|Year : 2018 | Volume
| Issue : 1 | Page : 28-34
Modifying effect of diabetes on the short-term effect of clopidogrel in patients with myocardial infarction
Wuxiang Xie1, Lin Feng2, Xian Li3, Runlin Gao4, Yangfeng Wu5
1 Peking University Clinical Research Institute, Peking University Health Science Center, Beijing, China
2 Peking University Clinical Research Institute, Peking University Health Science Center; Peking University First Hospital, Beijing, China
3 The George Institute for Global Health at Peking University Health Science Center, Beijing, China
4 Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
5 Peking University Clinical Research Institute, Peking University Health Science Center; The George Institute for Global Health at Peking University Health Science Center, Beijing, China
|Date of Web Publication||4-Feb-2019|
Dr. Yangfeng Wu
Peking University Clinical Research Institute and School of Public Health, Peking University Health Science Center, No. 38 Xueyuan Road; The George Institute for Global Health at Peking University Health Science Center, No. 6 Zhichun Road, Haidian District, 100088, Beijing
Source of Support: None, Conflict of Interest: None
Background: Patients with diabetes are reported having inadequate response to clopidogrel treatment compared with patients without diabetes. The present study aims to investigate the effect of clopidogrel treatment in lowering in-hospital major adverse cardiovascular events (MACEs) among hospitalized myocardial infarction (MI) patients with and without diabetes. Materials and Methods: This is a post hoc analysis of the third phase of Clinical Pathways in Acute Coronary Syndromes program study. Between October 2011 and November 2014, a total of 14,997 patients with MI were consecutively recruited from 101 county hospitals without the capacity to perform onsite percutaneous coronary intervention (PCI). Results: The mean age of the 14,997 patients with MI was 64.8 ± 12.2 years, and 67.5% of the participants were male. Of these patients, 1920 (12.8%) were classified as diabetes when presenting at the hospital, and 12,875 (85.9%) patients received in-hospital clopidogrel treatment. In total, 167 patients (8.7%) with and 955 patients (7.3%) without diabetes experienced an in-hospital MACE. Multivariable-adjusted relative risk (RR) associated with clopidogrel treatment for in-hospital MACEs was 0.79 (95% confidence interval [CI]: 0.68–0.93) among all MI patients, and it was also consistent between patients with (RR = 0.79, 95% CI: 0.54–1.16) and without diabetes (RR = 0.79, 95% CI: 0.65–0.95; P for interaction = 0.970). Propensity score-matched subgroup analyses yielded similar results. Conclusion: Our large-scale study of real-world data from non-PCI-capable hospitals in China demonstrated that clopidogrel treatment was associated with a lower risk of in-hospital MACEs in MI patients, and this effect was not modified by diabetes.
Keywords: Clopidogrel, diabetes, major adverse cardiovascular events, myocardial infarction
|How to cite this article:|
Xie W, Feng L, Li X, Gao R, Wu Y. Modifying effect of diabetes on the short-term effect of clopidogrel in patients with myocardial infarction. Heart Mind 2018;2:28-34
|How to cite this URL:|
Xie W, Feng L, Li X, Gao R, Wu Y. Modifying effect of diabetes on the short-term effect of clopidogrel in patients with myocardial infarction. Heart Mind [serial online] 2018 [cited 2019 Apr 24];2:28-34. Available from: http://www.heartmindjournal.org/text.asp?2018/2/1/28/251482
| Introduction|| |
Myocardial infarction (MI) remains one of the leading causes of mortality globally., Early initiation of dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is the cornerstone of treatment for patients with MI., Recent studies have indicated that patients with diabetes exhibit an inadequate response to the currently available antiplatelet agents compared with patients without diabetes,, leading to significantly increased recurrent cardiovascular events and mortality associated with diabetes. Clopidogrel has been the most widely prescribed P2Y12 receptor antagonist so far. Subgroup data from several randomized clinical trials comparing clopidogrel and aspirin with aspirin alone have shown that diabetes weaken the effect of clopidogrel on recurrent cardiovascular events and all-cause death, although the interactions are not significant.,, A large-scale cohort study reported that clopidogrel treatment was associated with lower reduction in 1-year mortality in MI patients with diabetes compared with those without diabetes. However, the current clinical evidence that the effect of clopidogrel is weaken with the present of diabetes is still not convinced, and whether the short-term effect of clopidogrel on in-hospital major adverse cardiovascular events (MACEs) is modified by diabetes remains unclear.
In the latest guidelines of the European Society of Cardiology, it has been suggested that clopidogrel is an alternative to both patients with ST-segment elevation MI (STEMI) and non-ST-segment elevation acute coronary syndromes (non-STE ACS), only if ticagrelor and prasugrel are not available, or are contraindicated., However, clopidogrel is still the first-line therapy for MI patients in China,, especially in low-resource county hospitals. Therefore, the objective of the present study was to evaluate the effect of clopidogrel treatment on in-hospital MACEs after MI in patients with and without diabetes using the data from the third phase of Clinical Pathways in Acute Coronary Syndromes program (CPACS-3) study.
| Materials and Methods|| |
The CPACS-3 trial's rationale and design had been previously reported in detail. In brief, CPACS-3 is a stepped-wedge cluster randomized trial among resource-constrained hospitals in China to determine whether the routine use of clinical pathway-based, multifaceted quality of care initiative (QCI) will lead to a measurable reduction in the number of in-hospital MACEs in patients with ACS. From eligible hospitals that agreed to participate, ACS patients were consecutively enrolled in five 6-month cycles. No intervention was applied in the first cycle, after which hospitals were randomly allocated to commence the intervention in one of the four remaining cycles. The intervention was applied at the level of hospital, with outcomes measured at the patient level. All patients over 18 years old and with a final diagnosis of ACS at discharge or death were recruited consecutively within each 6-month cycle. We excluded patients who were dead on arrival or those who died within 10 min of hospital arrival. Between October 2011 and November 2014, a total of 29,346 patients with ACS were recruited into the CPACS-3 study from 101 county hospitals without the capacity to perform onsite percutaneous coronary intervention (PCI). Of these, 14,997 patients with MI were used for this post hoc analysis.
The Institutional Review Board of Peking University reviewed and approved the CPACS-3 trial, and all the participating patients provided written informed consent. The CPACS-3 study was registered on www.clinicaltrails.gov (NCT01398228).
A trained hospital staff member who was not involved in the management of patients with ACS was responsible for collecting and entering the data into a dedicated web-based data management system. Data for each patient were collected from the medical record and from survivors prior to hospital discharge. The data included sociodemographic information; symptoms and signs relating to the presenting ACS; medical history; electrocardiographic and biomarker findings; investigations performed; treatments administered prior to admission, during hospitalization, and at death or hospital discharge; final diagnosis and discharge status; major in-hospital clinical events; personal insurance status; and the total cost of hospitalization. Data quality was maintained through in person and online study monitoring activities.
Diabetes was defined according to the medical history of diabetes or current use of antidiabetic therapy at the time of enrollment. Hypertension was defined according to the medical history of hypertension, systolic blood pressure (SBP) ≥140 mmHg, or diastolic blood pressure ≥90 mmHg when presenting at the hospital.
The primary outcome of the study was in-hospital MACEs, defined as all-cause mortality, recurrent MI, or nonfatal stroke. We chose all-cause mortality rather than cardiac death because our definition of in-hospital all-cause mortality not only included patients who died at the hospital, but also those who were discharged against medical advice and died within 1 week and those who transferred to upper-level hospitals but died within 24 h. For the two latter cases, we were not able to have reliable data to differentiate cardiac death from other deaths. The secondary outcomes included all-cause mortality, recurrent MI, stroke, and severe bleeding. All outcome events were adjudicated by an independent committee blinded to the hospital's randomization status.
The results were presented as percentages for categorical variables and mean ± standard deviations for continuous variables. The baseline characteristics of the participants with and without clopidogrel treatment were compared using the t-test or Chi-square test. Poisson regression using PROC GENMOD (DIST = Poisson and LINK = log) was performed to assess the strength of associations (relative risk [RR]) between clopidogrel treatment and outcomes, and generalized estimating equations were used to adjust for clustering within hospitals. The first model included clopidogrel treatment, age, sex, QCI intervention, and intervention cycle, stratified by diabetic status. To evaluate the modifying effects of diabetes on the associations between clopidogrel treatment and outcomes, we used Z-test to compare the difference between the two regression coefficients from subgroup analysis, using the method proposed by Altman and Bland. The second model additionally adjusted for education, occupation, current smoking status, body mass index, STEMI, thrombolysis, concomitant pharmacotherapy, SBP lower than 90 mmHg when presenting at the hospital, and heart rate higher than 100 beats/m when presenting at the hospital.
To ensure robustness of our findings and reduce the impact of treatment selection bias, additional propensity-based subgroup analyses were performed. In these, patients using clopidogrel were matched with patients not using clopidogrel (1:1) on all baseline characteristics from [Table 1], using the Greedy matching macro.
|Table 1: Baseline characteristics between participants who did and did not receive clopidogrel treatment, by the presence of diabetes|
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Statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA). All analyses were two sided, with an alpha value of 0.05 considered as the threshold for statistical significance.
| Results|| |
The mean age of the 14,997 patients with MI was 64.8 ± 12.2 years, and 67.5% of the participants were male. The median hospital stay was 10 days (interquartile range: 6–13 days). Of these MI patients, 1920 (12.8%) were classified as diabetes when presenting at the hospital, and 12,875 (85.9%) patients received in-hospital clopidogrel treatment. Characteristics of patients with and without clopidogrel therapy stratified by diabetes status are summarized in [Table 1].
Dose of clopidogrel
In MI patients treated with clopidogrel, the percentage of receiving high loading dose (300–600 mg) was higher among patients without diabetes than that among those with diabetes (56.6% vs. 51.0%, P < 0.001), but there was no significant difference in the percentages of 75-mg daily dose between patients with and without diabetes (89.7% vs. 89.7%, P = 0.990).
Primary and secondary outcomes
In total, 167 patients (8.7%) with and 955 patients (7.3%) without diabetes experienced an in-hospital MACE. Of these, 153 (8.0%) with and 904 (6.9%) without diabetes died. Crude incidence rates for outcomes in patients with and without diabetes stratified by clopidogrel treatment are summarized in [Table 2].
Associations between clopidogrel treatment and outcomes
As summarized in [Table 3], fully adjusted RR associated with clopidogrel treatment for in-hospital MACEs was consistent in patients with diabetes (RR = 0.79, 95% confidence interval [CI]: 0.54–1.16) and without diabetes (RR = 0.79, 95% CI: 0.65–0.95; P for interaction = 0.970). Similarly, there was no evidence toward a differential effectiveness of clopidogrel treatment on all-cause death in patients with and without diabetes after multivariable adjustment [Figure 1]. The associations between clopidogrel treatment and other secondary outcomes were not analyzed using regression analysis because of the small number of events.
|Table 3: Associations of clopidogrel treatment with risk of in-hospital major adverse cardiovascular events among patients with and without diabetes|
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|Figure 1: Associations of clopidogrel treatment with all-cause mortality among patients with and without diabetes. aUnadjusted, bAdjusted for age, sex, intervention, and cycle, cFurther adjusted for education, occupation, current smoking, body mass index, ST-elevation myocardial infarction, thrombolysis, concomitant pharmacotherapy, systolic blood pressure lower than 90 mmHg when presenting at hospital, and heart rate higher than 100 beats/min when presenting at hospital. RR = Relative risk, CI = Confidence interval, MI = Myocardial infarction|
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Propensity score analysis
The propensity-score matching identified 430 patients with diabetes and 3170 patients without diabetes. Baseline characteristics were comparable between patients treated with clopidogrel and those who were not [Supplementary Material Online, [Table S1][Additional file 1]. Similar to the main analysis, these analyses showed that diabetes did not alter the efficacy of clopidogrel in preventing in-hospital MACEs, although the efficacy was no longer significant in both groups because of the small sample size [Table 4].
|Table 4: Associations of clopidogrel treatment with risk of in-hospital major adverse cardiovascular events among patients with and without diabetes: Results of propensity score-matched subgroup|
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| Discussion|| |
In this post hoc analysis of CPACS-3 study, we found that the presence of diabetes did not modify the effect of clopidogrel treatment on in-hospital MACEs in 14,997 MI patients who received conservative treatments in non-PCI-capable hospitals. Besides, our results observed a 21% RR reduction of in-hospital MACEs associated with clopidogrel treatment in both patients with and without diabetes. These findings support that clopidogrel has beneficial effects in MI patients and that a higher dose of clopidogrel does not need to be delivered specifically to patients with diabetes during hospitalization.
Clopidogrel, a second-generation P2Y12 inhibition, is the antiplatelet treatment of choice for patients with MI., The clinical benefit associated with clopidogrel treatment has been observed in patients with non-STE ACS since 2001. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, 12,562 patients with non-STE ACS were randomly assigned to receive either clopidogrel plus aspirin or aspirin alone for 3–12 months. The CURE trial found that clopidogrel was associated with a RR reduction of 20% in the combined outcome of cardiovascular death, nonfatal MI, or stroke. And then, the clinical benefit of clopidogrel has also been demonstrated in patients with STEMI in 2005., The Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial randomly assigned 3491 patients with STEMI to receive clopidogrel or placebo in addition to aspirin and fibrinolytic therapy and observed a RR reduction of 31% in the primary end point which was the composite of 30-day all-cause death or recurrent MI. Another large-scale trial conducted in China, the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), enrolled 45,852 MI patients and randomly allocated them into clopidogrel treatment or matching placebo in addition to aspirin. The COMMIT trial confirmed the clinical benefit of adding clopidogrel to aspirin in patients with acute MI, although the RR reduction (9%) with clopidogrel seemed to be comparatively smaller with that from other trials. The results of our study are generally consistent with those from previous trials and support that clopidogrel should still be considered as the first-line antiplatelet therapy for MI patients who received conservative treatment.
Based on the latest evidence from head-to-head randomized trials, the current guidelines of the current guidelines of the European Society of Cardiology recommend that clopidogrel is inferior to ticagrelor and prasugrel as a P2Y12 inhibitor for patients with STEMI or non-STE ACS., In the Platelet Inhibition and Patient Outcomes (PLATO) trial, 18,624 patients with STEMI or non-STE ACS were randomized to either clopidogrel or ticagrelor therapy for up to 12 months. The PLATO trial reported a RR reduction of 16% associated with ticagrelor therapy in the primary composite end point (cardiovascular death, MI, or stroke). In the trial, to assess improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38), 13,608 patients with ACS with scheduled PCI were randomly assigned to receive either prasugrel or clopidogrel for 6–15 months. The primary efficacy end point, a composite of cardiovascular death, MI, or stroke, was significantly reduced with prasugrel compared with clopidogrel (hazard ratio = 0.81, 95% CI: 0.73–0.90). Similarly, the latest American College of Cardiology/American Heart Association guidelines recommend that “it is reasonable to use ticagrelor in preference to clopidogrel in patients with non-STE ACS who are managed with medical therapy alone.” However, it should be noted that both prasugrel and ticagrelor are associated with an increased risk of major bleeding compared with clopidogrel. Besides, as evidence from direct head-to-head comparisons of short-term effect between P2Y12 inhibitors is still lacking in MI patients who received conservative treatment, clopidogrel should not be considered as an inferior antiplatelet agent during hospitalization. The CPACS-3 study conducted in non-PCI-capable hospitals presents an opportunity to observe the short-term effect of clopidogrel in MI patients who received medical therapy alone. Our results provide unique evidence for MI patients presenting to a non-PCI-capable hospital in resource-constrained areas in low- and middle-income countries.
A randomized trial has found that a 150-mg maintenance dose of clopidogrel is associated with enhanced antiplatelet effects compared with 75 mg in patients with diabetes and coronary artery disease. Moreover, some other studies have observed the clinical significance of individual response variability to clopidogrel. Most of these studies were conducted in patients undergoing selective PCI and found that low response to clopidogrel is independently associated with a higher risk of stent thrombosis, or cardiovascular events.,,,, Then, several studies have identified the underlying mechanisms linking diabetes with increased platelet reactivity, including increased platelet receptor expression, intracellular downstream signaling abnormalities, P2Y12 mutations, and expression levels., Therefore, it is reasonable to hypothesize that clopidogrel treatment after MI is associated with lower reduction in the risk of cardiovascular event in patients with diabetes compared to patients without diabetes. Andersson et al. analyzed the data from the Danish nationwide administrative registries containing 58,851 MI patients and found that clopidogrel treatment after MI was associated with lower reduction in the risk of 1-year all-cause death and cardiovascular death in patients with diabetes compared to those without diabetes. The results of the large-scale cohort study were not consistent with our results, and we consider that one of the main reasons for the conflicting results is the different periods of follow-up.
A major strength of the present study is that this is a large-scale study conducted in MI patients who received conservative treatments in non-PCI-capable hospitals. The CPACS-3 study is the first well-powered randomized controlled trial to investigate the effect of the QCIs on in-hospital outcomes. The study design, conduct, and data analyses were oversighted by an experienced steering committee composed of international expertise in cardiology, epidemiology, and biostatistics. The primary and secondary end points were adjudicated by the independent committee, and the study process was closely monitored by a dedicated quality control team. Nevertheless, the present findings should be considered in the context of some potential limitations. Most important limitations include that this is a post hoc analysis of the CPACS-3 study and patients were not randomized within diabetic and nondiabetic groups. Although propensity score-matched subgroup analyses yielded similar results, unmeasured covariates might have influenced our results. A further limitation is inherent to all observational studies as follows: we are not able to infer any definite causal relationships. Third, medication use and adverse events after discharge were not collected in the present study; therefore, we could not analyze the associations between clopidogrel treatment and long-term outcomes. Fourth, the duration and severity of diabetes were important confounding factors, but we did not adjust for them as the detailed information on these factors had not been collected. Fifth, adenosine diphosphate-induced platelet aggregation is an essential surrogate end point to evaluate clopidogrel resistance in a short-term follow-up study. The current study cannot conclude that diabetes does not affect clopidogrel resistance without the results of platelet aggregation. Finally, although we adjusted for a number of potential confounders, the possibility of residual confounding cannot be ruled out.
| Conclusion|| |
The present study demonstrated that clopidogrel treatment was associated with a lower risk of in-hospital MACEs in MI patients who received conservative treatments in non-PCI-capable hospitals and diabetes did not modify the effect of clopidogrel treatment. These findings support that clopidogrel has beneficial effects in MI patients and that a higher dose of clopidogrel does not need to be delivered specifically to MI patients with diabetes during hospitalization in resource-constrained areas.
The authors would like to thank the CPACS-3 Study Steering Committee (sorted by the first letter of the family name): Kalipso Chalkidou (National Institute for Health and Clinical Excellence), Runlin Gao (co-principal investigator) (Cardiovascular Institute and Fuwai Hospital), Dayi Hu (Peking University People's Hospital), Yong Huo (Peking University First Hospital), Yahui Jiao (National Health and Family Planning Commission [NHFPC] of China), Lingzhi Kong (NHFPC of China), Anushka Patel (The George Institute for Global Health), Eric Peterson (Duke Clinical Research Institute), Fiona Turnbull (The George Institute for Global Health), Mark Woodward (The George Institute for Global Health), Yangfeng Wu (co-principal investigator) (The George Institute for Global Health at PUHSC).
Financial support and sponsorship
Source of funding used to support the research and creation of the article is from Sanofi, China, through an unrestricted research grant. The George Institute for Global Health at PUHSC sponsored the study and owns the data. However, the authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]