Clinical Surveillance vs. Anticoagulation for Low-risk Patients with Isolated Subsegmental Pulmonary Embolism: A Multicenter Randomized Placebo-Controlled Non-Inferiority Trial

The widespread introduction of multi-detector computed tomography pulmonary
angiography (CTPA) was followed by an 80% increase in the diagnosis of acute
pulmonary embolism (PE). As multi-detector CTPA allows better visualization of
the peripheral pulmonary arteries, small emboli limited to the subsegmental
pulmonary arteries, so-called isolated subsegmental PE (SSPE), are increasingly
detected and currently comprise 10-15% of cases with PE.
The clinical significance of isolated SSPE and whether isolated SSPE represents
*true* PE, a clinically more benign form of PE, a physiologic lung clearing
process, or a false positive result (artifact) is currently unclear and hence,
whether patients with isolated SSPE benefit from anticoagulant treatment is
uncertain. Despite growing evidence from retrospective and prospective studies
that withholding anticoagulation may be a safe option in selected patients with
isolated SSPE (i.e., those without concomitant deep vein thrombosis, cancer,
etc.), most patients with isolated SSPE receive anticoagulant treatment and
have a 90-day risk of major bleeding of up to 5%.

This study has been transitioned to CTIS with ID 2023-506943-40-00 check the CTIS register for the current data.

The overall objective of this trial will be to evaluate the efficacy and safety
of clinical surveillance without anticoagulation in low-risk patients with
isolated SSPE.
Objective 1: To compare the frequency of symptomatic, recurrent venous
thromboembolism (VTE) in low-risk patients with isolated SSPE randomized to
receive clinical surveillance or anticoagulation.
Objective 2: To compare the frequency of clinically significant bleeding and
all-cause mortality in low-risk patients with isolated SSPE randomized to
receive clinical surveillance or anticoagulation.
Objective 3: To compare health-related quality of life, functional status, and
medical resource utilization in low-risk patients with isolated SSPE randomized
to receive clinical surveillance or anticoagulation.

This trial is designed as an international, multicenter, placebo-controlled,
double-blind, parallel-group non-inferiority trial. Consenting low-risk
patients with isolated SSPE without concomitant DVT will be randomly assigned
in a 1:1 ratio to receive placebo (*clinical surveillance group*) or
anticoagulant treatment with rivaroxaban (*anticoagulation group*). Eligible
patients will be recruited at 27 high volume hospitals in Switzerland, The
Netherlands, and Canada.

Patients in the clinical surveillance group will receive a matching rivaroxaban
placebo following the same schedule as patients in the control group. Clinical
surveillance will be done by follow-up phone calls 2 times during the first 30
days (at 10 and 30 days) and at 90 days following randomization. Depending on
local practice, the follow-up phone calls can be substituted by in person
visits. At each contact, trained study personnel will complete an assessment of
symptoms and review for suspected recurrent VTE and bleeding using a checklist
of pre-defined questions. Patients will also be instructed to contact study
personnel or report to the ED immediately if any symptoms/signs compatible with
recurrent VTE or significant bleeding occur.

Expected benefits for Patients, Society, and Research
The standard treatment for PE is anticoagulant therapy for at least 3 months.15
As outlined in section 3.1., anticoagulant treatment effectively reduces the
risk of recurrent VTE,16 but comes at the cost of an increase in the risk of
potentially disabling and life-threatening bleeding, which is associated with
reduced quality of life and increased distress,24 medical resource utilization
and costs,11 and can even result in disability or death.10,17 Therefore, the
benefits of anticoagulation need to be carefully weighed against its risks.
Based a growing body of evidence from observational studies indicating that
withholding anticoagulation may be safe in selected patients with isolated
SSPE,31,41,46-53 the latest guidelines suggest that clinical surveillance
rather than anticoagulation is a management option in low-risk patients with
isolated SSPE and no concomitant proximal DVT.15,55,56 However, the quality of
evidence supporting these guideline recommendations is low (grade 2C). Our
trial therefore addresses an important gap of knowledge, the optimal management
of SSPE, and represents the first randomized, direct comparison of clinical
surveillance alone vs. anticoagulant treatment for low-risk patients with
isolated SSPE. Our project is important from a public health, physician, and
patient perspective. First, acute PE is a common disease, with an incidence of
about 112 cases per 100,000 adults.27 Currently, SSPE represents about 10-15%
of cases with PE, but with the further dissemination/advancement of
multi-detector CTPA technology, the number of patients with SSPE who will
eventually receive anticoagulant treatment is likely to rise in the future. We
expect the clinical and economic benefit of withholding anticoagulation to be
primarily due to a decrease in bleeding episodes, and to a lesser extent, to a
reduction in medication costs (about $500 for a 3-month course with direct oral
anticoagulants). Projections from 6 European countries with 300 million
inhabitants demonstrate that about 300,000 episodes of PE occur every year.70
Assuming a prevalence of isolated SSPE of 15% (45,000 cases), a major bleeding
rate of 2% within the first 3 months of treatment,17 a ratio of major to
clinically relevant non-major bleeding of 8,19,21 and that anticoagulation
could be withheld in about 50% of patients with isolated SSPE, about 500 major
bleedings and about 4000 clinically relevant non-major bleedings could be
avoided per year. Given the high case-fatality (11%) and prevalence of
intracranial hemorrhage (10%) in patients with major bleeding17 and the costs
per major ($4300-13,000) and non-major bleeding ($200-2800) episode,71-73 a
substantial reduction in mortality, morbidity, and cost could be achieved. In
Switzerland, an estimated 8000 cases of PE were diagnosed in 2016,74 of which
up to 1200 cases are isolated SSPE.
Because no study has compared the level of resource utilization and
productivity between patients with isolated SSPE who are managed by clinical
surveillance alone or anticoagulation, our trial will also assess common
measures of resource utilization and productivity, such as the initial length
of hospital stay (LOS), subsequent hospitalizations, emergency department (ED)
and outpatient physician visits, and the time to return to work or usual
activities. To date, no studies have examined health-related quality of life in
patients with SSPE. Because patients managed with clinical surveillance alone
are less likely to develop bleeding events, we expect clinical surveillance to
be associated with a higher quality of life and will assess this outcome as
part of this trial.
Successful completion of this study will provide a strong scientific basis for
withholding anticoagulation in low-risk patients with isolated SSPE and may
therefore to improve quality and efficiency of care by reducing bleeding
episodes and resource utilization and increasing health-related quality of
life. Our project will have value to physicians who are committed to optimizing
patient safety and providing high-quality, cost-effective care and fits well
with the Choosing Wisely initiative and other efforts to reduce unnecessary
care and patient harm.75,76
For the individual participating patient, we cannot guarantee any benefits
arising from study participation. It may be possible that potential
complications such as recurrent VTE or bleeding events can be recognized more
quickly given that regular follow-up phone calls or visits are performed.


Potential risks
Potentially, withholding anticoagulation in patients with VTE (including SSPE)
may be associated with an increased risk of recurrent VTE. However, we expect
that clinical surveillance without anticoagulation does not pose additional
risks in terms of VTE-recurrence or mortality for study participants compared
to anticoagulation, because (1) only clinically stable patients at low risk of
VTE recurrence will be enrolled (see eligibility criteria in section 7.1), and
(2) prior comparative studies do not suggest a risk difference in VTE
recurrence or mortality between patients with isolated SSPE who receive
anticoagulant treatment or not.54 We expect to find a lower risk of significant
bleeding in patients in whom anticoagulants are withheld.49,50
Anticoagulation treatment is associated with an increased risk of bleeding.


Measures to mitigate the risks
Patients with a high risk of bleeding or conditions that can increase
rivaroxaban-associated bleeding risk (e.g. severe renal failure, use of strong
CYP3A4 inhibitors) will be excluded from the study (see section 7.1) in order
to decrease the risk of anticoagulation-related bleeding. Patients with a high
risk of recurrent VTE, namely patients with concomitant DVT, active cancer,
previous episodes of unprovoked VTE, or clinical instability (see section 7.1)
will be excluded from the study, in order to decrease the risk of recurrent
VTE.
At the baseline visit, patients will be informed about symptoms and signs
suggestive for recurrent VTE and bleeding orally and in writing (in the patient
information and in the information booklet distributed to the participants),
and will be instructed to immediately present to the study site*s ED for
evaluation in case of suspected recurrent VTE or bleeding. Study personnel will
contact patients 10, 30, and 90 days after randomization to assess outcomes and
ask for signs and symptoms compatible with recurrent VTE or significant
bleeding and if present, patients will be instructed to immediately present to
the study site*s ED for evaluation. The higher frequency of contacts during the
first month following enrolment will decrease the likelihood that that symptoms
or signs of recurrent VTE will be missed during the period of highest risk for
recurrence.65
The investigator*s contact information and an emergency telephone number (with
24h availability) will be provided in the information booklet if signs and
symptoms of VTE or bleeding occur, or if participants have questions/concerns
relating to study drugs/procedures. In addition, a credit-card sized
information card will be provided to the patients containing basic information
about the patient*s participation in the study and the investigator*s contact
information and the emergency phone number.
In pre-defined clinical situations (need for anticoagulation reversal,
recurrent VTE, or new pregnancy) emergency unblinding is possible (see section
6.3).
Finally, the trial will be under the surveillance of an independent Data Safety
and Monitoring Board (DSMB) that will evaluate unblinded VTE outcomes on a
regular basis and make recommendations to the Steering Committee to amend or
terminate the trial should any safety concerns arise (see section 11.3).