Published online before print November 3, 2008, doi: 10.1161/CIRCULATIONAHA.108.787143
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(Circulation. 2008;118:2139-2145.)
© 2008 American Heart Association, Inc.
Health Services and Outcomes Research |
Antiplatelet Therapy Use After Discharge Among Acute Myocardial Infarction Patients With In-Hospital Bleeding
From the Duke Clinical Research Institute and Duke University Medical Center, Durham, NC (T.Y.W., K.P.A., S.V.R., E.D.P.); Mid America Heart Institute and University of Missouri–Kansas City, Kansas City, Mo (L.X., M.N.K., J.A.S.); and the Denver Veterans Affairs Medical Center, Denver, Colo (J.S.R.).
Correspondence to Tracy Y. Wang, MD, MHS, Duke Clinical Research Institute, 2400 Pratt St, Room 0311, Terrace Level, Durham, NC 27705. E-mail wang0085{at}mc.duke.edu
Received April 18, 2008; accepted September 12, 2008.
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Abstract |
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Background— Bleeding among patients with acute myocardial infarction (AMI) is associated with worse long-term outcomes. Although the mechanism underlying this association is unclear, a potential explanation is that withholding antiplatelet therapies long beyond resolution of the bleeding event may contribute to recurrent events.
Methods and Results— We examined medication use at discharge, 1, 6, and 12 months after AMI among 2498 patients in the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) registry. Bleeding was defined as non–coronary artery bypass graft–related Thrombolysis of Myocardial Infarction major/minor bleeding or transfusion among patients with baseline hematocrit 
28%. Logistic regression was used to evaluate the association between bleeding during the index AMI hospitalization and medication use. In-hospital bleeding occurred in 301 patients (12%) with AMI. Patients with in-hospital bleeding were less likely to be discharged on aspirin or thienopyridine (adjusted odds ratio=0.45; 95% CI, 0.31 to 0.64; and odds ratio=0.62; 95% CI, 0.42 to 0.91, respectively). At 1 month after discharge, although patients with in-hospital bleeding remained significantly less likely to receive aspirin (odds ratio=0.68; 95% CI, 0.50 to 0.92), use of thienopyridines in the 2 groups started to become similar. By 1 year, antiplatelet therapy use was similar among patients with and without bleeding. Postdischarge cardiology follow-up was associated with greater antiplatelet therapy use than either primary care or no clinical follow-up.
Conclusions— Patients whose index AMI is complicated by bleeding are less likely to be treated with antiplatelet therapies during the first 6 months after discharge. Early reassessment of antiplatelet eligibility may represent an opportunity to reduce the long-term risk of adverse outcomes associated with bleeding.
Key Words: anticoagulants • antiplatelet therapy • bleeding • myocardial infarction
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Introduction |
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Antiplatelet and antithrombotic medications and invasive vascular procedures are important strategies for the management of acute myocardial infarction (AMI).1,2 Although these therapies have decreased the rates of mortality and subsequent cardiac events,3 they have also increased the risk for bleeding complications.4,5 Prior studies have established an association between bleeding during AMI and worse short- and long-term outcomes.5–7 One potential explanation for this association may be that a bleeding event during AMI hospitalization alters the patient’s subsequent ability and/or likelihood of receiving secondary prevention therapies such as antiplatelet medications at hospital discharge or during follow-up after AMI hospitalization. Discharge use of aspirin and clopidogrel has been demonstrated in trials to reduce death and recurrent myocardial infarction (MI) after AMI and is recommended by the American College of Cardiology/American Heart Association guidelines.8 Although discontinuing these medications in the setting of active bleeding is logical, failure to reintroduce these secondary prevention medications after the bleeding event has resolved may predispose such patients to future cardiac events. To date, little is known about the rates of antiplatelet agent use among AMI patients with an in-hospital bleeding event.
Clinical Perspective p 2145
To investigate this association, we used data from the multicenter Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) study to compare patterns of antiplatelet medication use after hospital discharge among AMI patients whose hospitalizations were and were not complicated by bleeding. We hypothesized that patients who experienced bleeding during their index AMI hospitalization would be significantly less likely to be discharged on antiplatelet therapy and would remain significantly less likely to receive these medications over 1 year of follow-up after their bleeding complication had resolved. In contrast, we hypothesized that other guidelines-recommended secondary prevention medications (β-blockers and statins) would be used similarly among patients with and without a bleeding complication.
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Methods |
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Study Population
Between January 1, 2003, and June 28, 2004, 2498 patients with AMI from 19 US hospitals were prospectively screened and enrolled into the PREMIER study. The details of the PREMIER study have been reported previously.9 Patients were eligible if they were aged
18 years and had evidence supporting the diagnosis of AMI, including prolonged (>20 minutes) ischemic signs/symptoms or ECG ST-segment changes. Patients who were transferred into an enrolling site >24 hours from symptom onset or who developed cardiac marker elevation as a complication of elective coronary revascularization were excluded. Institutional review board approval at each participating hospital and individual patient informed consent were obtained.
Data Collection
The PREMIER data collection form prospectively captured demographic and clinical characteristics at enrollment, in-hospital use of coronary angiography and revascularization procedures, and discharge medications. Telephone interviews conducted at 1, 6, and 12 months collected information on current medications and any interval hospitalizations. A final query of the Social Security Administration Death Masterfile was conducted in August 2007 to determine survival through 3 years. Of the 2498 enrolled patients, 2481 patients were discharged alive, and follow-up was completed for 2096 patients (83.9%) at 1 month, 2064 patients (82.6%) at 6 months, and 1960 patients (78.5%) at 1 year.
Data Definitions
Data for the PREMIER registry were collected with the use of a standardized set of data elements and definitions (www.cvoutcomes. org/groups/PREMIER%20QI%20Registry/). In-hospital bleeding was defined as Thrombolysis in Myocardial Infarction major or minor bleeding or receipt of 1 U of allogeneic red blood cell transfusion. Thrombolysis in Myocardial Infarction bleeding has been defined previously as intracranial hemorrhage, observed blood loss with hemoglobin drop 3 g/dL, and unobserved blood loss with hemoglobin drop 4 g/dL.10 To increase the specificity of this definition, patients who had a transfusion alone were not considered to have had a bleeding event if they had anemia at the time of admission (hematocrit <28%) or underwent coronary artery bypass grafting (CABG). Hypertension was defined as blood pressure >140/90 mm Hg on at least 2 occasions or currently receiving antihypertensive pharmacological therapy. Prior heart failure refers to evidence of dyspnea, fluid retention, low cardiac output secondary to cardiac dysfunction, rales, jugular venous distention, or pulmonary edema before the current admission. Renal insufficiency was defined as a documented history of renal failure with baseline creatinine >1.5 mg/dL.
Statistical Analyses
The study population was stratified by the occurrence of an in-hospital bleeding event. We first performed a univariate comparison of baseline demographic and clinical characteristics, in-hospital procedures, and postdischarge medication use between the 2 groups. Continuous variables were compared with the use of Student t tests, and categorical variables were compared with the use of 
2 tests.
The association between in-hospital bleeding and medication use at discharge, 1 month, 6 months, and 1 year was examined separately for aspirin, thienopyridines, β-blockers, and statins. For each medication, a marginal repeated-measures logistic regression model (SAS PROC GLIMMIX) was constructed, including age, sex, hypertension, diabetes, heart failure, presenting heart rate and systolic blood pressure, admission creatinine clearance and hematocrit, in-hospital percutaneous coronary intervention (PCI) or CABG, and insurance status as time-dependent fixed effects and an unstructured correlation structure among the 4 time points. The effect of bleeding on medication use was estimated at each time point. In the analysis of thienopyridine use, stent use during PCI was also added as a covariate. Variables used for adjustment were selected on the basis of previously published factors associated with bleeding in the AMI population,7 as well as other variables likely to factor into the decision for medication use. For postdischarge medication use, rehospitalization was added as a covariate given concerns that subsequent cardiac or bleeding events might also influence medication use; a dummy variable for rehospitalization using a single value was used as a place holder in the longitudinal model for the discharge time point. Follow-up provider specialty (cardiologist/cardiac surgeon versus internist/family practitioner versus none) was also investigated as a covariate for medication use after discharge. To account for multiple comparisons among bivariate analyses of the 4 different medications, we adjusted the significance level from 0.05 to 0.0197 on the basis of a Bonferroni-type correction adjusted for correlations among the medications.11 A 2 test was used to assess the significance of the interaction between bleeding and clinical follow-up specialty on postdischarge medication use.
To further assess the robustness of our findings, we repeated the analysis after (1) limiting it to only patients who underwent PCI, (2) limiting it to only patients who were initially medically managed, and (3) excluding all patients with an interval hospitalization as a surrogate for clinical stability and presumed safety of continuing or reinitiating antiplatelet medications.
A probability value of <0.05 was considered statistically significant for all tests. All analyses were performed with the use of SAS software, version 9.1 (SAS Institute, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Baseline Characteristics
Among the 2498 AMI patients enrolled in PREMIER, 301 patients (12%) experienced an in-hospital bleeding event. Bleeding source was gastrointestinal in 69 patients (23%) and related to the cardiac catheterization site in 64 patients (21%). Red blood cell transfusions were given to 198 patients, with a median of 2 U transfused (interquartile range, 2 to 4 U). As shown in Table 1, patients with a bleeding event were older, more likely to be female, and more likely to have comorbidities such as hypertension, prior heart failure, and chronic renal insufficiency. Patients with and without bleeding events had similar rates of in-hospital coronary revascularization with either PCI or CABG (67.8% versus 71.4%; P=0.19).
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Use of Medications at Hospital Discharge Among Patients With and Without Bleeding
As shown in Table 2, AMI patients with in-hospital bleeding were significantly less likely to be prescribed aspirin (82.8% versus 93.3%; P<0.001), thienopyridine (58.8% versus 67.6%; P=0.002), β-blocker (86.5% versus 91.1%; P=0.01), or statins (78.1% versus 83.6%; P=0.02) at hospital discharge. The difference in aspirin and thienopyridine use persisted after multivariable adjustment with adjusted odds ratios (OR) (95% CI) of 0.45 (0.31 to 0.64) and 0.62 (0.42 to 0.91), respectively (Figure 1).
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Postdischarge Therapies
At 1 month after discharge, patients with in-hospital bleeding remained less likely to be treated with aspirin (66.1% versus 76.8%; P<0.001; adjusted OR=0.68 [95% CI, 0.50 to 0.92]), thienopyridine (54.1% versus 60.6%; P=0.05; adjusted OR=0.83 [95% CI, 0.59 to 1.17]), or statin (60.4% versus 72.9%; P<0.001; adjusted OR=0.65 [95% CI, 0.48 to 0.87]) compared with patients who did not have a bleeding event (Table 2, Figure 1). β-Blocker use was similar at 1 month between those with and without bleeding (adjusted OR=1.05 [95% CI, 0.76 to 1.44]).
At 6 months after discharge, aspirin use was still lower among patients who had bled previously (65.4% versus 77.0%; P<0.001; adjusted OR=0.63 [95% CI, 0.46 to 0.87]). However, thienopyridine, β-blocker, and statin use were similar between the 2 groups (Figure 1). By 1 year, no significant differences in the use of aspirin, thienopyridine, β-blocker, and statin remained among patients with or without in-hospital bleeding events (Table 2). A similar pattern of medication use was observed among the subset of patients (n=1432) treated with percutaneous coronary stents, as well as among patients who were initially medically managed (n=725).
In a secondary analysis that excluded all patients with interval rehospitalization, similar trends were observed in the use of postdischarge antiplatelet and other secondary prevention medications. At 6 months after discharge, adjusted ORs of aspirin, thienopyridine, β-blocker, and statin use were 0.54 (95% CI, 0.35 to 0.82), 1.04 (95% CI, 0.70 to 1.55), 0.94 (95% CI, 0.60 to 1.48), and 0.88 (95% CI, 0.58 to 1.35), respectively. At 1 year, there were no significant differences in medication use among patients with and without in-hospital bleeding.
Among patients who experienced a bleeding event, those seen in follow-up by either a cardiologist or a cardiac surgeon had a higher rate of antiplatelet therapy use than those seen in follow-up by an internist or family practitioner (Figure 2). Patients without any clinical follow-up had the lowest rates of antiplatelet therapy use regardless of bleeding status (rates of aspirin and thienopyridine use at 1 month after discharge among patients with cardiology versus internist versus no clinical follow-up were 76% versus 65% versus 58% [P for trend=0.04] and 66% versus 56% versus 42% [P=0.006], respectively).
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Discussion |
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Although bleeding in the setting of AMI has been linked with worse long-term mortality, the explanation for this association remains uncertain. Our study is one of the first to examine both discharge and posthospitalization medication regimens of patients who experienced bleeding complications during the course of their AMI. We found that patients with in-hospital bleeding were less likely to be discharged on several evidence-based therapies, including antiplatelet therapy. The differences in antiplatelet use persisted to 6 months and were more apparent among those patients not receiving follow-up care by a cardiology subspecialist.
The combination of antithrombotic medications and coronary revascularization procedures has been shown to lower morbidity and mortality among patients with AMI.12–16 However, use of these class IA recommended therapies2 comes at the price of increased bleeding risk. Bleeding occurs at a rate between 0.4% and 10% among hospitalized patients with AMI depending on the population studied and the bleeding definition used,7,17 and transfusion use has been reported in up to 15% of patients with acute coronary syndromes.18 Our study is consistent with these results, with >12% of patients experiencing either in-hospital bleeding or requiring non–CABG-related transfusion.
Bleeding as a complication of MI care is associated with poor long-term outcomes; higher rates of mortality, recurrent infarction, and stroke have been reported up to 6 months after the initial bleeding event.5,7 Although it is intuitive why severe bleeding, such as intracranial hemorrhage, is associated with increased mortality, it is less clear why milder degrees of hemorrhage (so-called nuisance bleeding) would also be independently associated with long-term adverse outcomes. Consistent with previously published studies,7 we show that patients who bled were older and more likely to have comorbidities such as renal insufficiency, hypertension, or heart failure, which can also contribute to their worse long-term outcomes. Other studies have suggested that proinflammatory and prothrombotic effects as a result of bleeding or transfusion may persist well beyond the immediate bleeding period and set the substrate for future thrombotic events.18–23
Although the aforementioned mechanisms may indeed play a role, a more direct explanation might be that patients with bleeding are less aggressively treated with guidelines-recommended AMI therapies. Randomized trial data to guide treatment of AMI patients with recent bleeding are lacking. There is legitimate concern that patients may rebleed if exposed to antiplatelet agents before healing from the bleeding event is complete. Moreover, other secondary medications such as β-blockers or statins may be reasonably withheld in the setting of hemodynamic uncertainty surrounding a bleeding event. As such, it is understandable that a transient bleeding episode would prevent clinicians from discharging patients on appropriate secondary prevention medications.
Clinicians may also defer reinitiation of antiplatelet therapy until the patient is deemed "safe" from further bleeding. Our data demonstrate that the treatment gap persists for quite some time after the initial in-hospital event: beyond 6 months, for example, for aspirin. Although we were unable to determine whether patients could have been reinitiated on therapies earlier, it is interesting that patients with a bleed who were seen in follow-up by a cardiologist were more likely to be treated with antiplatelet agents than those seen in follow-up by a primary care practitioner or those receiving no follow-up. This may reflect a certain inertia in clinical follow-up to reinitiate medications perceived to have adverse consequences, as well as the specialists’ greater awareness of the need for therapy intensification to achieve the goals of cardiovascular risk reduction.24 This highlights the importance of close postdischarge follow-up among patients with bleeding, as patients without follow-up miss the opportunity to be evaluated for possible reinitiation of therapy.25,26
Randomized controlled trial data on patients with recent bleeding are lacking, and thus the timing of reinstituting antiplatelet therapies is often based on clinical intuition. The results of this study argue for further investigation addressing the safety and potential benefit of early antiplatelet therapy reinitiation.12,27
Study Limitations
Several potential issues should be considered in the interpretation of these results. The bleeding population included patients who received 1 U of red blood cell transfusion. Although most patients received between 2 and 4 U of red blood cells, the relationship between the number of units transfused and posthospitalization medication use could not be studied with this small population. Given the limited sample size and number of bleeding events, we also did not have enough power to assess how the timing of antiplatelet medication resumption influenced long-term outcomes. The PREMIER study did not capture the detailed clinical rationale behind adjustments made to the medication regimen after discharge, nor did it capture bleeding complications after hospital discharge that may have occurred as a result of resuming antiplatelet agents. Outpatient follow-up, including intensity of follow-up, was not prespecified; as such, conclusions about how follow-up influences medication selection cannot be drawn. As with any other observational analysis, the results are subject to unmeasured confounders despite multivariable adjustment.
Conclusions
We found that patients who bleed during their index AMI hospitalization are less likely to be treated with antiplatelet therapies for up to 6 months after their AMI event, which may be a potential contributor to the higher long-term mortality associated with bleeding in patients with AMI. Although the decision to treat AMI patients with antiplatelet medications after bleeding is based largely on clinical intuition, continuity of care is critical because patients without postdischarge follow-up miss the opportunity to be evaluated for possible reinitiation of medications and may be at higher risk for downstream events. These results should drive clinicians to continually assess for the opportunity to safely reinitiate these effective secondary prevention medications after resolution of the bleeding event.
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Acknowledgments |
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Sources of Funding
The PREMIER Quality Improvement Registry was organized by Cardiovascular Outcomes, Inc, a nonprofit 501(c)(3) organization dedicated to the advancement of outcomes research and improvement of cardiovascular healthcare quality, and is funded by Cardiovascular Therapeutics, Inc, Palo Alto, Calif. More information on the PREMIER Quality Improvement Registry can be found at http://www.cvoutcomes.org. Funding and support for this publication were provided by the Duke Clinical Research Institute, Durham, NC. Funding for statistical analysis was provided by CV Therapeutics, Inc, Palo Alto, Calif.
Disclosures
Tracy Wang, MD, MHS reports having received research grants from The Medicines Company and Heartscape, Inc; Lan Xiao, MS: no relationships to disclose; Karen Alexander, MD: speakers’ bureaus for Amgen, Pfizer, and Schering-Plough; Sunil Rao, MD: no relationships to disclose; Mikhail Kosiborod, MD: no relationships to disclose; John Rumsfeld, MD, PhD: serves on the Scientific Advisory Board for United Healthcare and is Chief Science Officer for the American College of Cardiology National Cardiovascular Data Registries; John Spertus, MD, MPH: no relationships to disclose; Eric Peterson, MD, MPH: research grants from Bristol-Myers Squibb, Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals Partnership, Bristol-Myers Squibb/Merck, and Schering-Plough Corporation.
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[Abstract/Free Full Text]
CLINICAL PERSPECTIVE
Although bleeding in the setting of an acute myocardial infarction is known to be associated with worse long-term outcomes, the mechanism is unclear. Our study suggests an explanation: Proven secondary prevention therapies, such as antiplatelet agents, are withheld long beyond the resolution of the bleeding event. Postdischarge cardiology follow-up was associated with greater antiplatelet therapy use than either primary care or no clinical follow-up. Thus, early reassessment of antiplatelet eligibility may represent an opportunity to reduce the long-term risks associated with bleeding, and future larger studies examining the impact of early antiplatelet medication resumption on ischemic and bleeding outcomes are warranted.
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