Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thromboembolism compared to usual care: A randomized controlled trial

Geert-Jan Geersing; Janneke M T Hendriksen; Nicolaas P A Zuithoff; Kit C Roes; Ruud Oudega; Toshihiko Takada; Roger E G Schutgens; Karel G M Moons

doi:10.1371/journal.pmed.1003142

. 2020 Jun 26;17(6):e1003142. doi: 10.1371/journal.pmed.1003142

Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thromboembolism compared to usual care: A randomized controlled trial

Geert-Jan Geersing ^1,^*, Janneke M T Hendriksen ¹, Nicolaas P A Zuithoff ¹, Kit C Roes ^1,², Ruud Oudega ¹, Toshihiko Takada ¹, Roger E G Schutgens ³, Karel G M Moons ¹

Editor: Suzanne C Cannegieter⁴

PMCID: PMC7319277 PMID: 32589630

Abstract

Background

Patients with unprovoked (i.e., without the presence of apparent transient risk factors such as recent surgery) venous thromboembolism (VTE) are at risk of recurrence if anticoagulants are stopped after 3–6 months, yet their risk remains heterogeneous. Thus, prolonging anticoagulant treatment should be considered in high-risk patients, whereas stopping is likely preferred in those with a low predicted risk. The Vienna Prediction Model (VPM) could aid clinicians in estimating this risk, yet its clinical effects and external validity are currently unknown. The aim of this study was to investigate the clinical impact of this model on reducing recurrence risk in patients with unprovoked VTE, compared to usual care.

Methods and findings

In a randomized controlled trial, the decision to prolong or stop anticoagulant treatment was guided by predicted recurrence risk using the VPM (n = 441), which was compared with usual care (n = 442). Patients with unprovoked VTE were recruited from local thrombosis services in the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede) between 22 July 2011 and 30 November 2015, with 24-month follow-up complete for all patients by early 2018. The primary outcome was recurrent VTE during 24 months of follow-up. Secondary outcomes included major bleeding and clinically relevant non-major (CRNM) bleeding. In the total study population of 883 patients, mean age was 55 years, and 507 (57.4%) were men. A total of 96 recurrent VTE events (10.9%) were observed, 46 in the intervention arm and 50 in the control arm (risk ratio 0.92, 95% CI 0.63–1.35, p = 0.67). Major bleeding occurred in 4 patients, 2 in each treatment arm, whereas CRNM bleeding occurred in 20 patients (12 in intervention arm versus 8 in control arm). The VPM showed good discriminative power (c-statistic 0.76, 95% CI 0.69–0.83) and moderate to good calibration, notably at the lower spectrum of predicted risk. For instance, in 284 patients with a predicted risk of >2% to 4%, the observed rate of recurrence was 2.5% (95% CI 0.7% to 4.3%). The main limitation of this study is that it did not enroll the preplanned number of 750 patients in each study arm due to declining recruitment rate.

Conclusions

Our results show that application of the VPM in all patients with unprovoked VTE is unlikely to reduce overall recurrence risk. Yet, in those with a low predicted risk of recurrence, the observed rate was also low, suggesting that it might be safe to stop anticoagulant treatment in these patients.

Trial registration

Netherlands Trial Register NTR2680

Geert-Jan Geersing and colleagues investigate the clinical impact of the Vienna Prediction model on reducing recurrence risk in patients with unprovoked venous thromboembolism, compared to usual care.

Author summary

Why was this study done?

Patients with clots in the leg or lung without a clear explanation are treated with anticoagulants.
After the initial treatment phase is complete (after 3–6 months), a relatively large group of patients will then experience new clots if treatment is then discontinued.
Physicians struggle with identifying the group of patients in need of prolonged anticoagulant treatment, which can be protective for recurrent clots, yet also inherently introduces bleeding risk.

What did the researchers do and find?

The researchers performed a randomized trial comparing the use of a prediction tool with usual care.
This prediction tool can help identify patients at increased risk of recurrent clots. Treatment can then be tailored accordingly.
The study found that, overall, the risk of recurrent clots was not reduced by applying this tool. The prediction tool, however, was able to identify a group of patients with a low risk of recurrent clots.

What do these findings mean?

On a population level, the researchers were unable to find a difference in the risk of recurrent clots by using this prediction tool.
The study, however, did suggest that it might be safe to stop anticoagulant treatment after the initial treatment phase in those with a low predicted risk of recurrent clots.

Introduction

Venous thromboembolism (VTE)—i.e., deep vein thrombosis (DVT) or pulmonary embolism (PE)—is a major healthcare burden [1]. An initial course of treatment for 3 to 6 months is recommended to prevent clot progression and VTE-related acute morbidity and mortality. After this initial phase, prolonging anticoagulant treatment reduces recurrence risk but at the price of increasing bleeding risk. Notably, patients with unprovoked VTE may benefit from prolonging treatment as it is widely appreciated that recurrence risk in them is highest [2]. However, both recurrent VTE events and major bleeding—reduced and induced by prolonged anticoagulation, respectively—carry a substantial mortality and morbidity risk. Clinically it is often difficult to balance both risks optimally on an individual level.

A Cochrane review with meta-analysis reported that currently there is insufficient evidence to support prolonging anticoagulant treatment in all patients with unprovoked VTE [3]. The main reason for this is that VTE recurrence risk in the mixed population of patients with unprovoked VTE is too heterogeneous. Ideally, therapeutic decision-making in these patients should be guided by individualized risks, whereby prolonging treatment is only considered in those with a high expected recurrence risk.

We therefore designed the VISTA study. The primary aim was to evaluate the effect of a risk-tailored patient management approach, compared to usual care, in an open-label, pragmatic randomized trial. The risk-based treatment approach included the use of the previously developed Vienna Prediction Model (VPM). This prognostic model predicts VTE recurrence risk in patients with unprovoked VTE [4], and based on this predicted risk, anticoagulant treatment was only continued if the predicted annualized risk was equal to or higher than 5%. This index strategy was compared with usual care as control strategy, which at the time of VISTA enrollment consisted of stopping anticoagulant treatment after the initial treatment phase in most patients, yet left this decision at the discretion of the treating physician. A secondary aim was to externally validate the VPM in a different setting and country from where it was derived (i.e., Austria) for its ability to predict VTE recurrence in terms of discrimination and calibration.

Methods

Trial design and ethical approval

VISTA was an investigator-initiated, multi-center, pragmatic, unblinded randomized trial. Patients were recruited by local thrombosis services in the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede). The trial was designed and overseen centrally at the University Medical Center Utrecht, the Netherlands. The study protocol was approved by the medical ethics research committee from the University Medical Center Utrecht, and the trial was registered in the Netherlands Trial Register (https://www.trialregister.nl) with registration number NTR2680. The protocol is available in S1 Text. The trial was performed in accordance with the principles of the Declaration of Helsinki. All participants provided written informed consent. Throughout this paper, we adhere to the CONSORT reporting guidelines for randomized controlled clinical trials (see S1 CONSORT Checklist) [5].

Participants

Adult patients (age 18 years or higher) with unprovoked VTE were eligible for participation in this trial. Patients were recruited by 9 thrombosis services throughout the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede) between 22 July 2011 and 30 November 2015. Unprovoked was defined as the patient having had no previous surgery (lasting longer than 30 minutes under general or spinal anesthesia) or casting after lower-limb injury within 3 months prior to the VTE event, and not being pregnant or in puerperium (up to 6 weeks postpartum). Oral-contraceptive-related VTE in female patients was allowed, given the uncertainty whether these events should be classified as provoked or unprovoked [6,7]. Patients with a history of VTE within the past 10 years were excluded, as were patients with an active malignancy (i.e., latest treatment less than 6 months prior to the VTE event or in palliative care): In both of these patient groups, there is not much debate that recurrence risk is high, warranting prolonged anticoagulant treatment. Finally, patients were also excluded from participation in this trial if there was a clear other indication for anticoagulant treatment at the time of the VTE event, such as atrial fibrillation or prosthetic heart valves.

Randomization and blinding

All participants included in the study first followed an initial treatment course with vitamin K antagonists for 3 to 6 months, after low-molecular-weight heparin (LMWH) lead-in. Shortly before the end of this initial treatment phase—i.e., after 3–6 months for most patients—participants were randomized 1:1 to the index strategy (risk-tailored approach) or the control strategy (usual care). Patients were deliberately randomized at the end of the initial treatment phase because in some patients new clinical circumstances—such as diagnosis of an occult malignancy during the first treatment months—may dictate whether or not prolonged treatment is potentially recommendable. Blocked randomization was performed within strata for center and for type of VTE. Blinding of the participants and treating physicians was not possible given the pragmatic nature of this study and the index strategy.

Index group

In the risk-tailored management strategy, the VPM was used to estimate the risk (or probability) of recurrence. The 3 predictors of the model were measured from each patient randomized to the index strategy and were used to estimate the patient’s recurrence risk. These predictors are the extent of VTE (defined as distal DVT, proximal DVT, or PE), patient sex, and D-dimer concentration (on a continuous scale measured as micrograms/liter). Results from this risk prediction were communicated over phone to the patient, followed by a discussion on the clinical consequences of this risk. Subsequently, the treating physician was informed, along with being given an explanation of the risk model used. These phone conversations were performed by the 2 medical doctors (GJG or JMTH) with knowledge of prediction research and thrombosis management. For an illustration of how the model was applied to individual patients, see http://www.meduniwien.ac.at/user/georg.heinze/zipfile/ViennaPredictionModel.html.

Based upon consensus from the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH), extending treatment in the index group was recommended only if the annualized predicted risk of recurrence was equal to or higher than 5%. Otherwise, treatment was discontinued [8]. We explicitly opted for a so-called model-assisted treatment recommendation (in which both the patient and treating physician discussed the predicted risk to determine whether or not to continue in shared decision-making), instead of a directive or enforced recommendation [9].

Risk estimation was performed twice, namely shortly before treatment cessation at the end of the initial treatment period (thus while still using anticoagulant treatment; VPM 1) and approximately 1 month after treatment cessation (VPM 2). This second assessment was done because D-dimer levels can be lowered by the use of anticoagulant treatment, thus falsely leading to lower predicted risk of VTE recurrence (higher D-dimer levels correlate with higher risk). This second assessment was skipped if the first risk estimation already identified a patient as high risk.

Control group

In patients randomized to the control group, usual care was followed. This meant that the decision to stop or prolong anticoagulant treatment after the initial treatment phase was left at the discretion of the treating physician and patient, conforming to prevailing current care. This was thus without a formally guided risk estimation and communication.

Outcome measures

The primary outcome was the occurrence of recurrent VTE during 24 months of follow-up after randomization, thus during the 24 months after the completion of the initial anticoagulant treatment phase. Recurrent VTE was defined as proximal DVT or fatal or nonfatal PE, as confirmed by compression ultrasonography for DVT and by computer tomographic pulmonary angiography (CTPA) for PE, accompanied by management with anticoagulation treatment. Outcome assessment was done after scrutinizing all available hospital discharge information. Given the pragmatic nature of our trial, outcomes were not adjudicated blinded to randomized allocation.

Secondary outcomes were the occurrence of major bleeding and clinically relevant non-major (CRNM) bleeding, as reported by the patient or treating physician. Prompted by the reporting of bleeding by either the patient or his/her physician, bleeding was classified as major if it was retroperitoneal or intracranial bleeding, was accompanied by a lowering of hemoglobin level of at least 20 g/l, or resulted in transfusion of at least 2 units of blood, surgical intervention, or invasive procedures to stop the bleeding. Data on CRNM bleeding (all bleeding events not meeting the criteria stated above for which a physician consultation was needed, e.g., epistaxis, large hematoma, or rectal bleeding) were collected by questionnaires sent to patients by mail.

Follow-up appointments

Patients were followed up by phone at 3, 12, and 24 months after randomization, thus for 24 months in total after the completion of the initial treatment phase of (typically) 3–6 months. They were also instructed to call a research nurse in case of a potential recurrent VTE event, bleeding event, or any other serious adverse event. When we were unable to reach patients over the phone at one of the follow-up time points, we contacted their primary care provider to collect clinical information on the occurrence of recurrent VTE and bleeding. If a recurrent event was suspected, i.e., either spontaneously reported by the patient or detected during one of the scheduled contacts, all additional clinical data were retrieved including information from general practitioners and hospital discharge information. Next, if such medical information clearly indicated recurrent DVT or recurrent PE (using our above-described definitions), a patient was classified as having had a recurrent event, after which follow-up was discontinued.

Statistical analyses and power calculations

In a randomized trial on D-dimer-guided duration of anticoagulant treatment, patients with a persisting (over 1 month) positive D-dimer test after the initial treatment phase (i.e., “high risk patients”) were randomized to prolonged (intervention) or discontinued anticoagulant treatment (control) [10]. In this study, the observed occurrences (during a median follow-up of 18 months) of recurrent VTE in the index versus control group were 15.0% versus 2.9%, with a risk reduction of more than 80% with the intervention [10]. We used a different design in which we randomized patients to whether or not a risk-based strategy was applied, thereby also including patients with a low predicted risk. Accordingly, we assumed a lower risk reduction than 80%, namely 50%. We conservatively estimated the occurrence of recurrent VTE in our control group would be 7% during follow-up. Thus, at a 2-sided alpha of 0.05 and a power of 80%, 692 patients in each treatment arm were needed given our assumed relative risk reduction of 50%, leading to a target population of 750 patients per treatment arm allowing for loss to follow-up.

The primary analysis (following the intention to treat [ITT] principle) compared the incidence of VTE recurrence within 24 months after the initial anticoagulant therapy phase—in both patient groups, presented as a risk ratio, as well as a risk difference (both with corresponding 95% confidence intervals). Both the risk ratio and the risk difference were estimated with generalized linear models for binomial distributions with the log link and identity link, respectively. Next, given that we had an assistive risk-based index approach, we also wanted to explore non-adherence to the recommended treatment strategy. This secondary analysis was not preplanned in the protocol, but was deemed informative by the study group to explore treatment effectiveness in those more likely to be adherent to the intervention strategy. We first fitted a propensity score model (in the intervention group only) with protocol non-adherence as binary outcome, defined as either not obtaining a D-dimer measurement or not following the treatment recommendation from the VPM. We applied logistic regression analysis, using the prognostic factors from the VPM as predictors (for D-dimer concentration using natural cubic splines as the association between D-dimer concentration and non-adherence was not linear), in addition to oral contraceptive use given the imbalance between groups (see S1 Table). The resulting propensity score model was then applied in all patients to estimate the probability of protocol non-adherence in both arms of the trial for each imputed dataset separately [11]. Next, the primary ITT analysis was repeated, comparing patients in the intervention and control arms with a similar estimated high probability of protocol adherence, i.e., patients within the 75th quartile of predicted probability of protocol adherence, thus keeping the randomization status in place.

Additionally, we evaluated the predictive performance of the VPM. For this analysis, we used only the data of patients in the index and control groups who did not prolong anticoagulant treatment, to account for the treatment effect of anticoagulation on the incidence of the outcome. Discrimination and calibration were assessed using the c-statistic and a calibration plot for the outcome at 12 months of follow-up, using the baseline hazard function of the VPM at this time point, which we received from the authors of the original publication. This was done deliberately as thereby we explicitly used the same baseline hazard and prediction model that was used in the original derivation paper as well as in the index arm of our trial, as there also the predicted risk of recurrent VTE at 12 months (≥5% versus <5%) was used to recommend decisions on prolonged treatment. Finally, post hoc and prompted by the reviewers from PLOS Medicine and using the full spectrum of 24 months of trial follow-up, we plotted the observed risk of recurrent VTE in a Kaplan–Meier graph for different predicted risks of recurrent VTE based upon the VPM (i.e., for an annualized predicted risk of 0% to 2%, >2% to 4%, >4% to 5%, and above 5%). These additional analyses are described in more detail in S2 Text.

Missing values

Both for the explorative analysis of the impact of non-adherence to the recommended strategy based upon the VPM (fitting of the propensity model, see above) and for the validation analysis of the VPM, missing values for D-dimer concentration were imputed using chained equations. D-dimer concentration was missing in 251 patients (28.4%), and these missing values were imputed using all available information including the patients’ baseline characteristics as well as the observed outcome. Ten imputed sets were created, and the results of analyses were pooled based on methodological recommendations.

Results

In total 957 patients were deemed potentially eligible for inclusion. After an initial treatment phase, which lasted 3 to 6 months in the vast majority of patients, 883 patients were randomized to the intervention (n = 441) or control (n = 442) (Fig 1). The study did not enroll the preplanned number of 750 patients per treatment arm. Declining patient accrual into the study, mainly due to the changing anticoagulant landscape with the introduction of non-vitamin K antagonist oral anticoagulants (NOACs), which are not managed by thrombosis services in the Netherlands, in addition to budget constraints, prevented us from continuing inclusion into the trial. In close collaboration with our data and safety monitoring board, as well as the granting organization, we therefore decided to end inclusion on 30 November 2015. Thus, given that patients were treated first for 3–6 months, after which they were randomized and followed up for 24 months, follow-up of all study participants was complete in early 2018.

Fig 1 — VPM 1 performed shortly before treatment cessation at the end of the initial treatment period; VPM 2 performed approximately 1 month after treatment cessation. ^ψUsual care was left at the discretion of the treating physician; median duration of treatment in this group was 6 months. ^#Not all patients followed VPM recommendation: 58 patients were non-adherent (see main text). ^ΦThese patients had a recurrent VTE event shortly after VPM 1 and thus before VPM 2 (see S2 Table). DVT, deep vein thrombosis; Rx, treatment; VPM, Vienna Prediction Model; VTE, venous thromboembolism.

Mean age of the included 883 patients was 55 years, and in total 443 patients (218 in the index group and 216 in the control group) had proximal or distal DVT as the index event, and 440 patients had PE with or without DVT. Patient characteristics were well balanced between the groups (Table 1).

Table 1. Patient characteristics of randomized patients.

Characteristic	VPM patients (n = 441)	Control patients (n = 442)
Male sex	253 (57%)	254 (58%)
Age (years)	55 (14)	55 (14)
Diabetes mellitus	24 (5%)	30 (7%)
Previous cardiovascular disease	26 (6%)	31 (7%)
Index event
Isolated distal or proximal DVT	218 (49%)	216 (49%)
PE with or without DVT	223 (51%)	226 (51%)
Hormonal therapy^$	90 (20%)	94 (21%)
Known thrombophilia	44 (10%)	36 (8%)
History of DVT or PE^*	21 (5%)	21 (5%)
Initial treatment duration
3 to <6 months	425 (96%)	432 (98%)
6 to <12 months	16 (4%)	10 (2%)

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Data are presented as number (%) or mean (standard deviation).

^$Hormonal therapy included both oral contraceptive use and hormonal replacement therapy, for women only.

*History of DVT or PE more than 10 years ago.

DVT, deep vein thrombosis; PE, pulmonary embolism; VPM, Vienna Prediction Model.

Outcomes and effect measures

During 24 months of follow-up, 96 recurrent proximal DVT or PE events were observed (10.9%): 46 in the intervention arm (10.4%) and 50 in the control arm (11.3%), yielding a risk ratio of 0.92 (95% CI 0.63 to 1.35, p = 0.67) and risk difference of −0.8% (95% CI −5.0% to 3.2%).

Major bleeding (after randomization) occurred in 4 patients (no fatal events): 2 major bleeding events in the intervention arm (i.e., 0.5%, 95% CI 0.1%–1.6%) and 2 in the control arm (i.e., 0.5%, 95% CI 0.1%–1.6%). CRNM bleeding occurred in 20 patients, 12 in the intervention arm (i.e., 2.7%, 95% CI 1.4%–4.7%) and 8 in the control arm (i.e., 1.8%, 95% CI 0.8%–3.5%), during any time point of follow-up. Based upon the VPM risk estimation, a total of 124 patients were labeled as having a high risk of recurrence and followed the VPM recommendation to continue anticoagulant treatment. During follow-up, this number gradually dropped to 111 patients still using anticoagulant treatment at the end of follow-up. In the control group a smaller number of 65 patients, declining to 35 patients at the end of follow-up, also continued anticoagulant treatment, not guided by a risk prediction model but rather under usual care at the discretion of the treating physician (see Fig 2).

Fig 2 — Rx, treatment; VPM, Vienna Prediction Model; VTE, venous thromboembolism.

Rate of adherence to the trial regimen was—as would be expected—not 100%. In fact, 46 patients in the index group did not obtain any risk estimation, and an additional 58 patients were, for a variety of reasons, unable to comply with the treatment recommendation (i.e., a total of 104 [23.6%]), leading to an adherence rate of 76.4% (Fig 1). These 104 patients were defined as non-adherent in our secondary analysis. Using the 75th quartile of treatment adherence from the propensity model yielded in our secondary analysis a risk ratio similar to that of the primary analysis of 1.02 (95% CI 0.62 to 1.66).

Finally, 5 patients (1%) had a recurrent VTE event shortly after initial treatment was stopped and after VPM 1, and as such did not receive VPM 2 (see S2 Table).

Predictive performance of the VPM

In the 694 patients from the index and control groups who did not receive prolonged treatment, the VPM showed good discriminative performance, with a c-statistic of 0.76 (95% CI 0.69 to 0.83). However, the model underestimated recurrence risk around and above the threshold of 5% (see Fig 3). For instance, among 134 patients with predicted probability of >4% to 5%, the observed incidence of the outcome was 6.7% (95% CI 2.5% to 10.9%), which we believe will be considered too high by many, although the 95% confidence interval here is also relatively wide due to imprecision. At lower predicted risks, however, the model showed good calibration, for instance exemplified by the observation that in the group with a predicted risk of >2% to 4% (n = 284), the observed risk of recurrence was also low, at 2.5% (95% CI 0.7% to 4.3%) (see Fig 4).

Fig 3 — Left panel: discriminative performance of the Vienna Prediction Model with 95% CI (blue shading): c-statistic 0.76 (95% CI 0.74 to 0.78). Right panel: calibration plot comparing predicted risk of recurrent venous thromboembolism by the Vienna Prediction Model (x-axis) with observed recurrence rate (y-axis).

Fig 4 — At 12 months of follow-up, the observed incidence of recurrent VTE was 0% (95% CI 0%–0%), 2.5% (0.7%–4.3%), 6.7% (2.5%–10.9%), and 14.4% (9.9%–18.9%) for the predicted probability categories 0% to 2% (n = 40), >2% to 4% (n = 284), >4% to 5% (n = 134), and higher than 5% (n = 236), respectively. VPM, Vienna Prediction Model; VTE, venous thromboembolism.

Discussion

Main findings

The randomized VISTA trial was primarily set up to determine whether applying a risk prediction model to estimate recurrence risk in patients with unprovoked VTE, with subsequent risk-based tailoring of prolonged anticoagulant treatment, would lower the risk of recurrence as compared to usual care. Our findings showed that we were unable to demonstrate such a reduction. In terms of predicting the risk of recurrent VTE, the VPM that we used showed good discriminative power and moderate to good calibration, in particular at the clinically relevant lower spectrum of predicted risk.

Comparison with existing literature

Other approaches exist to predict the risk of recurrence in unprovoked VTE, albeit only validated in prospective cohorts, thus without a control group. For instance, Rodger et al. reported on the prospective application of the HERDOO2 rule [12]. This rule classifies all men as high risk (recommending prolonging anticoagulant treatment), and additionally all women with the presence of 2 or more of the HERDOO2 rule items (hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/l; obesity [body mass index ≥ 30 kg/m²]; or older age, i.e., age ≥ 65 years). The study enrolled a total of 2,785 participants, and in total 631 women were classified as low risk (23% of the total study population). In this low-risk group, 591 women actually stopped anticoagulant treatment, and 17 of them had a recurrent VTE event, yielding a recurrence rate of 3.0% per year (95% CI 1.8% to 4.8%). In another study by Kearon et al., the D-dimer test was used to guide the decision of whether or not to extend anticoagulant treatment [13]. In this study, a total of 410 patients were enrolled, and 319 patients had a negative D-dimer test 1 month after treatment discontinuation (i.e., 78% of the total study population). These patients stopped antithrombotic treatment, and recurrent disease occurred in 42 patients, for a yearly recurrence rate of 6.7% (95% CI 4.8% to 9.0%). Comparing these observational cohorts with non-treated patients in our study, we observed that the VPM showed good discriminative performance for estimating the risk of recurrent VTE. In particular, for patients with lower predicted risks (up to around 4%), the model showed good calibration. At higher predicted risk, the model underestimated recurrence risk in our population, which, importantly, is similar to the results of a pooled individual participant data meta-analysis externally validating the VPM, which also showed that the model tended to underestimate recurrence risk in patients with unprovoked VTE [14]. Yet, should we define low risk as a predicted risk of recurrent VTE up to 4%, the VPM identified 47% (324 out of 694 patients) as low risk. These findings thus compare favorably with the existing observational evidence, with the important observation that the group identified as “low risk” is substantially larger for the VPM as compared to the HERDOO2 rule. Moreover, the observed yearly recurrence rate in this group at a low predicted risk of recurrent VTE is lower when compared to “only” using D-dimer level to guide treatment continuation, as was done in the study by Kearon et al.

Strengths and limitations

For full appreciation of our findings, several limitations should be discussed. A major strength of our study is the randomized design. The sobering finding that we did not observe a difference in recurrence between a strategy of applying a prediction model versus usual care exemplifies that the impact of prediction models should also be studied in randomized trials.

Several factors may have contributed to the inability of our trial to detect a difference in recurrence. First, the population included in our trial may be considered as being at relatively low risk of recurrence. For instance, the observed risk of recurrence was only slightly higher than 5% per year in the control group, albeit this may partly be explained by the fact that, in at least part of the control group, treatment was prolonged. Additionally, we included women with oral-contraceptive-related VTE, which could be considered debatable given that oral contraceptive use is currently seen as a minor transient risk factor in the most recent definitions from ISTH [15].

Second, given the pragmatic nature of our trial, not all patients complied with the treatment recommendation of the VPM. Similarly, some hospital specialists caring for patients in our control group may have been influenced due to the trial participation of others of their patients. Nevertheless, they did not receive any information on the result of D-dimer testing. Yet obviously, both issues may dilute any effect that would be observed should all patients and physicians have been “forced” to be compliant with our risk-tailored approach. Therefore, we performed secondary (post hoc) analyses, which yielded similar results. For these secondary analyses, we used a propensity-model-based approach, comparing patients (between the index and control arms) above the 75th propensity quartile of being adherent. Albeit clinically an intuitive approach, other more advanced statistical approaches exist, such as inverse probability weighting [16]. Prompted by PLOS Medicine reviewer comments, we used these approaches as well, which yielded very similar inferences (see S2 Text for these additional analyses).

Third, during study inclusion, patient accrual rates in our trial slowly dropped, likely due to the introduction of NOAC treatment (which is not managed by thrombosis services, thus these patients were not identified by our study-protocol-defined recruitment approach). This changing anticoagulant landscape that occurred exactly during the conduct of the VISTA trial, as well as budget constraints, prevented us from changing our study design or prolonging patient accrual into our study. We believe our observations permit us to draw conclusions on the effect size of implementing the VPM on recurrence risk in patients with unprovoked VTE, given that this effect size is at the line of unity. Moreover, our study sample did allow us to a draw firm conclusion on the predictive performance of the VPM.

Fourth, recurrent VTE evens were classified after scrutinizing all available hospital discharge information and as such were adjudicated in a non-blinded manner. Similarly, this was a pragmatic trial, and we did not use blinded treatment. However, we believe the potential influence of these biases is likely very low (or even negligible) in our trial. Hospital specialists were not actively involved in this trial as participating study sites, nor was there any motive for them to favor the outcomes in the intervention or control arm of our trial.

Finally, our analyses of the predictive performance of the VPM were restricted to those not receiving anticoagulant treatment (n = 694), thus to relatively lower risk patients (as higher risk patients were more likely to receive prolonged anticoagulant treatment). Therefore, prompted by PLOS Medicine reviewer comments and to explore the potential influence of this analysis approach on the predictive performance of the VPM, we performed 2 types of additional analyses: (i) including both treated and non-treated patients and (ii) using inverse probability weighting to account for the treatment effects of anticoagulant treatment [17]. These analyses yielded similar inferences on the performance of the VPM (see S2 Text for detailed explanation of these analyses).

Clinical applicability and research implications

Given our inability to demonstrate a reduction in recurrence risk by risk-stratifying care, and in light of the publication of recent extended NOAC trials that showed superiority of extended NOAC treatment over either placebo or aspirin for reducing recurrence risk in patients with (mainly) unprovoked VTE, it may be tempting to consider prolonging anticoagulant treatment in all patients with unprovoked VTE [18,19]. Nevertheless, in these trials, follow-up duration was still limited and frail elderly were underrepresented, as were patients with a high bleeding risk, all limiting generalizability to real-life clinical care. Moreover, our findings do indicate that in a large proportion of patients (nearly half of the population included in our trial), a low predicted risk (up to an annualized rate of 4%) is correlated with a similarly low observed risk, suggesting that it might be safe to stop anticoagulant treatment. The threshold for what then defines “low VTE recurrence risk,” or what residual recurrence risk is still acceptable, is open for clinical debate. Prompted by PLOS Medicine reviewer comments, we additionally explored the following hypothetical cohort of patients: Assume a hypothetical cohort of 1,000 patients with unprovoked VTE. Based upon VISTA observations, 950, 600, and 430 patients will be classified as having an annualized recurrence risk >2% to 4% (low risk), >4% to 5% (moderate risk), or >5% (high risk). Using the observed rates of recurrence from VISTA for these strata, as well as the known hazard ratio of 0.25 for prolonged anticoagulant treatment (compared to placebo [18,19]), we can estimate the number of recurrent VTE events for different treatment strategies over a time period of 5 years. Similarly, this can be done for the number of bleeding events, assuming 3 different major bleeding rates (0.5%/year, 1.0%/year, and 1.5%/year). See S3 Table and S2 Text for further and detailed explanation. Next, we can plot the number of additional VTE and major bleeding events induced by prolonging anticoagulant treatment for certain risk thresholds above which patients are recommended to prolong treatment. In Fig 5, it may be appreciated that this threshold should perhaps be somewhere around 3% to 4%, as then the number of additional VTE events induced because we treat fewer patients is more or less the same as the number of additional bleeding events that occur given that antithrombotic treatment strategy. This threshold is lower than 5%, which is currently still the recommended threshold of “low risk” as defined by ISTH standards. Also, we should acknowledge that in particular at this threshold of 5%, the VPM is less well calibrated, further exemplifying that perhaps a threshold of 3% or 4% is more likely to be clinically meaningful.

Fig 5 — The x-axis gives the threshold above which prolonged anticoagulant treatment is recommended, based upon annualized risk estimates from the Vienna Prediction Model. The y-axis gives the number of additional VTE and major bleeding events induced depending on the threshold above which prolonged anticoagulant treatment is recommended. The bar below the graph illustrates the proportion of patients treated with anticoagulants depending on the threshold above which prolonged anticoagulant treatment is prescribed. Major bleeding rates are as expected for prolonged non-vitamin K antagonist oral anticoagulant treatment, based upon available trial evidence. VTE, venous thromboembolism.

Conclusions

Our results show that an assistive risk-based treatment strategy in all patients with unprovoked VTE is unlikely to reduce recurrence risk as compared to usual care. In those with a low predicted risk as estimated by the VPM, the observed recurrence rate is similarly low, suggesting that it might be safe to stop anticoagulant treatment in these patients.

Supporting information

S1 CONSORT Checklist. CONSORT checklist for the VISTA trial.

(DOC)

Click here for additional data file.^{(218.5KB, doc)}

S1 Table. Comparison of patients included in the ITT analysis and patients with non-adherence as included in the PP analysis.

DVT, deep vein thrombosis; ITT, intention to treat; PE, pulmonary embolism; PP, per protocol.

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

S2 Table. Description of 5 patients with a recurrent venous thromboembolic event in the interval between VPM 1 and VPM 2.

All DVT index events were proximal. ^$D-dimer concentration as obtained at the first time the VPM was obtained (VPM1). ^#Depicts the days after VPM 1 is performed (see Fig 1). DVT, deep venous thrombosis; F, female; M, male; PE, pulmonary embolism.

(DOCX)

Click here for additional data file.^{(12.5KB, docx)}

S3 Table. Clinical outcomes in a hypothetical cohort of 1,000 VTE patients followed up for 5 years.

^#These estimates come from the following line of reasoning: We know that the proportion of patients categorized in the following risk strata of annualized VTE recurrence risk of 0% to 2%, >2% to 4%, >4% to 5%, and >5% are 4.9%, 35.1%, 17.1%, and 42.9%, thus 49, 351, 171, and 429 patients in a hypothetical cohort of 1,000 patients, respectively. Based upon our VISTA data, we also know the observed annualized rates of recurrent VTE in these risk strata if anticoagulant treatment is withheld, i.e., 0.0%, 2.5%, 6.7%, and 14.4%, respectively. We know from the NOAC extension trials that these risks of recurrent VTE can be lowered with NOAC treatment, with an observed hazard ratio in these trials of about 0.25, thus yielding annualized rates of recurrent VTE, if managed with prolonged NOAC treatment, of 0.0%, 0.63%, 1.68%, and 3.6%, respectively. Now, let’s assume the annualized rates of recurrent VTE to be constant over a 5-year period. This is a conservative assumption, as we know that the rates of recurrent VTE are highest in the first year after the initial event and typically a little bit lower in the subsequent years. Using these data, we can estimate the number of VTE events over a 5-year period in our hypothetical cohort of 1,000 VTE patients for the following scenarios: (i) prolong treatment in all patients, (ii) prolong only if the estimated risk of recurrence is >2%, (iii) prolong only if the estimated risk of recurrence is >4%, (iv) prolong only if the estimated risk of recurrence is >5%, or (v) do not prolong anticoagulant treatment in any patients. In fact, the number of recurrent VTE events for these scenarios would be 103, 103, 135, 178, and 410 events, or, compared to prolonging treatment in all patients (first scenario), 0, 0, 33, 76, and 308 additional events, respectively. Similarly, we can estimate the number of major bleeding events induced in these different scenarios. Unfortunately, the annualized rate of major bleeding in VTE patients on prolonged NOAC treatment is less certain, so let’s assume the number of major bleeding events for 3 different annualized rates of major bleeding: 0.5%/year, 1.0%/year, and 1.5%/year. Over a 5-year period, we can then calculate the number of major bleeding events for these different rates of major bleeding.

(DOCX)

Click here for additional data file.^{(12.7KB, docx)}

S1 Text. Protocol of the VISTA trial as approved by the ethics committee.

(PDF)

Click here for additional data file.^{(299.6KB, pdf)}

S2 Text. Detailed explanation of additional analyses prompted by reviewers from PLOS Medicine.

(DOCX)

Click here for additional data file.^{(1.9MB, docx)}

Acknowledgments

The authors would like to thank Anna E. C. Kingma for her help in data collection, as well as all patients and physicians, and the participating thrombosis services for their collaboration while conducting this trial.

Abbreviations

CRNM: clinically relevant non-major
DVT: deep vein thrombosis
ISTH: International Society on Thrombosis and Haemostasis
ITT: intention to treat
NOAC: non-vitamin K antagonist oral anticoagulant
PE: pulmonary embolism
VPM: Vienna Prediction Model
VTE: venous thromboembolism

Data Availability

Data from this randomized controlled trial cannot be shared publicly because this study includes human research participant data and prior to sharing data, consulting an ethics committee is needed to ensure data are shared in accordance with participant consent and all applicable local laws. Data are available from the Institutional Data Access (contact via SecretariaatHAG-Onderzoek@umcutrecht.nl) for researchers who meet the criteria for access to confidential data, accompanied with a protocol describing the research questions aimed to answer.

Funding Statement

The study received funding from the Netherlands Organisation for Health Research and Development (ZonMw grant number 171002214, KGMM was the receiving grant holder, URL: www.zonmw.nl). KGMM received a grant from The Netherlands Organization for Scientific Research (ZonMw 91810615 and 91208004; URL: www.zonmw.nl). GJG is supported by a VENI and VIDI grant from the Netherlands Organisation for Health Research and Development (ZonMw numbers 016.166.030 and 016.196.304; URL: www.zonmw.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS Med. doi: 10.1371/journal.pmed.1003142.r001

Decision Letter 0

Adya Misra

13 Feb 2020

Dear Dr. Geersing,

Thank you very much for submitting your manuscript "Tailoring of anticoagulant treatment by a recurrence risk prediction model in patients with venous thrombo-embolism compared to usual care; a validation and impact study." (PMEDICINE-D-20-00044) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

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Sincerely,

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Senior Editor

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Requests from the editors:

Article meta-data- please ensure you provide article meta-data such as financial information, competing interests and data availability statements. If you have questions about this please contact us at plosmedicine@plos.org

Title- Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).

Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions).

Abstract- could you include a sentence to describe unprovoked venous thrombo-embolism

Please complete the CONSORT checklist and ensure that all components of CONSORT are present in the manuscript, including [how randomization was performed, allocation concealment, blinding of intervention, definition of lost to follow-up, power statement].

Abstract Methods and Findings:

* Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

* Please include the study design, population and setting, number of participants, years during which the study took place, length of follow up, and main outcome measures.

* Please quantify the main results (with 95% CIs and p values)

* Please include a summary of adverse events if these were assessed in the study. * In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

Abstract primary outcome does not match the primary outcome noted in the CT registry, please clarify

Please provide brief information about the VISTA study and introduce the term on first view

Line 102, study protocol URL appears to be the journal URL, please provide the study protocol as SI files or provide the correct link

The information about ethics approval and written informed consent should ideally be provided together within the methods section

Please provide dates of patient recruitment and follow up more clearly in the methods section.

The CONSORT checklist should be cited within the methods section and page numbers should be removed as these are likely to change during publication. Please instead refer to paragraphs and sections.

Comments from the reviewers:

Reviewer #1: This article presents the results of a randomised trial testing whether using the Vienna prediction model decreases the incidence of recurrent venous thrombo-embolism (VTE) compared to usual care in patients with previous unprovoked VTE. It also seeks to assess the predictive ability of the Vienna model by treating the study as a cohort. While the results are clearly presented and I have no major concern, I have a number of minor comments listed below:

Major comments:

* No major comments.

Minor comments:

* Please update the title to include the study design as per PLOS Medicine conventions.

* In the conclusion of the abstract, please consider changing the last sentence to make the statement less definitive/certain. For example, by writing: "in those with a low predicted risk of recurrence, the observed rate was also low; suggesting that it might be safe to stop anticoagulant treatment in these patients".

* Please clarify whether the primary outcome (see lines 167-168) was measured 24 months after randomisation or 24 months after the end of this initial treatment phase. I believe this is in fact the same time point but it would be good to make it more explicit when defining the outcome.

* Please clarify whether outcome assessment was performed and/or adjudicated in a blinded manner and, if not, please discuss the potential risks associated with reporting/ascertainment bias.

* Line 221 mentions imputed datasets; however, data imputation is not discussed prior to this statement (it is mentioned in the last sentence of the methods). Please clarify the nature of the imputation including variables imputed, variables included in the imputation model and the number of imputed datasets. Please also indicate whether the imputation was pre-specified in the protocol or analysis plan or post-hoc.

* When restricting the analysis to patients with a high estimated probability of adherence, please report the degree of comparability between the index and control group. i.e. were they well matched or did some baseline imbalance remain between the two groups after selecting those with a high probability of adherence? Please consider adding the corresponding baseline table to the online supplement. In case of baseline imbalances (e.g. standardised difference greater than 0.1), please consider adjusting the analysis.

* I am confused by the fact that the predictive performance analysis excluded patients who continued anticoagulant treatment. In patients randomised to the index group, only those at higher risk (according to the Vienna prediction model itself) would have continued anticoagulant treatment. Therefore, excluding these patients limits the validation exercise to only those at lower risk. Please confirm/clarify.

* Please clarify why 12 months of follow-up were selected for the validation when the primary outcome of the trial was measured at 24 months.

* The authors (lines 231-232) mention using the baseline hazard function from the original publication. Does this imply that the risk score used in the validation is different to the risk score used in the randomised trial? If so, please clarify the reason for choosing different equations.

* Figure 2: It is difficult to see the proportions in white font over the bubbles even after downloading the original .tiff version. Please consider using a different font and/or color.

* The 'validation' analysis suggest that the authors were able to calculate the risk from the Vienna prediction model in both the index and control group. Please consider reporting the number and proportion at high risk separately for each randomised group. This could potentially be added to Table 1.

* I would suggest moving Table 2 (Description of 5 patients with interval recurrent venous thrombo-embolic event) to the online supplement as it does not appear essential to the main 'story'.

* The authors state that "the model underestimated recurrence risk around and above the threshold of 5%" (see lines 318-319); however, according to Figure 3 (right panel) the predicted line seems very close to every observed estimate (triangles) and certainly well within the confidence bands. Please clarify.

* Pending clarification of the above comment, could it be that the 'apparent' underestimation around the 5% threshold is linked to the fact that some (most?) patients with a risk above 5% continued treatment and were therefore excluded from the validation exercise. To address this concern, I would encourage the authors to consider repeating the validation analysis without excluding any patient (i.e. regardless of whether they continued treatment) as a sensitivity analysis.

* I believe that the data should be made publicly accessible instead of available on request as per PLOS Medicine policy but will defer to the editor's guidance on this aspect.

-Laurent Billot

Reviewer #2: The manuscript by Geersing et al. describes the results from a randomized trial conducted with the aim of comparing decision making of treatment duration of oral anticoagulant treatment after venous thromboembolism (VTE) by use of the VIENNA prediction model (VPM). The overall hypothesis was lower recurrence risk among patients assessed using a risk-based strategy (VPM) than recurrence risk found in a control group. In the VPM arm, a total of 441 was enrolled and 442 VTE patients were randomized to usual care. The duration of follow-up was 24 months.

The study was an investigator-initiator trial conducted on multiple sites with block-randomizing (site and type of VTE) of patients to either VPM or usual care. The trial followed principles of a pragmatic trial with no blinding. A CONSORT description was available and the trial was registered in a Dutch trial database. Participants presented with VTE and were eligible if no so-called 'provoking' risk factors were prevalent including active cancer. Indications for long-term treatment with an oral anticoagulant treatment was also an exclusion criteria.

Initially all patients were treated with warfarin 3 to 6 months after low molecular weight heparin lead-in. Before end of this treatment period, patients were randomized to either usual care (discretion of the physician) or to a risk-tailored approach using VPM.. Extended (i.e. longer duration of the initial three to six months) duration of treatment was offered to those with a predicted risk of 5% per year or above in accordance with the ISTH recommendations. Model risk assessment was done twice, first time short before treatment cessation and second time approximately one month after. In the control group, the treatment cessation time was based on the discretion of the physician. Patients were followed up at 3, 12, and 24 months.

Major comments:

The current clinical equipoise relates to when oral anticoagulant treatment can safely be withheld in patients presenting with VTE and no apparent clinical risk factors. Anticoagulation is effective in preventing VTE recurrence but the use of oral anticoagulant treatment has an inheriting risk of bleeding. Hence, the duration of treatment should be based on an assessment of the net clinical benefit. Therefore, it is important to present the proportion of patients (stratified according to randomization) with treatment duration in e.g. quartiles, which has been the traditional length of treatment in VTE patients (3, 6, 9, or 12 months). This would allow the reader some insights into the initial decision making that was left to the discretion of the treating physician. Preferably, this could also be sub-categorized into patients presenting with DVT or PE.

It is not entirely clear when the randomization occurred. Since this was a pragmatic (non-blinded) study design, it could be hypothesized that knowing the assignment of the individual treatment arm would affect the behavior (and preferences) of the patients and/or physicians. The authors are encouraged to reflect on the consequences of using a no-blinded study design, and on the direction and magnitude of this potential bias on the effect estimates. Furthermore, the Vienna model consists of three parameters: the extent of VTE, patient sex, and D-dimer concentration. This is obvious information, also for physicians determining anticoagulant treatment duration without VPM. In consequence, this is likely to result in no difference between the two treatment arms. This dilemma could be discussed in the article.

The secondary analysis, which was not pre-planned, is of interest as these estimates may reflect a more realistic effect of what would be seen in everyday clinical practice. However, the implementation of the approach is lacking details. The authors are encouraged to consult this reference DOI: 10.1056/NEJMsm1605385, which outlines an appropriate analytic plan to conduct per-protocol analyses specifically for pragmatic trials that minimizes the risk of selection bias in relation to censoring. Additionally, the following sentence is unclear: (p7) "we used patients within the 75th quartile of predicted probabilities of protocol adherence." Was the data restricted based on the propensity score? If so, it would be important to characterize the patients who did not enter this analysis - what were the main differences in terms of baseline characteristics? Perhaps an approach like inverse probability of treatment (or rather protocol adherence) weighting could allow for a more efficient use of the available data?

What is the argument for assessing performance only among patients who did not receive prolonged treatment? This would be a selected group of patients with a presumed low recurrence risk. Calibration in high risk patients would be of clinical relevance.

The performance, in terms of calibration, of VPM is assessed using 4 probability categories (0-2%; 2-4%; 4-5%; and >5%). However, the clinical relevant cut off point is at 5%, as stated by the International Society of Thrombosis and Hemostasis. At this threshold the VPM is not well calibrated. The authors should deliberate on the consequence of bad calibration at this clinically meaningful cut-off point.

It would be relevant to include relative estimates with 95% CI between treatment arms on risk of bleeding.

Minor comments:

Could the authors please check the order of the figures/tables in the supplemental material?

Please provide labels on the y-axis for Figure 2.

What is meant with the term "impact study" in the title? Consider to leave it out.

The study excludes patients with a history of VTE within 10 years. Yet, table 1 list patients with a "history of DVT or PE". Please clarify, if this is a VTE more than 10 years ago? (and supplementary table S1)

Table 1: proportion of patients receiving hormonal therapy - please clarify if this proportion is for women only. (and supplementary table S1)

It could be mentioned (and discussed) that VPM has previously been externally validated.

It could be highlighted that the authors are not identical with the ones developing the VPM.

Table 1: "Index" could be rephrased to "VPM patients"

Figure 1: 10 patients are excluded because of clear indication for short treatment. Why and what is this?

Reviewer #3: In this randomized controlled trial, the Vienna Prediction Model (VPM) was tested to determine whether implementing the model would reduce recurrence risk. 883 patients were randomised to using the VPM compared with usual care. No difference in number of recurrent VTE events was observed, and slightly more CRNM bleeding in the intervention arm. The authors conclude that application of the VPM in patients with unprovoked VTE is unlikely to reduce overall recurrence risk.

This is a well-described, honest and important account of how a promising prediction model can fail to translate in improved clinical care, and therefore imperative to be noticed by both clinicians and researchers. For this reason it is also, possibly even more so than for 'positive' studies, necessary to describe in detail what happened.

Most important comments:

1) This study in fact investigates 2 things at the same time: the performance of the VPM and the related antithrombotic strategy. The authors now conclude that the absence of a difference in risk is related to the application of the model. However, it could also simply be due to insufficient treatment related to the result of the model. Theoretically the recurrence risk in both study arms should be equal. So, to find a difference in actual VTE occurrence, a strategy should have been in place that would strongly impact this risk. This has not really happened, so it seems, considering that the rate of prolonged treatment was in fact low in both arms, although a bit higher in the intervention arm: about 25 vs 10% (if I infer correctly from fig 2). So all effect from applying the model should have come from this small difference in treated subjects, which seems implausible. This option, of an insufficient treatment difference between the arms, could receive more attention in the Discussion.

2) In fact I think it could be modelled (e.g. as in a Mendelian Randomisation analysis) how many more cases could have been prevented if the difference should have been larger between the groups (and likewise the bleedings). This would clearly not be the same as in a true RCT but it might shed some light on the respective role of the VPM and the applied treatment strategy in the observed results of this study.

3) Why was the rate of treatment so low anyway? Was only such a small proportion of patients classified above 5% per year? I find this information not easy to find in the manuscript: which patients took OAC or not at what predicted risks and what were their observed risks, with and without treatment. This would also give some information on effectiveness of the treatment given equal estimated risks. It could also be discussed how the low treatment rate relates to the current guidelines in which everybody with an unprovoked first event is recommended to continue unless a high bleeding risk is present.

Other comments:

4) Please mention how the criteria used for defining an unprovoked event relate to other definitions (from other scores or guidelines, such as the ISTH's)

5) " Risk estimation was performed twice, namely shortly before treatment cessation at the end of the initial treatment period (thus while still using anticoagulant treatment) and approximately one month after treatment cessation" This is rather confusing for both patients and doctors? Could this have affected the results and would this strategy impede implementation of the model?

6) How were possible recurrent events adjudicated as such?

7) Were all patients followed for 24 months or until recurrence occurred? Not clear if people were lost to follow-up?

8) " 46 patients in the index group did not obtain any risk estimation whereas an additional 58 patients (total of 104) were for a variety of reasons unable to comply to the treatment recommendation" It is unclear which 58 patients is referred to from fig 1.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2020 Jun 26;17(6):e1003142. doi: 10.1371/journal.pmed.1003142.r002

Author response to Decision Letter 0

20 Mar 2020

Attachment

Submitted filename: Rebuttal_R1.docx

Click here for additional data file.^{(1.9MB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003142.r003

Decision Letter 1

Adya Misra

21 Apr 2020

Dear Dr. Geersing,

Thank you very much for re-submitting your manuscript "Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thrombo-embolism compared to usual care: a randomized controlled trial." (PMEDICINE-D-20-00044R1) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

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We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Apr 28 2020 11:59PM.

Sincerely,

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

Abstract

Please mention the aim in the background section

Please state where the trials took place and provide brief patient demographics

Conclusions should start with “our results show” or similar

On page 3 please include the sub heading “Author Summary” and include bullet points for readability

Please note all references should be within square brackets and the bibliography should be modified to Vancouver style

The Data Availability Statement (DAS) requires revision. For each data source used in your study: a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number). b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data. c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

Methods

Line 121- could you provide the name of the local thrombosis services or mention the names of cities where these services are based (as you have in line 132)

Please remove the reference to the study protocol online and add a brief sentence that this information is in the SI files

Please correct November 30rd to 30th

Please provide citations to or copies of questionnaires used in the study as Si files

Please move the role of the funding source to the financial disclosure section of the article meta-data

Line 453- we do not allow instances of data not shown, so please provide these data or remove this sentence

Please revise the discussion for readability, as it is currently rather long and the main messages are somewhat lost. The discussion of strengths, limitations, clinical application of your work is important but please do see if these sections can be shortened. For instance: Lines 486-496 can be considered for removal. I appreciate the additional information regarding the hypothetical cohort here and the discussion around the 5% low risk threshold, but I would recommend shortening this section so that the main message is clearly highlighted for the reader.

Figure 5-can this be placed within supplementary information?

Conclusions

Please start this section with “our results show” or something similar

This section requires some revision, as it currently doesn’t seem to sum up you work sufficiently clearly. Could you rephrase Lines 537-539 so clarify your findings about low risk recurrence

Fig1 – could you ensure this adheres to CONSORT style

Fig 2- the X-axis needs a label

Comments from Reviewers:

Reviewer #1: The authors have responded thoroughly to my queries and conducted a range of useful sensitivity analyses.

I note that in a few instances, the results of the sensitivity analyses are not reported. Instead a sentence mentions that the results were consistent with the main analyses and adds "(data not shown)". I would encourage the authors to include the results of the sensitivity analyses in the supplement or, in the case of a short result such as a point estimate and its confidence interval, to include it in the text.

Please try and make as explicit as possible which analyses were pre-planned vs post-hoc (e.g. multiple imputations). I would also encourage the authors to explicitly state which analyses were performed to address comments from the PLOS Medicine reviewers.

-Laurent Billot

Reviewer #2: The authors have responded sufficient to the comments raised.

Reviewer #3: all my comments were well addressed

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. doi: 10.1371/journal.pmed.1003142.r004

Decision Letter 2

Adya Misra

3 Jun 2020

Dear Dr. Geersing,

On behalf of my colleagues and the academic editor, Dr. Suzanne C. Cannegieter, I am delighted to inform you that your manuscript entitled "Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thrombo-embolism compared to usual care: a randomized controlled trial." (PMEDICINE-D-20-00044R2) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

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If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

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PROFILE INFORMATION

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Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 CONSORT Checklist. CONSORT checklist for the VISTA trial.

(DOC)

Click here for additional data file.^{(218.5KB, doc)}

S1 Table. Comparison of patients included in the ITT analysis and patients with non-adherence as included in the PP analysis.

DVT, deep vein thrombosis; ITT, intention to treat; PE, pulmonary embolism; PP, per protocol.

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

S2 Table. Description of 5 patients with a recurrent venous thromboembolic event in the interval between VPM 1 and VPM 2.

(DOCX)

Click here for additional data file.^{(12.5KB, docx)}

S3 Table. Clinical outcomes in a hypothetical cohort of 1,000 VTE patients followed up for 5 years.

(DOCX)

Click here for additional data file.^{(12.7KB, docx)}

S1 Text. Protocol of the VISTA trial as approved by the ethics committee.

(PDF)

Click here for additional data file.^{(299.6KB, pdf)}

S2 Text. Detailed explanation of additional analyses prompted by reviewers from PLOS Medicine.

(DOCX)

Click here for additional data file.^{(1.9MB, docx)}

Attachment

Submitted filename: Rebuttal_R1.docx

Click here for additional data file.^{(1.9MB, docx)}

Data Availability Statement

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PERMALINK

Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thromboembolism compared to usual care: A randomized controlled trial

Geert-Jan Geersing

Janneke M T Hendriksen

Nicolaas P A Zuithoff

Kit C Roes

Ruud Oudega

Toshihiko Takada

Roger E G Schutgens

Karel G M Moons

Roles

Abstract

Background

Methods and findings

Conclusions

Trial registration

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Trial design and ethical approval

Participants

Randomization and blinding

Index group

Control group

Outcome measures

Follow-up appointments

Statistical analyses and power calculations

Missing values

Results

Fig 1. Flow of patients in the study.

Table 1. Patient characteristics of randomized patients.

Outcomes and effect measures

Fig 2. Patients using anticoagulant treatment during follow-up.

Predictive performance of the VPM

Fig 3. Discrimination and calibration of the Vienna Prediction Model.

Fig 4. Cumulative observed VTE risk for different strata of predicted risk.

Discussion

Main findings

Comparison with existing literature

Strengths and limitations

Clinical applicability and research implications

Fig 5. Clinical tradeoff between additional VTE and major bleeding in a hypothetical cohort in 1,000 VTE patients.

Conclusions

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Adya Misra

Roles

Author response to Decision Letter 0

Decision Letter 1

Adya Misra

Roles

Decision Letter 2

Adya Misra

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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