Published in Circulation 2005 Percutaneous Coronary Intervention Versus Conservative Therapy in Nonacute Coronary Artery Disease: A Meta-Analysis Demosthenes

Published in Circulation 2005Published in Circulation 2005

Percutaneous Coronary Intervention Versus Percutaneous Coronary Intervention Versus Conservative Therapy in Nonacute Coronary Artery Conservative Therapy in Nonacute Coronary Artery

Disease: A Meta-AnalysisDisease: A Meta-Analysis

Percutaneous Coronary Intervention Versus Percutaneous Coronary Intervention Versus Conservative Therapy in Nonacute Coronary Artery Conservative Therapy in Nonacute Coronary Artery

Disease: A Meta-AnalysisDisease: A Meta-Analysis

Demosthenes G. Katritsis, MD, PhD; Demosthenes G. Katritsis, MD, PhD;

John P.A. Ioannidis, MDJohn P.A. Ioannidis, MD

PCI vs. Conservative Therapy: BackgroundPCI vs. Conservative Therapy: BackgroundPCI vs. Conservative Therapy: BackgroundPCI vs. Conservative Therapy: Background

• The potential benefits of percutaneous coronary intervention The potential benefits of percutaneous coronary intervention (PCI) in the management of stable patients with coronary artery (PCI) in the management of stable patients with coronary artery disease (CAD) in nonacute settings have been debated for disease (CAD) in nonacute settings have been debated for more than a decade.more than a decade.

• Although PCI has been shown to improve symptoms compared Although PCI has been shown to improve symptoms compared with conservative treatment in patients with stable CAD, there with conservative treatment in patients with stable CAD, there is limited evidence on the effect of PCI with regards to death, is limited evidence on the effect of PCI with regards to death, myocardial infarction (MI), and subsequent revascularization.myocardial infarction (MI), and subsequent revascularization.

• The results of a meta-analysis from 11 studies in patients with The results of a meta-analysis from 11 studies in patients with angiographically documented coronary artery stenosis in angiographically documented coronary artery stenosis in nonacute CAD settings are reported.nonacute CAD settings are reported.

• The potential benefits of percutaneous coronary intervention The potential benefits of percutaneous coronary intervention (PCI) in the management of stable patients with coronary artery (PCI) in the management of stable patients with coronary artery disease (CAD) in nonacute settings have been debated for disease (CAD) in nonacute settings have been debated for more than a decade.more than a decade.

• Although PCI has been shown to improve symptoms compared Although PCI has been shown to improve symptoms compared with conservative treatment in patients with stable CAD, there with conservative treatment in patients with stable CAD, there is limited evidence on the effect of PCI with regards to death, is limited evidence on the effect of PCI with regards to death, myocardial infarction (MI), and subsequent revascularization.myocardial infarction (MI), and subsequent revascularization.

• The results of a meta-analysis from 11 studies in patients with The results of a meta-analysis from 11 studies in patients with angiographically documented coronary artery stenosis in angiographically documented coronary artery stenosis in nonacute CAD settings are reported.nonacute CAD settings are reported.

Katritsis DG & Ioannidis J.P.A., Circulation 2005; 111:2906-2912Katritsis DG & Ioannidis J.P.A., Circulation 2005; 111:2906-2912Katritsis DG & Ioannidis J.P.A., Circulation 2005; 111:2906-2912Katritsis DG & Ioannidis J.P.A., Circulation 2005; 111:2906-2912

PCI vs. Conservative Therapy: Study DesignPCI vs. Conservative Therapy: Study DesignPCI vs. Conservative Therapy: Study DesignPCI vs. Conservative Therapy: Study Design

Primary Endpoint: Death, Cardiac Death or nonfatal MI, CABG, and PCI during Primary Endpoint: Death, Cardiac Death or nonfatal MI, CABG, and PCI during follow-up (in the target vessel or other vessel/segment). follow-up (in the target vessel or other vessel/segment).

- All data used pertained to the longest follow-up available per outcome from each study- All data used pertained to the longest follow-up available per outcome from each study

Primary Endpoint: Death, Cardiac Death or nonfatal MI, CABG, and PCI during Primary Endpoint: Death, Cardiac Death or nonfatal MI, CABG, and PCI during follow-up (in the target vessel or other vessel/segment). follow-up (in the target vessel or other vessel/segment).

- All data used pertained to the longest follow-up available per outcome from each study- All data used pertained to the longest follow-up available per outcome from each study

PCIPCIn=1476n=1476

PCIPCIn=1476n=1476

Conservative TherapyConservative Therapyn=1474n=1474

Conservative TherapyConservative Therapyn=1474n=1474

2950 patients from randomized trials comparing coronary revascularization by PCI 2950 patients from randomized trials comparing coronary revascularization by PCI versus conservative medical therapy for treatment of patients with CAD documented by versus conservative medical therapy for treatment of patients with CAD documented by

angiographic evidence of stenosis of 1 or more coronary vessels angiographic evidence of stenosis of 1 or more coronary vessels Meta-AnalysisMeta-Analysis

Mean age range 53-61 years, predominantly or exclusively male population, mean follow-up in 5 trials (with 1790 patients) Mean age range 53-61 years, predominantly or exclusively male population, mean follow-up in 5 trials (with 1790 patients) exceeded 2 years, more limited follow-up data available in other 6 trials (1160 patients), no trial used DESexceeded 2 years, more limited follow-up data available in other 6 trials (1160 patients), no trial used DES

2950 patients from randomized trials comparing coronary revascularization by PCI 2950 patients from randomized trials comparing coronary revascularization by PCI versus conservative medical therapy for treatment of patients with CAD documented by versus conservative medical therapy for treatment of patients with CAD documented by

angiographic evidence of stenosis of 1 or more coronary vessels angiographic evidence of stenosis of 1 or more coronary vessels Meta-AnalysisMeta-Analysis

Mean age range 53-61 years, predominantly or exclusively male population, mean follow-up in 5 trials (with 1790 patients) Mean age range 53-61 years, predominantly or exclusively male population, mean follow-up in 5 trials (with 1790 patients) exceeded 2 years, more limited follow-up data available in other 6 trials (1160 patients), no trial used DESexceeded 2 years, more limited follow-up data available in other 6 trials (1160 patients), no trial used DES


PCI vs. Conservative Therapy: Primary PCI vs. Conservative Therapy: Primary EndpointEndpoint

PCI vs. Conservative Therapy: Primary PCI vs. Conservative Therapy: Primary EndpointEndpoint

• There were a total of 196 There were a total of 196 deaths, 235 patients had deaths, 235 patients had cardiac death or MI, 153 cardiac death or MI, 153 patients had nonfatal MIs, patients had nonfatal MIs, 215 patients underwent 215 patients underwent CABG, and 462 had PCI CABG, and 462 had PCI during follow-up.during follow-up.

• Despite some differences, Despite some differences, there was no statistically there was no statistically significant between-study significant between-study heterogeneity for death, heterogeneity for death, cardiac death or MI, cardiac death or MI, nonfatal MI, and need for nonfatal MI, and need for CABG; thus, random and CABG; thus, random and fixed effects estimates fixed effects estimates were very similar for these were very similar for these outcomes. outcomes.

Number events per treatment group (# patients)Number events per treatment group (# patients)

# pa

tient

s#

patie

nts

95126

87109

219

101 109

66

106

243

0

50

100

150

200

250

Death Cardiacdeath/MI

nonfatalMI

CABG follow-upPCI

PCI Conservative

95126

87109

219

101 109

66

106

243

0

50

100

150

200

250

Death Cardiacdeath/MI

nonfatalMI

CABG follow-upPCI

PCI Conservative


• There was large There was large between-study between-study heterogeneity in the risk heterogeneity in the risk ratios for PCI during ratios for PCI during follow-up.follow-up.

• There was no difference There was no difference shown in the summary shown in the summary estimates between PCI estimates between PCI and the conservative and the conservative group in the mortality group in the mortality risk.risk.

• The 95% confidence The 95% confidence intervals excluded intervals excluded relative risk differences relative risk differences of 28%.of 28%.

PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for DeathDeath

PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for DeathDeath



PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for Cardiac Death or MICardiac Death or MI

PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for Cardiac Death or MICardiac Death or MI

• There was a trend for more cardiac There was a trend for more cardiac deaths or MIs (Figure B), especially deaths or MIs (Figure B), especially nonfatal MIs (Figure C) in patients nonfatal MIs (Figure C) in patients who underwent PCI.who underwent PCI.

• The point estimate suggests The point estimate suggests approximately a 30% increase in the approximately a 30% increase in the relative risk of nonfatal MI with PCI.relative risk of nonfatal MI with PCI.


PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for CABGCABG

PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for CABGCABG

• Between the two Between the two compared treatment compared treatment strategies, there was no strategies, there was no difference in the need difference in the need for CABG.for CABG.

• The 95% confidence The 95% confidence intervals also excluded intervals also excluded differences in the differences in the relative risk exceeding relative risk exceeding 20% in favor of PCI and 20% in favor of PCI and 33% in favor of 33% in favor of conservative treatment.conservative treatment.


PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for PCI during follow-upPCI during follow-up

PCI vs. Conservative Therapy: Risk Ratio for PCI vs. Conservative Therapy: Risk Ratio for PCI during follow-upPCI during follow-up

• Although there was no Although there was no overall difference in the overall difference in the risk for PCI during risk for PCI during follow-up, the random follow-up, the random effects 95% confidence effects 95% confidence intervals were more intervals were more substantial given the substantial given the considerable variability considerable variability between study between study heterogeneity.heterogeneity.


PCI vs. Conservative Therapy: Sub Group PCI vs. Conservative Therapy: Sub Group AnalysisAnalysis

PCI vs. Conservative Therapy: Sub Group PCI vs. Conservative Therapy: Sub Group AnalysisAnalysis

• Subgroup analyses showed that availability of stents did not make a substantial difference for any of the 5 Subgroup analyses showed that availability of stents did not make a substantial difference for any of the 5 end points.end points.

• In trials with follow-up exceeding 2 years, there were no differences between PCI and conservative In trials with follow-up exceeding 2 years, there were no differences between PCI and conservative treatments, with RR estimates very close to 1.00 for all outcomes.treatments, with RR estimates very close to 1.00 for all outcomes.

• Trials with more limited follow-up suggested an increase in deaths, MI, and nonfatal MI in PCI-treated Trials with more limited follow-up suggested an increase in deaths, MI, and nonfatal MI in PCI-treated patients, and the difference reached formal statistical significance for cardiac death or MI, with almost a patients, and the difference reached formal statistical significance for cardiac death or MI, with almost a doubling of risk conferred by PCI; however, the CIs overlapped with the results from longer term trials.doubling of risk conferred by PCI; however, the CIs overlapped with the results from longer term trials.


PCI vs. Conservative Therapy: LimitationsPCI vs. Conservative Therapy: LimitationsPCI vs. Conservative Therapy: LimitationsPCI vs. Conservative Therapy: Limitations

• Data were not available consistently across these trials to Data were not available consistently across these trials to separate procedure based infarctions from subsequent MI.separate procedure based infarctions from subsequent MI.

• It is unlikely that myocardial enzymes were routinely checked It is unlikely that myocardial enzymes were routinely checked after PCI so that risk of post PCI MI may have been after PCI so that risk of post PCI MI may have been underestimated.underestimated.

• Also, minor procedure-related infarctions without definitive Also, minor procedure-related infarctions without definitive ECG changes may have been largely underreported in the PCI ECG changes may have been largely underreported in the PCI arms.arms.

• Several of these trials were conducted in the time period Several of these trials were conducted in the time period before the routine use of stents in clinical practice.before the routine use of stents in clinical practice.

• The disease background of the patients included was The disease background of the patients included was different across trials.different across trials.

• Data were not available consistently across these trials to Data were not available consistently across these trials to separate procedure based infarctions from subsequent MI.separate procedure based infarctions from subsequent MI.

• It is unlikely that myocardial enzymes were routinely checked It is unlikely that myocardial enzymes were routinely checked after PCI so that risk of post PCI MI may have been after PCI so that risk of post PCI MI may have been underestimated.underestimated.

• Also, minor procedure-related infarctions without definitive Also, minor procedure-related infarctions without definitive ECG changes may have been largely underreported in the PCI ECG changes may have been largely underreported in the PCI arms.arms.

• Several of these trials were conducted in the time period Several of these trials were conducted in the time period before the routine use of stents in clinical practice.before the routine use of stents in clinical practice.

• The disease background of the patients included was The disease background of the patients included was different across trials.different across trials.

• Additionally, patient populations differed across trials with Additionally, patient populations differed across trials with respect to intensity of angina symptoms, functional respect to intensity of angina symptoms, functional demonstration of ischemia, and angiographic extent of CAD.demonstration of ischemia, and angiographic extent of CAD.

• The included trials did not routinely use the full spectrum of The included trials did not routinely use the full spectrum of conservative interventions currently available for CAD conservative interventions currently available for CAD management.management.

• Overall the varying and potentially suboptimal medical Overall the varying and potentially suboptimal medical management across trials is a limitation of the meta-management across trials is a limitation of the meta-analysis; however, one would expect better outcomes if the analysis; however, one would expect better outcomes if the management were optimized.management were optimized.

• Lastly, the present meta-analysis did not consider the option Lastly, the present meta-analysis did not consider the option of CABG in patients with stable chronic CAD and preserved of CABG in patients with stable chronic CAD and preserved LV function.LV function.

• Additionally, patient populations differed across trials with Additionally, patient populations differed across trials with respect to intensity of angina symptoms, functional respect to intensity of angina symptoms, functional demonstration of ischemia, and angiographic extent of CAD.demonstration of ischemia, and angiographic extent of CAD.

• The included trials did not routinely use the full spectrum of The included trials did not routinely use the full spectrum of conservative interventions currently available for CAD conservative interventions currently available for CAD management.management.

• Overall the varying and potentially suboptimal medical Overall the varying and potentially suboptimal medical management across trials is a limitation of the meta-management across trials is a limitation of the meta-analysis; however, one would expect better outcomes if the analysis; however, one would expect better outcomes if the management were optimized.management were optimized.

• Lastly, the present meta-analysis did not consider the option Lastly, the present meta-analysis did not consider the option of CABG in patients with stable chronic CAD and preserved of CABG in patients with stable chronic CAD and preserved LV function.LV function.


PCI vs. Conservative Therapy: Limitations PCI vs. Conservative Therapy: Limitations (cont.)(cont.)

PCI vs. Conservative Therapy: Limitations PCI vs. Conservative Therapy: Limitations (cont.)(cont.)

• Compared with conservative therapy, PCI does not Compared with conservative therapy, PCI does not decrease mortality or the risk of MI during follow-up in decrease mortality or the risk of MI during follow-up in patients with chronic CAD.patients with chronic CAD.

• A trend for increased risk of MI in patients undergoing A trend for increased risk of MI in patients undergoing PCI was observed, which may reflect the risk inherent PCI was observed, which may reflect the risk inherent in the invasive procedure itself. in the invasive procedure itself.

• Although early literature suggests that PCI may cause Although early literature suggests that PCI may cause an increased need for CABG, there was no evidence for an increased need for CABG, there was no evidence for an increased need for CABG in the PCI group an increased need for CABG in the PCI group compared with the conservative strategy group.compared with the conservative strategy group.

• Compared with conservative therapy, PCI does not Compared with conservative therapy, PCI does not decrease mortality or the risk of MI during follow-up in decrease mortality or the risk of MI during follow-up in patients with chronic CAD.patients with chronic CAD.

• A trend for increased risk of MI in patients undergoing A trend for increased risk of MI in patients undergoing PCI was observed, which may reflect the risk inherent PCI was observed, which may reflect the risk inherent in the invasive procedure itself. in the invasive procedure itself.

• Although early literature suggests that PCI may cause Although early literature suggests that PCI may cause an increased need for CABG, there was no evidence for an increased need for CABG, there was no evidence for an increased need for CABG in the PCI group an increased need for CABG in the PCI group compared with the conservative strategy group.compared with the conservative strategy group.


PCI vs. Conservative Therapy: SummaryPCI vs. Conservative Therapy: SummaryPCI vs. Conservative Therapy: SummaryPCI vs. Conservative Therapy: Summary

•Similarly, there was no difference in the risk of Similarly, there was no difference in the risk of requiring PCI during follow-up with interventional requiring PCI during follow-up with interventional versus conservative therapy; however, there was versus conservative therapy; however, there was considerable variability in this outcome across trials. considerable variability in this outcome across trials. One possible explanation for this heterogeneity is that One possible explanation for this heterogeneity is that although indications for CABG are relatively clear-cut, although indications for CABG are relatively clear-cut, indications for PCI are more subjective, meaning that indications for PCI are more subjective, meaning that different investigators and sites may have had different investigators and sites may have had different biases toward the use of PCI during follow-up different biases toward the use of PCI during follow-up based on whether or not it was used prior.based on whether or not it was used prior.

PCI vs. Conservative Therapy: Summary (cont.)PCI vs. Conservative Therapy: Summary (cont.)PCI vs. Conservative Therapy: Summary (cont.)PCI vs. Conservative Therapy: Summary (cont.)

• Importantly, even when analyses were limited to studies that Importantly, even when analyses were limited to studies that used stents, this meta-analysis found no evidence of superiority used stents, this meta-analysis found no evidence of superiority for the PCI strategy.for the PCI strategy.

• In conclusion, in the absence of acute coronary syndromes, for In conclusion, in the absence of acute coronary syndromes, for patients with chronic CAD and good LV function, PCI does not patients with chronic CAD and good LV function, PCI does not confer any clear benefit in terms of long-term hard clinical confer any clear benefit in terms of long-term hard clinical outcomes compared with conservative medical therapy.outcomes compared with conservative medical therapy.

• Randomized trials in the modern era of pharmacotherapy and Randomized trials in the modern era of pharmacotherapy and new device interventions is lacking.new device interventions is lacking.

• Importantly, even when analyses were limited to studies that Importantly, even when analyses were limited to studies that used stents, this meta-analysis found no evidence of superiority used stents, this meta-analysis found no evidence of superiority for the PCI strategy.for the PCI strategy.

• In conclusion, in the absence of acute coronary syndromes, for In conclusion, in the absence of acute coronary syndromes, for patients with chronic CAD and good LV function, PCI does not patients with chronic CAD and good LV function, PCI does not confer any clear benefit in terms of long-term hard clinical confer any clear benefit in terms of long-term hard clinical outcomes compared with conservative medical therapy.outcomes compared with conservative medical therapy.

• Randomized trials in the modern era of pharmacotherapy and Randomized trials in the modern era of pharmacotherapy and new device interventions is lacking.new device interventions is lacking.


PCI vs. Conservative Therapy: Summary (cont.)PCI vs. Conservative Therapy: Summary (cont.)PCI vs. Conservative Therapy: Summary (cont.)PCI vs. Conservative Therapy: Summary (cont.)

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Published in Circulation 2005 Percutaneous Coronary Intervention Versus Conservative Therapy in Nonacute Coronary Artery Disease: A Meta-Analysis Demosthenes