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Clinical importance of thrombocytopenia in patients with acute coronary syndromes: a systematic review and meta-analysis

Running head: Thrombocytopenia in acute coronary syndromes

Vanessa Discepola1,2 Mireille E. Schnitzer3 E. Marc Jolicoeur1,2 Guy Rousseau1,4 and Marie Lordkipanidzé2,3

1Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada;

2Research Center, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada; 3Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada; and

4Research Center, Hôpital du Sacré-Cœur de Montréal, Montreal, Quebec, Canada

Correspondence to: Dr. Marie Lordkipanidzé, Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada

Tel.: +1 514 376 3330 Ext 2694; Fax: +1 514 376 0173 e-mail: marie.lordkipanidze@umontreal.ca

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Abstract

Thrombocytopenia (TP) is common in hospitalized patients. In the context of acute coronary syndromes (ACS), TP has been linked to adverse clinical outcomes. We present a systematic review and meta-analysis of the evidence on the clinical importance of pre-existing and in-hospital acquired TP in the context of ACS. Specifically, we address (a) the prevalence and associated factors with TP in the context of ACS; and (b) the association between TP and all-cause mortality, major adverse cardiovascular events (MACE) and major bleeding. We conducted systematic literature searches in MEDLINE and Web of Science. For the meta-analysis, we fit linear mixed models with a random study-specific intercept for the aggregate outcomes. A total of 16 studies and 190,915 patients were included in this study. Of these patients, 8.8% ± 1.2% presented with pre-existing TP while 5.8% ± 1.0% developed TP after hospital admission. Pre-existing TP was not statistically significantly associated with adverse outcomes. Acquired TP was associated with greater risk of all-cause mortality (risk difference (RD): 4.3%; 95% confidence interval (CI): 2% - 6%; p=0.04), MACE (RD: 8.5%; 95% CI: 1% -16.0%; p=0.037) and major bleeding (RD: 11.9%; 95% CI: 5% - 19%; p=0.005). In conclusion, TP is a prevalent condition in patients admitted for an ACS and identifies a high-risk patient population more likely to

experience ischemic and bleeding complications, as well as higher mortality.

Registration: PROSPERO 2017: CRD42017054518

Keywords: Acute coronary syndrome, Bleeding, Ischemia, Major adverse cardiac events, Mortality, Thrombocytopenia

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Introduction

Thrombocytopenia (TP) defined as a platelet count <100 – 150 x 109/L, can occur as a result of a reduced production, increased splenic sequestration, or enhanced platelet destruction [1]. This haematological abnormality is common in hospitalized patients, and poses a challenge to clinical care as it is associated with an increased risk of bleeding [2-13]. In the context of acute coronary syndromes (ACS), the clinical trajectory of patients who present with TP is dealt with on a case-by-case basis. Although several case reports have linked TP with adverse clinical outcomes [14-21] and the clinical significance of acquired TP in this clinical setting has been previously critically appraised [22], the heterogeneity in length of follow-up limited the study to multiple sub-analyses and insufficient power to detect substantial risk differences in cardiovascular endpoints between study populations.

We therefore sought to undertake a systematic review and meta-analysis of the evidence on the clinical importance of both pre-existing and acquired TP in the context of an ACS. Specifically, we assessed (a) the frequency and associated factors with TP in the context of ACS; and (b) the association of TP with all-cause mortality, major adverse cardiovascular events (MACE) and bleeding in patients hospitalized for ACS.

Methods

The systematic review is in compliance with the PRISMA statement [23]. The approach used is detailed below and was registered with PROSPERO (CRD42017054518).

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Search strategy

Systematic literature searches for relevant articles published from inception to May 2016 were conducted using the MEDLINE database and updated in July 2017. The following terms were used: “Purpura, Thrombocytopenic”, “Purpura, Thrombotic Thrombocytopenic”,

“Thrombocytopenia”, “Blood Coagulation Disorder(s)”, “Blood Platelet Disorder”, “Platelet Count”, “Mean Platelet Volume”, “Acute Coronary Syndrome”, “Myocardial Infarction”, “Angina, Unstable”, “Stroke”, “Percutaneous Coronary Intervention”, “Coronary Thrombosis”, and “Thrombosis”. Restrictions were applied to studies performed on humans and to articles published in English/French. Conference proceedings from the last two years were searched on the Web of Science Core Collection (Thomson Reuters). Additional articles were retrieved by hand-searching references of relevant articles. Articles that were not clinical studies such as reviews, case reports/series, and editorials were excluded. In addition, articles which analyzed a data set that was later included in a larger follow-up from the same investigators were considered duplicates and excluded from the analysis.

Selection criteria

Clinical studies that evaluated pre-existing or in-hospital acquired TP in patients admitted for an ACS (i.e. unstable angina, non-ST elevated MI, ST-elevated MI), and which presented rates of ischemic or bleeding events at follow-up (i.e. in-hospital, 30 days, 1 year) were considered. Clinical outcomes of interest included all-cause mortality and composite endpoints i.e. study-reported MACE; secondary endpoints included individual ischemic components: cardiac death, non-fatal, target vessel revascularization, and haemorrhagic events. Studies focussing on perioperative TP were excluded.

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Quality assessment

A modified Cochrane tool for the assessment of risk of bias in cohort studies was used to rate the quality of reporting and risk of bias of the included studies [24, 25]. Potential sources of bias were assessed in three domains: “study design”, “comparability”, and “assessment of outcomes”. A high risk of bias was assigned to a domain if any of the questions within it failed to meet the criteria. If the study did not report sufficient information to judge the risk of bias, the sub-domain was classified as “Unclear” and was equally considered as high risk of bias.

Data extraction

Data extraction was conducted by one reviewer (V.D.) and independently checked by a second (M.L). Any disagreements were resolved through discussion. This process was carried out through use of a standardised, piloted data extraction form. Data related to the following domains were extracted: study design and characteristics, patient characteristics, prevalence of TP,

outcome measures and length of follow-up. Raw event rates as well as study-specific unadjusted and adjusted risk estimates were extracted. Studies were grouped according to whether patients had pre-existing or in-hospital acquired TP.

Statistical analysis

Baseline clinical characteristics of patients with or without TP were pooled. Due to the heterogeneity among studies, the random effects model was used to estimate the pooled prevalence and standard error of pre-existing as well as acquired TP [26].

All available aggregate data was used to fit linear mixed models with a random study-specific intercept for the aggregate outcomes. Due to heterogeneity in the type of adjusted risk

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computation reported in the different studies (i.e. ORs, HRs and RRs), analyses were restricted to raw event rates. Statistical analyses were conducted through use of the R statistical software version 3.2.2 with packages lme4 and lmerTest. Each data point corresponded with a study arm, stratified by the presence of pre-existing or acquired TP, evaluated at a specific time point. Due to the heterogeneity in follow-up times among the included studies, models were adjusted for the time at which the outcome was evaluated. In addition, some studies reported outcomes at

multiple time points and these results were allowed to enter the analysis as repeated measures. These models were weighted by the inverse of the study-specific standard error of the mean outcome, and were adjusted for the mean age (standardized) as well as proportion of females in the study arm. Risk differences (RDs) and 95% confidence intervals (CIs) were used as summary statistics in order to denote the risk attributed to thrombocytopenic patients in relation to ischemic and bleeding outcomes. In addition, cumulative event rates for all-cause mortality and MACE were computed by pooling all available event rates at short-term (i.e. 7 to 30 days) and long-term follow-up for each individual study.

The between-study heterogeneity was assessed by testing the inclusion of the study indicator as a random effect in the linear mixed model. Statistical heterogeneity for the pooled analysis was summarized for each outcome by the chi-squared test.

Role of the funding source

The funder of the study, Faculty of Pharmacy, Université de Montréal, had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The

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the decision to submit for publication. No payment was received by a pharmaceutical company or other agency to write this article.

Results

Search results and characteristics of included studies

The search strategy identified 4,759 studies, and an additional 61 articles were identified by hand-searching the reference list of articles related to the topic resulting in a total of 4,820 records which were screened for relevance (Figure 1). Removal of duplicate records and screening of titles and abstracts resulted in 625 potentially relevant articles, for which full texts were assessed. A total of 16 studies were included in the systematic review; one was a

prospective study [27], two were retrospective studies [2, 28], and 13 were post-hoc analyses from randomized trials and large ACS registries [3-13, 29, 30].

Of the 16 articles that informed this systematic review and meta-analysis, 4 studies investigated pre-existing TP [2, 27-29], one study investigated both pre-existing and acquired TP [30], and 11 studies investigated in-hospital acquired TP [3-13]. The main study characteristics are presented in Table 1. Study-specific definitions for mortality, major adverse cardiovascular events and major bleeding are presented in Table 2.

Assessment of study quality

The risk of bias assessment for the included studies is presented in Online Table 1. All studies provided clear selection criteria for patients with or without TP. However, comparability lead to a high risk of bias, as three studies specifically reported a different antithrombotic treatment in patients with and without TP, during hospitalization and at discharge [4, 12, 28]. Most studies

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failed to report how antithrombotic treatment varied between individuals with and without TP. Outcome measures of interest were predefined in all studies and included a follow-up time of 7 days, 30 days, or 1 year. However, it was not always clear how authors dealt with incomplete outcome data, leading to a classification of high risk of bias for six of the included studies [2, 8, 9, 11, 13, 30].

Prevalence of TP and associated factors in the context of ACS

Of the 190,915 patients included in this analysis, 8·8% ± 1·2% presented with pre-existing TP and 5·8% ± 1·0% developed in-hospital TP (Table 1). Pre-existing TP was defined across studies as a platelet count at presentation below 150 x 109/L. For acquired TP however, definitions were less well standardized (Table 2). While the majority of studies defined acquired TP as an

absolute platelet count nadir below 100 or 150 x 109/L, some investigators further stratified severity of TP based on the absolute platelet nadir reached. A secondary definition was sometimes added based on the magnitude of decline in platelet count [3, 4, 6-8, 10, 12, 13].

As summarized in Table 3, compared to patients without TP, those with TP were older, weighed less and presented a higher prevalence of diabetes mellitus and hypertension. They were also more likely to have experienced a recent MI and undergone a previous PCI or CABG.

Clinical outcomes in patients with TP

The pooled data was adjusted for the age and sex of the patients as well as the timing of the reported outcomes to allow for a robust and cohesive analysis (Table 4 and Figure 2). A secondary analysis was undertaken to explore the temporality of the association (Figures 3 and 4).

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Mortality

Acquired TP was associated with an increased risk of all-cause mortality compared to no TP (RD, 4%; 95% CI, 2% – 6%; p < 0·05) (Table 4 and Figure 2A). This was seen at all times points studied (Figures 3 and 4). Pre-existing TP was not associated with all-cause mortality in the overall analysis (Table 4 and Figure 2B). Exploratory analyses showed an absence of association at early time points (up to 30 days), but a positive association at 1 year (Figure 4B). Major adverse cardiac events

Acquired TP was associated with a significant difference in risk of developing MACE (RD, 9%; 95% CI, 1% – 16%; p < 0·05) in comparison to patients without TP (Table 4 and Figure 2A). Similarly to mortality, there was no significant difference in the risk of MACE (RD, 5%; 95% CI, -4% – 14%; p > 0·05) when comparing patients with pre-existing TP and those with normal platelet counts (Table 4 and Figure 2B). In exploratory analyses, the rate of MACE was

considerably greater among patients with acquired TP vs. patients with pre-existing or no TP, in particular at the 7-day and 30-day follow-up (Figure 3B). A positive association was seen between pre-existing TP and MACE at 1 year, but not at earlier time points (Figure 4B). Bleeding

The risk of major bleeding was significantly greater in patients with acquired TP (RD, 12%; 95% CI, 5% – 19%) but not in those with pre-existing TP (Table 4 and Figure 2).

Discussion

The present systematic review and meta-analysis assessing the clinical importance of TP in the context of ACS is the largest analysis comparing patients with pre-existing TP, and acquired TP to those with normal platelet counts. The principal findings of this analysis were that: (1) the approximate frequency of pre-existing and in-hospital acquired TP were 8·8% and 5·8%,

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respectively; (2) TP was more common in older patients, who were more likely to be male and present with diabetes, recent MI and who had previously undergone PCI or CABG; (3)

significant differences in the risks of all-cause mortality, MACE and major bleeding were found when comparing patients who developed TP following their hospitalization and those who did not. These associations were not present when comparing patients with pre-existing TP upon ACS presentation and those without.

Pre-existing thrombocytopenia

Only five studies investigated patients presenting with an ACS and a baseline platelet count within the thrombocytopenic range. In our pooled analysis, there was no significant association between the presence of pre-existing TP and the occurrence of death, MACE or bleeding. It should be noted however that heterogeneity for this analysis was high and exploratory analyses suggested increased all-cause mortality at 1 year.

The cause of death in these patients was not reported in most studies. However, Raphael and colleagues showed significantly higher rates of mortality due to noncardiac causes such as cancer and chronic diseases at a 5-year follow-up in patients with pre-existing TP admitted for an ACS (28% vs. 21%; p = 0·02) [28]. This suggests that the association between pre-existing TP and death rather reflects an underlying disease that both decreases platelet count and predisposes to death than a direct relationship.

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Acquired Thrombocytopenia

Twelve studies reported ischemic and bleeding outcomes in patients who developed TP following their admission for ACS. When pooled together, the results show a significant association

between in-hospital acquired TP with MACE and all-cause mortality, as well as major bleeding.

An interesting consideration from the systematic review that was not captured by the meta-analysis is the graded relationship between in-hospital acquired TP and ischemic outcomes. In a post-hoc analysis of the OASIS-2 study, Eikelboom and colleagues reported a strong correlation between the severity of TP and the occurrence of death (with the risk being 35 times higher in patients with a platelet count < 50 x 109/L as compared with those in the normal range) and MACE (with a 3-fold higher risk in patients with a platelet count < 50 x 109/L) [5].

Thrombocytopenia remained independently associated with these outcomes after adjustment for important covariates, including sex, age, baseline platelet count, and treatment with heparin vs. hirudin [5]. Similar findings were reported in the CATCH registry, which included in-patients with and without ACS receiving heparin; a stepwise and independent association was shown, with the risk of in-hospital death being highest in patients with a decline in platelet count >70% from baseline (OR, 13·4; 95% CI, 6.5 – 27·6), followed by those who had a platelet count reduction of 50 to 70% (OR, 4·01; 95% CI, 2·14 – 7·53), despite adjustments for important covariates [31].

Another consideration that is worthy of comment is the fact that many of the antithrombotic agents used in the context of ACS have been previously associated with the development of TP (i.e. Abciximab [2·5 - 5·6%], Eptifibatide [1·2 - 5%]), Tirofiban [1·5%], unfractionated heparin [2-3%]) [32-36].{Chong, 2006 #27544;Shantsila, 2009 #8439;Brener, 2002 #29455;Dyke, 2000

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#9762} Notwithstanding, it appears that the association between TP and mortality was independent of the treatment allocation in studies on acquired TP. For example, in the large GRACE registry that included 52,647 patients with ACS, 1·6% of whom developed TP, the investigators categorized TP as having occurred in the setting of clinically recognized heparin-induced thrombocytopenia (HIT), with the use of glycoprotein IIb/IIIa inhibitors or neither [6]. Patients with TP were at similarly increased risk of death, MACE and bleeding, whether they had developed it in the context of antithrombotic therapy or not. Hence, the aetiology of TP, when available, did not appear to influence the natural history of these patients in the context of ACS.

The link between TP and the incidence of adverse bleeding outcomes is intuitive and proportional to the severity of platelet count drop as shown by many of the studies informing this

meta-analysis [4, 5, 8, 9, 12, 13]. In a post-hoc meta-analysis evaluating in-hospital and long-term bleeding risks in patients with NSTE-ACS, patients with mild or severe acquired TP had significantly higher rates of in-hospital GUSTO moderate -severe bleeding compared to those without TP (7·7% and 28·2% vs. 5·2% respectively, p < 0·001) [12]. In fact, the development of severe TP was associated with a 7-fold increase in bleeding hazard (adjusted HR 6·93; 95% CI 4·55 – 10·56). Post-discharge bleeding after PCI has been associated with a dramatically increased risk of all-cause mortality, including cardiac death [37]. More importantly, the patients who present with bleeding are also more likely to see their antiplatelet therapy interrupted or discontinued, thus leaving them unprotected against potentially fatal ischemic events. While this has been acknowledged in several studies, the peri-TP modifications in treatment are often not reported. In a post-hoc analysis of the SYNERGY trial, Vora and colleagues demonstrated that patients with severe acquired TP were less likely to be prescribed antiplatelet agents such as aspirin and clopidogrel upon hospital discharge in comparison to patients with mild or no TP [12]. In the

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ACFAS study, TP patients were less likely to receive long-term clopidogrel [27]. Taken together, these findings highlight the possibility that patients who develop TP in the context of ACS may be less likely to receive optimal antithrombotic therapy due to a perceived higher risk of

bleeding, which may in turn lead to further ischemic complications and death.

Limitations

We used raw event rates in our meta-analysis model, which we adjusted for age and sex from aggregate baseline characteristics. Although study-specific adjusted risk estimates might have provided a more robust association [38], the disparity in study-specific measures, choice of covariates and the statistical method by which the adjustment was undertaken in each study made this impossible. The presence of unmeasured confounding variables at the individual level in this high-risk patient population is possible. Not all of the studies informing this meta-analysis reported the evaluated outcomes at every time point (i.e. 7 days, 30 days, and 1 year); this raises the possibility of selection and survival bias. In addition, given that the composite of ischemic endpoints varied among the included studies, we defined MACE according to study investigators (see Table 2 for study-specific definitions), which may be reflected in the higher than expected level of MACE seen in our meta-analysis.

Conclusion

Thrombocytopenia is a prevalent condition in patients admitted for an ACS and identifies a high-risk patient population more likely to experience ischemic or bleeding complications, as well as mortality. The findings presented in this meta-analysis contribute to the growing body of evidence that supports the importance of recognizing this haematologic abnormality as a

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develops during hospitalization. Further studies are warranted in order to establish whether the association between TP and adverse outcomes is causal or a marker of illness acuity in patients admitted for an ACS.

Acknowledgments

This work was funded by a grant from the Faculty of Pharmacy, Université de Montréal. V.D. was supported by an internal award from the Faculty of Medicine, Université de Montréal. M.E.S. is a Canadian Institutes of Health Research (CIHR) New Investigator. E.M.J. is supported by research grants from the Fonds de Recherche du Québec en santé (FRQS), the Canadian Institutes for Health Research (CIHR), the Canada Foundation for Innovation (CFI), the AGE-WELL Network of Centres of Excellence (NCE), and by the Fondation de l’Institut de

Cardiologie de Montréal. M.L. is supported by research grants from the Fonds de Recherche du Québec en santé (FRQS), the Canadian Institutes for Health Research (CIHR), the Canada Foundation for Innovation (CFI), Diabetes Quebec, and by the Fondation de l’Institut de Cardiologie de Montréal.

Declaration of interest

V.D., M.E.S. and G.R. have no relationship with industry to disclose. E.M.J. holds research grants from AstraZeneca. M.L. has received in-kind and financial support for investigator-initiated grants from Roche Diagnostics, Aggredyne and LEO Pharma.

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Table 1. Main characteristics of included studies

Study / Design Main Underlying Condition (Patients with ACS, %) Incidence of TP Sample size Baseline Factors Independently Associated with TP Follow-Up Time Clinical Outcomes Main Findings PRE-EXISTING THROMBOCYTOPENIA Overgaard et al., 2008 Retrospective study Elective PCI; Urgent ACS (UA, NSTEMI, STEMI)

(100%)

5·9%

n = 10,821 Not reported HospitalIn- mortality, MI,All-cause MACE, Major Bleeding ↑ Mortality ↑ MACE ↑ Major Bleeding Kiviniemi et al., 2013 Prospective analysis from AFCAS registry Atrial fibrillation and PCI for stable

angina, UA, NSTEMI, STEMI

(57%)

11%

n = 861 Not reported months12 All-causemortality,

MACCE, MI, TIA/Stroke, Stent thrombosis, Revascularization, Major/Minor Bleeding No significant differences in risk for ischemic or bleeding outcomes were detected Yadav, 2016 Post-hoc analysis from ACUITY and HORIZONS-AMI trials NSTEMI (100%) 5·7%

n = 10,603 Older Age (perMale gender, year), Diabetes, Previous CABG, baseline haemoglobin (g/dL) 30-day, 1

year mortality, CardiacAll-cause Death, MACE, Recurrent MI, TLR, Major /Minor Bleeding ↑ Mortality ↑ Cardiac Death ↑ MACE ↑ TLR Ali, 2016 Post-hoc analysis from hospital registry STEMI (0·5%), NSTEMI (8%), ACS (39%) and Stable Angina 11·4%

n = 7,505 Not reported hospital,

In-1 year All-cause mortality, MACE, Recurrent MI, Urgent TLR, Major /Minor Bleeding ↑ Mortality ↑ MACE ↑ Recurrent MI ↑ Major bleeding

(22)

study Major /Minor

Bleeding ischemic orin risk for bleeding outcomes were detected

IN-HOSPITAL ACQUIRED THROMBOCYTOPENIA

Harrington et al., 1994 Post-hoc analysis

from TAMI trial

STEMI (100%) 16·4%

n = 874

Not Reported

In-Hospital All-cause mortality ↑ Mortality McClure et al., 1999 Post-hoc analysis from PURSUIT trial NSTEMI (100%) 7·0% n = 9,101

Age (per 10-year increments), Female Gender, Baseline PC, CABG, Eptifibatide, IABP, History of PTCA, Moderate/Severe Bleeding 30 days All-cause mortality, MACE, MI ↑ Mortality ↑ MACE ↑ MI Kereiakes et al., 2000 Post-hoc analysis from EPIC, EPILOG and EPISTENT trials Ischemic heart disease, Stable Angina UA, AMI

(74%) 2·4% n = 7,290 Age >65y, Weight <90kg, Baseline PC (<200 x 109/L), Abciximab 30 days All-cause mortality, MI, Revascularization, Bleeding ↑ Mortality ↑ Major & Minor Bleeding Eikelboom et al., 2001 Post-hoc analysis from OASIS-2 trial NSTEMI (100%) 1%

n = 8,913 Not reported 7 days, 6months mortality, MI,All-cause Refractory angina ↑ Mortality ↑ MACE Merlini et al., 2004 Post-hoc analysis from TARGET trial

Stable CAD, ACS (proportion not

reported)

2·4%

n = 4,797 Not reported 30 days mortality, MI,All-cause Urgent TVR,

↑ Mortality ↑ MACE ↑ Urgent

(23)

Post-hoc analysis from CADILLAC trial Baseline PC (<200 x 109/L), Admission statins, Admission aspirin, Abciximab ↑ MACE Yeh et al., 2007 Post-hoc analysis from TIMI 11B trial UA, NSTEMI

(100%) n = 3,9102·4% Not reported 14 days mortality, MI,All-cause

Urgent revascularization, Major Bleeding ↑ Mortality ↑ MACE ↑ MI ↑ Major Bleeding Wang et al., 2009 Post-hoc analysis from CRUSADE registry NSTEMI (100%) 13%

n = 36,182 Low BMI, LowFemale gender, baseline PC, Low CrCl, High admission HR, Low admission systolic BP, PCI, ST depression, White race

In-Hospital mortality, MajorAll-cause Bleeding ↑ Mortality ↑ Major Bleeding Gore et al., 2009 Post-hoc analysis from GRACE registry STEMI, NSTEMI,

UA (100%) n = 52,6471·6% Not Reported HospitalIn- mortality, MI,All-cause Stroke, Major Bleeding ↑ Mortality ↑ MI ↑ Major Bleeding Caixeta et al., 2011 Post-hoc analysis from ACUITY trial

Moderate and

High-Risk ACS (100%) n = 10,8366·8% Older age, Male,gender, PCI triage, Prior MI,

Prior CABG

30 days,

1 year mortality, MI,All-cause Unplanned revascularization, NACE, Major/Minor Bleeding ↑ Mortality ↑ MACE ↑ Revasculari zation ↑ Major/Mino r Bleeding Vora et al., 2014 Post-hoc analysis from SYNERGY trial NSTEMI (100%) 11%

n = 7,435 Not Reported 1 year All-causemortality,

moderate/severe bleeding ↑ Mortality ↑ Major/Mino r Bleeding Ali et al., 2016 Post-hoc analysis from hospital registry STEMI (0.5%), NSTEMI (8%), ACS (39%) and Stable Angina 6%

n = 7,505 Older age, Malegender, Low baseline PC, STEMI indication, IABP use In-hospital, 1 year All-cause mortality, MACE, Recurrent MI, Urgent TLR, Major /Minor Bleeding ↑ Mortality ↑ MACE ↑ Recurrent MI ↑ Major bleeding

(24)

infarction; NSTEMI, non-ST segment elevation myocardial infarction; PC, platelet count; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack; TLR, target lesion revascularization; TP, Thrombocytopenia; TVR, target vessel revascularization; UA, unstable angina.

(25)
(26)

PRE-EXISTING THROMBOCYTOPENIA

Overgaard

et al., 2008 < 150 All-cause mortality

Composite of in-hospital patient death and

post-procedural myocardial infarction As per TIMI major bleedingcriteria*

Kiviniemi

et al., 2013 < 150 All-cause mortality

Composite of all-cause mortality, myocardial infarction, repeat revascularization, stent thrombosis, transient ischemic attack (TIA), stroke, other arterial embolism

and venous embolism

As per BARC major bleeding criteria†

Yadav et

al., 2016 < 150

Primary outcome: All-cause mortality, Secondary outcome: Cardiac and

non-cardiac death

Composite of death, reinfarction and target vessel

revascularization As per HORIZONS-AMI majorbleeding criteria‡ Ali et al.,

2016 < 150 All-cause mortality

Composite of death, reinfarction, urgent repeat

revascularization and stroke As per HORIZONS-AMI majorbleeding criteria‡ Raphael et

al., 2016 < 100 All-cause mortality

Composite of in-hospital death, Q-wave myocardial

infarction, emergent CABG and stroke As per BARC major bleedingcriteria†

IN-HOSPITAL ACQUIRED THROMBOCYTOPENIA

Harrington et al., 1994

<100 or <50% of

baseline All-cause mortality Not reported Not reported

McClure et

al., 1999 <100 of <50% ofbaseline All-cause mortality Composite of death and nonfatal myocardial infarction Not reported

Kereiakes

et al., 2000 < 100 All-cause mortality

Composite of all-cause mortality, myocardial infarction

and urgent coronary revascularization As per TIMI major bleedingcriteria*

Eikelboom

et al., 2001 < 100 All-cause mortality

Composite of death, reinfarction, refractory angina and requiring an additional percutaneous or surgical

intervention

Fatal bleeding, life threatening and permanently or significantly disabling or requiring transfusion of

≥ 2 units of blood or surgical intervention

Merlini et al., 2004

<100 or ≥ 25% decrease from

baseline All-cause mortality

Composite of death, myocardial infarction or urgent

target revascularization As per TIMI major bleedingcriteria*

Nikolsky et

al., 2005 ≤100

Primary outcome: All-cause mortality, Secondary outcome:

Cardiac death

Death from any cause, reinfarction, target vessel revascularization as a result of ischemia or disabling

stroke Not reported

Yeh et al., 2007

<100 or >50% decrease from

baseline All-cause mortality

Composite of all-cause mortality, recurrent myocardial infarction or urgent revascularization

Overt bleeding resulting in death; retroperitoneal, intracranial, or intraocular bleeding; a decrease in haemoglobin ≥ 3g/dL or the need to

(27)

plus haemoglobin drop of 3 to <5 g/dL, any transfusion with overt bleeding (2) Type 3b: Overt bleeding plus haemoglobin drop ≥5 g/dL, cardiac tamponade, bleeding requiring surgical intervention for control, bleeding requiring intravenous vasoactive agents (3) Type 3c: Intracranial haemorrhage (does not include microbleeds or haemorrhagic transformation, does not include intraspinal), subcategories confirmed by autopsy or imaging or lumbar puncture, intraocular bleeding compromising vision. ‡HORIZONS-AMI defined major bleeding as intracranial or intraocular haemorrhage; bleeding at the access site, with a haematoma that was ≥ 5 cm, or that required intervention; a decrease in haemoglobin level of ≥ 4g/dL without an overt bleeding source of ≥ 3g/dL with an overt bleeding source, repeated surgery for bleeding.

(28)

Note: Continuous variables are represented as meta-analytic weighted mean ± standard deviation.

BMI, body mass index; CABG, coronary artery bypass graft; MI, myocardial infarction; N/A, not available; PCI, percutaneous coronary intervention; TP, thrombocytopenia.

No TP (n = 179,717) Pre-existing TP(n = 2,407) Acquired TP(n = 8,791) Gender Male 118,645 (66%) 1,976 (82%) 5,844 (66%) Age, y 65·0 ± 8·8 68·1 ± 10·9 69·8 ± 6·2 Weight, kg 81·7 ± 19·7 N/A 79·2 ± 11·6 BMI 28·3 ± 3·0 27·6 ± 5·2 27·9 ± 2·5

Baseline Platelet Count (×109/L) 245·5 ± 48·8 123·5 ± 24·6 184·9 ± 20·3

Current Smoker 22,239 (30%) 589 (27%) 687 (23%) Diabetes 48,759 (27%) 931 (39%) 2,919 (33%) Hyperlipidemia 61,213 (62%) 1,302 (74%) 4,352 (57%) Hypertension 118,007 (66%) 1,823 (76%) 6,264 (71%) Recent MI 55,931 (31%) 742 (31%) 2,914 (34%) Prior PCI 37,419 (22%) 498 (32%) 1,974 (24%) Prior CABG 26,629 (15%) 544 (22%) 1,929 (22%)

(29)

presenting with an ACS

Outcome Pre-existing TP Acquired TP Heterogeneity

Risk Difference Standard Error t value p Risk Difference Standard Error t value p p - valueχ2

1. All-Cause Mortality 1·8% 1·3% 1·38 0·17 4·3% 0·9% 4·46 0·04 0·005 2. Cardiac Death 12·7% 5·9% 2·16 0·27 8·7% 5·9% 1·48 0·38 0·002 3. MACE 5·0% 4·8% 1·04 0·31 8·5% 3·9% 2·20 0·037 1·00 4. Myocardial Infarction 1·4% 2·3% 0·59 0·56 1·8% 1·5% 1·19 0·25 0·005 5. Revascularization 1·2% 1·9% 0·63 0·55 3·1% 1·6% 2·02 0·07 1·00 6. Major Bleeding 2·6% 4·1% 0·64 0·53 11·9% 3·6% 3·29 0·005 0·05 7. Minor Bleeding 5·2% 3·7% 1·42 0·21 7·8% 4·0% 1·95 0·09 0·01

(30)

Figure 1. Flow diagram showing study selection.

CAD: coronary artery disease; IPF: immature platelet fraction; MPV: mean platelet volume; PC: platelet count; PCI: percutaneous coronary intervention; PDW: platelet distribution width; TP: thrombocytopenia.

Figure 2. Forest plot of pooled analysis for studies in patients presenting with ACS presenting with (A) in-hospital acquired TP and (B) pre-existing TP.

SE: Standard Error; IV: Inverse Variance; CI: Confidence Interval; MACE: Major Adverse Cardiovascular Events; TP: Thrombocytopenia.

Note: For certain outcomes (i.e. cardiac death, Figure 2B) reported p values may not correspond to 95% confidence intervals given that they were computed using different methods: (1) Mixed models were fit using R package lme4 and function lmer (2) t-tests used Satterwaite approximations to degrees of freedom (default method in lmer) (3) 95% confidence intervals were calculated using the lme4 package. Models were adjusted for age and sex.

Figure 3. Event rates for all-cause mortality (A) and MACE (B). MACE: Major Adverse Cardiovascular Events; TP: Thrombocytopenia.

Figure 4. Forest plots demonstrating pooled risk-differences for all-cause mortality, MACE and major bleeding at 7 days, 30 days and 1 year for studies investigating ACS patients with (A) in-hospital acquired TP and (B) pre-existing TP.

(31)
(32)

(B)

(33)
(34)
(35)

A

(a) All-cause Mortality

(b) MACE

(c) Major Bleeding

B

(36)

Figure

Table 1. Main characteristics of included studies

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