Table 1 Clinical characteristics of studies investigating major adverse cardiac events and all-cause mortality included in the systematic review

 Biccirè 2021 [17]

STEMI

132

64

19.1

R

In-hospital

Adverse events (cardiogenic shock, resuscitated cardiac arrest and death).

Events vs control group: log-transformed D-dimer 6.8 ± 1.1 vs 6.3 ± 0.8, p = 0.019

Patients experiencing in-hospital adverse events had higher values of D-dimer compared to those free from events.

 Huang 2020 [18]

STEMI

1165

63.5

17

R

In-hospital

CVEs including cardiac death, non-fatal AMI, revascularization, and stroke.

≥ 800 vs < 800 ng/mL

Increased D-dimer level predicted CVEs (OR 8.408, 95% CI 4.065–17.392, P = 0.001). D-dimer AUC was 0.840 (95% CI 0.769–0.911). The best cut-off value was 640 ng/mL.

In the subgroup with no-reflow phenomenon, increased D-dimer predicted CVEs (OR 8.114, 95%CI 1.598–41.196, p = 0.012)

 Luo 2020 [19]

STEMI

400

62.5

21

R

12

CVEs (all-cause death, TVR, MI, UA, HF, stroke or TIA)

Groups (μg/L)

1: 74.0;

2: 146.0;

3: 256.5;

4: 576.0.

The incidence of CVEs and all-cause mortality within 30 days (p < 0.001), 6 months (p = 0.001), and 1 year (p = 0.001) after PCI in the highest quartile of the D-dimer groups were higher than those in the other 3 groups.

 Qi Zhou 2020 [20]

STEMI

872

63.7

19.8

R

29

All-cause mortality

Groups (μg/mL)

1: ≤0.33;

2: 0.33–0.64;

3: 0.64–1.33;

4: ≥1.33.

Higher in-hospital HF (40.2 vs 10.2%, p < 0.0001), malignant arrhythmia (14.2 vs 2.3%, p < 0.0001), and all-cause mortality (5.9 vs 0%, p < 0.0001) rates were observed in Group 4.

84 patients died. Group 4 was a predictor of all-cause mortality (HR: 2.53, 95%CI 1.02–6.26, p = 0.045).

 Lin 2020 [21]

STEMI

550

63.5

12.2

P

16

CI-AKI, in-hospital outcomes and long-term mortality and CVEs §

D-dimer quartiles (μg/mL):

1: < 0.38;

2: 0.38–0.67;

3: 0.68–1.03;

4: > 1.03 .

D-dimer > 0.69 μg/mL was an independent risk factor for long-term mortality (HR: 3.41 [95% CI, 1.4–8.03], p = 0.005) and CVEs

 Zhang 2018 [22]

STEMI

926

52.6

54.7

P

In-hospital

Mortality

383.1 ng/mL ± 264.2

Patients without pre-infarction angina with high D-dimer level on admission had significantly increased in-hospital mortality compared to the other patients (p = 0.041).

 Gao 2018 [23]

STEMI with T2DM

822

62.5

46.1

P

100

Mortality

D-dimer 430.0 ng/mL ± 256.8

Patients with high plasma D-dimer level on admission showed a significantly shorter survival time (p < 0.001 in the log-rank test).

 Hansen 2018 [24]

STEMI

971

61

20

cross-sectional cohort study

55

Composite of all-cause mortality, reinfarction, stroke, unscheduled revascularization, HF rehospitalization

Secondary outcome was total mortality

Median D-dimer

456 ng/mL (IQR 286–801).

Adjusted OR for composite endpoints for D-dimer above 456 ng/mL: 1.179 (95% CI, 0.814–1.706 p = 0.384)

Adjusted OR for total mortality for D-dimer above 456 ng/mL: 2.01 (95% CI, 1.06–3.83; p = 0.034)

 Sarli 2015 [25]

STEMI

266

64

38

P

in-hospital

CVEs: nonfatal MI, in-stent thrombosis, and in-hospital mortality during hospitalization.

D-dimer (μg/l):

686 (±236) vs 418 (±164), p < 0.001.

D-dimer level predicted CVEs (OR: 1.002; 95% CI: 1.000–1.004; p = 0.029).

Optimal cut-off value was 544 μg/mL for CVEs.

 Erkol 2014 [15]

STEMI

569

56

16

A

38

Mortality and CVEs (death, non-fatal MI, stroke, revascularization, and advanced HF at long-term follow-up)

D-dimer overall 0.40 mg/L (0.20–0.87).

Univariable HR for long-term mortality 1.56 (95%CI, 1.24–1.95, p < 0.001) and CVEs 1.60 (95%CI, 1.37–1.83, p < 0.001); not significant association at multivariable analysis.

 HORIZONS-AMI substudy 2014 [26]

STEMI

461

1st: 55.8

2nd: 61.0

3rd: 70.2

20.61

R

36

CVEs (composite of all-cause death, recurrent MI, stroke, or TVR for ischemia.)

Tertiles (μg/mL):

1: < 0.30 (n = 215)

2: 0.30–0.71

(n = 161)

3: ≥0.71 (n = 85)

D-dimer levels ≥0.71 μg/mL on admission predicted CVEs (HR 2.58 [95% CI, 1.44–4.63], p = 0.0014), compared to the lowest group.

 Ozgur Akgul 2013 [27]

STEMI

453

55.6

19.65

P

6

Mortality

High D-dimer group: > 0.72 μg/mL;

Low D-dimer group: lowest two tertiles

(≤0.72 μg/mL).

Highest tertile of D-dimer associated with in-hospital CV mortality and 6-month all-cause mortality (7.2 vs. 0.6%, p < 0.001 and 13.9 vs. 2%, p < 0.001, respectively).

Fatal reinfarction, advanced HF, and CVEs

were more frequent in high D-dimer group (p < 0.001).

 Pineda 2010 [28]

AMI STEMI (85.9%)

142

41

8.45

P

36

Adverse CV events included stroke, ACS, CABG/PCI, hospitalisation due to congestive HF, CV and global mortality.

Event 360.0 ng/mL vs no event 297.5 ng/mL, p = 0.314

No significant differences in D-dimer levels in the event group.

 Lu 2021 [29]

NSTEMI

1357

65

31.4

P

12

Mortality and CVEs including all-cause death, hospital admission for UA and/or HF, nonfatal recurrent MI and stroke)

0.380 μg/mL (0.27–0.65)

Event group (mortality at 1 year): 0.95 (0.50, 2.00)

Control group: 0.37 (0.26, 0.60)

HR for D-dimer for 1-year death and CVEs: 2.12 (95%CI, 1.50–2.99, p < 0.0001).

 Hulusi Satilmisoglu 2017 [30]

NSTEMI

234

57.2

24.8

R

14

Mortality

Non-survivors: 1568 ± 1489 ng/mL

Survivors: 632 ± 995 ng/mL

D-dimer correlated with GRACE (r = 0.215, p = 0.01) and TIMI scores (r = 0.253, p < 0.001). Higher levels recorded for D-dimer assay (p = 0.003) in non-survivors. At multivariate analysis, D-dimer assay no significant predictor of increased mortality risk.

 Tello-Montoliu 2007 [31]

NSTEMI

358

67.4

35.8

R

6

Death, new ACS, revascularization, and HF

Overall D-dimer level: 340 (211–615) ng/mL

Admission D-dimer levels did not predict events [HR: 1.26 (0.79–2.02), p = 0.337).

 Fu 2020 [32]

AMI with ESRD

113

69.2

33.6

R

In-hospital

Mortality

Mortality: 3.2 mg/L

Survival: 1.1 mg/L

p = 0.023

D-dimer ≥2.4 mg/L predicted in-hospital mortality (OR 2.771 [95% CI, 1.017–8.947], p < 0.001).

 Wang 2020 [33]

AMI

197

Male 61.8

Female 74.2

20

P

6

All-cause mortality (in- and out-of-hospital deaths) or readmission.

Male D-dimer (mg/L) 0.4 vs 1.0 P < 0.001

Female D-dimer (mg/L) 0.4 vs 0.6

p = 0.015.

HR for continuous D-dimer in women 2.029 (95%CI, 1.403–2.933; p < 0.001). D-dimer ≥0.43 mg/L as an independent predictor of poor prognosis in female AMI patients.

 Zhang 2020 [34]

AMI

4495

62

31.03

P

24

All-cause mortality

< 145 ng/mL

≥145 ng/mL

Elevated D-dimer was associated with mortality (univariable HR 1.20, 95%CI, 1.04–1.37, p = 0.01) and in the patients in different groups (HFpEF, HFrEF, non-HF).

 Yu 2019 [35]

AMI

5923

62.2

30.5

P

In-hospital

Mortality

D-dimer tertiles (ng/mL):

Low: ≤88; Intermediate: 89–179; High: > 179.

After multivariable adjustment, D-dimer significantly predicted in-hospital mortality (OR 1.060 [95% CI, 1.026–1.094], p < 0.001).

D-dimer levels significantly improved the prognostic performance of GRACE score (C-statistic: p = 2.269, p = 0.023; IDI: 0.016, p = 0.032; no-reflowI: 0.291, p = 0.035).

 REBUS study 2017 [36]

AMI

412

67

22.3

P

24

Composite endpoint (all-cause death, MI, congestive HF, or all-cause stroke)

Median D-dimer was 677 μg/L at inclusion

D-dimer was not associated with the composite endpoint (HR 1.22 [95% CI 0.99–1.51], p = 0.06, for one SD increase).

 Smid 2011 [37]

AMI

135

61

26

P

12

CV death, recurrent MI, a second PCI or CABG and ischemic stroke.

On admission D-dimer: 370 (260–718) ng/mL

D-dimer on admission was higher in patients with recurrent thrombotic CV event (medians 550 vs. 365 ng/mL, p = 0.06)

OR for D-dimer against endpoints: 2.9 (95%CI 0.9–8.8)

 THROMBO study 2000 [38]

AMI

1045

Male 58

Female 62

24.3

P

26

Recurrent cardiac events (nonfatal reinfarction or cardiac death)

D-dimer mean in men 508 ± 690 ng/mL vs women 564 ± 430 ng/mL

D-dimer had prognostic value in men (HR 2.35, 95%CI 1.27–4.35], p = 0.006) but not in women (HR 1.58, 95%CI 0.59–4.22, p = 0.360).

 Chen 2018 [39]

CAD (76.9% AMI)

238

64.4

21.1

P

24

All-cause mortality and CVEs (cardiac death and nonfatal outcomes: recurrent MI, TVR or re-admission due to advanced HF).

Mean D-dimer: 0.7 ± 1.1 mg/L.

OR for long-term CVEs: 1.526 (95% CI, 1.174–1.983), p = 0.002.

D-dimer in multivariate Cox regression of CVEs: 1.420 (1.069–3.014), p = 0.046

 Kosaki 2018 [40]

ACS (76.3% AMI)

400

71.1

27.2

P

27

CVEs (all-cause mortality, recurrent MI, unplanned repeat revascularization, surgical revascularization, fatal arrhythmia, admission for HF, and stroke.

Patients without CVEs: 1.67 mg/mL ±2.49

Patients with CVEs: 2.11 mg/mL ±2.72

p = 0.0003

Univariate analysis for D-dimer ≥0.84 mg/mL predicting CVEs: OR 2.49 (95%CI 1.54–4.11), p = 0.0001

 ATLAS ACS-TIMI46 Trial Substudy 2018 [41]

ACS (73.9% AMI)

1834

Placebo 57.9

Rivaroxaban 57.2

23.2

Post-hoc RCT

6

Composite endpoint of CV death, myocardial infarction, or stroke

Baseline D-dimer (μg/mL) Placebo 0.39 (0.24–0.73) vs Rivaroxaban 0.42 (0.24–0.78) p = 0.370

Continuous D-dimer prognostic factor for composite outcome: univariate OR 1.15 (1.03–1.29) p = 0.015, multivariate OR 1.13 (1.0–1.28) p = 0.048

 Mjelva, 2016 [42]

CAD (44.3% AMI)

871

69.5

38.7

P

84

All-cause mortality; a combined endpoint consisting of death or recurrent non-fatal MI; recurrent non-fatal MI alone.

194 (106–437) μg/L

Median D-dimer in survivors vs non-survivors

were for 153 vs 346 μg/L (p < 0.001)

D-dimer above 436 μg/L independently predicted mortality (4th vs 1st quartile HR 1.83 [95% CI 1.20–2.78], p = 0.005)

Death or MI (4th vs 1st quartile HR 1.38 [95% CI 0.96–1.98], p = 0.08)

Recurrent MI (4th vs 1st quartile HR 0.70 [95% CI 0.43–1.15], p = 0.16)

 Gong 2016 [43]

CAD (29.2% AMI)

2209

58.58

25.9

P

18

Cardiac death, nonfatal MI, recurrence of MI, and stroke

Tertiles (μg/mL)

1: < 0.23, n = 816;

2: 0.23–0.36, n = 629;

3: >  0.36, n = 764.

D-dimer was linked to the severity of CAD (95% CI: 1.20–6.84, p = 0.005)

Continuous D-dimer predictor of total outcome (HR = 1.22, 95% CI: 1.09–1.37, p = 0.001).

 Charoensri 2011 [44]

ACS (61% AMI)

74

66

54.1

R

In-hospital

CHF, arrhythmias and death

D-dimer levels (μg/L)

CHF: 1475 vs No CHF 385; Arrhythmia 5422 vs No arrhythmia 550; Death 5118 vs No death 2550

D-dimer levels correlated with complication of ACS (CHF; p < 0.001, arrhythmia; p = 0.007 and death; p = 0.009). D-dimer was significantly increased with the number of coronary arteries affected (p = 0.03).

 Brugger-Andersen 2008 [45]

STEMI (15%), NSTEMI (29,3%), UA (9,4%), No ACS (46,3%)

871

69.6

39

P

24

All-cause mortality, CVEs (cardiac death or recurrent positive troponin T)

Quartiles of D-dimer (μg/l):

Q1 < 106,

Q2 ≥ 106–191,

Q3 ≥ 191–438,

Q4 ≥ 438.

In the univariate analysis highest D-dimer quartile predicted all-cause mortality compared with the lowest quartile (Q1) (OR 7.78 [95%IC, 3.95–15.33], p < 0.001), but not confirmed at multivariable logistic regression analysis (OR 1.80 [95%IC, 0.81 to 3.97]; p = 0.148).

 Prisco 2001 [46]

CAD (52,9% AMI)

54

60 (44–75)

65 (38–81)

11.1

P

18

Restenosis

D-dimer before PCI: AMI (group 1) 55 ng/mL vs elective PCI (group 2) 29.0 ng/mL, p < 0.001

In group 1, D-dimer levels at the end of the procedure were higher in patients with restenosis than in those without (p < 0.005). Increased D-dimer in patients with restenosis (61%) than those without (25%, p < 0.05).

 Oldgren 2001 [12]

ACS

320

66

–

P

29

Death, MI, and refractory angina during and after anticoagulant treatment in unstable CAD

< 82 μg/L (N = 105); 82–149 μg/L (N = 106);

>  149 μg/L (N = 103)

No difference in clinical outcome at 72 h, 7 days and 30 days. During long-term follow-up, there was a relation between higher baseline levels of D-dimer and increased mortality (p = 0.003).