Evidence for the Use of Rivaroxaban Following an EKOS Procedure for PE

Evidence for the use of Rivaroxaban following an EKOS procedure for PE

Contents

1. Introduction

1.1 Therapeutic problem………………………………………………………..

2. Literature Search

3. Guidelines

4. Critical evaluation of the literature

4.1 Appraisal of Paper 1 – Kelley et al¹⁷

4.2 Appraisal of Paper 2 – Schreinlechner et al¹⁸

5. Discussion

6. Recommendation

7. References

 1. Introduction

Pulmonary embolism (PE) is a condition caused by a blocked blood vessel occluding blood flow into the lungs. It usually occurs when a blood clot formed in a blood vessel elsewhere moves and obstructs the pulmonary arterial system. This obstruction is known as an emboli, resulting in a severe respiratory dysfunction since the lung area affected is no longer perfused.^1,2

The therapy choice will depend on several factors; the severity of the condition, contraindication to a particular treatment, the presence of comorbidities, the licenced indication of the drug and patient’s preference.¹ Specialists will usually make clinical decisions on the treatment choice (Figure 1) and the duration of treatment.¹ Pharmacological treatment is preferred in haemodynamically stable patients.  If the patient is not haemodynamically stable, mechanical interventions such as thrombectomy might be required.³ In the past years, novel endovascular procedures have emerged to revolutionise thrombosis treatment. Some of these non-surgical procedures use a combination of pharmacological and mechanical treatment with a catheter-directed thrombolysis.⁴

Figure 1: Summary of Pulmonary Embolism treatment options.

Platelets are activated when a blood vessel wall is broken and they start to aggregate in the injured area. The activated platelets trigger the initiation of the clotting cascade to stop the bleeding. Fibrinogen, a soluble plasma protein, will become fibrin as final result of this cascade.⁵ Fibrin is an insoluble protein displayed in long fibrous chains that entangle more platelets and other blood cells.⁶ This builds up a mesh that gradually hardens forming a blood clot.
 

Fibrin interfere the flow of thrombolytic drugs to the blood clot core, requiring higher doses to be effective. The acoustic pulse field created by ultrasound waves weakens fibrin formation unravelling the mesh blood clot. This technique allows more thrombolytic agent to reach effectively the entire clot.⁷ It aims to reduce treatment time and the dose of thrombolytic agent required in catheter-directed thrombolysis (CDT) alone.³

These techniques use an ultrasound enhanced catheter directed thrombolysis (UE-CDT) also known as ultrasound-assisted catheter-directed thrombolysis (USAT). One of these devices is branded as EkoSonic^™ Endovascular system (EKOS^™), which gives name to this procedure. EKOS^™ uses high frequency, low energy ultrasonic waves in a catheter that contains a thrombolytic agent infusion to target a specific area (Figure 2)⁷. This combination of ultrasound waves and a catheter-directed thrombolysis therapy is currently used to dissolve blood clots for the treatment of PE, Deep Vein Thrombosis (DVT) and Peripheral Arterial Occlusions.⁸

Figure 2: Ekosonic Ultrasonic Endovascular Thrombolysis system⁹.

1.1 Therapeutic problem

The cardiology team within the Trust have been prescribing Rivaroxaban PE treatment dose following an EKOS procedure. Rivaroxaban is an oral anticoagulant licensed in the UK for the treatment of PE and is not licensed for patients with PE who have had an intervention such as EKOS¹⁰. Thrombolysis is associated with a risk of haemorrhagic complications including stroke. This risk could potentially increase in patients who receive antithrombotic treatment following a thrombolysis therapy intervention.

The aim of this therapeutic review is to appraise the available evidence in order to assess the safety and appropriateness of Rivaroxaban following an EKOS procedure. This will allow for an informed recommendation to be made as to whether the cardiology team should continue to prescribe it under these circumstances.

2. Literature Search

A search was conducted using tertiary sources (Micromedex, UpToDate, DynaMed Plus, Martindale) to gain an overview of the therapeutic area. An extensive literature research was undertaken on Cochrane Library, EMBASE, and Medline databases via NHS Evidence’s Healthcare Databases Advanced Search (HDAS) to identify relevant papers (Tables 1-4). After completion of the literature search as per Figure 3,  three papers were identified for critical analysis (Table 5). The MeSH browser and EMTREE were used to match the search terms on Medline and Cochrane (Table 6).

Due to the small number of hits on these databases, it was not necessary to apply limitations to the search, such as date or language restriction. The full text of the remaining studies were then assessed using the inclusion criteria (Table 7).

Table 1: EMBASE search (conducted on 16/06/2019)

Table 2: MEDLINE search (conducted on 16/6/2019)

Table 3: Cochrane Library search (conducted on 16/06/2019)

Table 4: Key for search strategy with definitions

Figure 3. Literature search strategy using EMBASE, Medline and Cochrane Library.

Table 6: Explanation of search terms

Table 7: Exclusion and inclusion criteria for identification of relevant studies

3. Guidelines

A search for local, national and international guidelines was conducted using NHS Evidence and DynaMed Plus. The guidelines available (Table 8) illustrated very limited information about this therapeutic area, which highlights the need for further investigations regarding the therapeutic plan for patients with intermediate-high risk PE.⁹

None of these guidelines mention a specific anticoagulation regime plan post CDT or USAT. Due to the lack of recommendations for the use of Rivaroxaban for PE following an EKOS procedure an analysis of primary literature is required to determine if there is sufficient evidence to support its use.

Table 8. Guidance relating to the use of Rivaroxaban following an USAT for PE.

4. Critical evaluation of the literature

Three papers were deemed suitable for review from the literature search: a review, a case series and a retrospective observational cohort study. The STROBE tool¹⁵ (to support observational studies) and CASP tool¹⁶ (for analysing cohort studies) were used to appraise the papers. Principles of the CASP tool were used as a guide to appraise review paper.

The following studies were appraised to help determine the role for Rivaroxaban in the treatment of PE following EKOS procedure.

4.1 Appraisal of Paper 1 – Kelley et al¹⁷

A total of 76 patients aged 18 years and above were retrospectively selected to receive either a DOAC or VKA following USAT for VTE. The methodology of this study is vague (Table 9). Whilst the exclusion criteria are clearly stated, the requirements for the eligibility criteria were not described.

It is difficult to determine whether or not the cohort was representative of the population who actually received treatment following USAT procedure over two years because this information is not provided. It is unknown if it is a small or relevant sample size, which increases the risk of selection bias in the study and prevents generalisation of the results.

The treatment groups were evenly balanced in most baseline characteristics, however DOACs were more commonly prescribed in patients with PE, and VKA was preferred for patients with VTE. The fact that the treatment groups had different diagnosis could potentially lead to biased general conclusions.

There is no description of the actual USAT procedure for any groups. There is no mention whether the thrombolysis therapy doses used were steady for both groups. Patients receiving higher doses of thrombolytic agent are more likely to suffer bleeding events affecting the primary outcome.

DOACs appear to have similar safety/efficacy profile as VKA following USAT. The DOACs have a slightly higher rate of a 90-day bleeding or recurrent thrombotic event compared to VKAs with no significant difference (9.5% vs 5.9% respectively, P=0.686). Three months may not be sufficient to expect a measurable outcome of the intervention.

The use of DOAC therapy for VTE post-USAT was not associated with higher rates of bleed/recurrent VTE compared to VKA. There is limited evidence to suggest the dose of Rivaroxaban is safe and appropriate for clinical practice.

Table 9. Summary of paper 1 appraisal.

4.2 Appraisal of Paper 2 – Schreinlechner et al¹⁸

This is a case series study, considered a lower grade of evidence, as it is only an initial exploration of an issue related to a proposed evaluation. This case series’ objective reports the use of Rivaroxaban following USAT in 5 patients (Table 10). Although a clear timeline is established, the methodology of identifying eligible patients with a confirmed diagnosis of symptomatic intermediate high-risk PE is not stated. This potentially introduces a selection bias that represents a threat to the validity of the study. The internal validity of the study is also very low due to the lack of a comparator group and no statistical analysis.

Four of the patients are aged over 70 with identical diagnosis – extensive pulmonary emboli with central involvement of the main pulmonary arteries; four out of five cases were bilateral occlusions. This reduces generalisability of the results to younger patients or those ones with not so severe diagnosis.

No recurrent thromboembolic events or bleeding episodes were reported during the 3 month follow up period; this data is not reflective of a wider population and may be down to chance. There are several limitations to this paper, which make it difficult to replicate the results to clinical practice.

Table 10. Summary of paper 2 appraisal.

4.3 Appraisal of Paper 3 – Mohsen Sharifi¹⁹

This paper reviews the most important literature in regards to percutaneous endovenous intervention (PEVI) such as USAT or CDT over conventional treatment of VTE. While this review also discusses the post-procedure anticoagulation treatment from the author’s perspective, it doesn’t address a clearly focused aim.

Most relevant studies, especially the randomized clinical trials (RCTs) mentioned in this paper, the author didn’t assess the quality of them. The author reviews all the studies available based on his experience from clinical practice considering the evidence currently available.

Over 100 patients were treated with Rivaroxaban 20 mg daily 2 hours after PEVI with no bleeding or other complications observed. EKOS procedure is categorised as USAT, which falls under PEVI umbrella, but the author has not specified the sample size of patients who had USAT. This lower dose of Rivaroxaban was selected as patients requiring thrombolysis were excluded from the trials that contributed to license Rivaroxaban. A lower anticoagulant dose is sensible when tissue plasminogen activator is been given to minimise bleeding risk.  Bleeding rate with low dose rivaroxaban was <1% which the author compares to the bleeding rate of 2.2% in the TORPEDO trial²⁰ which uses a higher dose. There is no mention of what outcomes were measured and the monitoring involved.

After all, it is extremely difficult to determine if there is confirmation bias and the author only focused on those perspectives suited to his pre-existing views, while dismissing other papers that refute them. This paper can only be considered as anecdotal evidence.

5. Discussion

Systemic thrombolysis for the treatment DVT is usually problematic due to poor penetration into the blood clot. This contributed to the development of new devices that could overcome this obstacle like USAT. Systemic thrombolysis through a peripheral vein is very effective for PE treatment as the drug is fully gathered into the lungs due to the venous flow direction converging into the lungs.²⁵ Furthermore, according to current guidelines, for patients with high-risk PE and shock or hypotension, systemic thrombolysis is preferred to USAT¹¹. In view of how NHS is increasingly focused in delivering cost effective care; it is very likely that the use of EKOS devices for PE treatment will still be very limited. Patient recruitment into large sample size studies will be difficult.

The lack of evidence about the use of Rivaroxaban treatment dose is not unforeseen given that patients receiving thrombolysis were excluded from the trials (EINSTEIN-PE) that established Rivaroxaban as licensed treatment for PE.²³ The main objective of all the RCTs was to demonstrate no inferiority of USAT treatment versus conventional thrombolysis or anticoagulation therapy (PEITHO, ULTIMA, SEATTLE II and GUSTO) do not even mention what post-procedure anticoagulation treatment was used.^22-25 ULTIMA trial acknowledges that the post-procedure anticoagulation treatment was left to discretion of the investigators.²³

Papers 1 and 2 used the same dose of Rivaroxaban (15 mg twice daily) whilst Paper 3 used a lower dose (20 mg daily). Neither offer a justification of why PE treatment dose was preferred over prophylaxis dose.^23,25 Case-reports are subject to a high probability of bias and are not a reliable form of evidence in comparison to RCTs or a meta-analysis. They are essential for the awareness of rare diseases and their management.

Paper 1 did not specify the USAT device whilst Paper 2 used the EKOS endovascular system. EKOS procedure uses of a fraction (10-20%) of the conventional dose of the thrombolytic agent. It is intuitive to believe this promptly improves the clinical condition of the patient without considerable increase in bleeding risk. Bleeding risk increases when combined thrombolysis with anticoagulation PE treatment. Further studies are needed to look at other dosing regimens and their effects with different thrombolysis therapy interventions.

All studies had a small sample size with no statistical significant measure stated. Prudent consideration is required when considering using Rivaroxaban following an EKOS procedure for PE because inappropriate use of may result in major bleeding complications.

6. Recommendation

There is no evidence available that specifically assesses the safety and efficacy of the use of Rivaroxaban. Anecdotal reports suggest that PE treatment dose is the most commonly used in practice. More robust and well-designed prospective double-blind RCTs that minimise bias are needed to demonstrate more strengthened conclusions from the data. After evaluation of the available evidence, the use of Rivaroxaban following an EKOS procedure for PE cannot be recommended due to a lack of high-quality evidence.

There may be a role for Rivaroxaban in conjunction with thrombolysis therapies to reduce VTE recurrent events. The evidence-base for this unlicensed use is currently limited to anecdotal reports. A reasonable recommendation would be to review and consider dose regime on an individual basis until further guidance is available. Taking into consideration patient’s factors like bleeding risk, co-morbidites, emboli resolution status after procedure as well as assessing the risk/benefit.

Rivaroxaban is a licensed medicine that in these cases will be used ‘off label’. Therefore, the consultant must complete a request form for the ‘off label’ use of a licensed medicine as per London North West University Healthcare Unlicensed Medicines policy. Clinical data, risk management, funding plan and any evidence to support this use must be endorsed with this form prior submission to Drug and Therapeutic Group (DTG).

DTG will review the application based on the evidence provided and will make a decision on individual basis. If Rivaroxaban is approved for this ‘off label’ use by the DTG, the cardiology team will be advised to discuss this limited evidence with their patients as well as possible side effects such as bleeding incidents or haemorrhagic stroke. If the patient still wished to trial this unlicensed use this should be initiated and monitored. Patient-centred approach should be taken when determining the appropriateness of the treatment with special consideration to treatment goal: prevent death and improving quality of life in the long term.

The consultant should then be encouraged to write a case-report, which may help corroborate future evidences.

7. References

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