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Original Studies

Early Invasive Versus Selectively Invasive Strategy inPatients With Non-ST-Segment Elevation Acute

Coronary Syndrome: Impact of Age

Fabio Angeli,1* MD, Paolo Verdecchia,2 MD, Stefano Savonitto,3 MD, Nuccia Morici,4 MD,Stefano De Servi,5 MD, and Claudio Cavallini,6 MD

Background: It is unclear whether the benefits of an early invasive strategy (EIS) inpatients with non-ST-segment elevation acute coronary syndromes (NSTEACS) equallyapply to younger and older individuals. Elderly patients are generally less likely toundergo EIS when compared with younger patients. Objectives: We conducted ameta-analysis to compare the benefit of an EIS versus a selectively invasive strategy(SIS) in patients with NSTEACS. We tested the hypothesis that the magnitude of benefitof an EIS over a SIS mainly applies to older individuals. Methods: We extracted datafrom randomized controlled trials (RCTs) identified through search methodology filters.The primary outcome of the analysis was the composite of all-cause death and myo-cardial infarction (MI). Secondary outcomes were death and MI taken alone and re-hospitalization. Results: Nine trials (n 5 9,400 patients) were eligible. The incidence ofthe composite end-point of MI and all-cause death was 16.0% with the EIS and 18.3%with the SIS (OR: 0.85, 95% CI: 0.76–0.95). The incidence of MI was 8.4% with the EISand 10.9% with the SIS (OR: 0.75, 95% CI: 0.66–0.87). Similar results were obtained forrehospitalization (OR: 0.71, 95% CI: 0.55–0.90). The incidence of all-cause death did notdiffer between the two groups. The EIS reduced the composite end-point andre-hospitalization to a greater extent in elderly than in younger patients (P for inter-action 5 0.044 and <0.0001, respectively). These findings were confirmed in meta-regression analyses. Conclusions: In patients with NSTEACS, a routine EIS reducesthe risk of rehospitalization and the composite end point of recurrent MI and death toa greater extent in elderly than in younger individuals. VC 2013 Wiley Periodicals, Inc.

Key words: acute coronary syndrome; percutaneous coronary intervention; earlyinvasive strategy; prognosis; meta-analysis

INTRODUCTION

Individual patients with non-ST-segment elevationacute coronary syndrome (NSTEACS) have a wide spec-

trum of risk of subsequent complications such as death,recurrent myocardial infarction (MI), or recurrent anginarequiring revascularization [1–5]. Although most patientswith NSTEACS undergo coronary arteriography and

1Division of Cardiology and Cardiovascular Pathophysiology,Teaching Hospital “S.M. della Misericordia,” Perugia, Italy2Department of Internal Medicine, Hospital of Assisi, Assisi,Italy3Division of Cardiology, IRCCS “Arcispedale S. Maria Nuova,”Reggio Emilia, Italy4Department of Cardiology, Hospital “Niguarda Ca’ Granda,”Milano, Italy5Division of Cardiology, “Ospedale Civile,” Legnano, Italy6Department of Cardiology, Teaching Hospital “S.M. della Mis-ericordia,” Perugia, Italy

Conflict of interest: Nothing to report.

*Correspondence to: Fabio Angeli, MD, Division of Cardiology and

Cardiovascular Pathophysiology, Teaching Hospital “S.M. della

Misericordia,” Perugia, Italy. E-mail: [email protected]

Received 16 July 2013; Revision accepted 22 November 2013

DOI: 10.1002/ccd.25307

Published online 26 November 2013 in Wiley Online Library

(wileyonlinelibrary.com)

VC 2013 Wiley Periodicals, Inc.

Catheterization and Cardiovascular Interventions 83:686–701 (2014)

revascularization during the early phase of index hospi-talization, some findings from clinical studies suggest alack of significant benefit of an early invasive strategy(EIS) in low-risk patients [6–9]. For this reason, currentguidelines [3–5] recommend an EIS over a more con-servative strategy for the management of patients withNSTEACS at high risk for recurrent events.

Older age itself is a major risk factor for adverseoutcome in NSTEACS and reports from individual tri-als showed that the benefit from an invasive strategy ismainly observed in patients >65 years of age [10,11].Nevertheless, in real-world practice NSTEACS elderlypatients are substantially less likely to undergo an inva-sive strategy than younger patients and many centerstend to use a routine EIS (including the routine use ofdiagnostic catheterization and revascularization as indi-cated) in younger patients, and a more selectiveapproach (i.e., selectively invasive strategy [SIS]) inolder individuals [12–15]. These data emphasize thegrowing importance of developing invasive strategymodalities in elderly patients with NSTEACS [16–18].

Thus, we performed a meta-analysis to further eluci-date the benefit of an EIS compared to a more con-servative management of NSTEACS patients. Inparticular, we explored outcome in relation to age anddifferent patient- and trial-level characteristics in orderto identify subsets of patients with NSTEACS whowould benefit most from an early invasive approach.

METHODS

We extracted data from randomized controlled trials(RCTs) evaluating the prognostic implications of anEIS in NSTEACS patients and met all of the followingselection criteria:

i. diagnosis of NSTEACS as inclusion criteria forRCTs;

ii. allocation of at least 100 patients to an EIS or aninitially conservative management, where early inter-vention was defined as coronary angiography per-formed within 4 days from hospitalization orrandomization. Initially conservative managementwas defined by early conventional medical therapyor selective invasive management if indicated by re-fractory or recurrent symptoms or inducible ischemia(ischemia-driven or symptom-driven angiography);

iii. outcome data ascertained during a follow-up of atleast 6 months;

iv. publication before 30 April 2013 in peer-reviewedjournals indexed in Medline and Google Scholar. Wealso searched clinical trial registries (www.clinicaltrials.gov and www.controlled-trials.com) for unpublishedstudies.

We searched for eligible studies, using researchMethodology Filters [19]. The following research termswere used: “randomized controlled trials,” “myocardialinfarction,” “acute coronary syndrome,” “angioplasty,balloon, coronary,” “percutaneous coronary inter-vention,” “revascularization,” “coronary artery bypassgraft,” “outcome,” and “prognosis.” We checked thereference list of identified articles and previous system-atic reviews to find other potentially eligible studies.We also performed hand-searching of conference pro-ceedings, pharmaceutical industry files and personalcommunication from experts in the field [20], to iden-tify any other relevant study. No language restrictionwas applied, to avoid discriminating papers not writtenin the English language (“tower of Babel bias”) [21].

Data extraction was done independently by twoauthors (PV and FA) and divergences were discussedand resolved in conference. The present meta-analysiswas done according to established methods and to theQuality of Reporting of Meta-analyses (QUORUM)statement [22,23].

Outcome of patients allocated to an EIS was com-pared to NSTEACS patients randomized to an initiallyconservative management. The primary outcome of theanalysis was the composite of all-cause death and MI.Secondary outcomes were death and MI taken aloneand rehospitalization.

We accepted the definition of NSTEACS as reportedin the individual clinical trials. Recurrent MI was gen-erally defined as new or recurrent ischemic symptomsand an increase of the creatine kinase-MB (CK-MB) ortroponin levels or electrocardiographic changes. Reho-spitalization was generally defined as readmission forcardiovascular causes.

For each end point, the longest follow-up availablein each study was chosen.

We calculated odds ratios (ORs) and 95% confi-dence intervals (CIs) for all-cause death, myocardialreinfarction, rehospitalization and for the compositeend-point of overall mortality and myocardial reinfarc-tion for each clinical study separately and for the com-bination of studies according to random- and fixed-effects models [23,24]. The null hypothesis of homoge-neity across individual studies was tested by using theQ-test. Pooled estimates were assessed for heterogene-ity by using the I2 and s2 statistics [25]. Typically, val-ues of I2 above 50% are deemed to suggest largeamong-study heterogeneity, values of 25–50% aredeemed to show moderate heterogeneity, and valuesbelow 25% denote low heterogeneity [25]. Heterogene-ity was explored by conducting the analysis in the fol-lowing sets of pre-planned subgroups [26] of RCTs: (i)mean age of patients (<62 years; 62–64 years; �65years); (ii) mean time of catheterization in the early

Age and Early Invasive Strategy 687

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invasive strategy arm (�24 hr; >24 hr); (iii) publica-tion year (before 2001 vs. after 2001); (iv) prevalenceof diabetes mellitus (<18%; 18–27%; �28%); (v)prevalence of previous MI (<26%; 26–31%; �32%);(vi) prevalence of female patients (�30%; >30%); and(vii) duration of follow-up (�12 months; >12 months).

The potential effect modifiers, as identified fromsubgroup analysis, were further evaluated by randomeffect meta-regressions [26]. This method uses eachstudy’s estimate and its standard error to separatewithin-study from between-study variability [26].

The fit of each model was assessed using the per-centage of among-study variance explained, togetherwith a significance test for each covariate. Reductionof among-study variance was estimated by the changein t2 statistics [27].

Publication bias was tested by visual inspection ofthe funnel plot and, more formally, with a modifiedregression test based on sample size [28].

Analyses were performed using Stata, version 12(StataCorp LP, College Station, Texas) and R version2.9.2 (R Foundation for Statistical Computing, Vienna,Austria).

RESULTS

Search Strategy

Overall, we screened 1586 records. We identified 32relevant clinical trials (Fig. 1). Of these 32 trials[11,16,17,29–62], 12 studies were excluded for beingnoncontemporary [40–51] (i.e., low use of dual oral anti-platelet therapy and stenting, or use of fibrinolyticagents), 8 studies were excluded because they had com-pared an early to a delayed invasive strategy [52–58] orearly systematic angiography and revascularisation versusearly elective strategy [59] (angiography and selectiverevascularisation), 1 was excluded because it hadrandomized only 88 patients [60], 1 was excluded beinga subanalysis on female patients [61] and 1 trial wasexcluded because it was a randomized comparison ofcoronary-artery bypass surgery and medical therapy [62].

Nine trials [11,16,17,29–39] involving 9,400 patients(4702 EIS and 4698 more conservative management)met the inclusion criteria and were included in theanalysis.

Figure 1 shows the flow diagram with informationabout the selected, included, and excluded clinical studies.

Main Features of RCTs

Table I summarises the main features of trialsincluded in the analysis. Of the nine trials[11,16,17,29–39], five reported long-term follow-up[11,29,30,32–37]. Three RCTs included patients with a

mean age >65 years [11,17,29,36,39]. Prevalence ofdiabetes mellitus and history of MI ranged from 12[11,29,36] to 36% [16,17] and from 22 [11,29,36] to43% [30], respectively.

Composite End-Point

Individual and pooled ORs for the composite end-point of mortality and myocardial reinfarction in theRCTs are depicted in Fig. 2. The EIS was associatedwith a significant reduction in the risk of the compositeend-point when compared to an initially conservativemanagement (OR 0.85, 95% CI: 0.76–0.95, P¼ 0.004).However, there was significant heterogeneity acrossthe studies (I2¼ 50.4%). The extent of benefit waslarger in RCTs with a mean age of �65 years (OR0.75; 95% CI: 0.63–0.91) as compared to trials withyounger study populations (P¼ 0.044 for heterogeneitybetween subgroups, Table II).

Recurrent Myocardial Infarction

Compared to patients allocated to an initially con-servative management, the risk of recurrent MI waslower in patients randomized to an EIS (OR 0.75, 95%CI: 0.66–0.87, P< 0.0001; Fig. 3). With regard to MI,the RCTs were similar in their risk of bias and the for-mal tests for publication bias did not achieve statisticalsignificance (P¼ 0.544). No heterogeneity was notedacross trials (I2¼ 0.0%).

The effect of an EIS was consistent in all of the pre-planned subgroups (Table III). However, compared tothe conservative approach, the EIS reduced the risk ofMI to a greater extent in elderly than in younger peo-ple (age <62 years: OR 0.89, 95% CI: 0.64–1.26; age62–64 years: OR 0.78, 95% CI: 0.63–0.97; age �65years: OR 0.67, 95% CI: 0.54–0.84).

Mortality

Four-hundred-thirty nine of 4702 patients (9.3%) inthe early invasive groups died compared with 462 of4,698 patients (9.8%) in the initially conservativegroups (OR, 0.95, 95% CI: 0.83–1.09, P¼ 0.486; Fig.4). The formal tests for publication bias did notachieve statistical significance (P¼ 0.744). However,there was substantial heterogeneity (I2¼ 45.4%).

As shown in Table IV, the pooled estimate was con-sistent across subgroups defined by age, history of MIor prevalence of diabetes mellitus, time of catheteriza-tion in the EIS group and publication year.

Re-hospitalization

During follow-up, 28.6% of patients in the earlyinvasive groups were re-hospitalized compared with

688 Angeli et al.


Fig. 1. Flow diagram with information about the selected,included and excluded clinical studies. FRISC-II 5 fragmin andfast revascularization during instability in coronary disease;ICTUS 5 invasive versus conservative treatment in unstablecoronary syndromes investigators; ACS 5 acute coronary syn-drome; MATE 5 medicine versus angiography in thrombolyticexclusion;RITA-3 5 randomized intervention trial of unstableangina; TACTICS TIMI-18 5 treat angina with aggrastat and

determine the cost of therapy with an invasive or conservativestrategy-thrombolysis in myocardial infarction; TRUCS 5 treat-ment of refractory unstable angina in geographically isolatedareas without cardiac surgery; VANQWISH 5 the veteransaffairs Non-Q-wave infarction strategies in hospital;VINO 5 value of first day coronary angiography/angioplasty inevolving non-ST-segment elevation myocardial infarction.

TABLE I. Main Features of Clinical Trials Included in the Analysis

Trial (n. enrolled patients) Year

FU

(months)

Age*

(years) Design

PCI (Exp/Cont) Prevalence (%) of

% Time (h)þFemale

patients Diabetes

Previous

MI

ST-segment

depression

FRISC 2 [27,34,35] (n¼ 2,457) 1999 60 65 Open, factorial plan 62/69 96/408 30 12 22 46

ICTUS [30,33] (n¼ 1,200) 2005 48 62 Open, parallel groups 88/88 23/283 27 14 23 46

Italian elderly ACS study [10]

(n¼ 313)

2012 12 82 Open, parallel groups 96/97 24/67 49 36 31 64

MATE [36] (n¼ 201) 1998 21 59 Open, parallel groups NA 3.5 36 18 21 23

RITA 3 [31,32] (n¼ 1810) 2002 60 62 Open, parallel groups 88/90 48/1020 38 13 39 37

TACTIS-TIMI 18 [29]

(n¼ 2,220)

2001 6 62 Open, parallel groups 83/86 22/79 34 28 39 31

TRUCS [37] (n¼ 148) 2000 12 63 Open, parallel groups 85/85 48/120 27 29 27 NA

VANQWISH[28] (n¼ 920) 1998 23 61 Open, parallel groups NA 14 3 26 43 41

VINO [38] (n¼ 131) 2002 6 66 Open, parallel groups 44/50 6.2/1464 39 25 26 46

Legend: FU¼ follow-up; MI¼myocardial infarction; *¼mean value: 1¼median value (for MATE and VANQWISH only time to PCI for the over-

all population was reported). FRISC-II¼ fragmin and fast revascularization during instability in coronary disease; ICTUS¼ invasive versus conserva-

tive treatment in unstable coronary syndromes investigators; ACS¼ acute coronary syndrome; MATE¼medicine versus angiography in thrombolytic

exclusion; RITA-3¼ randomized intervention trial of unstable angina; TACTICS TIMI-18¼ treat angina with aggrastat and determine the cost of

therapy with an invasive or conservative strategy-thrombolysis in myocardial infarction; TRUCS¼ treatment of refractory unstable angina in geo-

graphically isolated areas without cardiac surgery; VANQWISH¼ the veterans affairs non-Q-wave infarction strategies in hospital; VINO¼ value of

first day coronary angiography/angioplasty in evolving non-ST-segment elevation myocardial infarction.

Fig. 2. Individual and summary odds ratios for the composite end-point of all-cause deathand myocardial reinfarction in clinical trials comparing early invasive versus more conserva-tive strategy. Solid squares represent the odds ratios in individual studies (weights from ran-dom effect model). Bars and diamond denote the 95% confidence intervals for individualstudies and pooled estimates, respectively.

690 Angeli et al.


TABLE II. Preplanned Subgroups Analyses for Clinical Trials Evaluating the Prognostic Impact on the Composite End-Point ofAll-Cause Death and Myocardial Reinfarction of an Early Invasive vs. a More Conservative Strategy

Subgroup No. of studies

DeathþMI/Number at risk

Odds ratio (95% CI)

P for heterogeneity

between subgroups

Early invasive

strategy

More conservative

strategy

Age (mean, years)

<62 2 168/573 150/548 1.13 (0.87–1.48) 0.044

62–64 4 334/2689 390/2689 0.84 (0.71–0.98)

�65 3 249/1440 319/1461 0.75 (0.63–0.91)

Prevalence (%) of previous MI

<26 3 338/1937 376/1921 0.87 (0.74–1.03) 0.287

26–31 3 38/294 61/298 0.60 (0.38–0.94)

�32 3 375/2471 422/2479 0.87 (0.74–1.01)

Prevalence (%) of diabetes mellitus

<18 3 464/2721 543/2746 0.83 (0.73–0.96) 0.147

18–27 3 172/637 165/615 1.05 (0.81–1.36)

�28 3 115/1344 151/1337 0.74 (0.57–0.95)

Prevalence (%) of female patients

�30 4 480/2364 516/2361 0.91 (0.79–1.05) 0.133

>30 5 271/2338 343/2337 0.77 (0.65–0.91)

Time of catheterization in the early invasive

strategy group (mean, hours)

�24 5 234/2047 260/2018 0.88 (0.73–1.07) 0.679

>24 4 517/2655 599/2680 0.84 (0.73–0.96)

Publication year

Before 2001 5 472/2985 537/2961 0.84 (0.73–0.97) 0.879

After 2001 4 279/1717 322/1737 0.86 (0.72–1.03)

Duration of follow-up

<12 months 4 119/1408 166/1404 0.70 (0.54–0.90) 0.086

>12 months 5 623/3294 693/3294 0.89 (0.79–1.01)

Odds ratios and 95% confidence intervals were computed according to fixed-effect model. Legend: MI¼myocardial infarction.

Fig. 3. Individual and summary odds ratios for recurrent myocardial infarction in clinical tri-als comparing early invasive versus more conservative strategy. Solid squares represent theodds ratios in individual studies (weights from random effect model). Bars and diamonddenote the 95% confidence intervals for individual studies and pooled estimates, respec-tively.

TABLE III. Preplanned Subgroups Analyses for Clinical Trials Evaluating the Prognostic Impact on Recurrent MyocardialInfarction of an Early Invasive vs. a More Conservative Strategy

Subgroup

No. of

studies

MI/Number at risk

Odds ratio (95% CI)

P for heterogeneity

between subgroups

Early invasive

strategy

More conservative

strategy

Age (mean, years)

<62 2 76/573 82/548 0.89 (0.64–1.26) 0.349

62–64 4 165/2689 207/2689 0.78 (0.63–0.97)

�65 3 154/1440 222/1461 0.67 (0.54–0.84)


<26 3 195/1937 251/1921 0.75 (0.62–0.92) 0.598

26–31 3 16/294 30/298 0.55 (0.29–1.05)

�32 3 184/2471 230/2479 0.78 (0.64–0.96)


<18 3 250/2721 323/2746 0.76 (0.64–0.90) 0.693

18–27 3 78/637 92/615 0.83 (0.60–1.16)

�28 3 67/1344 96/1337 0.68 (0.49–0.94)


�30 4 266/2364 332/2361 0.78 (0.65–0.92) 0.599

>30 5 129/2338 179/2337 0.72 (0.57–0.91)



�24 5 120/2047 159/2018 0.74 (0.58–0.95) 0.873

>24 4 275/2655 352/2680 0.76 (0.64–0.90)

Publication year

Before 2001 5 273/2985 356/2961 0.74 (0.62–0.87) 0.645

After 2001 4 122/1717 155/1737 0.79 (0.62–1.02)


<12 months 4 69/1408 106/1404 0.64 (0.47–0.88) 0.276

>12 months 5 326/3294 405/3294 0.78 (0.67–0.92)


Fig. 4. Individual and summary odds ratios for overall mortality in clinical trials comparingearly invasive versus more conservative strategy. Solid squares represent the odds ratios inindividual studies (weights from random effect model). Bars and diamond denote the 95%confidence intervals for individual studies and pooled estimates, respectively.

36.7% of patients in the conservative groups (OR,0.71, 95% CI: 0.55–0.90, P< 0.0001; Fig. 5). No pub-lication bias was detected (P¼ 0.421). Nevertheless,there was heterogeneity (I2¼ 77.9%, P< 0.0001)across the studies. The analyses in the preplanned sub-groups of patient- and trial-level covariates are reportedin Table V.

Sensitivity Analysis

Sensitivity analyses for each endpoint (done byremoving each of the RCTs one at a time), demon-strated that no single study influenced the overall esti-mate and changed the statistical significance of theoverall results (Fig. 6).

Meta-regression Analysis

Stratified analyses were used to test the hypothesisthat the risk of overall mortality and of the compositeend-point varied between subgroups. Comparisonsbetween subgroups are more suitable for meta-regressionanalyses when within-subgroup heterogeneity is moder-ate or large [27]. We used separate random-effect meta-regression analysis to investigate the role of potentialeffect modifiers on residual between-trial variance (see

Methods). Because of the lack of heterogeneity regardingrecurrent MI, meta-regression was restricted to the com-posite end-point, overall mortality and rehospitalization.Among the pre-planned subgroups of trial- and patient-level covariates (age, sex, prevalence of previous MI,prevalence of diabetes mellitus, time of catheterization,publication year and duration of follow-up) only age sig-nificantly affected the overall among-study heterogeneity(Table VI).

For the composite end-point of all-cause death andrecurrent MI (Table VI, upper panel), meta-regressionanalysis showed that categories defined by age mark-edly affected the estimate of the effect of EIS. Thebenefit of EIS in reducing the composite end-point waslarger in RCTs enrolling patients with a mean age �65years than in RCTs with a mean age <62 years (OR0.65; 95% CI: 0.42–0.98; P¼ 0.043).

For re-hospitalization (Table VI, middle panel), ageexplained 100% of among-study variance: RCTsenrolling ACS-patients with a mean age �65 yearsshowed a 49% risk reduction (OR 0.51; 95% CI: 0.38–0.68) for this outcome when compared with trials witha mean age <62 years (P< 0.0001).

Compared to the SIS, the EIS was associated with alower risk of death in RCTs with patients aged �65

TABLE IV. Preplanned Subgroups Analyses for Clinical Trials Evaluating the Prognostic Impact on All-cause Death of an EarlyInvasive vs. a More Conservative Strategy

Subgroup

No. of

studies

Death/number at risk

Odds ratio (95% CI)

P for heterogeneity

between subgroups

Early invasive

strategy

More conservative

strategy

Age (mean, years)

<62 2 92/573 68/548 1.37 (0.97–1.92) 0.069

62–64 4 209/2689 239/2689 0.87 (0.71–1.06)

�65 3 138/1440 155/1461 0.90 (0.71–1.15)


<26 3 196/1937 192/1921 1.01 (0.82–1.25) 0.240

26–31 3 24/294 40/298 0.61 (0.35–1.06)

�32 3 219/2471 230/2479 0.95 (0.78–1.16)


<18 3 286/2721 315/2746 0.91 (0.77–1.08) 0.180

18–27 3 94/637 77/615 1.26 (0.90–1.75)

�28 3 59/1344 70/1337 0.85 (0.59–1.21)


�30 4 267/2364 251/2361 1.07 (0.89–1.29) 0.047

>30 5 172/2338 211/2337 0.81 (0.65–1.00)



�24 5 137/2047 138/2018 0.99 (0.77–1.27) 0.726

>24 4 302/2655 324/2680 0.94 (0.79–1.11)

Publication year

Before 2001 5 249/2985 240/2961 1.04 (0.86–1.25) 0.187

After 2001 4 190/1717 222/1737 0.86 (0.70–1.06)


<12 months 4 61/1408 79/1404 0.79 (0.55–1.12) 0.252

>12 months 5 378/3294 383/3294 0.99 (0.85–1.15)




Fig. 5. Individual and summary odds ratios for rehospitalization in clinical trials comparingearly invasive versus more conservative strategy. Solid squares represent the odds ratios inindividual studies (weights from random effect model). Bars and diamond denote the 95%confidence intervals for individual studies and pooled estimates, respectively.

TABLE V. Preplanned Subgroups Analyses for Clinical Trials Evaluating the Prognostic Impact on Rehospitalization of an EarlyInvasive vs. a More Conservative Strategy

Subgroup

No. of

studies

Death/number at risk

Odds ratio (95% CI)

P for heterogeneity

between subgroups

Early invasive

strategy

More conservative

strategy

Age (mean, years)

<62 2 300/573 307/548 0.89 (0.70–1.14) <0.0001

62–64 4 559/2657 669/2656 0.77 (0.67–0.89)

�65 3 475/1440 738/1461 0.46 (0.39–0.53)


<26 3 520/1937 788/1921 0.48 (0.42–0.56) <0.0001

26–31 3 37/294 51/298 0.69 (0.44–1.10)

�32 3 777/2439 875/2446 0.81 (0.71–0.93)


<18 3 874/2689 1204/2713 0.58 (0.51–0.65) 0.003

18–27 3 306/637 319/615 0.86 (0.68–1.10)

�28 3 154/1344 191/1337 0.77 (0.62–0.97)


�30 4 783/2364 1072/2361 0.55 (0.48–0.62) <0.0001

>30 5 551/2306 642/2304 0.80 (0.69–0.92)

Time of catheterization in the early

invasive strategy group (mean, hours)

�24 5 216/2047 270/2018 0.76 (0.62–0.92) 0.067

>24 4 1118/2623 1440/2647 0.61 (0.55–0.69)

Publication year

Before 2001 5 887/2985 1180/2961 0.59 (0.53–0.67) 0.012

After 2001 4 447/1685 534/1704 0.77 (0.65–0.90)


<12 months 4 160/1408 203/1404 0.76 (0.61–0.95) 0.123

>12 months 5 1174/3262 1511/3261 0.62 (0.56–0.69)


years (P¼ 0.085) and 62–64 years (P¼ 0.054) than inRCTs with patients aged <62 years, but differencesdid not yield significance (Table VI, lower panel).

At visual inspection, RCTs with patients aged �65years recruited a larger proportion of female patients(Fig. 7, middle panel) suggesting a potential interactionbetween age and sex. Accordingly, we also exploredthe effect of sex as potential effect modifier for thebenefit documented in patients randomized to an EIS.

In multivariable meta-regression models, no signifi-cant interactions between age and sex was observed for

both rehospitalization (P¼ 0.645) and the compositeend-point (P¼ 0.090) of death and MI. In addition, thebenefits of the EIS observed in patients aged �65 forrehospitalization and the composite end-point of deathand MI were unaffected after adjustment for prevalenceof female patients (Fig. 7, upper and lower panels).

DISCUSSION

Our meta-analysis of 9 RCTs in 9,400 NSTEACSpatients provided three major findings. First, we

Fig. 6. Sensitivity analyses for the evaluation of trials’ influence on the overall estimate.



extended the available evidence on the prognosticvalue of an invasive strategy in NSTEACS resultingfrom individual trials [10,11] and pooled analyses[18,63]. EIS was associated with a significant 15% riskreduction of the composite end-point of all-cause deathand recurrent MI when compared to a more selectiveapproach, and that this benefit is greater in elderlycompared to younger patients. Second, we showed thatan EIS is superior to a more conservative approach inreducing rehospitalization and that this benefit emergesmainly among elderly NSTEACS patients.

Finally, the results of the present analysis indicatethat the benefit of an EIS seems to be unaffected bygender, thus suggesting that an EIS should be consid-ered in women on the same basis as in men.

Comparison With Previous Findings

Elderly patients represent one third of patients withNSTEACS but are under-represented in clinical trials[64]. A systematic early invasive approach, which in theaverage population of the relevant trials has improvedoutcomes compared to an initially conservativeapproach [63], might seem a double edged sword in el-derly patients since, from one side these patients are athigher risk of ischemic events, but from the other theyare more subject to the iathrogenic complications frominterventional procedures and aggressive antithrombotic

therapies. In this context, we confirmed the protectiverole of an initial invasive management in elderlypatients suggesting that advanced age should not beregarded as a contraindication to invasive management.

Our results are consistent with previous studies. Inparticular, the data from the 5-year follow-up of theFIR collaboration were particularly impressive [18].This report, including pooled individual patient data(n¼ 5,467) from the FRISC II, ICTUS, and RITA 3studies, showed no benefit from an early invasiveapproach in patients younger than 65 years at enrol-ment and a significant benefit in elderly patients.

Similarly, an analysis from TACTIS-TIMI 18 trial[65] showed that elderly patients may derive a greaterbenefit from an invasive strategy than younger patients.Among the 2,220 trial participants, no significant bene-fit was observed from an early invasive approach inpatients of age <65 years, whereas older patients expe-rienced a significant reduction in death and MI at 30days (5.7% vs. 9.8%) and 6 months (8.8% vs. 13.6%).Moreover, among patients >75 years of age, the advant-age of an EIS in reducing the incidence of death or MIat 6 months was even more marked (10.8% vs. 21.6%).

More recently, the Italian Elderly ACS trial [16] an-alyzed the risk versus benefit ratio of an early aggres-sive approach in patients aged �75 years with NSTE-ACS. The primary outcome (composite of death, MI,disabling stroke, and repeat hospital stay for

TABLE VI. Results of Meta-regression Analyses Exploring the Role of Potential Effect Modifiers on Residual Between-TrialVariance

Covariate OR Std. Err. 95% Conf. Interval p-value

Proportion of between-study

variance explained by the model

Composite end-point

Age (mean, years)

<62 1 (ref.)

62–64 0.73 0.15 0.50–1.08 0.119 58%

�65 0.65 0.14 0.42–0.98 0.043


�30 1 (ref.)

>30 0.82 0.13 0.60–1.12 0.213 44%

Re-hospitalization

Age (mean, years)

<62 1 (ref.)

62–64 0.86 0.12 0.65–1.14 0.304 100%

�65 0.51 0.08 0.38–0.68 <0.0001


�30 1 (ref.)

>30 1.28 0.26 0.86–1.91 0.222 43%

All-cause death

Age (mean, years)

<62 1 (ref.)

62–64 0.65 0.14 0.41–1.01 0.054 74%

�65 0.65 0.16 0.40–1.06 0.085


�30 1 (ref.)

>30 0.75 0.12 0.55–1.02 0.068 75%

696 Angeli et al.


cardiovascular causes or severe bleeding within 1 year)occurred in 27.9% of the patients in the early invasivegroup and 34.6% in the initially conservative group(hazard ratio [HR]: 0.80; 95% CI: 0.53–1.19;P¼ 0.26). However, statistically significant heterogene-ity in treatment effect was observed with regard to tro-ponin levels at entry: although patients with normaltroponin levels on admission had no benefit from anearly invasive approach, those with elevated troponinshowed a significant 57% reduction in the primaryendpoint rate.

The data from randomized trials seem to be con-firmed by registry data from Germany [66] investigatingthe impact of an invasive treatment in patients aged�75 years presenting with NSTEACS. Patients were di-vided into two groups: 1,005 (51.9%) underwent coro-nary angiography and/or revascularization and 931

(48.1%) received conservative treatment. In-hospitalmortality (6.0% vs. 12.5%, P< 0.0001) and the com-bined endpoint of death and nonfatal reinfarction (9.6%vs. 17.3%, P< 0.0001) were lower in elderly patientsundergoing cardiac catheterization compared with thegroup with conservative strategy. After adjustment forthe confounding factors in the propensity score analysisthe invasive strategy remained superior for mortality(OR 0.55, 95% CI 0.35–0.86) and death or non-fatal MI(OR 0.51, 95% CI 0.35–0.75).

Effect of Age: Potential Mechanisms

Although interpretation of the benefit of an EIS inelderly remains speculative, some possible explanationsneed to be discussed.

It is well known from RCTs that the higher the base-line risk, the greater the benefit of an invasive strategyin patients with NSTEACS [67]. In this context, age isa surrogate for assessing the patients’ baseline risk andin older patients, the spontaneous age-related cardio-vascular risk exceeds that of coronary artery proce-dures with a resulting benefit of an early and routineinvasive strategy.

In addition, the extent of coronary artery diseaseincreases with age. An early and routine invasive strat-egy in elderly might permit to identify patients withmore severe coronary artery disease promoting coronaryrevascularization (including coronary artery surgery pro-cedures) and improving long-term protection [65].

Furthermore, a significant difference according toage exists in the distribution of other risk markers andcomorbidities in NSTEACS, including elevated tropo-nin levels and marked ST-segment depression [16,18].

Gender Issues

Whether gender influences the outcome of invasivestrategy in NSTEACS is still controversial. In our study,the benefit of an EIS remained evident after testing forthe interaction between age and sex, suggesting that sexdid not affect the significant benefit of an EIS in elderlysubjects. Similar results have been documented in a pro-spective analysis of women and men enrolled in theTACTICS-TIMI 18 trial [68]. In this report, althoughmen had more severe coronary artery disease, womenhad a 28% odds reduction in the primary end point(composite of death, MI, or rehospitalization) with anearly invasive strategy, similar to the benefit observedin men (P¼ 0.60 for sex interaction) [68].

Conversely, other reports indicated that the benefitof invasive strategies was restricted to male patients,with no benefit in women [11,18]. In particular, a sig-nificant sex interaction was found in the FRISC II trial,in which an invasive strategy showed a significant

Fig. 7. Association between age, sex and effect of an earlyinvasive strategy on the risk of rehospitalization and compositeend-point of death and MI. Prevalence (%) and standard errorof female patients are depicted as circle and bars, respectively(middle panel). Black and grey squares (upper and lower pan-els) represent the odds ratio for the outcome as computed byunivariable and multivariable analysis, respectively. OR 5 oddsratio; CI 5 confidence interval; MI 5 myocardial infarction;SE 5 standard error; ref 5 reference category.



improvement in the reduction of death and MI in menbut not in women [11].

Study Limitations

The present analysis has some limitations. First, weperformed a meta-analysis on aggregate patient- andtrial-level data. Although individual patients data (IPD)are generally acknowledged as the standard methodol-ogy for carrying out a meta-analysis, the added valueof an IPD analysis over a summary measure analysis isstill debated [69,70]. In particular, meta-regressionusing summary patient-level data is not biased and ifthis statistical approach does pick up an effect, then itis probably a large and important one [69,71]. Second,only four RCTs reported data on major bleeding andwe were unable to quantify its association with theearly invasive approach in the elderly. Third, baselinerisk of patients estimated by current risk scores [4,9]was not included in our meta-regression analysisbecause of only a minority of RCTs reported this find-ing. A strength of the study was the inclusion of somerelevant features (i.e., age, sex, previous MI, ST-segment depression and diabetes) as potential effectmodifiers.

CONCLUSION

Managing NSTEACS by EIS is currently recom-mended in high risk patients to improve long-term sur-vival and to reduce late MI and rehospitalization forunstable angina [3–5]. This recommendation is sup-ported by a collaborative meta-analysis [67] and post-hoc analyses of RCTs which identified subgroups ofpatients that benefited most from early invasive therapycompared to a more conservative management. Theseincluded patients with elevated serum troponin, previ-ous MI and history of diabetes.

However, the role of an EIS in elderly patientsremains a subject of debate. In this context, the find-ings of the present study suggest that a routine EISreduces the risk of rehospitalization and the compositeend point of recurrent MI and death in patients withNSTEACS, and that such effect appeared to be morepronounced in elderly than in younger individuals.

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