 Therefore, the risk/benefit ratio of CAD therapy may differ importantly from that of younger patients and their number asking for medical advice is increasing rapidly.
The recent Trial of Invasive vs. Medical therapy in Elderly patients with Chronic Angina (TIME) was the first prospective randomised treatment trial in elderly patients with chronic symptomatic CAD.8 It showed that these patients had a greater benefit from an invasive strategy as compared to optimised drug therapy regarding symptom relief, improvement in quality of life (QoL) and reduction in major adverse clinical events (MACE) after 6 months. In this study, patients could be re-vascularised either by PCI or by CABG surgery. An early revascularisation hazard was observed, although the mortality difference between treatment groups was not significant (8.5% in patients assigned to the invasive, vs. 4.1% in those assigned to the optimised, medical strategy, ). After one year, outcome in MACE as well as angina severity and measures of QoL were very similar based on the intention-to-treat analysis.9 However, since patients were included and randomised based on their clinical presentation as in everyday practice and not based on angiographic findings, cross-overs occurred between both strategies. In fact, 46% of medical treatment assigned TIME patients had to be re-vascularised during the one-year follow-up due to medically uncontrolled symptoms, whereas only 73% of all invasive management assigned patients were actually re-vascularised, making an assessment of the true effects of medical and revascularisation strategies difficult. It was therefore the aim of the present pre-specified "on-treatment" analysis of the TIME data to more fully describe the effects of optimised medical therapy and revascularisation on angina severity, measures of QoL and MACE in patients of the same advanced age.
Methods
Details of the TIME study have been reported previously.8 In short, in this prospective multi-centre Swiss trial, patients aged 75 years or older with chronic angina of at least Canadian Cardiac Society (CCS) class II despite at least two anti-anginal drugs, were randomised to an optimised medical therapy or an invasive strategy with coronary angiography followed by revascularisation (PCI or CABG surgery) if feasible. The primary end-point was QoL-assessed by standardised questionnaires and the presence or absence of MACE (all death, non-fatal myocardial infarction or hospitalisation for uncontrolled symptoms/acute coronary syndrome with or without need for revascularisation) after 6 months. Myocardial infarction was a clinical diagnosis based on chest pain, typical ECG changes and enzyme elevations apart from the acute intervention. Patients were not included if they had an acute myocardial infarction within the previous 10 days, concomitant valvular or other heart disease, pre-dominant congestive heart failure or gave no consent for a possible revascularisation procedure. After collection of baseline data, QoL was assessed by self-administered questionnaires containing the Short Form 36 (SF36),10 the Duke Activity Status Index (DASI)11 and the Rose angina questionnaire.12 The study was approved by the Ethics Committee of the Swiss Academy of Medical Sciences and by the local Ethics Committee of each of the 14 Swiss centres. Patients gave written informed consent. After both 6 months and one year, all surviving patients were seen again and underwent the same clinical, symptom and QoL assessments as at baseline.
For this "on-treatment" analysis, all patients with revascularisation attempted during the one-year observation period (REVASC) were compared to all patients with medical therapy alone (MED) with regard to symptoms, QoL and MACE up to one year after randomisation. Thus, for this analysis, hospitalisation for medically uncontrolled symptoms leading to revascularisation was not a major event but counted as index revascularisation and all events in REVASC patients having occurred before the index revascularisation were disregarded; accordingly, the day of revascularisation was day one for these patients. To assess the "treatment hazard" and to put it into perspective, the 30-day mortality on treatment received was determined and compared. To analyse the effect of late revascularisation in patients assigned to medical treatment on both angina severity and QoL, a special on-treatment analysis was performed in this subgroup assigned to medical treatment.
Patient details
The 174 patients in whom revascularisation was attempted (REVASC) were compared to all 123 patients who received medical therapy alone (MED) (Fig. 1). The REVASC group consisted of 112 patients assigned to PCI or CABG surgery (109 re-vascularised early as per protocol and three late after initial refusal) and 62 patients initially randomised to optimal medical therapy but who needed revascularisation due to refractory symptoms during follow-up. Seventy-nine percent of these revascularisations were performed in the first 6 months of the study. The MED group consisted of 86 patients who were initially randomised to medical therapy and who stayed on that therapy and also 41 patients randomised to invasive management but in whom revascularisation was not attempted because they had no significant CAD , revascularisation did not seem possible
or was refused by the patients
; one patient died before revascularisation.
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Results
Baseline characteristics and treatments performed
The baseline characteristics of MED and REVASC patients were similar (Table 1) with a mean age of 80 years and a high proportion of women in each group. There were no significant differences in risk factors, history of CAD, non-invasively determined left ventricular ejection fraction or rate of co-morbidities and the same was true for angina severity and measures of QoL. Eighty percent of MED patients received at least one additional anti-ischaemic drug and in 55% drug dosages were increased. In the REVASC group, 115 patients (66%) had PCI (86% at least one stent) and 59 patients (34%) had CABG surgery (83% at least one arterial conduit). In addition, all patients were advised regarding lipid lowering and risk factor modification.
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On-treatment findings in medical strategy-assigned TIME patients
The intention-to-treat analysis of the TIME data showed an early intervention hazard with the invasive strategy8 and a late benefit in symptom relief/improvement in QoL with the optimised medical strategy, such that after one year no significant differences in outcome between the two groups remained.9 In this regard, the on-treatment analysis provided important insights. The relatively high 6-month mortality rate of 8.5% in patients assigned to invasive treatment (compared to 4.1% in patients assigned to medical treatment, ) was actually 7.3% in 109 invasive patients receiving and 11.4% in 44 invasive patients not receiving, revascularisation as per protocol. Since all 11 invasive patients without significant CAD survived, the 6-month mortality of 33 non-re-vascularised invasive patients with CAD was 15.2% double that of re-vascularised patients
. The late symptomatic and QoL benefit of patients assigned to medical treatment was exclusively found in patients with late revascularisation, whereas patients assigned to continual medical treatment remained more symptomatic with a lower level of well-being despite more drugs.
Discussion
In this prospective on-treatment analysis of the first randomised trial comparing an invasive, with an optimal medical, strategy in elderly patients with chronic symptomatic CAD, MED treated patients had a similarly high one-year mortality rate as REVASC patients of the same advanced age. This indicates that, compared to younger patients with CAD as usually studied, mortality is increased in these elderly CAD patients whatever treatment they received. In fact, the early intervention hazard observed previously8 was due to the high mortality of patients assigned to invasive treatment not being re-vascularised rather than because of the intervention. REVASC therapy induced a greater relief from angina and a greater improvement in measures of QoL, a finding which also explains the late benefit observed in patients assigned to medical treatment with intention-to-treat.9 Patients selected for PCI had a similar intervention mortality and a similar one-year death/non-fatal myocardial infarction rate to patients undergoing CABG surgery. However, CABG gave greater symptomatic relief and improvement in QoL after one year and was also associated with a higher rate of complete revascularisation. Obviously the choice of the revascularisation mode by operators led to a reasonable clinical outcome, since the overall effect of REVASC therapy regarding symptom relief and QoL assessment was significantly better than after MED therapy.
Comparison of revascularisation vs. medical therapy
In younger patients, the randomised CABG surgery, compared with medical therapy, studies have shown a survival advantage of surgery in high risk patient groups.1315 These studies also showed an improvement in symptomatic status and QoL, as noted in the TIME study for elderly patients. The Angioplasty Compared to Medical Therapy (ACME),16 the Randomised Intervention Treatment of Angina 2 (RITA-2),17 and the Atorvastatin Versus Revascularisation Treatment (AVERT)18 studies were the only true prospective comparisons between PCI and medical therapy, related to younger patients with single or double vessel disease. They demonstrated an improvement in the severity of angina after PCI, although this was at the cost of an excess mortality and myocardial infarction rate in RITA-2.19 The TIME study extended these findings for the first time to an elderly patient population and, importantly, demonstrated an increased risk also in elderly CAD patients on optimised drug therapy in the present on-treatment analysis. A recently published retrospective analysis of 6000 elderly patients indirectly supported these findings by showing that elderly patients have greater absolute risk reductions associated with surgical or percutaneous revascularisations than younger patients do.20
Comparison of PCI with CABG surgery
A meta-analysis of studies comparing PCI to CABG surgery21 showed a similar long-term mortality and re-infarction rate for both procedures but more repeated interventions and a poorer outcome regarding angina relief after PCI. Our findings in elderly patients are in accordance with these results. Restenosis was the main cause for the higher rate of repeat interventions; this may soon be minimised if the first results of drug-coated stents22 are further substantiated. As noted in the present analysis, completeness of revascularisation could not fully explain this difference in unselected elderly multi-vessel disease patients either, partly because surgeons achieved full revascularisation in only two-third of these patients. In younger patients it has been shown that complete revascularisation by angioplasty can improve outcome.23
Limitations of this study
The present pre-defined "on-treatment" analysis of a prospective randomised trial has its immanent limitations as to patient selection. Thus, the potential for bias is substantial because both treatment groups contain failures of the other treatment, i.e., failure of medical treatment among REVASC or the impossibility, or lack of necessity, to perform revascularisation among MED patients. In addition, the patient number is relatively low. This study, however, complements the primary intention-to-treat analysis and provides important clues for its interpretation and gives the first prospective trial data in elderly patients with chronic CAD. Finally, the optimised medical therapy was that which could be maximally achieved and tolerated by patients of this age group, which was less than what maximal lipid lowering and risk factor management could be; however. However, there is almost no direct evidence of their effectiveness in 80-year-old patients.
Conclusions
This prospective "on-treatment" analysis of the TIME patient population provides important insights into the effects of optimised medical and revascularisation therapy in these 80-year-old patients. The mortality of MED patients was similar to that of REVASC patients of the same advanced age, indicating that mortality is increased in these elderly CAD patients whatever treatment they receive. The early mortality hazard of invasive management was mainly due to the high mortality of CAD patients assigned to invasive management who could not be re-vascularised, rather than to the PCI or CABG surgery itself. Overall, revascularisation led to a significant improvement in angina severity and measures of QoL, compared to the optimised medical therapy. This finding could also explain the overall late benefit observed in patients assigned to medical treatment by intention-to-treat. Patients selected for PCI based on a "suitable" coronary anatomy had a similar early and one-year death/mortality rate as patients who underwent CABG surgery; however, their benefit in QoL and angina relief may be smaller. Therefore, elderly patients with chronic angina should be offered invasive evaluation and revascularisation, if feasible, because mortality is increased similarly with both treatments but improvements in symptoms and QoL are greater after successful revascularisation.
Acknowledgments
The TIME-Study was supported by grants from the Swiss Heart Foundation and the Adumed Foundation, Switzerland.
We gratefully acknowledge the contribution of all participating patients and the work done by all investigators, advisors and the critical event committee. Time Study centers and main investigators: University Hospital Basel: M. Pfisterer, P. Buser; Kantonsspital Aarau: A. Vuillomenet; University Hospital, Bern: F. Eberli; Regionalspital Biel: H. Schläpfer; Kantonsspital Bruderholz: P. Rickenbacher; Kantonsspital Chur: P. Dubach; Clara Hospital, Basel: U. Allemann; University Hospital, Lausanne; J.J. Goy; Kantonsspital Liestal: W. Estlinbaum; Cardiocentro Lugano: T. Moccetti; Kantonsspital Luzern: P. Erne; Kantonsspital St. Gallen: W. Angehrn; Triemli Hospital, Zürich: O. Bertel; University Hospital, Zürich: W. Amann, M. Pfisterer, Basel, Principal Investigator.
A complete list of all investigators can be found in Ref.8
This work was presented in part at the Annual Meeting of the European Society of Cardiology, Berlin, September 2002.
References