NEWS & VIEWS I N T E RV E N T I O N A L C A R D I O LO GY
Treating nonischaemic stable CAD lesions—safe to DEFER? Konstantinos C. Koskinas and Stephan Windecker Coronary revascularization has a prominent role in the management of chronic, stable coronary artery disease, but decision-making guided by angiography alone for identifying haemodynamically relevant lesions can be challenging. The DEFER study now demonstrates favourable 15‑year outcomes after deferral of revascularization in angiographically relevant, but functionally nonsignificant, coronary lesions. Refers to Zimmermann, F. M. et al. Deferral versus performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15‑year follow‑up of the DEFER trial. Eur. Heart J. http://dx.doi.org/10.1093/ eurheartj/ehv452
Although the armoury of diagnostic and thera peutic tools for patients with coronary artery disease (CAD) has been continuously expand ing, it remains challenging to determine which patients will benefit most from each available treatment option. Defining the prognostic rele vance and optimal management (that is, revas cularization versus medical therapy alone) of angiographically indeterminate lesions in patients with chronic, stable CAD is such an example. Coronary angiography is the gold standard for delineating real-time coronary anatomy, but lesion severity as assessed using this lumenography technique does not always correspond with the degree of blood flow reduction, nor the ensuing myocardial ischae mia1. Decision-making can be guided by non invasive ischaemia testing before angiography, by a comprehensive anatomical evaluation with intracoronary imaging, or by invasive haemo dynamic assessment of translesional pressure gradients by means of fractional flow reserve (FFR) at the time of angiography2. Against this background, Zimmerman and colleagues have presented the 15‑year results of the DEFER trial3. In the study, patients who had angiographically relevant, functionally non significant stenoses (exemplified by FFR val ues ≥0.75) were randomly assigned to undergo percutaneous coronary intervention (PCI; per form group; n = 90) or to medical therapy alone (defer group; n = 91). Patients with FFR 50% was an inclusion criterion3, but the actual values were 48 ± 10%
NATURE REVIEWS | CARDIOLOGY
and 48 ± 9% in the perform and defer groups, respectively4. A proportion of these lesions would probably not be considered eligible for revascularization based on their angiographic appearance in the first place; therefore, it is dif ficult to disentangle which part of the observed findings can be attributed to the incremental effect of the nonischaemic FFR, and which to the mere effect of the angiographically mod erate, or even nonsignificant, lesions being evaluated. The modest sample size (n = 325), and the differing FFR cutoff points used to define ischaemia in the DEFER trial (0.75)3, compared with current standards (0.80), also warrant consideration. The DEFER trial3, and subsequently the FAME6 and FAME‑2 (REF. 7) studies, had an important role in establishing the value of FFR for enhancing decision-making in angio graphically indeterminate lesions (FIG. 1). However, the methodological limitations that complicate the interpretation of these studies have been discussed extensively, including the definition of MI, which led to relatively high rates of periprocedural MI in the FAME trial6, and the open-label design in FAME‑2 (REF. 7), which might have introduced bias by lowering the threshold for revascularization in medically treated patients. Notwithstanding these considerations, current randomized trial-based evidence supports revasculariza tion of lesions with FFR ≤0.80, whereas lesions with FFR >0.80 can be managed medically in patients with chronic, stable CAD2. FFR is currently classified as a class Ia rec ommendation to identify haemodynamically relevant lesions when evidence of ischaemia is not available2. Technical improvements in haemodynamic assessment, including non invasive, CT‑based measurement and resting, vasodilator-independent testing, hold promise but require further validation. Importantly, the inherent limitations of the FFR methodology need to be acknowledged. The technique does not account for the effect on myocardial per fusion of collateral flow, and FFR thresholds might not be uniform in defining ischaemia depending on the focal, multifocal, or diffuse nature of the disease8. In left-main lesions, the obtained values can be falsely raised in the presence of substantial downstream disease. The value of FFR in defining nonculprit lesions requiring treatment in patients with acute coronary syndromes remains to be established. www.nature.com/nrcardio
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Patient management Angiography-guided, clinically indicated PCI
PCI
Trial
Primary outcomes
Principal conclusion
FAME6
Death, MI, and repeat revascularization
Better outcome when PCI was FFR-guided 18.3% vs 13.2% (angiography-guided vs FFR-guided PCI; P = 0.02)
FAME-27
Death, MI, and urgent revascularization
DEFER3
Death (15-year follow-up)
PCI ≤0.80 Coronary angiography
No PCI FFR >0.80
No PCI PCI
≥0.75 No PCI
Figure 1 | Summary of the findings from three randomized trials to evaluate FFR for decision-making and PCI guidance in patients with chronic, stable CAD. Collectively these trials demonstrated that deferring revascularization in lesions with high FFR is safe,
Even more importantly, FFR provides a onetime snapshot of pressure gradients without any information about the extent, composi tion, biological activity, or the dynamic nature of the underlying atherosclerotic plaque. Functionally nonsignificant, high-risk lesions that are subsequently likely to rupture and trig ger an acute coronary event cannot be captured by means of FFR. Along these lines, intra coronary imaging modalities also have a role in guiding management of angiographically intermediate lesions and, in addition, provide information on plaque morphology, which has been linked to subsequent clinical outcomes9. A strategy of pre-emptive interventions on the basis of high-risk intracoronary imaging characteristics, irrespective of angiographic and haemodynamic relevance, is currently being investigated in the PROSPECT‑II study (NCT02171065). At present, medical therapy and revascular ization are considered complementary treat ment options for patients with chronic, stable CAD. Revascularization by means of PCI or surgery is indicated when symptoms persist despite evidence-based medical therapy, and to improve prognosis2. In these patients, revas cularization results in better control of angina symptoms, greater reduction of ischaemia, and reduced need for repeat revasculariza tion compared with medical therapy alone2. Therefore, the observation that a substantial proportion of patients with nonischaemic FFR, who were initially assigned to medical treatment in the DEFER trial3 (and also in studies in which functional testing was not applied, such as the COURAGE trial10), sub sequently underwent revascularization calls into question whether, in some patients, the initial decision for medical therapy alone simply postpones, rather than obviates, an
Better outcome with PCI for FFR ≤0.80 4.3% vs 12.7% (PCI vs no PCI; P 0.80 No benefit of PCI for FFR ≥0.75 31.1% vs 33.0% (PCI vs no PCI; P = 0.79)
whereas in lesions with low FFR, revascularization results in| Cardiology Nature Reviews better outcomes compared with medical therapy alone. FFR, fractional flow reverse; MI, myocardial infarction; PCI, percutaneous coronary intervention.
interventional or surgical approach that can yield durable, long-standing benefits. Currently, our ability to identify which patients with stable CAD will have a favourable longterm prognosis when receiving medical ther apy alone, compared with those who will eventually require revascularization, seems to be suboptimal, and defining a nonischaemic FFR at index hardly precludes the need for subsequent intervention of the given lesion along the course of disease progression. The ISCHEMIA trial (NCT01471522) is designed to address whether an initial invasive strategy of optimal revascularization in patients with chronic, stable CAD provides benefit over evidence-based medical therapy alone, with presence of at least moderate ischaemia being the criterion for referral to catheterization. Summarizing the insights from the DEFER trial3 and other relevant studies6,7, current evidence demonstrates the benefit of revascularization in low‑FFR lesions compared with no benefit in high‑FFR lesions in patients with stable CAD. A strategy of prophylactic ‘shielding’ of certain functionally nonsignifi cant lesions, for example based on indices of presumed high-risk morphology, entails the oretical advantages, but evidence for such an approach is currently lacking. Because FFR can address, at a given time-point, only a sin gle aspect of coronary atherosclerosis, efforts should continue to focus on evaluating all relevant information, including anatomical measures (angiographic complexity, global plaque burden, morphological assessment of individual lesions), functional measures (inva sive haemodynamic assessment), and clinical characteristics, with the goal of optimizing individualized risk stratification and defining the most beneficial treatment strategy for each of our patients.
NATURE REVIEWS | CARDIOLOGY
Konstantinos C. Koskinas and Stephan Windecker are at the Department of Cardiology, Bern University Hospital, Freiburgstrasse 4 Bern, CH 3010, Switzerland Correspondence to S.W. [email protected] doi:10.1038/nrcardio.2015.173 Published online 19 Nov 2015 Topol, E. J. & Nissen, S. E. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 92, 2333–2342 (1995). 2. Windecker, S. et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 35, 2541–2619 (2014). 3. Zimmermann, F. M. et al. Deferral versus performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15‑year follow‑up of the DEFER trial. Eur. Heart J. http:/ / dx.doi.org/ 10.1093/eurheartj/ehv452. 4. Pijls, N. H. et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5‑year follow‑up of the DEFER Study. J. Am. Coll. Cardiol. 49, 2105–2111 (2007). 5. Windecker, S. et al. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 348, g3859 (2014). 6. Tonino, P. A. et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N. Engl. J. Med. 360, 213–224 (2009). 7. De Bruyne, B. et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N. Engl. J. Med. 367, 991–1001 (2012). 8. Gould, K. L. et al. Anatomic versus physiologic assessment of coronary artery disease: role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making. J. Am. Coll. Cardiol. 62, 1639–1653 (2013). 9. Stone, G. W. et al. A prospective natural-history study of coronary atherosclerosis. N. Engl. J. Med. 364, 226–235 (2011). 10. Boden, W. E. et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503–1516 (2007). 1.
Competing interests statement
S.W. declares that he has received institutional research grants from Abbott, Biotronik, Boston Scientific, Edwards, Medtronic, and St. Jude Medical, and that he has received speaker fees from Abbott, Astra Zeneca, Bayer, Biosensors, Biotronik, Boston Scientific, Edwards, and Medtronic. K.C.K. declares no competing interests.
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
Treating nonischaemic stable CAD lesions—safe to DEFER? Konstantinos C. Koskinas and Stephan Windecker Coronary revascularization has a prominent role in the management of chronic, stable coronary artery disease, but decision-making guided by angiography alone for identifying haemodynamically relevant lesions can be challenging. The DEFER study now demonstrates favourable 15‑year outcomes after deferral of revascularization in angiographically relevant, but functionally nonsignificant, coronary lesions. Refers to Zimmermann, F. M. et al. Deferral versus performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15‑year follow‑up of the DEFER trial. Eur. Heart J. http://dx.doi.org/10.1093/ eurheartj/ehv452
Although the armoury of diagnostic and thera peutic tools for patients with coronary artery disease (CAD) has been continuously expand ing, it remains challenging to determine which patients will benefit most from each available treatment option. Defining the prognostic rele vance and optimal management (that is, revas cularization versus medical therapy alone) of angiographically indeterminate lesions in patients with chronic, stable CAD is such an example. Coronary angiography is the gold standard for delineating real-time coronary anatomy, but lesion severity as assessed using this lumenography technique does not always correspond with the degree of blood flow reduction, nor the ensuing myocardial ischae mia1. Decision-making can be guided by non invasive ischaemia testing before angiography, by a comprehensive anatomical evaluation with intracoronary imaging, or by invasive haemo dynamic assessment of translesional pressure gradients by means of fractional flow reserve (FFR) at the time of angiography2. Against this background, Zimmerman and colleagues have presented the 15‑year results of the DEFER trial3. In the study, patients who had angiographically relevant, functionally non significant stenoses (exemplified by FFR val ues ≥0.75) were randomly assigned to undergo percutaneous coronary intervention (PCI; per form group; n = 90) or to medical therapy alone (defer group; n = 91). Patients with FFR 50% was an inclusion criterion3, but the actual values were 48 ± 10%
NATURE REVIEWS | CARDIOLOGY
and 48 ± 9% in the perform and defer groups, respectively4. A proportion of these lesions would probably not be considered eligible for revascularization based on their angiographic appearance in the first place; therefore, it is dif ficult to disentangle which part of the observed findings can be attributed to the incremental effect of the nonischaemic FFR, and which to the mere effect of the angiographically mod erate, or even nonsignificant, lesions being evaluated. The modest sample size (n = 325), and the differing FFR cutoff points used to define ischaemia in the DEFER trial (0.75)3, compared with current standards (0.80), also warrant consideration. The DEFER trial3, and subsequently the FAME6 and FAME‑2 (REF. 7) studies, had an important role in establishing the value of FFR for enhancing decision-making in angio graphically indeterminate lesions (FIG. 1). However, the methodological limitations that complicate the interpretation of these studies have been discussed extensively, including the definition of MI, which led to relatively high rates of periprocedural MI in the FAME trial6, and the open-label design in FAME‑2 (REF. 7), which might have introduced bias by lowering the threshold for revascularization in medically treated patients. Notwithstanding these considerations, current randomized trial-based evidence supports revasculariza tion of lesions with FFR ≤0.80, whereas lesions with FFR >0.80 can be managed medically in patients with chronic, stable CAD2. FFR is currently classified as a class Ia rec ommendation to identify haemodynamically relevant lesions when evidence of ischaemia is not available2. Technical improvements in haemodynamic assessment, including non invasive, CT‑based measurement and resting, vasodilator-independent testing, hold promise but require further validation. Importantly, the inherent limitations of the FFR methodology need to be acknowledged. The technique does not account for the effect on myocardial per fusion of collateral flow, and FFR thresholds might not be uniform in defining ischaemia depending on the focal, multifocal, or diffuse nature of the disease8. In left-main lesions, the obtained values can be falsely raised in the presence of substantial downstream disease. The value of FFR in defining nonculprit lesions requiring treatment in patients with acute coronary syndromes remains to be established. www.nature.com/nrcardio
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS Patient management Angiography-guided, clinically indicated PCI
PCI
Trial
Primary outcomes
Principal conclusion
FAME6
Death, MI, and repeat revascularization
Better outcome when PCI was FFR-guided 18.3% vs 13.2% (angiography-guided vs FFR-guided PCI; P = 0.02)
FAME-27
Death, MI, and urgent revascularization
DEFER3
Death (15-year follow-up)
PCI ≤0.80 Coronary angiography
No PCI FFR >0.80
No PCI PCI
≥0.75 No PCI
Figure 1 | Summary of the findings from three randomized trials to evaluate FFR for decision-making and PCI guidance in patients with chronic, stable CAD. Collectively these trials demonstrated that deferring revascularization in lesions with high FFR is safe,
Even more importantly, FFR provides a onetime snapshot of pressure gradients without any information about the extent, composi tion, biological activity, or the dynamic nature of the underlying atherosclerotic plaque. Functionally nonsignificant, high-risk lesions that are subsequently likely to rupture and trig ger an acute coronary event cannot be captured by means of FFR. Along these lines, intra coronary imaging modalities also have a role in guiding management of angiographically intermediate lesions and, in addition, provide information on plaque morphology, which has been linked to subsequent clinical outcomes9. A strategy of pre-emptive interventions on the basis of high-risk intracoronary imaging characteristics, irrespective of angiographic and haemodynamic relevance, is currently being investigated in the PROSPECT‑II study (NCT02171065). At present, medical therapy and revascular ization are considered complementary treat ment options for patients with chronic, stable CAD. Revascularization by means of PCI or surgery is indicated when symptoms persist despite evidence-based medical therapy, and to improve prognosis2. In these patients, revas cularization results in better control of angina symptoms, greater reduction of ischaemia, and reduced need for repeat revasculariza tion compared with medical therapy alone2. Therefore, the observation that a substantial proportion of patients with nonischaemic FFR, who were initially assigned to medical treatment in the DEFER trial3 (and also in studies in which functional testing was not applied, such as the COURAGE trial10), sub sequently underwent revascularization calls into question whether, in some patients, the initial decision for medical therapy alone simply postpones, rather than obviates, an
Better outcome with PCI for FFR ≤0.80 4.3% vs 12.7% (PCI vs no PCI; P 0.80 No benefit of PCI for FFR ≥0.75 31.1% vs 33.0% (PCI vs no PCI; P = 0.79)
whereas in lesions with low FFR, revascularization results in| Cardiology Nature Reviews better outcomes compared with medical therapy alone. FFR, fractional flow reverse; MI, myocardial infarction; PCI, percutaneous coronary intervention.
interventional or surgical approach that can yield durable, long-standing benefits. Currently, our ability to identify which patients with stable CAD will have a favourable longterm prognosis when receiving medical ther apy alone, compared with those who will eventually require revascularization, seems to be suboptimal, and defining a nonischaemic FFR at index hardly precludes the need for subsequent intervention of the given lesion along the course of disease progression. The ISCHEMIA trial (NCT01471522) is designed to address whether an initial invasive strategy of optimal revascularization in patients with chronic, stable CAD provides benefit over evidence-based medical therapy alone, with presence of at least moderate ischaemia being the criterion for referral to catheterization. Summarizing the insights from the DEFER trial3 and other relevant studies6,7, current evidence demonstrates the benefit of revascularization in low‑FFR lesions compared with no benefit in high‑FFR lesions in patients with stable CAD. A strategy of prophylactic ‘shielding’ of certain functionally nonsignifi cant lesions, for example based on indices of presumed high-risk morphology, entails the oretical advantages, but evidence for such an approach is currently lacking. Because FFR can address, at a given time-point, only a sin gle aspect of coronary atherosclerosis, efforts should continue to focus on evaluating all relevant information, including anatomical measures (angiographic complexity, global plaque burden, morphological assessment of individual lesions), functional measures (inva sive haemodynamic assessment), and clinical characteristics, with the goal of optimizing individualized risk stratification and defining the most beneficial treatment strategy for each of our patients.
NATURE REVIEWS | CARDIOLOGY
Konstantinos C. Koskinas and Stephan Windecker are at the Department of Cardiology, Bern University Hospital, Freiburgstrasse 4 Bern, CH 3010, Switzerland Correspondence to S.W. [email protected] doi:10.1038/nrcardio.2015.173 Published online 19 Nov 2015 Topol, E. J. & Nissen, S. E. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 92, 2333–2342 (1995). 2. Windecker, S. et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 35, 2541–2619 (2014). 3. Zimmermann, F. M. et al. Deferral versus performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15‑year follow‑up of the DEFER trial. Eur. Heart J. http:/ / dx.doi.org/ 10.1093/eurheartj/ehv452. 4. Pijls, N. H. et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5‑year follow‑up of the DEFER Study. J. Am. Coll. Cardiol. 49, 2105–2111 (2007). 5. Windecker, S. et al. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 348, g3859 (2014). 6. Tonino, P. A. et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N. Engl. J. Med. 360, 213–224 (2009). 7. De Bruyne, B. et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N. Engl. J. Med. 367, 991–1001 (2012). 8. Gould, K. L. et al. Anatomic versus physiologic assessment of coronary artery disease: role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making. J. Am. Coll. Cardiol. 62, 1639–1653 (2013). 9. Stone, G. W. et al. A prospective natural-history study of coronary atherosclerosis. N. Engl. J. Med. 364, 226–235 (2011). 10. Boden, W. E. et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503–1516 (2007). 1.
Competing interests statement
S.W. declares that he has received institutional research grants from Abbott, Biotronik, Boston Scientific, Edwards, Medtronic, and St. Jude Medical, and that he has received speaker fees from Abbott, Astra Zeneca, Bayer, Biosensors, Biotronik, Boston Scientific, Edwards, and Medtronic. K.C.K. declares no competing interests.
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
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