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Early Post-Discharge Bleeding and Antiplatelet Therapy Discontinuation Among Acute Myocardial Infarction Patients Treated With Percutaneous Coronary Intervention
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Early Post-Discharge Bleeding and Antiplatelet Therapy Discontinuation Among Acute Myocardial Infarction Patients Treated With Percutaneous Coronary Intervention To the Editor: Antiplatelet therapy is a cornerstone of treatment for patients with acute myocardial infarction (MI)dparticularly those treated with percutaneous coronary intervention (PCI)d yet bleeding is a major side effect of its use and can lead to therapy discontinuation (1). Premature antiplatelet therapy discontinuation has been associated with increased risks of stent thrombosis, MI, and death (2). The TRANSLATE-ACS study (Treatment with ADP receptor inhibitors-longitudinal assessment of treatment patterns and events after acute coronary syndrome) is an observational study of
Figure 1
JACC Vol. 63, No. 16, 2014 April 29, 2014:1698–702
Correspondence
ST-segment elevation and non–ST-segment elevation MI patients treated with PCI in the United States (3). The TRANSLATEACS study offers insight to the incidence of and response to early post-discharge bleeding in a contemporary MI population treated with clopidogrel or more potent adenosine diphosphate receptor inhibitors (ADPri) in routine practice. This analysis included 9,177 MI patients who were discharged alive on ADPri therapy from 219 United States hospitals from April 2010 to October 2012. At the 6-week follow-up interview, patients were asked to report any bleeding/severe bruising since discharge and any change in ADPri therapy. All bleeding-related repeat hospital stays and major adverse cardiovascular events (MACE)ddefined as death, recurrent MI, stroke, or unplanned coronary revascularizationdwere independently validated via medical record review (3). Bleeding events were classified according to the Bleeding Academic Research Consortium (BARC) criteria. We performed multivariable logistic regression modeling to determine the association of discharge second-generation ADPri (prasugrel or ticagrelor) use with bleeding, adjusting for covariates from the CRUSADE bleeding risk model. We examined the association of bleeding with 6-week risk of MACE with logistic regression models adjusting for the ACTION mortality risk score. Among 9,177 MI patients discharged on a regimen of ADPri therapy, 1,264 (14%) reported early bleeding/severe bruising, and 91 patients (7% of patients who reported bleeding) were rehospitalized with bleeding. Fatal bleeding occurred in 1 patient. There was no coronary artery bypass grafting–related bleeding within the first 6 weeks post-discharge; 3% were BARC type 3, and 54% were BARC type 2.
Post-Discharge Bleeding Among Patient Subgroups
Rate of post-discharge bleeding events among patient subgroups. AC ¼ anticoagulant; ADP ¼ adenosine diphosphate; CrCl ¼ creatinine clearance; EQ-5D ¼ EuroQol 5-Dimension score; PHQ-2 ¼ patient health questionnaire-2 (depression); 2nd gen ¼ second-generation.
JACC Vol. 63, No. 16, 2014 April 29, 2014:1698–702
Higher rates of post-discharge bleeding were observed among patients who were female or white and those with lower functional status or baseline depression (Fig. 1). The occurrence of major bleeding during the index hospital stay did not predict a higher rate of post-discharge bleeding. Patients discharged on a regimen of a second-generation ADPri were more likely to have early post-discharge bleeding than patients without bleeding. After multivariable adjustment, discharge on a second-generation ADPri regimen remained significantly associated with higher bleeding risk (odds ratio: 1.63, 95% confidence interval: 1.41 to 1.87). At 6 weeks post-MI, ADPri therapy was stopped or interrupted in 7% of bleeding patients. Patients who reported bleeding were more likely to permanently discontinue their ADPri than patients without bleeding (4.5% vs. 2.7%, p ¼ 0.004), although overall discontinuation rates were low. Notably, 28% of the patients who discontinued their ADPri had recently received a drug-eluting stent (DES). Early discontinuation was more common among bleeding patients on a regimen of first-generation than secondgeneration ADPris (5.8% vs. 2.4%, p ¼ 0.009). Patients with bleeding were also more likely to temporarily stop the ADPri than patients without bleeding (2.6% vs. 1.6%, p ¼ 0.007), although rates of temporary antiplatelet interruption were low. Rates of postdischarge switch from a second-generation ADPri to clopidogrel were not significantly different between patients with and without bleeding (6.6% vs. 5.7%, p ¼ 0.44). Notably, 43% of post-discharge bleeding events were never brought to clinical attention (BARC type 1), and 28% of ADPri therapy changes in response to bleeding were made without cardiologist involvement. Patients who did not report bleeding to a clinician were less likely to have had a follow-up outpatient appointment made for them before discharge than patients who did bring bleeding to clinical attention (66.3% vs. 70.2%, p ¼ 0.02). Rates of MACE were 4.2%, 3.8%, 4.5%, and 13.2% among patients with no bleeding, BARC type 1 bleeding, BARC type 2 bleeding, and BARC type 3 or higher bleeding, respectively. The BARC type 3 or higher bleeding was associated with a higher adjusted risk of MACE (odds ratio: 3.28, 95% confidence interval: 1.27 to 8.47) compared with no bleeding. The introduction of second-generation ADPri has raised the concern that their greater potency would increase bleeding risk. In our study, 1 in 7 post-MI patients on a regimen of contemporary ADPri therapy experienced bleeding/severe bruising early after discharge, yet repeat hospital stay for bleeding was rare. Only BARC type 3þ bleeding was significantly associated with higher risk of MACE. Treatment with a second-generation ADPri was a significant factor associated with early bleeding; however, rates of BARC type 3þ bleeding were low (<0.2%) among patients on a second-generation ADPri regimen. We observed low rates of early ADPri discontinuation in the first 6 weeks post-discharge, yet more than one-quarter of ADPri discontinuations occurred in the setting of recent DES implantation. Only one-half of bleeding events were brought to clinical attention, and a substantial proportion of patient decisions to prematurely discontinue ADPri therapy were made without cardiologist input. Patients commonly cite poor communication and lack of knowledge about the duration and purpose of treatment as the primary reasons for antiplatelet therapy discontinuation (4). In our study, patients who did not have a follow-up outpatient appointment arranged before discharge were less likely to report their bleeding
Correspondence
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event to a clinician. Therefore, ensuring early clinical followupdparticularly for patients at higher risk of bleeding (e.g., women, lower baseline functional status, discharge on a second-generation ADPri regimen, or concurrent oral anticoagulant prescription)d might be a key first step in both raising subsequent bleeding events to clinical attention and avoiding premature ADPri discontinuation. Although the risk of bleeding was higher among patients discharged on a regimen of second-generation ADPris, the rate of early treatment discontinuation did not differ significantly between first- and second-generation agents. In conclusion, bleeding occurs commonly in the early period after discharge among MI patients treated with PCI and ADPris and is not always brought to clinical attention. Although premature ADPri discontinuation was infrequent, a substantial proportion of these discontinuations occurred in the setting of recent DES implantation and without cardiologist input, indicating the need for continued patient education and close post-acute MI monitoring. Bleeding risk was higher among patients prescribed secondgeneration ADPris; however, use of these agents was not associated with higher rates of early antiplatelet therapy cessation.
*Tracy Y. Wang, MD, MHS, MScy Lisa McCoy, MSy Timothy D. Henry, MDz Mark B. Effron, MDx John C. Messenger, MDjj David J. Cohen, MD, MSc{ Daniel B. Mark, MD, MPHy Gregg W. Stone, MD# Marjorie Zettler, PhD, MPHx Mandeep Singh, MD** Gregg C. Fonarow, MDyy Eric D. Peterson, MD, MPHy for the TRANSLATE-ACS Study Investigators *Duke Clinical Research Institute Duke University Medical Center 2400 Pratt Street Durham, North Carolina 27705 E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2013.12.012
From the yDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; zMinneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, Minnesota; xLilly USA, LLC, Indianapolis, Indiana; jjUniversity of Colorado School of Medicine, Aurora, Colorado; {Saint Luke’s Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri; #Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, New York; **Mayo Clinic, Rochester, Minnesota; and the yyAhmanson-UCLA Cardiomyopathy Center, Los Angeles, California Please note: The TRANSLATE-ACS study (NCT01088503) is sponsored by Daiichi Sankyo and Lilly USA. The Duke Clinical Research Institute is the coordinating center for this study, which represents a collaborative effort with the American College of Cardiology. The authors thank Erin Hanley, MS, for her editorial contributions to this paper. Ms. Hanley did not receive compensation for her assistance, apart from her employment at the institution where this study was conducted. Dr. Wang has received research grant support (to institution) from Eli Lilly, Daiichi Sankyo, Gilead Sciences, GlaxoSmithKline, American College of
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JACC Vol. 63, No. 16, 2014 April 29, 2014:1698–702
Correspondence
Cardiology, and American Society of Nuclear Cardiology (all significant); and educational activities or lectures for AstraZeneca and the American College of Cardiology (both modest). Dr. Effron is an employee of Eli Lilly; and a shareholder of Lilly, USA. Dr. Cohen has received consulting services for Eli Lilly, Daiichi Sankyo, and AstraZeneca; and research grant support (to institution) for Eli Lilly and AstraZeneca. Dr. Mark has received research funding from Eli Lilly and Medtronic (significant). Dr. Stone is a consultant to Boston Scientific, Eli Lilly, Daiichi Sankyo, and AstraZeneca (all modest). Dr. Zettler is an employee of Eli Lilly. Dr. Fonarow is a consultant to Novartis (significant) and Janssen (modest). Dr. Peterson has received research funding for the American College of Cardiology, American Heart Association, Eli Lilly, Janssen, and Society of Thoracic Surgeons (all significant); and consulting (including continuing medical education) for Merck (modest), Boehringer Ingelheim, Genentech, Janssen, and Sanofi-Aventis (all significant). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
1. Wang TY, Xiao L, Alexander KP, et al. Antiplatelet therapy use after discharge among acute MI patients with in-hospital bleeding. Circulation 2008;118:2139–45. 2. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after DES placement: results from the PREMIER registry. Circulation 2006;113:2803–9. 3. Chin CT, Wang TY, Anstrom KJ, et al. Treatment with ADP receptor inhibitors-longitudinal assessment of treatment patterns and events after acute coronary syndrome (TRANSLATE-ACS) study design: expanding the paradigm of longitudinal observational research. Am Heart J 2011;162:844–51. 4. Garavalia L, Ho PM, Garavalia B, et al. Clinician-patient discord: exploring differences in perspectives for discontinuing clopidogrel. Eur J Cardiovasc Nurs 2011;10:50–5.
Early Post-Discharge Bleeding and Antiplatelet Therapy Discontinuation Among Acute Myocardial Infarction Patients Treated With Percutaneous Coronary Intervention To the Editor: Antiplatelet therapy is a cornerstone of treatment for patients with acute myocardial infarction (MI)dparticularly those treated with percutaneous coronary intervention (PCI)d yet bleeding is a major side effect of its use and can lead to therapy discontinuation (1). Premature antiplatelet therapy discontinuation has been associated with increased risks of stent thrombosis, MI, and death (2). The TRANSLATE-ACS study (Treatment with ADP receptor inhibitors-longitudinal assessment of treatment patterns and events after acute coronary syndrome) is an observational study of
Figure 1
JACC Vol. 63, No. 16, 2014 April 29, 2014:1698–702
Correspondence
ST-segment elevation and non–ST-segment elevation MI patients treated with PCI in the United States (3). The TRANSLATEACS study offers insight to the incidence of and response to early post-discharge bleeding in a contemporary MI population treated with clopidogrel or more potent adenosine diphosphate receptor inhibitors (ADPri) in routine practice. This analysis included 9,177 MI patients who were discharged alive on ADPri therapy from 219 United States hospitals from April 2010 to October 2012. At the 6-week follow-up interview, patients were asked to report any bleeding/severe bruising since discharge and any change in ADPri therapy. All bleeding-related repeat hospital stays and major adverse cardiovascular events (MACE)ddefined as death, recurrent MI, stroke, or unplanned coronary revascularizationdwere independently validated via medical record review (3). Bleeding events were classified according to the Bleeding Academic Research Consortium (BARC) criteria. We performed multivariable logistic regression modeling to determine the association of discharge second-generation ADPri (prasugrel or ticagrelor) use with bleeding, adjusting for covariates from the CRUSADE bleeding risk model. We examined the association of bleeding with 6-week risk of MACE with logistic regression models adjusting for the ACTION mortality risk score. Among 9,177 MI patients discharged on a regimen of ADPri therapy, 1,264 (14%) reported early bleeding/severe bruising, and 91 patients (7% of patients who reported bleeding) were rehospitalized with bleeding. Fatal bleeding occurred in 1 patient. There was no coronary artery bypass grafting–related bleeding within the first 6 weeks post-discharge; 3% were BARC type 3, and 54% were BARC type 2.
Post-Discharge Bleeding Among Patient Subgroups
Rate of post-discharge bleeding events among patient subgroups. AC ¼ anticoagulant; ADP ¼ adenosine diphosphate; CrCl ¼ creatinine clearance; EQ-5D ¼ EuroQol 5-Dimension score; PHQ-2 ¼ patient health questionnaire-2 (depression); 2nd gen ¼ second-generation.
JACC Vol. 63, No. 16, 2014 April 29, 2014:1698–702
Higher rates of post-discharge bleeding were observed among patients who were female or white and those with lower functional status or baseline depression (Fig. 1). The occurrence of major bleeding during the index hospital stay did not predict a higher rate of post-discharge bleeding. Patients discharged on a regimen of a second-generation ADPri were more likely to have early post-discharge bleeding than patients without bleeding. After multivariable adjustment, discharge on a second-generation ADPri regimen remained significantly associated with higher bleeding risk (odds ratio: 1.63, 95% confidence interval: 1.41 to 1.87). At 6 weeks post-MI, ADPri therapy was stopped or interrupted in 7% of bleeding patients. Patients who reported bleeding were more likely to permanently discontinue their ADPri than patients without bleeding (4.5% vs. 2.7%, p ¼ 0.004), although overall discontinuation rates were low. Notably, 28% of the patients who discontinued their ADPri had recently received a drug-eluting stent (DES). Early discontinuation was more common among bleeding patients on a regimen of first-generation than secondgeneration ADPris (5.8% vs. 2.4%, p ¼ 0.009). Patients with bleeding were also more likely to temporarily stop the ADPri than patients without bleeding (2.6% vs. 1.6%, p ¼ 0.007), although rates of temporary antiplatelet interruption were low. Rates of postdischarge switch from a second-generation ADPri to clopidogrel were not significantly different between patients with and without bleeding (6.6% vs. 5.7%, p ¼ 0.44). Notably, 43% of post-discharge bleeding events were never brought to clinical attention (BARC type 1), and 28% of ADPri therapy changes in response to bleeding were made without cardiologist involvement. Patients who did not report bleeding to a clinician were less likely to have had a follow-up outpatient appointment made for them before discharge than patients who did bring bleeding to clinical attention (66.3% vs. 70.2%, p ¼ 0.02). Rates of MACE were 4.2%, 3.8%, 4.5%, and 13.2% among patients with no bleeding, BARC type 1 bleeding, BARC type 2 bleeding, and BARC type 3 or higher bleeding, respectively. The BARC type 3 or higher bleeding was associated with a higher adjusted risk of MACE (odds ratio: 3.28, 95% confidence interval: 1.27 to 8.47) compared with no bleeding. The introduction of second-generation ADPri has raised the concern that their greater potency would increase bleeding risk. In our study, 1 in 7 post-MI patients on a regimen of contemporary ADPri therapy experienced bleeding/severe bruising early after discharge, yet repeat hospital stay for bleeding was rare. Only BARC type 3þ bleeding was significantly associated with higher risk of MACE. Treatment with a second-generation ADPri was a significant factor associated with early bleeding; however, rates of BARC type 3þ bleeding were low (<0.2%) among patients on a second-generation ADPri regimen. We observed low rates of early ADPri discontinuation in the first 6 weeks post-discharge, yet more than one-quarter of ADPri discontinuations occurred in the setting of recent DES implantation. Only one-half of bleeding events were brought to clinical attention, and a substantial proportion of patient decisions to prematurely discontinue ADPri therapy were made without cardiologist input. Patients commonly cite poor communication and lack of knowledge about the duration and purpose of treatment as the primary reasons for antiplatelet therapy discontinuation (4). In our study, patients who did not have a follow-up outpatient appointment arranged before discharge were less likely to report their bleeding
Correspondence
1701
event to a clinician. Therefore, ensuring early clinical followupdparticularly for patients at higher risk of bleeding (e.g., women, lower baseline functional status, discharge on a second-generation ADPri regimen, or concurrent oral anticoagulant prescription)d might be a key first step in both raising subsequent bleeding events to clinical attention and avoiding premature ADPri discontinuation. Although the risk of bleeding was higher among patients discharged on a regimen of second-generation ADPris, the rate of early treatment discontinuation did not differ significantly between first- and second-generation agents. In conclusion, bleeding occurs commonly in the early period after discharge among MI patients treated with PCI and ADPris and is not always brought to clinical attention. Although premature ADPri discontinuation was infrequent, a substantial proportion of these discontinuations occurred in the setting of recent DES implantation and without cardiologist input, indicating the need for continued patient education and close post-acute MI monitoring. Bleeding risk was higher among patients prescribed secondgeneration ADPris; however, use of these agents was not associated with higher rates of early antiplatelet therapy cessation.
*Tracy Y. Wang, MD, MHS, MScy Lisa McCoy, MSy Timothy D. Henry, MDz Mark B. Effron, MDx John C. Messenger, MDjj David J. Cohen, MD, MSc{ Daniel B. Mark, MD, MPHy Gregg W. Stone, MD# Marjorie Zettler, PhD, MPHx Mandeep Singh, MD** Gregg C. Fonarow, MDyy Eric D. Peterson, MD, MPHy for the TRANSLATE-ACS Study Investigators *Duke Clinical Research Institute Duke University Medical Center 2400 Pratt Street Durham, North Carolina 27705 E-mail: [email protected] http://dx.doi.org/10.1016/j.jacc.2013.12.012
From the yDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; zMinneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, Minnesota; xLilly USA, LLC, Indianapolis, Indiana; jjUniversity of Colorado School of Medicine, Aurora, Colorado; {Saint Luke’s Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri; #Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, New York; **Mayo Clinic, Rochester, Minnesota; and the yyAhmanson-UCLA Cardiomyopathy Center, Los Angeles, California Please note: The TRANSLATE-ACS study (NCT01088503) is sponsored by Daiichi Sankyo and Lilly USA. The Duke Clinical Research Institute is the coordinating center for this study, which represents a collaborative effort with the American College of Cardiology. The authors thank Erin Hanley, MS, for her editorial contributions to this paper. Ms. Hanley did not receive compensation for her assistance, apart from her employment at the institution where this study was conducted. Dr. Wang has received research grant support (to institution) from Eli Lilly, Daiichi Sankyo, Gilead Sciences, GlaxoSmithKline, American College of
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JACC Vol. 63, No. 16, 2014 April 29, 2014:1698–702
Correspondence
Cardiology, and American Society of Nuclear Cardiology (all significant); and educational activities or lectures for AstraZeneca and the American College of Cardiology (both modest). Dr. Effron is an employee of Eli Lilly; and a shareholder of Lilly, USA. Dr. Cohen has received consulting services for Eli Lilly, Daiichi Sankyo, and AstraZeneca; and research grant support (to institution) for Eli Lilly and AstraZeneca. Dr. Mark has received research funding from Eli Lilly and Medtronic (significant). Dr. Stone is a consultant to Boston Scientific, Eli Lilly, Daiichi Sankyo, and AstraZeneca (all modest). Dr. Zettler is an employee of Eli Lilly. Dr. Fonarow is a consultant to Novartis (significant) and Janssen (modest). Dr. Peterson has received research funding for the American College of Cardiology, American Heart Association, Eli Lilly, Janssen, and Society of Thoracic Surgeons (all significant); and consulting (including continuing medical education) for Merck (modest), Boehringer Ingelheim, Genentech, Janssen, and Sanofi-Aventis (all significant). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES
1. Wang TY, Xiao L, Alexander KP, et al. Antiplatelet therapy use after discharge among acute MI patients with in-hospital bleeding. Circulation 2008;118:2139–45. 2. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after DES placement: results from the PREMIER registry. Circulation 2006;113:2803–9. 3. Chin CT, Wang TY, Anstrom KJ, et al. Treatment with ADP receptor inhibitors-longitudinal assessment of treatment patterns and events after acute coronary syndrome (TRANSLATE-ACS) study design: expanding the paradigm of longitudinal observational research. Am Heart J 2011;162:844–51. 4. Garavalia L, Ho PM, Garavalia B, et al. Clinician-patient discord: exploring differences in perspectives for discontinuing clopidogrel. Eur J Cardiovasc Nurs 2011;10:50–5.