Systematic Review and Meta-Analysis of Thromboprophylaxis with Heparins Following
Intracerebral Hemorrhage
Epidemiological data show that in patients with intracerebral hemorrhage (ICH) the
occurrence of venous thromboembolism (VTE) is quite common[1]; some recent reports from the United States estimate that up to 3% of ICH patients
develop deep vein thrombosis (DVT) or pulmonary embolism (PE),[2] while other data indicate that the prevalence of symptomatic VTE could rise up to
10% of patients, of which 80% are asymptomatic episodes.[1] Still, thromboprophylaxis with heparin (either low-molecular-weight heparin [LMWH]
or unfractionated heparin [UFH]) is strongly underprescribed in ICH patients,[1]
[3] being prescribed in 8 to 17% of patients.[1]
[3] This is mainly driven by the fact that these patients are perceived to be of high
risk for bleeding by the treating physicians, as well as the limited related evidence
from randomized controlled trials which does not allow for high-quality strong clinical
recommendations ([Table 1]). The major guidelines that focus on the management of VTE risk or on the clinical
management of patients with ICH generally provide weak recommendation with an overall
low quality of evidence.[4]
[5]
[6]
[7]
[8]
[9] This is despite the intense interest into understanding the risk factors for bleeding
(especially in high-risk patient groups,[10]
[11]
[12] the long-term risks of bleeding after discontinuing anticoagulation therapy,[13] and improved efforts at bleeding risk stratification and balancing the risk–benefits
of reintroducing anticoagulation after a major bleeding event).[14]
[15]
Table 1
Guideline recommendations regarding thromboprophylaxis in patients with intracerebral
hemorrhage
|
Guideline
|
Year
|
Thromboprophylaxis recommended
|
Agent
|
Timing
|
Quality of evidence
|
|
ACCP[4]
|
2012
|
Yes[a]
|
LMWH/UFH
|
Not mentioned
|
Weak recommendation,
low quality of evidence (Grade 2C)
|
|
ESO[5]
|
2014
|
No
|
–
|
–
|
No formal recommendation
|
|
AHA/ASA[6]
|
2015
|
Yes
|
LMWH/UFH
|
1–4 days
|
Class IIb, level of evidence B
|
|
NCS[7]
|
2016
|
Yes
|
LMWH/UFH
|
Within 2 days
|
Weak recommendation,
low quality of evidence
|
|
ASH[8]
|
2018
|
Yes[a]
|
LMWH/UFH
|
Not mentioned
|
Strong recommendation,
moderate certainty of evidence
|
|
HSFC[9]
|
2020
|
Yes
|
LMWH
|
After 2 days
|
Evidence level B
|
Abbreviations: ACCP, American College of Chest Physicians; AHA, American Heart Association;
ASA, American Stroke Association; ASH, American Society of Hematology; ESO, European
Stroke Organization; HSFC, Heart and Stroke Foundation of Canada; LMWH, low-molecular-weight
heparin; NCS, Neurocritical Care Society; UFH, unfractionated heparin.
a Refers generically to critically ill patients and not specifically to intracerebral
hemorrhage.
In this issue of Thrombosis and Haemostasis, Chi and colleagues present a systematic review of the association between pharmacological
thromboprophylaxis with LMWH or UFH and the risk of VTE in patients with ICH.[16] After a methodologically robust systematic search and study selection, the authors
included 28 studies and a total of 3,697 hospitalized patients with ICH. The mean
patient age ranged between 50 and 72 years. The prevalence of risk factors and comorbidities
largely varied across studies. Among the studies which evaluated LMWH, dosing regimens
ranged between 20 and 40 mg daily (equal to 1,900 and 9,500 IU daily, respectively),
while among the studies evaluating UFH, doses varied between 5,000 IU/8 hours and
5,000 IU/12 hours. The outcomes assessed included DVT, PE, hematoma expansion or rebleeding,
major disability, and mortality.[16]
The investigators show that the use of pharmacological thromboprophylaxis was associated
with a significant reduction in the risk of DVT, both in fixed-effects model (risk
reduction [RR]: 0.24, 95% confidence interval [CI]: 0.28–0.32) and in the random-effects
model (RR: 0.27, 95% CI: 0.19–0.39). These estimates were corroborated by low grade
of heterogeneity (I
2 = 25%) and by a strict prediction interval (PI; 0.11–0.66), which is a statistical
tool used to examine the possible variation of pooled estimates according to future
studies performed in different clinical scenarios and with different clinical characteristics.
Furthermore, pharmacological thromboprophylaxis (RR: 0.33, 95% CI: 0.19–0.57 for the
fixed-effects model; RR: 0.37, 95% CI: 0.21–0.66 for the random-effects model) was
associated with a lower risk of PE without any heterogeneity (I
2 = 0%), with the PI substantially overlapping the estimates (CI: 0.20–0.69), strengthening
the results of the meta-analysis.[16] Moreover, pharmacological thromboprophylaxis was not associated with increased risk
for hematoma expansion or rebleeding (RR: 0.75, 95% CI: 0.48–1.18 for the fixed-effects
model; RR: 0.80, 95% CI: 0.49–1.30 for the random-effects model), with no heterogeneity
(I
2 = 0%) and overlapping PI. Also, a trend of reduced mortality was identified in patients
treated with pharmacological thromboprophylaxis (RR: 0.82, 95% CI: 0.65–1.03 for fixed-effects
model; RR: 0.83, 95% CI: 0.66–1.04 for the random-effects model; I
2 = 0%; PI: 0.60–1.15). Lastly, the fixed-effects model showed a higher risk for developing
major disability in patients treated with a pharmacological thromboprophylaxis (RR:
1.20, 95% CI: 1.04–1.38), but this estimate was based only on two studies, was characterized
by a high degree of heterogeneity (I
2 = 83%), and was not confirmed in the random-effects model analysis (RR: 1.02, 95%
CI: 0.62–1.65).[16]
To further support their results, the investigators performed several subgroup analyses
(according to study design, type of ICH and type of anticoagulant), which substantially
confirmed the main estimates. As a notable exception, the authors found that in patients
with spontaneous ICH, the effect of pharmacological thromboprophylaxis was not associated
with a reduction in VTE risk; however, this was based on a limited number of studies.
Also, the additional analyses showed that among randomized controlled trials, patients
receiving LMWH/UFH were associated with a lower risk of hematoma expansion or rebleeding
(RR: 0.53, 95% CI: 0.28–0.99; I
2 = 0%; p = 0.13 for test for subgroup differences).[16] Finally, it is noted that there was a significant overall risk of bias for most
of the studies enrolled, with eight studies being at high risk of bias.
The result of this meta-analysis adds some reassurance for the use of pharmacological
thromboprophylaxis with LMWH/UFH in patients with ICH and increases its implementation
in this patient group, given the low risk of DVT/PE, the trend in lower risk of death,
and the absence of any major bleeding complication (hematoma expansion or rebleeding).
Still, this conclusion needs to be further confirmed in future randomized trials.
During the last 13 years, the use of direct oral anticoagulants (DOACs) has increased
substantially and they largely replaced vitamin K antagonists as the treatment of
choice for most indications for oral anticoagulation.[17]
[18]
[19]
[20]
[21] In the management of VTE in medically ill patients, while DOACs showed a consistent
superiority over LMWH in the reduction of thromboembolic events, they were also associated
with an increase in the risk of major bleeding.[22] Notwithstanding this, a deeper analysis regarding the balance between the number
of fatal bleeding and fatal VTE events showed that the rate of fatal VTE is higher
than the rate of fatal bleeding. Also, a cost-effectiveness analysis indicated that
the use of DOACs for the prevention of VTE is cost-effective compared with the use
of LMWH.[22] Interestingly, none of the studies that tested DOACs for this indication included
patients with ICH, and three out of four of these studies listed ICH as an exclusion
criteria.[22] In this context, DOACs could be a candidate anticoagulation strategy to be tested
in patients with this specific clinical scenario in future trials.
Finally, these results have implications also for the wider population of patients
who have an indication for oral anticoagulation, but at the same time, they are at
increased risk of bleeding. Not infrequently, treating physicians are frequently skeptic
and reluctant to prescribe anticoagulant drugs in such patients and consequently,
these patients are less likely to be treated with anticoagulants, as it is the case
with atrial fibrillation patients who have a major bleeding during oral anticoagulant
treatment or with significant liver disease.[23]
[24]
[25]
[26] In these settings, the available evidence suggests an overall significant clinical
benefit if treated with oral anticoagulants.[25]
[26] The study by Chi and colleagues further strengthens this argument and underlines
that bleeding risk should not be a reason to withhold anticoagulation, but it should
rather serve as a flag for better control of bleeding risk factors.
In conclusion, in this large systematic review and meta-analysis, the authors demonstrated
that a pharmacological thromboprophylaxis with LMWH or UFH is associated with a significant
reduction in VTE ([Fig. 1]). While this study further underlines that higher bleeding risk should not be a
reason to withhold anticoagulant treatment, further studies are still needed to support
stronger recommendations and to further evaluate the use of other anticoagulant drugs
(i.e., DOACs) in these patients. Other considerations include better patient engagement
and highlighting the need for shared decision-making.[27]
Fig. 1 Risk reduction of venous thromboembolic events in patients with intracerebral hemorrhage
receiving thromboprophylaxis. LMWH, low-molecular-weight heparin; RRR, relative risk
reduction; UFH, unfractionated heparin.
