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Indian Heart Journal logoLink to Indian Heart Journal
. 2016 Jan 26;68(2):213–224. doi: 10.1016/j.ihj.2016.01.014

Administration of low molecular weight and unfractionated heparin during percutaneous coronary intervention

Sadegh Ali-Hassan-Sayegh a,⁎, Seyed Jalil Mirhosseini a, Azadeh Shahidzadeh a, Parisa Mahdavi a, Mahbube Tahernejad a, Fatemeh Haddad a, Mohammad Reza Lotfaliani a, Anton Sabashnikov b, Aron-Frederik Popov b
PMCID: PMC4867946  PMID: 27133344

Abstract

This systematic review with meta-analysis sought to determine the efficacy and safety of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) on clinical outcomes following percutaneous coronary intervention. Medline, Embase, Elsevier, and web of knowledge as well as Google scholar literature were used for selecting appropriate studies with randomized controlled design. After screening 445 studies, a total of 23 trials (including a total of 43,912 patients) were identified that reported outcomes. Pooled analysis revealed that LMWH compared to UFH could significantly increase thrombolysis in myocardial infarction grade 3 flow (p < 0.001), which was associated with similar target vessel revascularization (p = 0.6), similar incidence of stroke (p = 0.7), and significantly lower incidence of re-myocardial infarction (p < 0.001), major bleeding (p = 0.02) and mortality (p < 0.001). Overall, LMWH was shown to be a useful type of heparin for patients with MI undergoing PCI, due to its higher efficacy and lower rate of complication compared to UFH. It is also associated with increased myocardial perfusion, decreased major hemorrhage, and mortality.

Keywords: Unfractionated heparin, Low molecular weight heparin, Myocardial infarction, Percutaneous coronary intervention, Outcome

1. Introduction

Ischemic heart disease is the leading cause of morbidity and mortality worldwide, whereas it is expected to significantly increase the disease burden over the next 10 years.1 Ischemia-reperfusion injury (IRI) is a well-known phenomenon in thrombolysis, percutaneous coronary intervention, coronary artery bypass grafting, and cardiac transplantation. IRI is clinically manifested as a damage of myocardial cells due to myocardial stunning, microvascular injury, and myocyte necrosis.2 In patients with ST-segment elevation myocardial infarction (STEMI) or acute coronary syndrome without ST elevation (non-STEMI or unstable angina), early mechanical or pharmacological reperfusion, anti-thrombotic therapy with aspirin, thienopyridine, glycoprotein IIb/IIIa inhibitors, and unfractionated heparin (UFH) have become the standard of care and have been widely used for decreasing mortality and myocardial infarction (MI).3, 4 However, due to its structural defects, the utilization of UFH has many limitations, such as short half-life, low bioavailability, and non-specific binding to proteins that lead to variability of dose-anticoagulant effects.5, 6 On the other hand, UFH may activate platelets just a few minutes after administration and may lead to thrombocytopenia.5, 6 UFH has unpredictable pharmacokinetics; thus there is a need to monitor activated clotting time for adjusting the dose of UFH.7, 8, 9 Low molecular weight heparin (LMWH) is an alternative anticoagulant characterized by more predictable and stable anti-coagulation without the need for continuous infusion or tight monitoring of activated clotting time.7, 8, 9 Furthermore, it demonstrates less protein binding, less platelet activation and relatively greater inhibition of the coagulation cascade compared to UFH, as it has a ratio of 4.3:1 in its anti-factor Xa to anti-factor IIb activity.10 Several previous reports indicated that LMWH was shown to be non-inferior to UFH in terms of reducing the risk of morbidity and mortality at 30 days.11, 12, 13, 14 This systematic review with meta-analysis sought to determine the strength of evidence for evaluating the efficacy and safety of UFH and LMWH in patients with MI undergoing PCI.

2. Methods and materials

2.1. Literature search

A comprehensive literature search was conducted in major electronic databases (Medline/Pubmed, Embase, Elsevier, Web of Knowledge and Google Scholar) from their inception through July 20, 2014 to identify randomized controlled trials (RCTs) reporting on the use of UFH vs. LMWH including clinical outcomes in patients with MI undergoing percutaneous coronary intervention. Predefined search terms included: “unfractionated heparin”, “UFH”, “low molecular weight heparin”, “LMWH”, “enoxaparin”, and “myocardial infarction”, “MI”, “ST-segment myocardial infarction”, “STEMI”, “acute coronary syndrome”, “non-STEMI”, and “percutaneous coronary intervention”, “PCI”, and “angioplasty”. No language restrictions were applied. All retrieved references of the included RCT were also reviewed to determine additional studies not indexed in common databases. Studies were included into the analysis when they met the following criteria: (1) RCT, (2) reporting at least one of the outcomes of interest including: thrombolysis in myocardial infarction (TIMI) score, re-MI, stroke, thrombosis, major bleeding, target vessel revascularization (TVR), major adverse cardiovascular events (MACE), and mortality. Abstracts and manuscripts that did not undergo peer-review, duplicate reports and ongoing RCTs were not included.

2.2. Data extraction and outcome measures

Two investigators (S.A.-H.-S. and A.S.) extracted data independently, and discrepancies were resolved via a consensus standardized abstraction check-list used for recording data in each study. Data retrieved from trials included: author's name, country study design, details of therapeutic regimens, clinical scenario, sample size, follow-up duration, mean age and gender, and clinical outcomes of interest. For exploration of heterogeneity among the trials, a subgroup analysis of disparities in the patients’ characteristics was performed for1: follow-up (≤6 months vs. >6 months),2 clinical scenario of patients (STEMI vs. ACS and non-STEMI),3 type of administration (intravenous vs. subcutaneous),4 and sample size (≤500 vs. >500).

2.3. Definitions of endpoints

TVR was defined as ischemia-driven revascularization of the infarct-related artery with PCI and coronary artery bypass graft. Re-infarction was defined as recurrent symptoms suggestive of ischemia with ST-segment elevation and/or elevation of the levels of cardiac markers. TIMI 0 flow (no perfusion) refers to the absence of any antegrade flow beyond the occlusion; TIMI 1 flow (penetration without perfusion) is a faint antegrade flow beyond the occlusion, with incomplete filling of the distal coronary bed; TIMI 2 flow (partial perfusion) is a delayed or sluggish antegrade flow with complete filling of the distal territory; TIMI 3 flow (complete perfusion) is a normal flow, which fills the distal coronary bed completely. Mortality was considered cardiac, unless a non-cardiac cause of death could be established. MACE were defined as composition of death or MI or major cerebrovascular event.

2.4. Statistical analysis, publication bias and quality assessment

Data were analyzed by using STATA version 11.0 utilizing METAN and METABIAS modules. The effect sizes measured were odds ratio (OR) with 95% confidence interval (CI) for categorical variables. OR <1 favored LMWH and OR >1 favored UFH group. RCTs with no events in the two arms were discarded from pooled analysis. Forest plots were created for each outcome. Values of p < 0.1 for Q test or I2 > 50% indicated significant heterogeneity among studies. Heterogeneity among the trials was accounted for by applying a random effect model when indicated. The presence of publication bias was evaluated using Begg and Egger tests. Quality assessment of RCTs was performed using the Jadad score. The Jadad score assesses 3 items including randomization (0–2 points), blinding of study (0–2 points) and withdrawals and dropouts (0–1 points). Higher scores indicate better reporting (“high” quality: 5; “good” quality: 3–4; “poor” quality: 0–2). Results were considered statistically significant at a p-value <0.05.

3. Results

3.1. Literature search strategy and included trials

Our literature search retrieved a total of 445 studies from screened databases of which 295 (66.2%) were excluded after initial review (Fig. 1). Of 150 primary included studies, 127 were excluded after detailed evaluation due to insufficient information on endpoints of interest. Thus, the final analysis included 23 RCTs.

Fig. 1.

Fig. 1

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Forest plot of odds ratio (OR) for treatment with heparin on incidence of thrombolysis in myocardial infarction score 3 flow.

4. Study characteristics, effect measures and clinical outcomes

4.1. Thrombolysis in myocardial infarction grade 3 (TIMI-3)

A total of 14,276 patients were included from 6 RCTs reporting data on TIMI score (Table 1). Patient's populations of the RCTs ranged from 60 to 4676 patients. In this meta-analysis, 6890 patients were allocated to LMWH and 7385 to the UFH group. The overall incidence of TIMI-3 was 60.55% ranging from 9.89% to 97.49% (Table 2). Pooled treatment effect analysis revealed that LMWH compared to UFH therapy significantly increased TIMI-3 flow with an OR of 1.17 (95% CI: 1.074–1.284; p < 0.001) using the random effects model (Fig. 1). Significant heterogeneity was observed among the RCTs (chi-squared = 22.72, I2 = 78%, p < 0.001). A subgroup analysis is presented in Table 3. Pooled treatment effect analysis revealed that LMWH compared to UFH therapy significantly increased TIMI-3 flow in patients with STEMI (OR of 1.18; 95% CI: 1.07–1.29; p = 0.001) compared to ACS and non-STEMI patients (OR of 0.99; 95% CI: 0.60–1.68; p = 0.9), as well as intravenous administration (OR of 1.48; 95% CI: 1.29–1.71; p = 0.001) compared to subcutaneous administration (OR of 0.90; 95% CI: 0.70–1.14; p = 0.3). Begg and Egger tests showed that there were no potential publication bias among the included RCTs (Begg test, p = 0.188; Egger test, p = 0.188).

Table 1.

Demographic data of included studies.

Follow-up Study population Route of administration Male (%)
 Mean age (years)
 n
 Year/country Author (references)
UFH LMWH UFH LMWH UFH LMWH
In-hospital STEMI N.D. 70.4 66.3 65.7 67.9 5690 609 2008/Germany Zaymer15
In-hospital ACS N.D. 62.3 58.2 71.9 72.4 3628 1178 2006/Germany Zeymer16
1 month ACS Intravenous 69.3 68 67 67 2364 2323 2006/Germany SYNERGY Trial17
4 years STEMI Intravenous 73.3 76.6 61.2 60.5 60 60 2011/China Li18
1 month STEMI Intravenous 81.4 80.5 58 58 1431 1429 2005/USA CLARITY-TIMI 2819
1 month Angina pectoris Intravenous 73 83 60 61 30 30 1999/USA Rabah20
1 month Non-STEMI Intravenous 73.9 75.4 63.5 63.4 1230 2298 2006/France STEEPLE trial21
3 years STEMI and ACS N.D. 66.3 69.4 68.9 65.5 922 1932 2012/France FAST-MI22
1 month STEMI Intravenous 78 78.4 60 59 460 450 2011/France and Germany ATOLL trial23
1 month STEMI Combined 74.1 73.1 63 63 1693 759 2010/USA FINESSE trial24
1 month Non-STEMI Intravenous 72 77 64 59 100 100 2005/Canada ACTION trial25
8 months STEMI Subcutaneous 75.1 73.2 62.6 62.2 1841 1531 2010/Korea Li26
8 months Non-STEMI Subcutaneous 69.4 67.4 63.7 63.7 1219 1178 2012/Korea Li27
1 month STEMI Subcutaneous 82.5 82.3 55 56 448 498 2012/Canada TRANSFER-AMI trial28
1.2 years STEMI Combined 63.6 66.6 65 58 44 39 2008/USA Khoobiar29
1 month ACS Intravenous 63.3 67.6 64.4 61.2 71 68 2006/Korea Her30
1 month STEMI Combined 82.7 82.1 57 57 2404 2272 2007/Germany Ex-TRACT-TIMI trial31
In-hospital STEMI Intravenous 69.3 74 61 62 49 50 2002/Spain Galeote32
1 month STEMI and ACS N.D. 75 77 59 60 624 590 2003/Belgium ASSENT-3-PCI trial33
In-hospital STEMI and ACS Intravenous 56.8 54.9 54 54.6 271 222 2009/USA Diez34
1 month STEMI Intravenous 81.2 75.7 63.8 61.9 234 346 2010/Australia Brieger35
1 month STEMI and ACS Intravenous 75.8 76.7 63.7 63.3 132 129 2003/USA CRUISE trial36
1 month ACS Intravenous N.D. N.D. N.D. N.D. 440 436 2010/Switzerland Zeus37
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Table 2.

Clinical outcomes of included studies.

Jadad MACE
 Thrombosis
 Mortality
 Re-MI
 Major bleeding
 TVR
 TIMI 3 flow
 Stroke
 Author (references)
UFH LMWH UFH LMWH UFH LMWH UFH LMWH UFH LMWH UFH LMWH UFH LMWH UFH LMWH
1 842 62 N.D. N.D. 569 44 302 19 313 40 N.D. N.D. N.D. N.D. 46 9 Zeymer15
1 268 46 N.D. N.D. 123 32 149 14 163 61 N.D. N.D. N.D. N.D. 36 11 Zeymer16
4 336 304 N.D. N.D. 43 39 312 274 38 35 N.D. N.D. N.D. N.D. N.D. N.D. SYNERGY Trial17
2 4 2 1 1 3 1 3 3 1 0 1 1 N.D. N.D. N.D. N.D. Li18
4 180 109 400 315 68 44 101 54 31 23 N.D. N.D. 802 952 22 18 CLARITY-TIMI 2819
3 N.D. N.D. 0 0 0 0 0 0 1 1 N.D. N.D. 28 29 N.D. N.D. Rabah20
3 70 138 N.D. N.D. 5 13 65 126 34 28 8 22 N.D. N.D. N.D. N.D. STEEPLE trial21
2 N.D. N.D. N.D. N.D. 85 62 12 37 32 33 N.D. N.D. N.D. N.D. 8 19 FAST-MI22
3 155 126 2 4 29 17 20 10 22 20 N.D. N.D. 46 44 1 3 ATOLL trial23
4 135 40 N.D. N.D. 95 29 N.D. N.D. 78 21 N.D. N.D. N.D. N.D. N.D. N.D. FINESSE trial24
2 14 8 N.D. N.D. 0 0 14 8 0 0 0 0 N.D. N.D. 0 0 ACTION trial25
2 213 149 N.D. N.D. 116 45 8 2 11 8 26 27 1731 1428 N.D. N.D. Li26
2 92 89 N.D. N.D. 16 20 12 3 3 4 25 10 1189 1148 N.D. N.D. Li27
3 35 36 N.D. N.D. 11 12 21 22 18 17 N.D. N.D. N.D. N.D. N.D. N.D. TRANSFER-AMI trial28
2 4 3 0 1 3 1 N.D. N.D. 2 0 3 2 N.D. N.D. 2 0 Khoobiar29
2 N.D. N.D. 0 0 0 0 2 1 0 0 N.D. N.D. N.D. N.D. N.D. N.D. Her30
5 355 261 N.D. N.D. 71 66 53 53 39 32 N.D. N.D. 632 615 14 5 Ex-TRACT-TIMI trial31
3 7 7 10 12 0 1 3 4 4 1 N.D. N.D. N.D. N.D. N.D. N.D. Galeote32
2 23 18 N.D. N.D. 17 15 13 8 16 23 N.D. N.D. N.D. N.D. N.D. N.D. ASSENT-3-PCI trial33
2 N.D. N.D. 0 0 0 0 N.D. N.D. 6 2 N.D. N.D. N.D. N.D. N.D. N.D. Diez34
2 30 25 N.D. N.D. 17 11 6 2 21 27 N.D. N.D. N.D. N.D. N.D. N.D. Brieger35
3 10 11 1 1 0 0 10 11 2 3 1 0 N.D. N.D. N.D. N.D. CRUISE trial36
2 N.D. N.D. N.D. N.D. 0 0 N.D. N.D. 17 11 N.D. N.D. N.D. N.D. N.D. N.D. Zeus37
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Table 3.

Subgroup analysis for clinical outcomes.

Subgroup Studies (n) Odd ratio (95% CI) p-Value
S.G.A. for TIMI 3 flow according to OR
Sample size
 >500 5 1.174 (1.073–1.28) 0.001
 ≤500 1 2.071 (0.17–24.14) 0.561
Clinical scenario
 STEMI 4 1.181 (1.07–1.29) 0.001
 ACS and non-STEMI 2 0.999 (0.60–1.68) 0.997
Type of administration
 Intravenous 3 1.489 (1.29–1.71) 0.001
 Subcutaneous 2 0.900 (0.70–1.14) 0.396
Follow-up
 >6 2 0.900 (0.70–1.14) 0.396
 ≤6 4 1.224 (1.11–1.34) 0.001



S.G.A. for TVR according to OR
Sample size
 >500 3 0.938 (0.64–1.35) 0.733
 ≤500 3 0.674 (0.17–2.64) 0.571
Clinical scenario
 STEMI 3 1.193 (0.71–1.98) 0.499
 ACS and non-STEMI 2 0.727 (0.43–1.20) 0.218
Type of administration
 Intravenous 3 1.308 (0.62–2.74) 0.477
 Subcutaneous 2 0.821 (0.53–1.25) 0.362
Follow-up
 >6 4 0.820 (0.54–1.23) 0.341
 ≤6 2 1.334 (0.61–2.87) 0.463



S.G.A. for stroke according to OR
Sample size
 >500 6 0.964 (0.69–1.33) 0.827
 ≤500 1 0.215 (0.01–4.62) 0.326
Clinical scenario
 STEMI 5 0.898 (0.59–1.36) 0.611
 ACS and non-STEMI 1 0.940 (0.47–1.85) 0.859
Type of administration
 Intravenous 2 0.915 (0.50–1.65) 0.770
 Subcutaneous – – –
Follow-up
 >6 2 0.971 (0.44–2.10) 0.940
 ≤6 5 0.935 (0.65–1.33) 0.713



S.G.A. for major bleeding according to OR
Sample size
 >500 15 0.868 (0.76–0.99) 0.036
 ≤500 6 0.499 (0.21–1.16) 0.110
Clinical scenario
 STEMI 11 0.860 (0.71–1.03) 0.106
 ACS and non-STEMI 6 0.889 (0.71–1.10) 0.284
Type of administration
 Intravenous 11 0.720 (0.57–0.89) 0.004
 Subcutaneous 3 0.904 (0.54–1.50) 0.699
Follow-up
 >6 5 0.579 (0.38–0.87) 0.009
 ≤6 16 0.894 (0.77–1.02) 0.110



S.G.A. for re-myocardial infarction according to OR
Sample size
 >500 13 0.756 (0.67–0.84) 0.001
 ≤500 5 0.838 (0.49–1.43) 0.518
Clinical scenario
 STEMI 9 0.665 (0.54–0.80) 0.001
 ACS and non-STEMI 6 0.785 (0.68–0.90) 0.001
Type of administration
 Intravenous 10 0.809 (0.71–0.92) 0.001
 Subcutaneous 3 0.624 (0.37–1.02) 0.063
Follow-up
 >6 4 0.837 (0.52–1.33) 0.456
 ≤6 14 0.755 (0.67–0.84) 0.001



S.G.A. for mortality according to OR
Sample size
 >500 14 0.661 (0.58–0.74) 0.001
 ≤500 3 0.551 (0.14–2.06) 0.376
Clinical scenario
 STEMI 11 0.659 (0.56–0.76) 0.001
 ACS and non-STEMI 4 0.934 (0.72–1.20) 0.600
Type of administration
 Intravenous 7 0.705 (0.55–0.89) 0.004
 Subcutaneous 3 0.598 (0.45–0.79) 0.001
Follow-up
 >6 5 0.445 (0.33–0.55) 0.001
 ≤6 12 0.767 (0.66–0.88) 0.001



S.G.A. for thrombosis according to OR
Sample size
 >500 2 0.737 (0.62–0.87) 0.001
 ≤500 4 1.289 (0.56–2.92) 0.544
Clinical scenario
 STEMI 5 0.754 (0.63–0.88) 0.001
 ACS and non-STEMI – – –
Type of administration
 Intravenous 5 0.754 (0.63–0.88) 0.001
 Subcutaneous – – –
Follow-up
 >6 2 1.778 (0.23–13.58) 0.579
 ≤6 4 0.750 (0.63–0.88) 0.001



S.G.A. for major adverse cardiovascular events according to OR
Sample size
 >500 13 0.765 (0.71–0.82) 0.001
 ≤500 5 0.788 (0.48–1.29) 0.348
Clinical scenario
 STEMI 11 0.714 (0.65–0.78) 0.001
 ACS and non-STEMI 5 0.851 (0.75–0.95) 0.007
Type of administration
 Intravenous 9 0.804 (0.72–0.89) 0.001
 Subcutaneous 3 0.886 (0.74–1.04) 0.156
Follow-up
 >6 4 0.875 (0.73–1.04) 0.138
 ≤6 14 0.745 (0.68–0.80) 0.001
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4.2. TVR

A total of 9961 patients were included from 7 RCTs reporting data on the incidence of TVR. Patient's populations of RCTs ranged from 83 to 3528 patients (Table 1). 5335 patients were allocated to LMWH, whereas 4626 to the UFH group. The overall incidence of TVR was 1.29% ranging from 0.38% to 6.02%. TVR occurred in 1.18% in LWMH group and 1.41% in UFH group (Table 2). Pooled analysis revealed that the incidence of TVR was similar between patients receiving LMWH or UFH with an OR of 0.916 (95% CI: 0.641–1.309; p = 0.6) using the fixed effects model (Fig. 2). No significant heterogeneity was observed among the RCTs (chi-squared = 7.62, I2 = 34.4%, p = 0.17). Begg and Egger tests showed that there were no potential publication bias among the included RCTs (Begg test, p = 0.453; Egger test, p = 0.453).

Fig. 2.

Fig. 2

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Forest plot of odds ratio (OR) for treatment with heparin on incidence of target vessel revascularization.

4.3. Incidence of stroke

A total of 22,688 cases were included from 8 RCTs reporting data on the incidence of stroke. After removing an RCTs with no events in 2 arms, a total of 22,488 patients were included in the meta-analysis from 7 remaining studies (Table 1). Patient's population of RCTs ranged from 83 to 6299 patients. In this analysis 7909 patients were allocated to LMWH and 14,579 to the UFH group. The overall incidence of stroke was 0.86% ranging from 0.4% to 2.4%. Stroke occurred in 0.82% in LMWH group and 0.88% in UFH group (Table 2). Pooled analysis revealed that the incidence of stroke was similar between LMWH and UFH groups with an OR of 0.941 (95% CI: 0.680–1.302; p = 0.7) using the fixed effects model (Fig. 3). No significant heterogeneity was observed among the RCTs (chi-squared = 8.75, I2 = 31.4%, p = 0.18). Begg and Egger tests showed that there were no potential publication bias among the included RCTs (Begg test, p = 1.000; Egger test, p = 1.000).

Fig. 3.

Fig. 3

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Forest plot of odds ratio (OR) for treatment with heparin on incidence of stroke.

4.4. Re-myocardial infarction

A total of 40,008 patients were included from 19 RCTs reporting data on the incidence of re-MI (Table 1). After removing a single study with “zero columns” in 2 comparative arms, from 39,948 remaining cases, 17,041 patients were allocated to LMWH and 22,907 to UFH group. The overall incidence of re-MI was 4.39% ranging from 0.29% to 12.5%. Re-MI occurred in 3.8% in LMWH group and 4.8% in UFH group (Table 2). Pooled analysis indicated that LMWH compared to UFH significantly decreased the incidence of re-MI with an OR of 0.759 (95% CI: 0.681–0.847; p < 0.001) using the random effects model (Fig. 4). Significant heterogeneity was observed among the RCTs (chi-squared = 42.62, I2 = 60.1%, p = 0.001). A subgroup analysis is presented in Table 3. Pooled treatment effect analysis revealed that LMWH compared to UFH therapy significantly decreased incidence of re-MI in patients with STEMI (OR of 0.66; 95% CI: 0.54–0.80; p = 0.001) and ACS and non-STEMI (OR of 0.78; 95% CI: 0.68–0.90; p = 0.001), whereas intravenous administration (OR of 0.80; 95% CI: 0.71–0.92; p = 0.001) was more effective than subcutaneous administration (OR of 0.62; 95% CI: 0.37–1.02; p = 0.06). Begg and Egger tests showed that there were no potential publication bias among the included RCTs (Begg test, p = 0.506; Egger test, p = 0.506).

Fig. 4.

Fig. 4

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Forest plot of odds ratio (OR) for treatment with heparin on incidence of re-myocardial infarction.

4.5. Major bleeding

A total of 43,912 patients were included from 23 RCTs reporting data on the incidence of major bleeding (Table 1). After removing 2 studies with “zero columns” in 2 comparative arms, from remaining 43,573 cases enrolled in the analysis, 18,359 were allocated to LMWH and 25,214 to UFH group. The overall incidence of major bleeding was 2.85% ranging from 0.29% to 8.27%. Major bleeding occurred in 2.12% in LMWH group and 3.37% in UFH group (Table 2). Pooled analysis indicated that LMWH compared to UFH significantly decreased the incidence of major bleeding with an OR of 0.856 (95% CI: 0.751–0.976; p = 0.02) using the random effects model (Fig. 5). Significant heterogeneity was observed among the RCTs (chi-squared = 30.51, I2 = 34.4%, p = 0.06). A subgroup analysis is presented in Table 3. Intravenous administration (OR of 0.72; 95% CI: 0.57–0.89; p = 0.004) was more efficient than subcutaneous administration (OR of 0.90; 95% CI: 0.54–1.50; p = 0.6) for decreasing the incidence of major hemorrhage. Begg and Egger tests showed that there were no potential publication bias among the included RCTs (Begg test, p = 0.235; Egger test, p = 0.235).

Fig. 5.

Fig. 5

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Forest plot of odds ratio (OR) for treatment with heparin on incidence of major bleeding.

4.6. Incidence of stent thrombosis

A total 5025 patients were included from 9 RCTs that provided data on thrombosis. Overall incidence of thrombosis was 14.88%; 13.48% in LMWH group and 16.24% in UFH group. In fact, 3 out of 9 comparisons did not present any thrombosis events in 2 comparative arms; therefore, the remaining 6 RCTs (4333 patients) were used to perform the meta-analysis. Pooled analysis indicated that LMWH compared to UFH significantly decreased the incidence of thrombosis with an OR of 0.754 (95% CI: 0.63–0.89; p = 0.4) using the fixed effects model. No significant heterogeneity was observed among the RCTs (chi-squared = 7.52, I2 = 0.0%, p = 0.6). Begg and Egger tests showed that there were no potential publication bias among the included RCTs (Begg test, p = 0.297; Egger test, p = 0.297).

4.7. MACE

A total of 39,490 patients were included from 18 RCTs reporting on the incidence of MACE. Overall incidence of MACE was 10.65%; 9.05% in LMWH and 11.7% in UFH group (Table 2). Pooled analysis indicated that UFH compared to LMWH significantly increased the incidence of MACE with an OR of 0.766 (95% CI: 0.71–0.82; p < 0.001) using the random effects model. Significant heterogeneity was observed among the RCTs (chi-squared = 29.76, I2 = 42.9%, p = 0.02). A subgroup analysis is presented in Table 3.

4.8. Mortality

Twenty-three RCTs (43,912 patients) reported on death. Mortality occurred in 2.43% (452 patients) in LMWH group and 5% (1271 patients) in UFH group. In fact, 6 out of 23 comparisons did not present any postoperative death events in 2 comparative arms; therefore, the remaining 17 RCTs (41,883 cases) were used to perform the meta-analysis. Pooled treatment effect analysis revealed that LMWH significantly decreased mortality with an OR of 0.66 (95% CI: 0.58–0.74; p < 0.001) using the random effects model (Fig. 6). Significant heterogeneity was observed among the RCTs (chi-squared = 40.6, I2 = 60.6%, p = 0.001). A subgroup analysis is presented in Table 3. Pooled treatment effect analysis revealed that LMWH compared to UFH therapy significantly decreased mortality in patients with STEMI (OR of 0.65; 95% CI: 0.56–0.76; p = 0.001) compared to ACS and non-STEMI (OR of 0.93; 95% CI: 0.72–1.20; p = 0.6). Intravenous administration (OR of 0.70; 95% CI: 0.55–0.89; p = 0.004) and subcutaneous administration (OR of 0.59; 95% CI: 0.45–0.79; p = 0.001) had statistically similar effects in terms of mortality.

Fig. 6.

Fig. 6

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Forest plot of odds ratio (OR) for treatment with heparin on incidence of mortality.

5. Discussion

UFH during PCI is a mainstay of thrombotic therapy, whereas it has to be adjusted on the basis of patient's activated clotting time.4, 5, 6, 7 Difficulties in achieving reliable levels of anti-coagulation due to its higher degree of protein binding, inactivation by platelet factor, tendency toward platelet activation and the risk of heparin-induced nephropathy cause limitations of UFH application.8, 9, 10 LMWH represents an alternative anticoagulant that provides more stable and predictable anticoagulation with no need to continuous infusion and anticoagulant monitoring.8, 9, 10

It is still unclear as what type of heparin is the most appropriate, safe and efficient anticoagulant for MI patients undergoing PCI. Our findings revealed that using LMWH was associated with significantly better TIMI flow compared to UFH; therefore, administration of LMWH should be preferred in order to achieve complete perfusion. Sabatine et al.19 also previously suggested that in order to improve TIMI flow and achieve complete perfusion, LMWH should be used, which is consistent with our findings. Our subgroup analysis showed that the incidence of optimal TIMI flow after MI was significantly different between the receivers of LMWH and UFH in terms of the route of administration (either intravenous or subcutaneous) and clinical scenario (either ACS, non-STEMI or STEMI).

TVR was defined as ischemia-driven PCI of target lesions due to re-stenosis or re-occlusion within the stent or in the adjacent 5 mm of the distal or proximal segment. The findings of our study indicated that the incidence of TVR was similar between LMWH and UFH groups; thus both heparin types were associated with comparable TVR. Li et al. claimed that following administration of enoxaparin, the incidence of TVR decreased with a tendency toward reduced re-MI.26, 27 According to our findings enoxaparin also significantly decreased the incidence of re-MI. Previous studies proposed LMWH to be a more potent anticoagulant in terms of decreasing re-MI compared to UFH. Our analysis of a larger body of literature and more subjects confirmed this stronger prophylactic effect of LMWH compared to UFH.

The results of our sensitive analysis showed that in terms of decreasing re-MI LMWH was superior to UFH for both stable and unstable patients especially when administered intravenously. Prophylactic effects against re-MI were shown to be stronger in cases of intravenous compared to subcutaneous administration; therefore, it can be suggested that for patients with a history of MI, intravenous administration of LMWH may be more beneficial than subcutaneous administration or the administration of UFH with the view to avoiding recurrent infarction.

Several studies showed that increased efficiency of LMWH may be accompanied by an increased risk of hemorrhage, especially in high risk patients, such as elderly patients with history of chronic renal impairment. In cases of renal impairment there is definite accumulation of LMWH, whereas no antagonist to LMWH is available. This accumulation might subsequently increase the risk of major bleeding episodes. Thus, the dose of LMWH needs to be adjusted in this fragile population.38, 39, 40, 41 Nevertheless, the results of our study showed that the risk of hemorrhage was significantly lower in LMWH receivers compared to UFH, particularly when administered intravenously; it was associated with better therapeutic response as well as less major bleeding. Puymirat et al.22 also reported that LMWH significantly reduced the risk of major bleeding, and this complication particularly decreased in cases of intravenous injections, which is in agreement with our study. Montalescot et al. stated that subcutaneous administration of enoxaparin was more common in stable and occult coronary syndrome patients; however, intravenous injection could be well adopted to PCI and emergency conditions pharmacologically.21 In addition, it provided urgent and predictable anticoagulation, which is effective for full 2 h.23, 24 Our findings also revealed that intravenous injection was the most effective route of administration of heparin. This advantage is achieved with a protocol that is simpler than that typically used for UFH: one intravenous bolus without anticoagulation monitoring, the same dose with or without glycoprotein IIb/IIIa inhibitors, and immediate sheath removal after femoral or radial PCI.42

Several preoperative risk stratification models such as the additive European System for Cardiac Operative Risk Evaluation (EuroSCORE) and Cardiac Surgery Score (CASUS) are currently in daily use in cardiac surgery.43, 44 These scores are population-based and offer a probability of occurrence in a set of patients with similar characteristics. A prediction of individual outcome especially mortality might be achieved. The present study, analyzing 43,912 patients, claims that administration of LMWH in comparison to UFH, is able to significantly reduce the risk of mortality in patients with MI. Our subgroup analysis demonstrated that administration of LMWH in STEMI patients could considerably reduce mortality, however, that did not have such effect in stable and ACS patients. Also both intravenous administration and subcutaneous administration of LMWH were found to be able to decrease mortality. Silvain et al. reported that LMWH had a remarkable preference to UFH for decreasing the risk of mortality.45

Patients may develop in-stent-thrombosis following PCI. This complication is of critical importance due to formation of blood clot and reduction of blood supply to distal vessels, and a decrease in reperfusion to the myocardium surrounding the site of thrombosis. Our results indicated that patients under LMWH therapy may less frequently develop thrombosis and MACE during PCI compared to UFH.

Finally, we can conclude that the most appropriate type of heparin for patients with MI undergoing PCI seems to be LMWH with higher efficacy and lower incidence of complications compared to UFH. LMWH administration is also more convenient with no need for continuous infusion or tight anticoagulation monitoring. Nevertheless, it is imperative that the outcome after PCI as a procedure in patients receiving either forms of heparin is dependent on many other factors, namely gender, comorbidities, time from onset of symptoms to hospitalization etc.

Conflicts of interest

The authors have none to declare.

Acknowledgments

We would like to thank Dr. Ali Akbar Karimi, and Dr. Ali Mohammad Dehghan for their assistance in writing this manuscript, and Dr. Zahra Ghodratipour, Dr. Zahra Sarrafan, Dr. Arezoo Shahidzadeh, and Dr. Rahimizadeh for their assistance in collecting data and statistical analysis.

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