MSAC Application 1428
Mechanical thrombectomy
For acute ischaemic stroke due to large vessel occlusion
Submission to the
Medical Services Advisory Committee
June, 2016
MAIN BODY OF THE SUBMISSION
Submission prepared by:Medtronic Australasia Pty Ltd
97 Waterloo Road
North Ryde, NSW 2113 /
MSAC Application 1428
MEDTRONIC Executive summary
Executive Summary
Mechanical thrombectomy for acute ischaemic stroke due to large vessel occlusion
This submission-based Application by Medtronic Australasia requests a Medicare Benefits Schedule (MBS) listing for mechanical thrombectomy (MT) to treat acute ischaemic stroke (AIS) due to a large vessel occlusion (LVO). MT offers significantly superior post-stroke functional outcome when compared with usual care in carefully selected patients. Following favourable results from five recent randomised controlled trials (RCTs) and strong positive recommendations in international and local guidelines, stroke care pathways are rapidly being updated to incorporate MT as a treatment option. With strong evidence for superior clinical efficacy and cost benefits, MT has the potential to transform AIS treatment in Australia.
Alignment with agreed PICO confirmation
This Application addresses all of the PICO elements that were pre-specified in the decision analytic protocol (DAP) that was considered by the Protocol Advisory Sub-Committee (PASC). The criteria proposed for the final Protocol are reproduced in the table below.
Summary of PICO criteria to define research questions that assessment will investigate
Patients / Intervention / Comparator / Outcomes /Persons with a confirmed diagnosis* of acute ischaemic stroke
*Includes definite large vessel occlusion of the anterior circulation identified by imaging.
Patients selected for treatment according to acute stroke management guidelines. / Mechanical thrombectomy
Mechanical thrombectomy may be used in combination with intravenous thrombolytic drug therapy or without thrombolytic drug therapy for patients who are ineligible or fail thrombolytic therapy. / For indicated patients, intravenous thrombolytic therapy is a comparator to the proposed service.
For patients contraindicated for intravenous thrombolytic therapy, the alternative comparator to the proposed service is medical management with anti-thrombotic therapy. / Effectiveness
Revascularisation (e.g. TICI score)
Function (e.g. Barthel Index)
Disability (e.g. mRS)
Health-Related QoL Neurological deficit (e.g. NIHSS)
Rescue treatment
Mortality (all-cause; ischaemic stroke)
Safety
Device or procedure-related adverse events
Haemorrhage (e.g. symptomatic intracerebral haemorrhage, any cerebral haemorrhage)
New ischaemic stroke
Resource use
e.g. Rehabilitation; hospitalisation; length of stay (general ward, ICU)
Abbreviations: ICU, intensive care unit; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; QoL, quality of life; TICI, Thrombolysis in Cerebral Infarction perfusion scale grade.
Section A: CONTEXT
Rationale for Application
Stroke is a major cause of prolonged neurologic disability in adults and has significant clinical and cost burdens. Improved management of patients during the acute phase of stroke treatment can save patients’ lives and help to reduce both the clinical and cost burden of stroke.
For individuals who have an AIS, the key to effective treatment is early reperfusion of ischaemic brain without causing adverse effects. To achieve reperfusion, intravenous thrombolytic therapy is recommended in treatment guidelines – however, many patients fail to respond to, or are ineligible to receive thrombolytic therapy. MT has become a treatment option for these patients. In addition, for those patients who receive thrombolytic therapy, clinical outcomes can be improved when MT is used as an adjunct to thrombolytic therapy.
The inclusion of MT for AIS on the MBS is a key step to improving access to an effective treatment option and to addressing the clinical and cost burdens of stroke. Improvements in reperfusion following MT and subsequent avoidance of neurological complications result in higher rates of functional independence for AIS patients. Achieving higher rates of functional independence and avoiding stroke related disability translates to shorter hospital stays, less use of rehabilitation services, reduced carer burden, and reduced use of other healthcare resources - all of which have the potential to positively impact both clinical outcomes and healthcare costs over the longer-term. Improved access to MT has the potential for significant reduction in direct healthcare costs. Broader societal benefits and indirect cost savings from avoided impact on productivity costs and reduced carer burden are also anticipated.
Proposed medical service
MT is a highly specialised and time-critical treatment, with the greatest benefit achieved with early reperfusion of ischaemic brain. It requires a well organised system to identify suitable candidates for therapy, and should only be performed by highly trained neurointerventionists at suitable stroke units.
Delivery of the service involves the use of a specialised endovascular device to remove an obstructing clot from the artery, thereby restoring blood flow to the brain and minimising brain tissue damage. The devices used to perform MT include coil retrievers, aspiration devices and most recently, stent retrievers. All are delivered to occluded sites with the aid of microcatheters and guidewires, but each type of device uses a slightly different mechanical approach to remove the target clot. Although the Applicant manufactures and markets the Solitaire™ brand of stent retrievers, this submission considers evidence for all types of devices used in MT. MT may be used in addition to the current standard of care for AIS, thrombolysis with recombinant tissue plasminogen activator (IV tPA), or as a standalone in patients who are ineligible or contraindicated to IV tPA.
Proposal for public funding
Current clinical practice guidelines reflect MT’s favourable clinical evidence in patients with AIS caused by LVO who are eligible or ineligible for IV tPA. Whilst some evidence suggests that outcomes may be influenced by factors such as time from stroke onset, pattern of stroke damage, and disease severity, subgroup analyses of individual patient data show that the relative benefit of MT is largely consistent regardless of variation in patient selection criteria. On this basis, the item descriptor proposed in this submission takes a relatively non-prescriptive approach to patient selection. The table below presents the proposed MBS item descriptor. The Applicant notes that the evidence base for MT has evolved rapidly and will continue to evolve. Similar to any new therapy, patient selection criteria and procedure delivery will continue to be refined and this should be reflected in evolving clinical practice guidelines. Hence, the MBS descriptor for the proposed service should retain sufficient flexibility to accommodate changes in clinical practice, while aligning with clinical guidelines. Eligibility criteria for MT should retain sufficient flexibility to ensure clinician determination of patient suitability for MT on a case-by-case basis – taking into consideration the complete clinical circumstances in an acute emergency setting.
Proposed MBS item descriptor
Category 3 - THERAPEUTIC PROCEDURESMBS [item number]
Mechanical thrombectomy of patients with a confirmed diagnosis of acute ischaemic stroke caused by large vessel occlusion, of the anterior circulation; procedure to be started within 8 hours of stroke onset; including intra-operative imaging, but in association with preoperative diagnostic imaging itemsa
- either 56001 or 63064
Fee: $3,500
(Anaes.) (Assist.)
Explanatory notes:
• Diagnosis confirmed by imaging: ischaemic stroke with large vessel occlusion on CTA or MRI
• Patients selected for treatment according to acute stroke management guidelines.
• Clinician discretion for procedure use in selected patients beyond 8 hours of stroke onset, where clinical assessment indicates patient is likely to benefit from treatment (salvageable brain tissue identified on imaging).
• Service to be provided by suitably trained and accredited operators in suitably accredited hospitals [requirements TBD]. This should include contribution to systematic registry data for audit purposes [requirements TBD].
aExamples of relevant CT and MRI items included.
Abbreviations: TBD, to be determined; CTA, computed tomography angiography; MRI, magnetic resonance imaging
Consultation with relevant clinical societies is required to determine accreditation and registry participation requirements. Considered together, selection of patients in accordance with clinical practice guidelines and provision of the proposed service by suitably accredited operators and hospitals should ensure that MT is only provided to patients that will benefit from this therapy.
Comparators
MT is indicated as an additional therapy in patients who are eligible for IV-tPA, and as an alternative therapy in patients for whom IV-tPA is contraindicated. The comparators for these respective groups are:
· IV-tPA alone (where indicated), and
· Medical management (anti-thrombotic therapy) where IV thrombolytic therapy is contraindicated.
In this submission these comparators are referred to as ‘usual care’.
There are strict rules to determine if a patient is eligible for IV-tPA - it is recommended in clinical practice guidelines as first-line therapy approved for LVOs within 4.5 hours of symptom onset. Hence, presentation > 4.5 hours after stroke symptom onset will preclude access to IV-tPA. In addition, patients may be ineligible due to non-time based reasons, examples include: severe, uncontrolled hypertension; previous surgery; widespread ischaemia, patient receiving oral anticoagulants. The only treatment option available to patients who are ineligible for IV-tPA (time and non-time based reasons) is medical management, consisting of anti-thrombotic therapy with antiplatelet agents (aspirin) or anticoagulants.
Proposed clinical management algorithm
The proposed clinical algorithm is consistent with recommendations from clinical practice guidelines (CPGs) and Australian stroke protocols. MT is indicated as an additional therapy in patients who are eligible for treatment with IV-tPA, and as an alternative therapy in patients for whom IV-tPA is contraindicated.
Current and proposed clinical management algorithm
Abbreviations: LVO, large vessel occlusion; MT, mechanical thrombectomy
In line with clinical practice guidelines:
· If eligible for IV-tPA, this should be administered as early as possible, before or during assessment of patient suitability for MT (<4.5h from symptom onset).
· If suitable for MT, this should be performed without awaiting a clinical response to IV-tPA (<6h from symptom onset).
Section B: PRIMARY EVIDENCE
A literature search was conducted to identify all published and unpublished RCTs that could be used to directly compare the efficacy and safety of the use of MT plus usual care versus usual care alone as a treatment for patients with AIS due to a LVO. The search identified five eligible randomised trials of MT plus usual care and usual care alone ESCAPE; EXTEND-IA; MR CLEAN; REVASCAT; SWIFT PRIME which met the PICO-defined inclusion criteria. One of the pivotal studies, EXTEND-IA, was conducted in Australia and New Zealand, led by investigators from the Royal Melbourne Hospital.
The primary outcome presented in this submission was the modified Rankin scale (mRS) at 90 days, which is a measure of functional ability. This primary outcome was assessed as a “shift analysis” of disability scores (i.e. the odds of improving by one mRS point). Secondary outcomes included functional independence (mRS 0-2 at 90 days) and mortality.
For the primary outcome, the median mRS score at 90 days favoured the intervention treatment arms and was statistically significant in all five trials at 90 days compared to the control group, i.e. the lower the mRS score, the lower the degree of disability and increased functional independence. A post-hoc meta-analysis of these results, based on individual patient data (IPD), shows a pooled cOR of 2.26 (95% CI: 1.67, 3.06; p<0.0001) (Goyal et al, 2016). The corresponding number needed to treat with MT to reduce disability by at least one level on the mRS for one patient was 2·6.
For the secondary outcomes, 46.1% of patients in the intervention treatment arm (i.e. MT) compared to 26.4% of patients in the control arm (i.e. usual care) achieved functional independence at 90 days. This difference was statistically significant with an odds ratio (OR)=2.39 (95% CI: 1.88, 3.04), p<0.0001. For mortality, 15.3% of patients in the intervention treatment arm compared to 18.8% of patients in the control arm had died at 90 days. This difference was not statistically significant with an OR=0.78 (95% CI: 0.54, 1.12), p=0.18. The absence of heterogeneity in the meta-analyses strengthened conclusions about the consistency of effects across major subgroups of age and severity.
For the secondary outcomes, 46.1% of patients in the intervention treatment arm compared to 26.4% of patients in the control arm possessed a mRS score of 0-2 at 90 days. A mRS score of 0-2 indicated functional independence. Overall, 15.3% of patients in the intervention treatment arm compared to 18.8% of patients in the control arm had died at 90 days.
Meta-analysed outcomes in the pivotal trials of MT vs usual care
Outcome / Intervention – MT / Control – Usual care / OR [95% CI]n /N (%) / n /N (%)
Primary outcome
mRS score reduction (shift analysis) / - / - / 2.26 (1.67, 3.06) p<0·0001a
Secondary outcomes
mRS score 0-2 at 90 days / 292/633 (46.1%) / 170/645 (26.4%) / 2.39 [1.88, 3.04], p<0.00001b
Mortality at 90 days / 97/634 (15.3) / 122/649 (18.8) / 0.78 [0.54, 1.12], p=0.18b
Abbreviations: CI, confidence interval; mRS, modified Rankin scale; MT, mechanical thrombectomy; OR, odds ratio
a Common odds ratio indicating the odds of improvement of one point on the mRS. Based on IPD meta-analysis by Goyal (2016).
b OR [95% CI] calculated using Review Manager 5.3 for this submission.
In general, the pivotal trials also included a greater proportion of subjects who achieved early neurologic improvement, possessed milder impairment post-stroke and higher Barthel Index (BI, a measure of daily living capability) score compared to the control arm. Additionally, there was 100% reduction in the perfusion-lesion volume for patients treated with intervention treatment, compared to 37% reduction for those in the control arm.
Overall, the safety data suggest that MT is associated with an increased risk of certain complications compared to usual care alone; in particular, procedural complications and hematoma. However, these risks should be balanced against the poor prognosis of many patients with AIS and the net benefits of treatment with MT in terms of functional outcomes. Furthermore, any adverse effects resulting directly from the procedure would be expected to occur within the 90-day duration of the trial. Therefore, the long-term safety profile of MT relative to usual care is expected to be similar to the 90-day safety profile reported in the clinical trial.
The evidence presented demonstrates that treatment with MT in addition to usual care is superior to usual care alone in terms of effectiveness and non-inferior in terms of safety. A modelled cost-utility analysis is presented to support the cost-effectiveness of MT in addition to usual care.