The new edition of the National Institute for Health and Care Excellence (NICE) guideline
(NG158) regarding venous thromboembolic diseases (VTDs) was published on March 26,
2020 (https://www.nice.org.uk/guidance/ng158). Given the common occurrence and health care burden of venous thromboembolism (VTE)
in clinical practice, as well as the heterogeneity in its presentations, risk factors,
and outcomes,[1]
[2]
[3] the NICE guidance provides welcomed evidence-based recommendations, based on systematic
reviews, evidence appraisal, and cost effectiveness. This approach is different from
some other guidance, which may be more eminence-based rather than having a formally
appraised evidence-base.
Compared with the previous edition, there are some changes and new recommendations
on diagnosis and management of VTD in adults ([Fig. 1]).
Fig. 1 Diagnostic pathway of (A) deep vein thrombosis (DVT) and (B) pulmonary embolism (PE). Age-adjusted D-dimer testing is defined as the patient's
age multiplied by 10 μg/L for patients aged over 50, and 500 μg/L for younger patients,
respectively. The optimal thresholds may vary for different D-dimer assays.
The first main change we would like to discuss here is pulmonary embolism rule-out
criteria (the PERC rule). Pulmonary embolism (PE) is a potentially fatal disease with
various and unspecific presentations, ranging from vague chest discomfort with normal
vital signs to sudden death. As a result, D-dimer test and interim anticoagulation
treatment are often applied even when the clinician estimates the probability of PE
as very low.[1] The PERC rule is derived to provide safe exclusion criteria for suspected PE with
a likelihood lower than 15% based on a gestalt impression.[4] It is an eight-variable decision rule and the PERC negative, which is obtained when
the answer to all the eight questions is “no,” indicates no further investigation.
In a multicenter, prospective, observational study in emergency departments, patients
with suspected PE, a low implicit clinical probability and PERC negative assessment
had a PE prevalence of 1.2% (95% confidence interval, 0.4–2.9). A total of 4.7% patients
developed PE within a 3-month follow-up, and the proportion of patients meeting the
rule was 32%.[5] So far this rule is mainly used in emergency departments. Having to meet all the
eight criteria may also limit the usefulness of this rule, and whether modified PERC
would have better performance absolutely requires further validation before put into
clinical application.
Recently, a simplified diagnostic pathway—the YEARS algorithm—has been proposed and
found useful in suspected PE.[6] It includes three items (clinical signs of deep vein thrombosis [DVT], hemoptysis,
considering PE as the most likely diagnosis) and D-dimer level. When the D-dimer is < 500 μg/L
or < 1,000 μg/L in the absence of any item, PE is excluded. Otherwise, examination
with computed tomography of the pulmonary arteries (CTPA) is required for further
diagnosis. In a prospective, multicenter, cohort study of 3,616 patients with suspected
PE, 48% were managed without CTPA, compared with 34% when Wells rule and conventional
D-dimer threshold were used.[7] The false-negative rate was less than 1%. Further validation is still needed before
putting the YEARS diagnostic algorithm into clinical practice.
The NICE guideline proposes outpatient treatment for suspected or confirmed low-risk
PE, using a validated risk stratification tool. Indeed, outpatient management is common
in U.K. health care setting (as with many other countries). To facilitate the decision
process, the 2019 European Society of Cardiology guidelines for the management of
PE defined three sets of criteria for considering early discharge and home treatment.[8] These include (1) a low risk of early PE-related serious complications; (2) absence
of serious comorbidity or aggravating conditions; and (3) proper outpatient care,
taking into account the patient's anticipated compliance, family and social environment,
and the local infrastructure.[8] The Pulmonary Embolism Severity Index integrates clinical parameters of PE severity
and comorbidity, and may be used as a tool for selecting candidates for home treatment,
if combined with additional feasibility criteria.[9] As an alternative, the Hestia exclusion criteria represent a checklist of clinical
parameters that can be obtained at the bedside.[10]
[11] Beyond clinical findings alone, a recent meta-analysis[12] as well as a prospective management trial[13] suggest that it is also wise to exclude right ventricular dysfunction and free floating
right heart thrombi before discharge from hospital.
Before starting treatment of VTD, the NICE guideline recommends that hepatic function
is included among the blood tests. A very small proportion of patients would be excluded
from using oral anticoagulants based on poor liver function. Hepatic function tests
should be limited to the few with suspected severe liver cirrhosis, where this is
meaningful to assess contraindication to nonvitamin K antagonist oral anticoagulants
(NOACs), and then ascites and encephalopathy should also be evaluated to calculate
Child–Pugh score and exclude those with grade C.
For the initial anticoagulation, apixaban or rivaroxaban are favored, which is indeed
the clinical routine in many countries. This is followed by the statement that if
“neither apixaban nor rivaroxaban is suitable offer: low molecular weight heparin
(LMWH) for at least 5 days followed by dabigatran or edoxaban.” It is understandable
that LMWH may be preferable to apixaban or rivaroxaban initially in case of large
PE, where thrombolysis might become indicated, or for very large DVT for similar reason,
or if there is acute kidney injury that is expected to improve quickly, but a moot
point beyond the clinical trial or the prescribing label, is why would dabigatran
or edoxaban be better than any of the other two NOACs, after the 5 days of LMWH?
For patients with extreme body weight, NICE does not exclude NOACs but suggests “regular
monitoring of therapeutic levels for people with confirmed proximal DVT or PE who
weigh less than 50 kg or more than 120 kg, to ensure effective anticoagulation.” It
is probably sufficient to confirm once, after steady state has been reached, that
the level is well within the range seen in population pharmacokinetic studies. The
NICE guideline is up to date with suggestion for NOACs in case of active cancer. For
patients with severe renal failure (calculated creatinine clearance < 15 mL/min),
LMWH is suggested as an option but without any dosing recommendations, referring the
reader to local protocols or specialist advice. It is noteworthy that NICE has previously
published guidelines specific for each of the approved NOACs as Technology Appraisals.
The recommended treatment duration is in line with other guidelines, 3 months for
provoked VTE and up to 6 months if there is, for example, extensive thromboembolism.
There is little specific guidance regarding the duration for other groups of patients,
more than to take into account risks for bleeding, recurrence, adherence, patient
values, and preferences. Regarding bleeding, NICE suggests “stopping anticoagulation
if the HAS-BLED score is 4 or more and cannot be modified.” The HAS-BLED score was
originally derived and proposed for bleeding risk assessment in patients with atrial
fibrillation (AF),[14] and while some studies have tested the value of the HAS-BLED score for bleeding
risk prediction in VTE,[15]
[16] this recommendation from NICE is noteworthy. Nonetheless, bleeding risk assessment
tools are often misused by the ill-informed as an excuse to stop anticoagulation,
and inappropriate cessation can lead to poor outcomes. Instead, the HAS-BLED score
should be used to draw attention to modifiable bleeding risk factors (e.g., uncontrolled
blood pressure, concomitant use of nonsteroidal anti-inflammatory drugs or antiplatelets
in an anticoagulated patient, labile international normalized ratios, etc.), and to
flag up the high-risk patients for early review and follow-up (e.g., 4 weeks rather
than 4–6 months). Such a proactive strategy with appropriate use of dynamic risk assessment
and follow-up was associated with lowered bleeding events and improved anticoagulation
uptake, at least among patients with AF.[17]
There are overall many suggestions regarding practical management, for example, provision
of written information on signs and symptoms to be aware of, direct contact details
to health care professionals, and which products contain components of animal origin—heparins,
lactose from cow's milk in rivaroxaban and apixaban. The latter is pertinent for patients
with specific religious/ethical beliefs or food intolerance.
The NICE guidance specifies the clinical setting in which catheter-directed thrombolytic
therapy should be considered for symptomatic iliofemoral DVT. In acute PE, primary
reperfusion treatment, in most cases systemic thrombolysis, is the treatment of choice
for patients with hemodynamic instability. In contrast, for most cases of acute PE
without hemodynamic compromise, the risk-to-benefit ratio of thrombolysis appears
unfavorable.[18] Catheter-directed treatment, including ultrasound-enhanced, catheter-directed thrombolysis,
is mentioned by NICE as an alternative reperfusion option, particularly for patients
with bleeding risk or other contraindications to systemic (full-dose) thrombolysis.
The studies conducted so far have shown efficacy of this treatment as judged by surrogate
endpoints (in most cases, fast reduction of right ventricular dimensions on follow-up
imaging).[19]
[20]
[21] Catheter-directed treatment now needs to be tested in adequately sized randomized
trials with clinical primary outcomes. Independently from individual reperfusion options,
an amendment to NICE recommendations would be that set-up of multidisciplinary PE
response teams should be encouraged. Coordinated, personalized treatment of patients
with intermediate-high- and high-risk PE[8] addresses the needs of modern systems-based health care.[22]
Reinforcing and amending its past recommendations, the NICE guideline wisely advises,
like most international scientific societies, against routine cancer investigations (beyond physical examination and basic laboratory testing),
and also against routine thrombophilia testing of unselected patients with “unprovoked” DVT or PE.
In this context, it is important to emphasize that “provoked” DVT or PE requires the
presence of a recent (within 3 months) and transient strong clinical risk factor for thrombosis. NICE includes pregnancy, puerperium, and hormonal
therapy (including contraception) in the list of strong provoking factors, an opinion
not fully shared by other guidelines.[8] To avoid any misinterpretation of the NICE's balanced recommendations on thrombophilia
testing, it can also be explicitly mentioned that there is no indication for routine
antiphospholipid antibody testing as a prerequisite for starting or continuing treatment
with a direct oral anticoagulant after DVT or PE.
