Keywords
anticoagulation - bleeding - persistence - apixaban - venous thromboembolism
Introduction
After decades of VTE therapy with vitamin K antagonists (VKAs), nonvitamin K antagonizing
oral anticoagulants (NOACs) have replaced VKA in this indication, following successful
completion of large phase III trials some 10 years ago.[1] The main benefits of NOAC include a much more predictable dose–response relationship,
limited interactions with co-medications and, therefore, a better convenience for
patients who no longer require routine monitoring or frequent dose adjustments.[2]
[3]
Apixaban is a direct factor Xa inhibitor that has been approved for the treatment
of deep vein thrombosis (DVT) and pulmonary embolism (PE), following the finalization
of two large phase III trials (AMPLIFY and AMPLIFY EXTENSION)[4]
[5] and, more recently, the cancer VTE study CARAVAGGIO.[6]
In AMPLIFY, apixaban was tested against low molecular weight heparin (LMWH) followed
by VKA for the treatment of acute DVT and/or PE. Of note, in this study only patients
with unprovoked VTE or provoked VTE with persisting risk factors were included and
patients were excluded if they received other anticoagulants for initial VTE therapy
for more than 36 hours. In this study, apixaban demonstrated noninferiority in efficacy
and superiority for safety in comparison to LMWH/VKA.
In the three-armed AMPLIFY EXTENSION trial, two doses of apixaban (continued therapeutic
dosage of 5 mg BID vs. prophylactic dosage of 2.5 mg BID) were compared against placebo
in VTE patients who had completed a 6 to 12 months course of anticoagulation for acute
DVT and/or PE and in whom uncertainty existed whether anticoagulation should be continued
or stopped at this point in time. In this trial, both apixaban dosages drastically
reduced the risk of recurrent VTE (relative risk reduction 64 and 67% compared with
placebo) without increasing the risk of major bleeding.
Based on these results, apixaban has been approved and rapidly adopted in many countries
and current guidelines list apixaban as one of the preferred options for acute and
long-term VTE treatment.[2]
[3]
However, as with all phase III trials, the question of external validity arises, since
these trials apply rigorous inclusion and exclusion criteria, regulate all medical
interventions around the target disease, and apply close monitoring and strict outcome
assessments, ensuring maximal patient safety and data quality.[7] At the same time, these prespecifications may limit generalizability of trial data
to the daily care management of patients with acute or chronic VTE. Therefore, observational
studies are requested by physicians and authorities to complement phase III trial
findings. Furthermore, such observational studies can supplement phase III trial data
by evaluating patient selection patterns, outcome management, and treatment persistence
to anticoagulation, all of which is difficult to evaluate in a randomized setting
that applies strict prespecified management recommendations.
With this in mind, we set up the prospective multicentric cross-indication DRESDEN NOAC REGISTRY in 2011, which is still ongoing. Here, we report the collected data on acute VTE
management with apixaban.
Methods
Patients
The DRESDEN NOAC REGISTRY (NCT01588119) is a prospective registry in the administrative district of Dresden
(Saxony), Germany, covering a network of more than 230 enrolling physicians from private
practices and hospitals. Patients are eligible if they receive at least 3 months of
NOAC anticoagulation for any indication and are willing to participate in and available
for quarterly follow-up visits by phone, performed by the central registry office.
No exclusion criteria apply. The design and methodology of the Dresden NOAC Registry
has been published previously.[8]
As a noninterventional study, patients are not actively examined for recurrence. In
case of suspected outcome events, medical reports are requested from health care providers
and presented to an adjudication committee. If medical reports are inconclusive, the
worst-case approach is applied.
The protocol does not include a formal adjudication of the index DVT/PE, since diagnosis
of acute VTE in Germany is predominantly in the hands of vascular or cardiac specialists
and objective testing (mainly with ultrasound for suspected DVT and computed tomography
pulmonary angiography or V/Q scan for suspected PE) is readily available. The established
standard of care is consistently used across Germany, as has been demonstrated by
the TULIPA registry.[9]
For the presented analysis, only patients with acute PE and/or acute distal or proximal
lower limb DVT who started apixaban within 14 days after diagnosis of VTE and who
were enrolled within these 14 days were evaluated with regard to patient characteristics,
treatment persistence, and clinical outcomes.
Outcome Measures
To assess effectiveness of apixaban therapy in VTE, the annualized rate of the recurrent
VTE was evaluated. Cases of sudden death were adjudicated as fatal PE and counted
as a recurrent VTE event if other causes of death were not established, and PE could
not be ruled out.
The main safety outcome was the annualized rate of major bleeding according to the
International Society on Thrombosis and Haemostasis (ISTH) definition.[10] Further safety outcomes were rates of ISTH nonmajor clinically relevant (NMCR) bleeding,
minor bleeding, and all-cause mortality.
Crude outcome numbers are reported for days 90, 180, 365, and >365 and annualized
event rates for 180 and 365 days.
To put outcome event rates into perspective with available real-world data in the
discussion section, a formal literature search was performed on February 15, 2020
using the search terms “apixaban” in combination with “deep vein thrombosis or DVT,”
“pulmonary embolism or PE,” “venous thromboembolism or VTE,” and “real world.”
Treatment Discontinuation
In accordance with previously published analyses from our registry,[11] treatment discontinuation was defined as a permanent discontinuation or an unscheduled
interruption of apixaban for longer than 4 weeks without the initial plan to restart
apixaban. This included patients who were permanently switched to another anticoagulant.
In contrast, treatment persistence was defined as the continuation of apixaban therapy
over the entire follow-up period, allowing for temporary interruptions. At every visit,
any change in anticoagulant therapy is assessed. Reasons for switching to other anticoagulants
or stopping anticoagulation as well as the future treatment plan were obtained from
patients or attending physicians. Missing values were left blank and not replaced
by imputation.
Statistics
Two different analysis sets were defined and evaluated:
-
The overall rate of recurrent VTE was evaluated in the intention-to-treat analysis, including all VTE patients who were enrolled in the registry and received apixaban
for acute VTE at baseline. In this analysis, all effectiveness outcome events were
included that occurred throughout the follow-up period, despite the anticoagulation
status.
-
Rates of recurrent VTE and bleeding complication (all, major, and NMCR) during the
time of anticoagulation therapy (and up to 3 days after last intake) were evaluated
in the on-treatment analysis. Temporary treatment interruptions (up to 3 days) were
tolerated.
Data analysis was conducted according to a predefined statistical analysis plan. Baseline
characteristics are presented as absolute and relative frequencies, mean and standard
deviation, or median with interquartile range, where appropriate. Annualized event
rates (per 100 patient years) were calculated using Kaplan–Meier time-to-first-event
analysis and reported with the corresponding 95% confidence intervals (CIs). Due to
the small sample size, comparative statistics of subgroups were omitted.
In addition, the following sensitivity analyses were performed as Kaplan–Meier time-to-first
event analyses:
-
Recurrent VTE during the acute phase until day 90 for patients who started apixaban
within 72 hours; 3 to 7 days or 8 to 14 days after VTE diagnosis.
-
Recurrent VTE during the acute phase until day 90 for patients who were treated for
provoked VTE by major transient trigger versus minor transient or persistent trigger
versus unprovoked VTE. Major transient triggers included complete immobilization for
at least 3 days or major surgery within 4 weeks prior to VTE diagnosis or active cancer.
Surgery was deemed “major” if general anesthesia for greater than 30 minutes was performed.[12] Minor triggers included long-distance travel, acute infectious diseases without
immobilization, estrogen use, obesity with BMI >30, pregnancy or puerperium, family
history of VTE.
-
Net clinical benefit was observed (defined as recurrent VTE and/or major bleeding
and/or all-cause mortality) for patients who had a scheduled end of treatment at 6
months and stopped apixaban between days 150 and 210 versus those who were selected
to continue apixaban beyond 210 days (who, in case of later treatment cessation, were
censored at the day of apixaban discontinuation).
All statistical analyses were performed using the IBM SPSS Statistics version 25,
MedCalc version 14.8.1.
Results
Between December 1st, 2011 and October 31, 2018, a total of 4,385 patients were enrolled
into the DRESDEN NOAC REGISTRY. Of these, 469 were receiving apixaban for VTE treatment and 352 (75.1%) fulfilled
the selection criteria for the present analysis. Reasons for exclusion are demonstrated
in [Fig. 1].
Fig. 1 Flowchart of study cohort.
The VTE index event was an isolated DVT without confirmed PE in 276 (78.4%) cases
and 76 (21.6%) patients had an objectively confirmed PE with or without DVT. Overall,
51.4% were male and median age was 66 years (IQR 25 years). Details on patient characteristics
and index VTE are presented in [Table 1]. Mean time between VTE diagnosis and initiation of apixaban was 1.0 ± 2.7 days (median
0 days; IQR 0 days) and numerically longer for PE versus DVT (mean 2.9 ± 3.8 days
vs. 0.5 ± 1.9 days). At baseline, apixaban was prescribed at a dose of 10 mg BID in
90.9%, 5 mg BID in 7.1%, and 2.5 mg BID in 2.0% of patients. Reasons for not using
10 mg apixaban BID initially were pretreatment with therapeutic parenteral anticoagulants
for ≥7 days in 20 cases, comorbidities (e.g., bleeding history, renal impairment)
in seven cases, and not reported in the remaining five cases.
Table 1
Patient characteristics at baseline
|
All
n = 352
|
DVT
n = 276
|
PE ± DVT
n = 76
|
|
Male, n (%)
|
181 (51.4)
|
136 (49.3)
|
45 (59.2)
|
|
Median age (IQR), years
|
66.0 (25.0)
|
66.5 (25.0)
|
65.5 (23.0)
|
|
Number of concomitant drugs, mean (SD)
|
3.0 ± 3.0
|
2.8 ± 2.9
|
4.1 ± 3.2
|
|
Mean time between VTE diagnosis and initiation of apixaban (SD), days
|
1.0 ± 2.7
|
0.5 ± 1.9
|
2.9 ± 3.8
|
|
Unprovoked VTE, n (%)
|
118 (33.5)
|
87 (31.5)
|
31 (40.8)
|
|
Event VTE provoked by minor persistent or transient triggers, n (%)
|
173 (49.1)
|
136 (49.3)
|
37 (48.7)
|
|
Event VTE provoked by major transient triggers, n (%)
|
61 (17.3)
|
53 (19.2)
|
8 (10.5)
|
|
Recurrent VTE, n (%)
|
82 (23.3)
|
65 (23.6)
|
17 (22.4)
|
|
Proximal vs. distal DVT, n (%)
|
197 (56.0) vs. 79 (22.4)
|
197 (71.4) vs. 79 (28.6)
|
n.a.
|
|
Malignant disease, n (%)
|
42 (11.9)
|
33 (12.0)
|
9 (11.8)
|
|
• Active cancer, n (%)
|
5 (1.4)
|
1 (0.4)
|
4 (5.3)
|
|
Glomerular filtration rate (GFR) <50 mL/min, n (%)
|
31 (8.8)
|
23 (8.3)
|
8 (10.5)
|
|
• GFR 30–50 mL/min, n (%)
|
29 (8.2)
|
21 (7.6)
|
8 (10.5)
|
|
• GFR <30 mL/min, n (%)
|
2 (0.6)
|
2 (0.7)
|
0
|
Abbreviations: DVT, deep vein thrombosis; GFR, glomerular filtration rate; IQR, interquartile
range; PE, pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism.
During a mean follow-up (FU) of 21.7 ± 6.1 months (median 24 months; IQR 5.2; range
31–1,114 days), a total of 17 patients (4.8%) experienced a recurrent VTE, which translated
into a recurrence rate of 2.8/100 patient years (pt. years; 95% CI 1.6–4.4) for the
intention-to-treat population.
The mean time of apixaban exposure was 13.7 ± 9.8 months (median 12.4 months; IQR
20.4) and, during active treatment with apixaban, five patients experienced a recurrent
VTE. This translated into a recurrence rate of 1.3/100 pt. years (95% CI 0.4–3.0)
for the on-treatment population. VTE recurrence rates were highest during the first
90 days of therapy ([Table 2]; [Supplementary Fig. S1]).
Table 2
Outcome event rates according to treatment phase and treatment continuation
|
n = 352
|
Events 0–90 d
|
Events 91–180 d
|
Events 181–365 d
|
Events >365 d
|
|
ITT
|
On treatment
|
ITT
|
On treatment
|
ITT
|
On treatment
|
ITT
|
On treatment
|
|
Recurrent VTE; n (%)
|
3 (0.9)
|
2 (0.6)
|
1 (0.3)
|
0
|
5 (1.4)
|
0
|
8 (2.3)
|
3 (0.9)
|
|
Fatal VTE; n (%)
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Major bleeding; n (%)
|
3 (0.9)
|
0
|
2 (0.6)
|
0
|
4 (1.1)
|
3 (0.9)
|
6 (1.7)
|
3 (0.9)
|
|
Fatal bleeding; n (%)
|
0
|
0
|
1 (0.3)
|
0
|
0
|
0
|
0
|
0
|
|
Mortality; n (%)
|
1 (0.3)
|
0
|
3 (0.9)
|
0
|
2 (0.6)
|
0
|
6 (1.7)
|
1 (0.3)
|
Abbreviations: ITT, intention-to-treat population, which includes all outcome events
during follow-up, irrespective of anticoagulation status; VTE, venous thromboembolism.
A total of 124 patients (35.2%; 43/100 pt. years; 95% CI 35.7–51.2) reported any bleeding
events during apixaban exposure. ISTH major bleeding occurred in six cases (1.5/100
pt. years; 95% CI 0.6–3.3), including three intracranial bleedings, two cases of genitourinary
bleeding, and one case of postoperative bleeding with drop in hemoglobin >2 g/dL.
Furthermore, NMCR bleeding events occurred in 55 cases (15.6%; 15.3/100 pt. years;
95% CI 11.6–20.0), predominantly manifesting as skin/mucosal bleeding (61.8%), genitourinary
bleeding (20.0%), gastrointestinal bleeding (12.7%), or other bleeding types (5.5%).
During apixaban treatment, rates for recurrent VTE were numerically lower in patients
with DVT as an index event (1.1/100 pt. years; 95% CI 0.2–3.1) compared with PE as
an index event (1.8/100 pt. years; 95% CI 0.2–6.5) and similar trends were observed
for rates of major bleeding (1.1/100 pt. years for index DVT; 95% CI 0.2–3.1 vs. 2.7/100
pt. years for index PE; 95% CI 0.6–7.8). Effectiveness and safety profiles were consistent
across relevant subgroups ([Supplementary Table S1] and [Supplementary Fig. S2]). Furthermore, in another sensitivity analysis we did not detect a signal that early
(within 2 days after VTE diagnoses) or delayed (8–14 days after diagnosis) start of
apixaban therapy correlated to an increased risk of VTE recurrence ([Supplementary Fig. S3]).
A total of 12/352 patients died (1.9/100 pt. years; 95% CI 1.0–3.3) of which one death
occurred during or within 3 days after last intake of apixaban (0.25/100 pt. years;
95% CI 0–1.4). Causes of death were cancer (n = 5), fatal cardiovascular event (n = 2 including one case of sudden cardiac death and one case of congestive heart failure),
sepsis/infection (n = 2), age-related death (n = 2), and one case of fatal bleeding unrelated to apixaban exposure.
At 6 months (FU completed in 352 pts.), 341 patients (96.9%) were still alive. Of
these, 69.8% of patients were still taking apixaban, 24.6% had a scheduled end of
treatment, 6.5% were switched to other anticoagulants, and the remaining 2.3% had
unplanned complete discontinuation of anticoagulation.
At 12 months (FU completed in 328 pts.), 316 patients (96.3%) were still alive. Of
these, 57.9% of patients were still taking apixaban. The remaining patients having
a scheduled end of treatment (33.5%), were switched to other anticoagulants (8.5%)
or had an unplanned complete discontinuation of anticoagulation (3.8%).
Of the 188 patients stopping apixaban, 12 (6.4%) experienced a recurrent VTE (six
PE ± DVT, six DVT) and the mean time between stopping anticoagulation and VTE recurrence
was 5.2 ± 4.1 months. Despite discontinuation of oral anticoagulation in a total of
188 patients, major bleeding still occurred in nine patients (4.8%; [Supplementary Table S2]), which translated into an anticoagulation-unrelated major bleeding rate of 3.9/100
pt. years (95% CI 1.8–7.5), indicating that the major driver for bleeding is patient-related
and not anticoagulation-related, which likely contributed to the decision to stop
anticoagulation.
Discussion
In a large cohort of patients treated with apixaban for acute VTE in daily care, we
could demonstrate a general confirmation of the effectiveness and safety of apixaban
demonstrated in phase III studies. In the AMPLIFY phase III trial which did not report
annualized rates, absolute rates of recurrent VTE and ISTH major bleeding were 2.3
and 0.6%, respectively for patients treated for 6 months.[4]
[5] In our intention-to-treat analysis, recurrent VTE occurred in 4.8% of patients (2.8/100
pt. years) and ISTH major bleeding in 4.3% of patients (2.4/100 pt.years). The higher
event rates seen in our study may partly be explained by the fact that no exclusion
criteria were applied in our cohort of consecutive daily care patients, whereas phase
III trials prohibit enrolment of patients at unacceptably high risk for complications
by defining explicit inclusion and exclusion criteria. Furthermore, mean age of our
cohort (66 years) was considerably higher than that in the AMPLIFY (mean 57 years).[4] In addition, the majority of patients in AMPLIFY were patients with unprovoked VTE
(excluding patients with VTE shortly after major trauma or surgery, which may carry
a higher risk for VTE recurrence or bleeding especially in the early phase of anticoagulation),
whereas we included a total of 61 (17.3%) patients with VTE provoked by a major transient
risk factor such as recent surgery or trauma. Numerically, these patients presented
slightly higher rates of VTE recurrence (1.6 vs. 0.8% in patients with unprovoked
VTE; [Supplementary Table S1]) but the absolute difference was small and based on low numbers. Reassuringly, rates
for major bleeding were low in both cohorts. Another difference between AMPLIFY and
our cohorts' study was the length of observation (6 vs. 21 months). Therefore, neither
our crude bleeding incidences nor our annualized bleeding event rates, derived from
a cohort with considerably longer treatment and follow-up duration, can be directly
compared with the phase III data. However, at 6 months, our crude event rates of 1.1%
(recurrent VTE) and 1.4% (major bleeding; [Table 2]) were not far from those reported in AMPLIFY.
In addition to thromboembolic and bleeding outcomes we reported on treatment persistence
and reasons for discontinuation. We found a reassuringly low rate of unscheduled premature
discontinuation (2.3% at 6 and 3.7% at 12 months) and a clear trend toward prolonged
anticoagulant treatment with apixaban, since nearly 70% of patients were treated for
longer than 6 months. The low rate of unscheduled premature discontinuation is reassuring
and an indicator of high patient and physician satisfaction. The trend to prolonged
treatment is in line with the pronounced risk profile for VTE recurrence in our cohort
and, thus, in line with current guideline recommendations.
Our data are not the first real-life data for VTE treatment with apixaban. Several
large retrospective health record or claims data analyses from Denmark and the United
States have been published.[13]
[14]
[15]
[16]
[17] Although all these studies have evaluated much larger cohorts of VTE patients, by
definition they are retrospective in nature, mostly rely on ICD codes, and apply algorithms
to identify potential outcome events which are not centrally adjudicated. As such,
there are many known and unknown confounders in these studies, which also lack granularity
in details of patient selection, drug management, and reasons for treatment changes.
For this, prospective registry data are needed and, to our knowledge, only one such
prospective registry has been published do date.[18] In this prospective single center cohort of 300 apixaban patients, only those who
completed 3 months of treatment or had an outcome event were evaluated, resulting
in a total of 302 patients. Rates of recurrent event at 3 months was 2.3% and major
bleeding occurred in 11 patients (3.6%), which is somewhat higher than our data, although
no direct comparisons can be made, since treatment durations were different and no
details on drug dosage or exposure time were reported. It has also to be noted that
in this Mayo Clinic project, a total of 1,696 consecutive patients were enrolled,
of which only 17.8% received apixaban, which indicates a high degree of dedicated
patient selection. Strikingly, this group reported surprisingly low rates of NMCR
bleeding (2.3%) which is not in line with our data (15.6%) or those collected in AMPLIFY,
raising the question for a potential of under-reporting of nonmajor bleeding events
in their study.
In contrast, our study reports on a cohort of apixaban patients recruited at multiple
centers and we followed all patients (irrespective of premature treatment discontinuation)
for up to 2.5 years. We reported outcome events that occurred during active treatment
and after discontinuation and provided outcome data based on central event adjudication.
Our data also did not indicate that early start of apixaban or prolonged alternative
(usually LMWH) therapy for up to 2 weeks before apixaban initiation leads to different
rates in VTE recurrence, which is also reassuring, since AMPLIFY did not allow for
a pretreatment with LMWH for more than 36 hours. Furthermore, we assessed treatment
persistence and reasons for treatment changes, all of which have not been reported
so far. To put our findings into perspective with the abovementioned reports we have
summarized the main design items and results of published apixaban VTE cohorts in
[Table 3]. However, this is meant to be descriptive only and readers are cautioned not to
compare these very different studies directly. Despite the differences in patient
characteristics and outcome assessments, our data are very much in line with most
of the outcome data in previous real-world studies, which indicates that apixaban
real-world evidence confirms the effectiveness and safety of apixaban in VTE treatment
across a spectrum of very different methodologies, somewhat different populations,
and outcome event definitions.
Table 3
Available real-word data on the effectiveness and safety of VTE treatment with apixaban
|
Study
|
Study design
|
Central event adjudi-cation
|
Data on apixaban persistence
|
Data on apixaban dosing
|
Outcome data after stopping apixaban
|
Apixaban initiation in acute phase
|
Sample size apixaban cohort
|
Mean age
|
Pro-portion of PE
|
Unpro-voked VTE
|
Cancer
|
Duration of follow-up
|
VTE recurrence during apixaban treatment
|
Major bleeding during apixaban treatment
|
|
Present study
|
Prospective multicenter registry
|
Yes
|
Yes
|
Yes
|
Yes
|
Yes
|
352
|
66 y
|
21.6%
|
33.5%
|
11.9%
|
21.7 mo
|
1.4% (1.3/100 pt. years)
|
ISTH: 1.7% (1.5/100 pt. years)
|
|
Bott-Kitslaar et al[18]
|
Prospective single center registry
|
Yes
|
Yes
|
Ø
|
Ø
|
Yes
|
302
|
62.4 y
|
38.7%
|
16.6%
|
47.0%
|
3 mo
|
2.3%
|
ISTH: 3.6%
|
|
Haastrup et al[16]
|
Retrospective health record analysis
|
Ø
|
Ø
|
Yes
|
Ø
|
All first prescriptions (incl. nonacute VTE)
|
2,346
|
Unk
|
Unk
|
Unk
|
Unk
|
Unk
|
Unk
|
Unk
|
|
Lutsey et al[13]
|
Retrospective claim database analysis, U.S. MarketScan
|
Ø
|
Ø
|
Ø
|
Ø
|
All first prescriptions (incl. nonacute VTE)
|
4,128
|
56.8 y
|
Unk
|
Unk
|
Unk
|
Unk
|
Unk
|
Unk
|
|
Sindet-Pedersen et al[23]
|
Danish National Patient Register
|
Ø
|
Ø
|
Ø
|
Ø
|
Yes
|
1,504
|
Median: 70 y
|
53.5%
|
Unk
|
14%
|
Median: 180 d
|
Standardized 180 d risk 2.16%
|
Standardized 180 d risk 1.73%
|
|
Dawwas et al[14]
|
Retrospective claim database analysis
Truven, Medicare
|
Ø
|
Ø
|
Ø
|
Ø
|
All first prescriptions (incl. nonacute VTE)
|
3,091
|
61.6 y
|
100%
|
50.9%
|
17.7%
|
99 d
|
3/100 pt. years
|
3/100 pt. years
|
|
Dawwas et al[15]
|
Retrospective claim database analysis
(MediCare and others)
|
Ø
|
Ø
|
Ø
|
Ø
|
All first prescriptions (incl. nonacute VTE)
|
8,094
|
58.9 y
|
Unk
|
47.5%
|
16.2%
|
Unk
|
1.6%
|
1.1%
|
|
Weycker et al[17]
|
Retrospective U.S. claims database analysis
|
Ø
|
Ø
|
Ø
|
Ø
|
All first prescriptions (incl. nonacute VTE)
|
17,878
|
60.0 y
|
41.0%
|
77.2%
|
1.2%
|
143 d (estimated exposure 116 d)
|
2.3%
|
1.7% based on primary ICD codes
|
Abbreviations: ISTH, International Society on Thrombosis and Haemostasis; VTE, venous
thromboembolism.
Limitations
There are several limitations to our study, which have been discussed in detail in
previous publications.[8]
[19]
[20] For the presented analysis, some specific limitations apply.
Sample Size and Potential for Selection Bias
Our cohort consisted of 352 patients, and our sample size as well as the small number
of outcome events may have been too small to detect clinically relevant differences,
which is especially true for our descriptive subgroup analyses. The design of our
registry introduces the possibility of a selection bias because local physicians within
the network are not instructed on which of their patients should receive which type
or dosage of oral anticoagulant therapy.
Lack of Randomized Comparator
The lack of a direct randomized comparator group needs to be regarded as a limitation.
However, many large observational VTE treatment studies exist from the VKA era[21] and data on VKA complications and VKA treatment discontinuation are well established.[22] In addition, health record and large claim database analyses have attempted to compare
VTE treatment of apixaban with VKA[17]
[23] using matching procedures. Although this is certainly an important and valid statistical
approach it should be noted that matching will not completely rule out residual confounding,
also, because a relevant proportion of patients are often not eligible for matching.
Therefore, also the inclusion of a comparator group will cause problems for data analysis
and interpretation, as has been demonstrated in the XALIA registry.[24]
[25]
Despite all potential limitations, in comparison to existing real-world data on apixaban
VTE treatment, the long follow-up duration, the prospective data collection at patient
level in daily care patients, and the central adjudication of effectiveness, and safety
outcomes are significant advantages of our study.
Conclusion
In daily care, apixaban treatment for acute VTE is effective and acceptably safe.
We found initial apixaban dosing to be in accordance with label in over 90% of patients
and, at 6 and 12 months, persistence was high with low rates of unplanned complete
discontinuation. Fatal VTE and fatal bleeding are rare events during apixaban therapy
and all-cause mortality is mostly related to underlying diseases, age, or acute conditions.
Treatment discontinuation resulted in a relevant increase in VTE recurrence, of which
50% manifested as PE. Furthermore, bleeding complications were still frequently seen
in patients stopping apixaban therapy indicating a selection pattern of stopping anticoagulation
mainly in patients at high risk for (anticoagulation unrelated) bleeding despite high
risk for VTE recurrence. Consequently, the concept of low dose apixaban therapy in
secondary VTE prevention, established in AMPLIFY EXTENSION[5] needs further evaluation in real-world studies.
What Does This Paper Add? What Is Known About the Subject
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Treatment of venous thromboembolism (VTE) with apixaban was effective and safe in
the AMPLIFY/AMPLIFY EXTENSION trials. However, due to the strict selection criteria in phase III trials, post marketing
data are needed to confirm the generalizability of trial data.
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So far, real-world data on apixaban treatment for acute VTE are limited, often derived
from retrospective analyses and frequently lacking details on dosing, treatment persistence,
or long-term outcomes.
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Especially data for apixaban use in the treatment of patients with VTE provoked by
major transient risk factors are needed, since such patients were excluded from participation
in AMPLIFY.
What This Paper Adds
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Data from ongoing, prospective, noninterventional Dresden NOAC Registry aimed to confirm the phase III trial results in daily care and to provide outcome
data for up to 2 years.
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In daily care, acute venous thromboembolism (VTE) therapy with apixaban showed acceptably
low VTE recurrence and major bleeding rates over a follow-up duration of 2 years.
Adherence to dosing recommendations and treatment persistence were satisfactory.
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Apixaban demonstrated little differences in outcome rates for patients with provoked
versus unprovoked VTE, confirming a broad generalizability of AMPLIFY trial data.
