Accepted Manuscript Art and Science David R. Holmes Jr., M.D. PII:
S0735-1097(14)06154-3
DOI:
10.1016/j.jacc.2014.09.007
Reference:
JAC 20587
To appear in:
Journal of the American College of Cardiology
Received Date: 7 September 2014 Accepted Date: 8 September 2014
Please cite this article as: Holmes Jr. DR, Art and Science, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.09.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Art and Science David R. Holmes, Jr., M.D.
RI PT
Brief Title: Art and Science Nothing to disclose
AC C
EP
TE D
M AN U
SC
Address for correspondence: David R. Holmes, Jr., MD Mayo Clinic 200 First Street SW Rochester, MN 55905 507-255-5846 ph 507-255-2550 fax [email protected]
1
ACCEPTED MANUSCRIPT
Randomized clinical trials have formed the basis of the foundations of professional societal guidelines which are felt to be based on the highest level of science. It must be remembered however that the practice of medicine is based not only on science but remains an
RI PT
art requiring the integration of data into a wisdom matrix and then focusing and
individualizing it for the specific patient . In this latter regard, scientific study while crucial has some well-known limitations. Such limitations are highlighted in considerations related to
SC
randomized clinical trials (RCTs) including among others the fact that these trials typically enroll a small very carefully selected percentage of the total group of patients with the disease/therapy
M AN U
being studied, constrained highly focused endpoints, and rigid protocols. In addition, over the course of the study, the background treatment strategies may change; an important issue that can affect the power of the study to reach unequivocal conclusions. Finally, the incidence of the target endpoint may be so low that a composite endpoint is used, and then the most important
TE D
single endpoint may remain unresolved. Such issues make it difficult to translate the “science” into the art of taking care of a specific patient who may not fit exactly into the framework of the RCT.
EP
The conundrum which results from the above situation is exemplified in the SECURITY Trial (1), which aimed at studying the impact of a strategy of 6 months of DAPT versus 12
AC C
months in patients being treated with one of several second generation drug-eluting coronary stents. That question is of great clinical interest; being initially focused on the occurrence of stent thrombosis, a highly morbid and even mortal event (2). Early in the field, a variety of definitions for stent thrombosis were used confounding efforts at scientific study. The development of specific and widely accepted definitions has greatly improved the situation (3,4). This specific problem has been the subject of multiple single and multi-registry experiences as
2
ACCEPTED MANUSCRIPT
well as smaller RCT’s which have resulted in guidelines and practice patterns which vary around the world (5-13). The etiology has been accorded great attention. Crucial initial small observations focused on the central role of platelets as the most important putative mechanism,
RI PT
and accordingly a variety of antiplatelet strategies were put into place. The dominant one
involved dual antiplatelet agent therapy (DAPT). Such a strategy carries with it multiple issues including (i) bleeding, the risk which increases the longer a patient is on these agents, (ii) the
SC
cost and side effects of it and (iii) the clinical need of considering drug discontinuation should subsequent surgery be required. Each of these has great patient care implications. Given the
M AN U
timing of stent thrombosis which could range from being early to very late occurring up to several years following implantation, the duration of DAPT is the focus of substantial interest. Early on, without a substantial scientific basis and usually based on expert consensus, multiple different regiments were recommended. For example, the ACC/AHA guidelines currently
TE D
recommend 12 months of DAPT in patients treated with DES “if the patient is not at high risk of bleeding” (5), in contrast to the ESC guidelines which state that “routine extension of DAPT beyond 6 months after new-generation DES implantation in stable coronary artery disease cannot
EP
be recommended and ….observational data suggest that even shorter durations of DAPT may be sufficient.” (6). Even longer duration of DAPT is currently being tested in the largest RCT which
AC C
will be presented in the fall of 2014 (12). Both of the professional guidelines were initially based on first generation DES (which may have a different profile and higher frequency of stent thrombosis), and both were often based on expert consensus in addition to smaller RCTs often underpowered to provide definitive conclusions. Ideally, a study such as SECURITY might be able to answer the questions of duration of DAPT. It included 1,399 patients in a prospective randomized non-inferiority multicenter international trial, who were treated with one of several
3
ACCEPTED MANUSCRIPT
second-generation DES types. The patient groups were well matched: 31% had diabetes, 20.7% had a prior MI, 43.8% had more than single vessel disease and 38.4% had unstable angina. Conventional treatment with Clopidogrel 75/day for at least 3 days prior to the procedure or a
RI PT
loading dose of at least 300 mg in patients not on chronic clopidogrel was used. Although after their approval, newer antiplatelet agents were allowed by protocol amendment, greater than 95% of the patients were treated with clopidogrel. Post procedure, ASA was prescribed indefinitely.
SC
Randomization focused on either administering 75 mg of clopidogrel for 6 or for 12 months. At the 12 month primary endpoint follow, DAPT was still being used clinically in 33.8% of the 6
M AN U
month group (thus muddying the water); it had been continued in 96.1% of the 12 month group. The primary endpoint was the composite of cardiac death, MI, stroke, BARC type 3 or 5 bleeding and very importantly definite or probable stent thrombosis at 12 months. A noninferiority design was used with an absolute margin of 2.0% in the difference of the event
TE D
proportions. Using this margin, a power of 0.80 and a one-tail significance level of 0.05, an estimated 1,370 patients were needed per group. The trial was terminated early because of “enrollment futility because of minimal differences in the rate of the primary endpoint between
EP
the 2 groups…” since complication rates were indeed very low in both treatment arms (1) There were no significant differences in the primary composite endpoint, or in any of individual
AC C
components of that composite. Particularly there were no significant differences in either definite or probable stent thrombosis at either 12 or 24 months which occurred very infrequently at 0.3 and .04%. It is important to note that despite the longer duration of DAPT, type 3 or 5 BARC bleeding was not significantly increased in the 12 month therapy group although the numbers and rates of events were very small ( 4 [0.6 %] vs 8 [1.1%] p=0.283).
4
ACCEPTED MANUSCRIPT
The authors provide an excellent discussion of the literature with the different trials and trial designs which illustrates the complexity in the field with some studies focusing on target vessel failure, others on varying composites, as well as substantial variability in the duration of
RI PT
DAPT. In terms of the latter issue, some prior studies evaluated 3 versus 12 months, others on 6 versus 24 months. Other confounding variables in the literature have included the demographics of the patients studied (either acute coronary syndromes of more stable patients), and the
SC
boundaries of non-inferiority for statistical assessment. Colombo et al. conclude with the
limitations of their trial, which have much in common with the previous literature. These include
M AN U
the fact that their trial is underpowered, that the results cannot be generalized to higher risk patients and lesions, the fact that approximately one-third of the patients in the 6-month group continued with DAPT and the primary endpoint was lower than expected, the fact that several different second generation DES were used and finally the wide margin of non-inferiority used
TE D
for analysis. They did find that using multivariable adjustment DAPT duration was not an independent predictor of the primary endpoint but that factors related to the stenting procedure itself such as mean stent length, size and the number of stents were strong independent predictors
EP
of the primary endpoint as were some baseline characteristics such as age. Regarding specific stent type, no conclusions could be made because of the small sample sizes involved. Such
AC C
limitations have very real clinical implications for day to day practice. The scientific underpinnings of the crucial debate on the duration of DAPT required to optimize safety and efficacy of current more advanced generation DES remain somewhat wobbly; different societal guideline documents reviewing the same date have come to somewhat different conclusions. In this case, art and some attempt at wisdom needs to be used to help decide on what to recommend for Mr. or Mrs. Smith who you have just treated with one of
5
ACCEPTED MANUSCRIPT
several second generation DES. That process needs to include information about exactly who Mr. or Mrs. Smith are, what their lesions were like, details of the specific stent approach such as number of stents, stent size, and adequacy of the result, how did the procedure go, their risk for
RI PT
bleeding, the potential need for subsequent surgical procedures, their tolerance of unknowns, and mitigating often other but unmeasurable data. It is in the consideration of these issues, that art comes to play a prominent role. In the setting of patients similar to those entered into the
SC
SECURITY Trial, in the absence of rigorous data to the contrary, shorter duration of DAPT seems to be a very reasonable approach for consideration and is increasingly used in the art of
AC C
EP
TE D
M AN U
taking care of these patients.
6
ACCEPTED MANUSCRIPT
REFERENCES 1. Colombo A, Chieffo A, Frasheri A et al: Second generation drug-eluting stents
Randomized Clinical Trial. J Am Coll Cardiol. 2014 (in press)
RI PT
implantation followed by 6 vs 12 month dual antiplatelet therapy – the SECURITY
2. Holmes DR, Jr., Kereiakes DJ, Garg S et al. Stent thrombosis. J Am Coll Cardiol. 2010;56:1357-65.
SC
3. Cutlip DE, Windecker S, Mehran R et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.
M AN U
4. Mehran R, Rao SV, Bhatt DL et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47.
5. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for
TE D
Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol.
EP
2011;58:e44-122.
6. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on Myocardial
AC C
Revascularization. Euro Heart J: doi:10.1093/384heartj/ehu278, Aug. 29, 2014 7. Kim BK, Hong MK, Shin DH et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60:1340-8.
7
ACCEPTED MANUSCRIPT
8. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter
RI PT
study. Circulation. 2012;125:505-13.
9. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA.
SC
2013;310:2510-22.
10. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after
M AN U
drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014;129:30412.
11. Valgimigli M, Borghesi M, Tebaldi M, et al. Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the
TE D
PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY). Eur Heart J. 2013;34:909-19. 12. Mauri L, Kereiakes DJ, Normand SL, et al. Rationale and design of the dual antiplatelet
EP
therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects
AC C
undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am Heart J. 2010;160:1035-41, 1041 e1. 13. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dualantiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125:2015-26.
8
S0735-1097(14)06154-3
DOI:
10.1016/j.jacc.2014.09.007
Reference:
JAC 20587
To appear in:
Journal of the American College of Cardiology
Received Date: 7 September 2014 Accepted Date: 8 September 2014
Please cite this article as: Holmes Jr. DR, Art and Science, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.09.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Art and Science David R. Holmes, Jr., M.D.
RI PT
Brief Title: Art and Science Nothing to disclose
AC C
EP
TE D
M AN U
SC
Address for correspondence: David R. Holmes, Jr., MD Mayo Clinic 200 First Street SW Rochester, MN 55905 507-255-5846 ph 507-255-2550 fax [email protected]
1
ACCEPTED MANUSCRIPT
Randomized clinical trials have formed the basis of the foundations of professional societal guidelines which are felt to be based on the highest level of science. It must be remembered however that the practice of medicine is based not only on science but remains an
RI PT
art requiring the integration of data into a wisdom matrix and then focusing and
individualizing it for the specific patient . In this latter regard, scientific study while crucial has some well-known limitations. Such limitations are highlighted in considerations related to
SC
randomized clinical trials (RCTs) including among others the fact that these trials typically enroll a small very carefully selected percentage of the total group of patients with the disease/therapy
M AN U
being studied, constrained highly focused endpoints, and rigid protocols. In addition, over the course of the study, the background treatment strategies may change; an important issue that can affect the power of the study to reach unequivocal conclusions. Finally, the incidence of the target endpoint may be so low that a composite endpoint is used, and then the most important
TE D
single endpoint may remain unresolved. Such issues make it difficult to translate the “science” into the art of taking care of a specific patient who may not fit exactly into the framework of the RCT.
EP
The conundrum which results from the above situation is exemplified in the SECURITY Trial (1), which aimed at studying the impact of a strategy of 6 months of DAPT versus 12
AC C
months in patients being treated with one of several second generation drug-eluting coronary stents. That question is of great clinical interest; being initially focused on the occurrence of stent thrombosis, a highly morbid and even mortal event (2). Early in the field, a variety of definitions for stent thrombosis were used confounding efforts at scientific study. The development of specific and widely accepted definitions has greatly improved the situation (3,4). This specific problem has been the subject of multiple single and multi-registry experiences as
2
ACCEPTED MANUSCRIPT
well as smaller RCT’s which have resulted in guidelines and practice patterns which vary around the world (5-13). The etiology has been accorded great attention. Crucial initial small observations focused on the central role of platelets as the most important putative mechanism,
RI PT
and accordingly a variety of antiplatelet strategies were put into place. The dominant one
involved dual antiplatelet agent therapy (DAPT). Such a strategy carries with it multiple issues including (i) bleeding, the risk which increases the longer a patient is on these agents, (ii) the
SC
cost and side effects of it and (iii) the clinical need of considering drug discontinuation should subsequent surgery be required. Each of these has great patient care implications. Given the
M AN U
timing of stent thrombosis which could range from being early to very late occurring up to several years following implantation, the duration of DAPT is the focus of substantial interest. Early on, without a substantial scientific basis and usually based on expert consensus, multiple different regiments were recommended. For example, the ACC/AHA guidelines currently
TE D
recommend 12 months of DAPT in patients treated with DES “if the patient is not at high risk of bleeding” (5), in contrast to the ESC guidelines which state that “routine extension of DAPT beyond 6 months after new-generation DES implantation in stable coronary artery disease cannot
EP
be recommended and ….observational data suggest that even shorter durations of DAPT may be sufficient.” (6). Even longer duration of DAPT is currently being tested in the largest RCT which
AC C
will be presented in the fall of 2014 (12). Both of the professional guidelines were initially based on first generation DES (which may have a different profile and higher frequency of stent thrombosis), and both were often based on expert consensus in addition to smaller RCTs often underpowered to provide definitive conclusions. Ideally, a study such as SECURITY might be able to answer the questions of duration of DAPT. It included 1,399 patients in a prospective randomized non-inferiority multicenter international trial, who were treated with one of several
3
ACCEPTED MANUSCRIPT
second-generation DES types. The patient groups were well matched: 31% had diabetes, 20.7% had a prior MI, 43.8% had more than single vessel disease and 38.4% had unstable angina. Conventional treatment with Clopidogrel 75/day for at least 3 days prior to the procedure or a
RI PT
loading dose of at least 300 mg in patients not on chronic clopidogrel was used. Although after their approval, newer antiplatelet agents were allowed by protocol amendment, greater than 95% of the patients were treated with clopidogrel. Post procedure, ASA was prescribed indefinitely.
SC
Randomization focused on either administering 75 mg of clopidogrel for 6 or for 12 months. At the 12 month primary endpoint follow, DAPT was still being used clinically in 33.8% of the 6
M AN U
month group (thus muddying the water); it had been continued in 96.1% of the 12 month group. The primary endpoint was the composite of cardiac death, MI, stroke, BARC type 3 or 5 bleeding and very importantly definite or probable stent thrombosis at 12 months. A noninferiority design was used with an absolute margin of 2.0% in the difference of the event
TE D
proportions. Using this margin, a power of 0.80 and a one-tail significance level of 0.05, an estimated 1,370 patients were needed per group. The trial was terminated early because of “enrollment futility because of minimal differences in the rate of the primary endpoint between
EP
the 2 groups…” since complication rates were indeed very low in both treatment arms (1) There were no significant differences in the primary composite endpoint, or in any of individual
AC C
components of that composite. Particularly there were no significant differences in either definite or probable stent thrombosis at either 12 or 24 months which occurred very infrequently at 0.3 and .04%. It is important to note that despite the longer duration of DAPT, type 3 or 5 BARC bleeding was not significantly increased in the 12 month therapy group although the numbers and rates of events were very small ( 4 [0.6 %] vs 8 [1.1%] p=0.283).
4
ACCEPTED MANUSCRIPT
The authors provide an excellent discussion of the literature with the different trials and trial designs which illustrates the complexity in the field with some studies focusing on target vessel failure, others on varying composites, as well as substantial variability in the duration of
RI PT
DAPT. In terms of the latter issue, some prior studies evaluated 3 versus 12 months, others on 6 versus 24 months. Other confounding variables in the literature have included the demographics of the patients studied (either acute coronary syndromes of more stable patients), and the
SC
boundaries of non-inferiority for statistical assessment. Colombo et al. conclude with the
limitations of their trial, which have much in common with the previous literature. These include
M AN U
the fact that their trial is underpowered, that the results cannot be generalized to higher risk patients and lesions, the fact that approximately one-third of the patients in the 6-month group continued with DAPT and the primary endpoint was lower than expected, the fact that several different second generation DES were used and finally the wide margin of non-inferiority used
TE D
for analysis. They did find that using multivariable adjustment DAPT duration was not an independent predictor of the primary endpoint but that factors related to the stenting procedure itself such as mean stent length, size and the number of stents were strong independent predictors
EP
of the primary endpoint as were some baseline characteristics such as age. Regarding specific stent type, no conclusions could be made because of the small sample sizes involved. Such
AC C
limitations have very real clinical implications for day to day practice. The scientific underpinnings of the crucial debate on the duration of DAPT required to optimize safety and efficacy of current more advanced generation DES remain somewhat wobbly; different societal guideline documents reviewing the same date have come to somewhat different conclusions. In this case, art and some attempt at wisdom needs to be used to help decide on what to recommend for Mr. or Mrs. Smith who you have just treated with one of
5
ACCEPTED MANUSCRIPT
several second generation DES. That process needs to include information about exactly who Mr. or Mrs. Smith are, what their lesions were like, details of the specific stent approach such as number of stents, stent size, and adequacy of the result, how did the procedure go, their risk for
RI PT
bleeding, the potential need for subsequent surgical procedures, their tolerance of unknowns, and mitigating often other but unmeasurable data. It is in the consideration of these issues, that art comes to play a prominent role. In the setting of patients similar to those entered into the
SC
SECURITY Trial, in the absence of rigorous data to the contrary, shorter duration of DAPT seems to be a very reasonable approach for consideration and is increasingly used in the art of
AC C
EP
TE D
M AN U
taking care of these patients.
6
ACCEPTED MANUSCRIPT
REFERENCES 1. Colombo A, Chieffo A, Frasheri A et al: Second generation drug-eluting stents
Randomized Clinical Trial. J Am Coll Cardiol. 2014 (in press)
RI PT
implantation followed by 6 vs 12 month dual antiplatelet therapy – the SECURITY
2. Holmes DR, Jr., Kereiakes DJ, Garg S et al. Stent thrombosis. J Am Coll Cardiol. 2010;56:1357-65.
SC
3. Cutlip DE, Windecker S, Mehran R et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.
M AN U
4. Mehran R, Rao SV, Bhatt DL et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47.
5. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for
TE D
Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol.
EP
2011;58:e44-122.
6. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on Myocardial
AC C
Revascularization. Euro Heart J: doi:10.1093/384heartj/ehu278, Aug. 29, 2014 7. Kim BK, Hong MK, Shin DH et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60:1340-8.
7
ACCEPTED MANUSCRIPT
8. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter
RI PT
study. Circulation. 2012;125:505-13.
9. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA.
SC
2013;310:2510-22.
10. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after
M AN U
drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014;129:30412.
11. Valgimigli M, Borghesi M, Tebaldi M, et al. Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the
TE D
PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY). Eur Heart J. 2013;34:909-19. 12. Mauri L, Kereiakes DJ, Normand SL, et al. Rationale and design of the dual antiplatelet
EP
therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects
AC C
undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am Heart J. 2010;160:1035-41, 1041 e1. 13. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dualantiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125:2015-26.
8
