Pfisterer M, Buser P, Osswald S, Allemann U, Amann W, Angehrn W, Eeckhout E, Erne P, Estlinbaum W, Kuster G, Moccetti T, Naegeli B, Rickenbacher P, for the Trial of Invasive versus Medical therapy in Elderly patients
(TIME) Investigators . Outcome of Elderly Patients With Chronic Symptomatic Coronary Artery Disease With an Invasive vs Optimized Medical Treatment StrategyOne-Year Results of the Randomized TIME Trial. JAMA. 2003;289(9):1117–1123. doi:10.1001/jama.289.9.1117
Author Affiliations: Departments of Cardiology, University Hospitals, Basel (Drs Pfisterer, Buser, Osswald, and Kuster), Zurich (Dr Amann), Lausanne (Dr Eeckhout), State Hospitals, St Gallen (Dr Angehrn), Triemli Zurich (Dr Naegeli), Lucerne (Dr Erne), Liestal (Dr Estlinbaum), Lugano (Dr Moccetti), Bruderholz (Dr Rickenbacher), and Claraspital Basel (Dr Allemann), Switzerland.
Context The risk-benefit ratio of invasive vs medical management of elderly
patients with symptomatic chronic coronary artery disease (CAD) is unclear.
The Trial of Invasive versus Medical therapy in Elderly patients (TIME) recently
showed early benefits in quality of life from invasive therapy in patients
aged 75 years or older, although with a certain excess in mortality.
Objective To assess the long-term value of invasive vs medical management of chronic
CAD in elderly adults in terms of quality of life and prevention of major
adverse cardiac events.
Design One-year follow-up analysis of TIME, a prospective randomized trial
with enrollment between February 1996 and November 2000.
Setting and Participants A total of 282 patients with Canadian Cardiac Society class 2 or higher
angina despite treatment with 2 or more anti-anginal drugs who survived for
the first 6 months after enrollment in TIME (mean age, 80 years [range, 75-91
years]; 42% women), enrolled at 14 centers in Switzerland.
Interventions Participants were randomly assigned to undergo coronary angiography
followed by revascularization (if feasible) (n = 140 surviving 6 months) or
to receive optimized medical therapy (n = 142 surviving 6 months).
Main Outcome Measures Quality of life, assessed by standardized questionnaire; major adverse
cardiac events (death, nonfatal myocardial infarction, or hospitalization
for acute coronary syndrome) after 1 year.
Results After 1 year, improvements in angina and quality of life persisted for
both therapies compared with baseline, but the early difference favoring invasive
therapy disappeared. Among invasive therapy patients, later hospitalization
with revascularization was much less likely (10% vs 46%; hazard ratio [HR],
0.19; 95% confidence interval [CI], 0.11-0.32; P<.001).
However, 1-year mortality (11.1% for invasive; 8.1% for medical; HR, 1.51;
95% CI, 0.72-3.16; P = .28) and death or nonfatal
myocardial infarction rates (17.0% for invasive; 19.6% for medical; HR, 0.90;
95% CI, 0.53-1.53; P = .71) were not significantly
different. Overall major adverse cardiac event rates were higher for medical
patients after 6 months (49.3% vs 19.0% for invasive; P<.001), a difference which increased to 64.2% vs 25.5% after 12
Conclusions In contrast with differences in early results, 1-year outcomes in elderly
patients with chronic angina are similar with regard to symptoms, quality
of life, and death or nonfatal infarction with invasive vs optimized medical
strategies based on this intention-to-treat analysis. The invasive approach
carries an early intervention risk, while medical management poses an almost
50% chance of later hospitalization and revascularization.
Whereas randomized clinical trials have shown that younger patients
with chronic symptomatic coronary artery disease (CAD) benefit from revascularization
regarding symptom relief and quality of life,1- 4 no
such data exist for patients older than 75 years.5 However,
procedure-related mortality increases with age both after coronary artery
bypass graft (CABG) surgery6 and after percutaneous
coronary intervention (PCI).7 The recent Trial
of Invasive versus Medical therapy in Elderly patients (TIME) with chronic
symptomatic CAD was the first to show that patients older than 75 years with
chronic angina despite standard medical therapy benefit from anti-ischemic
therapy.8 This benefit was greater with invasive
than with optimized medical management regarding symptom relief and improvement
in quality of life, however, at a certain excess in early mortality. Whether
these short-term effects translate into long-term benefits for either treatment
strategy in these elderly patients is unknown as well as whether the observed
early intervention hazard may be balanced during longer-term follow-up.
We therefore planned and prospectively performed a follow-up evaluation
of all TIME patients after 1 year regarding symptoms, quality of life, and
major adverse clinical events (MACE). The specific aims of this follow-up
study were to assess whether the early effects of both treatment strategies
on anginal status and quality of life noted after 6 months would persist in
these elderly patients, whether observed differences in outcome between revascularization
and optimized medical therapy would still be present after 12 months, and
whether the expected mortality risk of invasive therapy in this elderly patient
group would decrease over time compared with medically managed patients.
Details of the TIME study protocol have been described previously.8 In short, in this prospective randomized multicenter
Swiss trial, 301 of 305 patients (4 protocol violations) aged 75 years or
older with chronic angina with Canadian Cardiac Society class 2 or higher
despite treatment with at least 2 anti-anginal drugs were randomized to an
optimized medical therapy (n = 148) or an invasive strategy (n = 153) with
coronary angiography followed by revascularization (PCI or CABG surgery),
if feasible (Figure 1). Patients
were excluded for acute myocardial infarction (MI) within the previous 10
days, concomitant valvular or other heart disease, predominant congestive
heart failure, or no consent for a possible revascularization procedure. Randomization
by center was performed by telephone to the coordinating center. The study
was approved by the ethics committee of the Swiss Academy of Medical Sciences
and by the local ethics committees of each of the 14 Swiss centers. Patients
gave written informed consent.
The primary end point was defined as quality of life assessed by standardized
questionnaires and freedom from MACE (death, nonfatal MI, or hospitalization
for uncontrolled symptoms or acute coronary syndrome with or without need
for revascularization) after 6 months. Late revascularization in either treatment
group was considered an event only if patients needed hospitalization for
angina at rest or with minimal exertion despite optimized medical therapy
and were transferred by their treating physicians not involved in the study
After collection of baseline data (Table 1), quality of life was assessed by a self-administered questionnaire
containing the Short Form 36,9 the Duke Activity
Status Index (DASI),10 the Rose11 angina
questionnaire, and questions about education and social status. For this prospective
1-year follow-up study, all surviving patients were observed again in the
outpatient clinics of each center. The same case report form and quality of
life questionnaires as at baseline and after 6 months were completed. Information
regarding survival and MACE could be obtained in all patients and quality
of life questionnaires (filled out by patients themselves in 73% of cases)
were analyzable in 86% of surviving patients.
All analyses presented were performed on an intention-to-treat basis
and statistical methods were the same as in the main trial.8 In
short, quantitative and score variables were summarized in terms of means
and SDs and the comparison between groups was performed by using a Wilcoxon
Mann-Whitney test. For the comparison of categorical values between groups,
Fisher exact test and the χ2 test were used. Changes in quantitative
variables within groups were assessed with the paired t test and the signed rank test, which was also used to assess changes
in score variables within groups. To avoid bias due to competing risks, deaths
were considered as censored events in all survival analyses involving nonlethal
end points. Time variables with censored values were described by Kaplan-Meier
Quality of life questionnaires were analyzed according to the specific
tests used. Group differences in average changes of quality of life scores
within 6 and 12 months, respectively, were first assessed separately using
the Wilcoxon Mann-Whitney test. In a second step, we used mixed linear models
to simultaneously estimate average changes during the first 6 and 12 months,
respectively, in either study group. Thereby, no constraints were imposed
on the covariance structure of the 2 residuals per patient. Alternative parametrizations
of these models were used to assess the statistical significance of group
differences in these estimates and in estimated average changes between the
2 follow-up assessments.
The primary end point was analyzed by intention-to-treat as a composite
end point and all components separately as secondary end points. P<.05 was considered a significant difference. SAS statistical software
version 8.2 (SAS Institute Inc, Cary, NC) was used for all analyses.
Sample size was estimated based on the findings of the Angioplasty Compared
to MEdicine (ACME) trial2 in which 100 patients
2 times led to significant differences in exercise time and symptoms. In the
elderly TIME population, we assumed we needed 150 patients who were assigned
to invasive management to reach 100 revascularized patients. A sample size
of 154 patients 2 times would allow to detect a significant difference in
primary end point events at a level of 5% with a power of 80%, if they occurred
at rates of 40% for optimized medical and 25% for invasive therapy, respectively.
Between February 1996 and November 2000, 305 patients were enrolled;
however, 4 were excluded by the critical event committee for protocol violation.
Of the 301 patients initially included in the TIME study, 282 patients (94%)
survived the first 6 months and were available for prospective follow-up after
12 months (Figure 1). The mean age
(range) of the 282 patients available for analysis was 80 years (75-91 years)
with a high prevalence of risk factors, a high prevalence of previous CAD
events, and relevant comorbidities in more than 60% of patients (Table 1). Forty-two percent of patients
At baseline, 235 of 301 patients (78%) had angina Canadian Cardiac Society
class 3 to 4 despite a mean (SD) of 2.5 (0.7) anti-anginal drugs. In 118 optimized
medical patients (80%), at least 1 anti-anginal drug was added and in 81 patients
(55%), anti-anginal drug dosages were increased; whereas, 79 invasive therapy
patients (52%) were treated by PCI, 30 (20%) by CABG surgery, and 43 (28%)
by medical therapy (11 [7%] no significant CAD, 19 [12%] revascularization
not possible, and 13 [8%] no consent).
Detailed data on MACE are summarized in Table 2 for each 6-month period (0-6 months and 7-12 months) as
well as for the total follow-up (0-12 months). Mortality rate for each 6-month
period decreased in invasive therapy patients from 8.5% to 2.9%, whereas it
stayed unchanged in optimized medical patients (4.1% and 4.2%, respectively).
The small early hazard of the invasive strategy reported earlier8 is
also reflected in the time to death or nonfatal MI as shown in Figure 2. Note that after 6 to 9 months, the curves crossed. Seven
of the 10 late deaths were cardiac: 2 of 140 (1.4%) invasive and 5 of 142
(3.5%) optimized medical patients. During the 1-year follow-up, 106 hospitalizations
for medically uncontrolled symptoms were noted in optimized medical vs 28
in invasive therapy (P<.001) and 68 patients (46%)
randomized to optimized medical management needed 71 revascularizations (PCI,
42 [27% patients]; CABG surgery, 29 [19% patients]) vs only 16 (10%) late
revascularizations (PCI, 13 [8%]; CABG, 3 [2%]) in patients initially randomized
to the invasive therapy strategy (P<.001). Overall
MACE rates were significantly higher for optimized medical patients after
6 months (73 [49.3%] vs 29 [19.0%] invasive therapy; P<.001),
a difference that increased to 95 (64.2%) of optimized medical vs 39 (25.5%)
of invasive therapy after 12 months (P<.001). Figure 3 illustrates these time trends in
overall MACE rates.
Angina severity, number of anti-anginal drugs used, and selected measures
of quality of life at baseline as well as after 6 and 12 months are shown
for both treatment groups as changes from baseline over time in Figure 4. There was a persistent marked relief of symptoms and improvement
in quality of life in both treatment groups until 12 months, but the difference
of these findings between the 2 treatment groups in favor of invasive therapy
noted after 6 months disappeared after 12 months based on the intention-to-treat
analysis. This was associated with a further improvement in these parameters
in optimized medical–assigned patients who underwent late revascularization;
whereas, there were no relevant additional changes in invasive therapy patients
during late follow-up.
This follow-up study of the first prospective randomized trial comparing
an invasive with an optimized medical strategy in elderly patients with chronic
angina demonstrates that the beneficial effect of both anti-ischemic therapies
on quality of life and MACE rates noted early persisted and that the early
unfavorable mortality trend observed with invasive therapy disappeared during
late follow-up. The advantage of invasive vs optimized medical therapy regarding
symptom relief and improvement in quality of life noted after 6 months disappeared
in the intention-to-treat analysis during late follow-up. Significantly more
optimized medical patients needed hospitalization for medically uncontrollable
symptoms and significantly more received late revascularization for that reason.
The intervention hazard in higher risk populations such as elderly patients
is well known to be increased.6,7 Previous
studies in younger patients have pointed to a longer-term benefit of revascularization.4 Whether these benefits can be extrapolated to elderly
patients is not clear. For example, the Should We Emergently Revascularize
Occluded Coronaries for Cardiogenic Shock (SHOCK) trial could show a survival
benefit only after late follow-up in a very high-risk patient group12; however, in that study, patients 75 years or older
did no longer benefit from invasive therapy.13 In
the present study, mortality rates from intervention were lower than previously
the fact that patients were selected on clinical presentation only and not
on a suitable coronary angiographic anatomy for revascularization and that
their risk factor, CAD history, and comorbidity rates were relatively high.
The observed mortality rate with current interventional techniques may serve
as further argument not to withhold revascularization to elderly patients
for fear of a high-intervention risk. A recent large cohort study supports
this interpretation suggesting that, in addition, elderly patients paradoxically
have greater absolute risk reductions associated with revascularization than
do younger patients.14
This study may be analyzed as a comparison between early and late revascularization:
PCI or CABG surgery was performed in 65% of invasive therapy patients early
(per protocol) and in 46% of optimized medical patients late (due to refractory
symptoms). A similarly high rate of crossovers from medical to revascularization
therapy has been noted in previous trials1,4,15 and
may not be surprising in view of the symptomatic status of TIME patients at
inclusion. In the present follow-up study, rates of death and death or nonfatal
MI were similar after 1 year and there was no longer a significant difference
in angina relief or improvement in quality of life between treatment groups.
So why not wait on medical therapy until revascularization becomes urgently
necessary? The present intention-to-treat analysis suggests that this is a
reasonable option for such patients if their symptoms are acceptably controlled
by medical therapy and they do not have to take the risk of revascularization;
however, if medical treatment fails, revascularization may be performed later.
However, if, at presentation, they cannot accept their angina and reduced
quality of life with a 50% chance of hospitalization with late revascularization,
they can choose early revascularization. After 1 year, outcome will be very
similar for both options, although death may well occur earlier with early
The early improvements in symptoms and quality of life noted in invasive
therapy patients were also observed with optimized medical patients during
late follow-up, in parallel with a large proportion of these patients being
revascularized. One may speculate whether these benefits of revascularization
on subjective well-being were merely a placebo-like effect of the intervention
similarly to the one recently observed after arthroscopic treatment of osteoarthritis16 or whether they reflect a true treatment effect.
The fact that subjective improvement persisted in invasive therapy patients
throughout the 12-month follow-up, an observation that is in accordance with
findings of previous randomized controlled trials on persistent symptomatic
improvements after CABG surgery17 or PCI18,19 vs medical management in younger
patients, favors the interpretation of a true symptomatic treatment benefit
of revascularization even in an elderly patient population. In view of the
limited number of invasive therapy–assigned patients effectively being
revascularized and the relatively large crossover rate of optimized medical–assigned
patients in the clinical settings of the present study, only an ontreatment
analysis of these effects over time may help to further differentiate placebo-like
from true treatment effects.
For this study, quality of life was defined as a primary end point consisting
of standardized self-administered questionnaires and freedom from MACE. Questionnaires
were given at baseline, after 6 and 12 months but not at the time of major
events. How, then, may events have influenced measures of quality of life?
If we would assume an arbitrary scale of quality of life and set well-being
at 10, then death (no quality of life) would be 0. This would be in disfavor
of the invasive therapy strategy (17 invasive vs 12 optimized medical deaths
after 1 year). Nonfatal MI would get a value of 1 to 2, an event that was
somewhat more frequent in optimized medical patients (20 vs 14 invasive therapy)
turning the quality of life balance more or less back to even level. Hospitalization
for acute coronary syndrome, also a predefined event incompatible with well-being,
might get a value of 3 to 4 on the quality of life scale. This was observed
significantly more often in optimized medical vs invasive therapy patients
(106 vs 28) and would reduce their quality of life outcome markedly. Hence,
incorporating events into quality of life may suggest an overall quality of
life benefit of invasive therapy; however, such a hypothetical analysis would
mainly be driven by hospitalization for symptoms at rest, the softest end
point. Because of this and because formal utilities were not obtained prospectively,
we presented measures of quality of life and results of MACE separately and
strictly according to the intention-to-treat principle.
The primary end point of this study was quality of life and not mortality.
To assess the effect of therapy on mortality, either a much larger sample
size or at least a much longer-term follow-up would be necessary. Despite
the relatively small number of patients included in TIME, the results of this
study are relevant for elderly patients in general because patients were included
based on clinical presentation and not on specific angiographic findings.
Major issues not fully addressed are the mode of revascularization (PCI vs
CABG surgery) and costs of the different management strategies, because costs
may be particularly relevant in the fast growing elderly population with CAD.
Finally, because results of studies in younger patients may not simply be
extrapolated to elderly populations, the same caution should be applied to
transfer the present findings in elderly patients to younger patients.
This follow-up study in elderly patients with symptomatic CAD demonstrates
that after 1 year there was no difference in quality of life between an early
invasive vs an optimized medical strategy. This takes into account that almost
half of the optimized medical therapy–assigned patients needed hospitalization
for acute coronary syndrome followed by revascularization during follow-up.
Thus, overall MACE rate was significantly higher in optimized medical vs invasive
therapy patients; however, death or nonfatal MI occurred at similar rates
after 1 year. This implies that elderly patients with angina pectoris refractory
to standard drug therapy have a choice between an early invasive strategy
that carries a certain early intervention risk and an optimized medical strategy
that carries a chance of late hospitalizations and revascularizations. After
1 year, quality of life outcome and survival will be similar.