D-dimer for risk stratification and antithrombotic treatment management in acute coronary syndrome patients: a systematic review and metanalysis

We conducted a systematic review of literature searching MEDLINE via PubMed and Scopus databases using a combination of the following keywords: “D-dimer” and “myocardial infarction” and “coronary artery disease” and “acute coronary syndrome”. There was no time restriction and the last search was run on May 1, 2021. We included only journal articles in English language with full text available. We excluded case-control studies, case reports, editorials/comments, letters, review and meta-analysis, and experimental studies. Supplementary Fig. 1 report strategy searches which were performed according to the PRISMA guidelines. The systematic review was registered at PROSPERO (https://​www.​crd.​york.​ac.​uk/​PROSPERO) with registration number CRD42021267233.

Two physicians (FGB, DP) independently screened the titles and abstracts of manuscripts identified through the database searches to identify studies potentially eligible for further assessment. A third physician (GT) reviewed eligible studies for appropriateness and completeness. The study selection was performed in multiple phases. In the first phase, potentially relevant studies were obtained by combined searches of electronic databases using the selected above-mentioned keywords and exclusion criteria. In the second phase, potentially eligible studies were reviewed to assess the appropriateness with the study question. Finally, the quality of pertinent studies included in the metanalysis was assessed by the Newcastle–Ottawa scale. Studies with a score ≥ 7 were considered of good quality. Quality assessment is reported in Supplementary Table 1.

The principal endpoint was a composite of cardiovascular events (CVEs) including MI, all-cause and cardiovascular mortality. The type of endpoint reported in each study is given in Table 1. Given the lack of high-quality studies, the association between D-dimer and no-reflow was not formally analysed but only systematically reviewed. Ethical approval was not required given the study type.

When available, hazard ratios (HRs) and odds ratios (ORs) were recorded from each study.

A separate meta-analysis was conducted for each endpoint, using a hierarchical Bayesian model which therefore would take into account heterogeneity among studies. This technique was chosen due to the limited number of studies included. Formally, each study-specific effect was assumed to be distributed according to a log-Gaussian random variable, centered on a pooled effect. The variance on the log-scale was assumed to correspond to 1.25 times the squared standard error, as evaluated through confidence intervals reported in each study.

All analyses were conducted with R version 3.5.1, using the ‘metafor and ‘adaptMCMC’ packages.

The association between D-dimer levels and clinical outcomes has been investigated in populations enrolled using different definitions of ischemic heart disease, such as CAD, ST segment elevation myocardial (STEMI), non-ST segment elevation myocardial infarction (NSTEMI), acute MI and acute coronary syndrome (ACS). Characteristics of these studies have been separately described according to each definition (Table 1). Supplementary Table 2 and Supplementary Table 3 display the method used to dose D-dimer, cut-off levels and antithrombotic therapy across included studies.

In the past decades, an increasing number of biomarkers have been tested to improve cardiovascular risk stratification in patients with ACS [6, 53]. In particular, some studies suggested that the use of a combination of multiple biomarkers may improve risk stratification. This is the case of D-dimer, which if used alone is currently recommended to only exclude acute venous thromboembolism, but its addition to other biomarkers/risk scores gave promising results.

Indeed, the addition of D-dimer has been investigated to some biomarkers such as C-reactive protein (CRP), NT-proBNP and clinical scores, such as the Global Registry of Acute Coronary Events (GRACE) risk score has been investigated. Fu et al. included D-dimer levels ≥2.4 mg/L FEU in a risk score model together with CRP, left ventricular ejection fraction, age ≥ 65 years old and heart rate [32]. In ROC curve analysis, this model demonstrated a good power in predicting in-hospital mortality (AUC = 0.895, 95% CI 0.814–0.96; p <  0.001), better than the predictive power of the GRACE risk score alone (AUC = 0.754, 95% CI 0.641–0.868; p <  0.001). D-dimer has been tested combined to GRACE score also in the study by Lin et al. who found that the combination of NT-pro-BNP and D-dimer improved the predictive accuracy of GRACE score for all-cause death [29]. In 5923 ACS patients undergoing PCI, GRACE score combined with D-dimer achieved a better prognostic performance than GRACE score, and D-dimer could significantly improve the prognostic performance of GRACE score [35]. This result is in keeping with that described by Yu et al., in which [35] D-dimer levels significantly improved the prognostic performance of GRACE score.

Altogether, current evidence suggest that D-dimer may identify patients at higher risk for a more severe CAD and worse prognosis. Of note, clotting activation is not lowered by antiplatelet therapy [54], as shown by previous studies reporting no effect of aspirin and DAPT in reducing D-dimer levels [55]. Conversely, oral and parenteral anticoagulation, in addition or not to DAPT, has been demonstrated to decrease D-dimer levels in patients with MI [41, 56, 57]. Thus, ATLAS ACS 2-TIMI 51 and COMPASS trials have recently proved the utility of adding low-dose anticoagulation to antiplatelet medications. In ATLAS ACS 2-TIMI 51, introduction of low-dose rivaroxaban therapy (2.5 mg or 5 mg twice daily, with 93% of patients on DAPT) has shown to be effective in reducing the risk of death from cardiovascular causes, myocardial infarction, or stroke [58], even if the use of rivaroxaban increased the risk of major bleeding and intracranial haemorrhages. Similarly, the COMPASS trial demonstrated that rivaroxaban plus aspirin was effective in decreasing the primary outcome of cardiovascular death, stroke or MI with a 22% reduction in the net clinical benefit endpoint (defined as the composite of primary outcome, fatal bleeding and symptomatic bleeding into a critical organ/area) [59]. Moreover, a sub-analysis of the COMPASS trial has shown that patients with high thrombotic profile (i.e., peripheral arterial disease) may benefit more from adding anticoagulation therapy to reduce residual thrombotic risk.

However, these studies did not stratified patients according to D-dimer levels. Data from the literature let to hypothesize that the benefit conferred by an association therapy of oral anticoagulation and antiplatelet therapy may be even more evident in patients with the features of clotting activation (i.e. high D-dimer). This aspect would deserve a specific investigation.

Another group of patients who deserve particular attention is represented by patients presenting with no-reflow. Preliminary data from the literature suggest an association between high-D-dimer levels and no-reflow. Moreover, in MI patients who cannot undergo cardiac catheterization, D-dimer concentrations may also be helpful to predict severity of coronary disease [60].

Finally, D-dimer levels might be helpful in identifying MI patients at high risk of complications and worse outcome. In Fig. 3, we propose a D-dimer guided strategy to tailored therapy in patients at higher thrombotic risk such as those with MI undergoing PCI. Firstly, MI patients with high D-dimer levels may benefit from specific pharmacological management and technical procedures to reduce the probability of no-reflow phenomenon. These include the use of glycoprotein IIb/IIIa inhibitors, higher heparin dose and direct stenting without predilation [61‐64]. Those high-risk patients might also take advantage from prolonged parenteral anticoagulation after PCI during in-hospital staying to reduce early complications. At discharge, patients presenting with high-risk features, including presence of comorbidities, multivessel disease, age > 65 years, recurrent MI, multiple stent insertion, may benefit from adding a low dose of oral anticoagulant agent to conventional antiplatelet therapy to reduce the residual thrombotic risk (i.e., rivaroxaban 2.5 mg twice daily).

Study limitations. A formal analysis for D-dimer against no-reflow phenomenon was not performed given the high variability in the methods of each study (cut-off of D-dimer used, measures of association) was not performed.