Scientific discussion about the treatment of intracranial stenosis

Introduction

Approximately 5-10% of all strokes worldwide are induced by intracranial atherosclerotic stenosis (1). In Germany, around 6-8% of all strokes can be attributed to a symptomatic stenosis of the intracranial arteries (2). However, in some ethnic groups, this proportion is considerably higher. The proportion of African Americans, for example, is 15-29% and is even as great as 30-54% for Asians (3,4). The biggest differences in population groups can be attributed to both genetic differences and also to a different distribution of risk factors.

Intracranial stenosis – the current situation in clinical research

It is clear that research in the area of intracranial atherosclerotic stenosis must be advanced further so that strokes induced by it can be treated better or even prevented completely. At present, the benefits of administering drugs and endovascular treatment with balloon catheters and stents (percutaneous angioplasty and stenting - PTAS) for the treatment of intracranial stenosis has been called into question.
Current clinical studies have made the treatment of intracranial stenosis with the aid of stents, in particular, the subject of controversy, leading to uncertainty for all concerned. We would therefore like to outline the current state of clinical research, though stopping short of giving treatment recommendations. This remains the preserve of treating doctors.

Clinical Studies

1. The SAMMPRIS Study
2. The VISSIT Study
3. Further Studies

  The SAMMPRIS Study

The most famous and most frequently referenced study in connection with intracranial stenting is the US SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) study. The goal of this study was to investigate the chances and risks of stenting with intracranial stenoses compared with medical therapy.
The first results of this study were published in 2011 (5), and the long-term results followed in 2014 (6). In summary, the results are as follows: within an average observation period (mean: 32.4 months), 34 out of 227 (15%) patients who were treated with drugs and 52 out of 224 (23%) patients who were treated with a stent (PTAS group) suffered a stroke or died within 30 days of inclusion, or of the intervention performed.   It was concluded that the application of a stent for symptomatic intracranial stenosis has no advantages over “aggressive medical therapy”, but shows an increased risk of stroke or death (5,6). In the wake of the SAMMPRIS study, the treatment of intracranial stenosis with stents underwent a significant decline, especially in Western states.

This generalised and blanket rejection of stenting has encountered criticism from many doctors and professional medical associations. This is because on the one hand the design and execution of the SAMMPRIS study showed weaknesses and on the other it leaves patients for whom medical therapy is ineffective without a treatment option.
The essential weaknesses of the SAMMPRIS study are as follows:

1. Inclusion criteria: The inclusion criteria of the SAMMPRIS study with regard to stent application went beyond the approval of the Wingspan® stent used and were defined in a significantly broader way than is usual in clinical practice. The normal approach is for patients to be treated with a stent only if medical therapy (the conservative treatment) fails, as these patients probably represent the group with the highest risk of a recurrent stroke. The SAMMPRIS data contain no information on drugs administered to patients before the referenced event or in respect of previous strokes (7,8,9).  

2. Medical product used: In the SAMMPRIS study, the Gateway® PTA balloon catheter and the Wingspan® stent (both by Boston Scientific, today Stryker Neurovascular, Fremont, CA, US) were deployed. Both products have been on the market since 2004/2005. Experts agree that the high complication rate caused by vessel injuries and haemorrhages are related to the relatively large stent system and the exchange manoeuvre of the Gateway-Wingspan® system (9).

3. Inexperienced practitioners: The complication rate in the SAMMPRIS study fluctuated greatly depending on the practitioner’s experience with the stent system. The percentage of haemorrhagic complications (haemorrhages) with practitioners who have included more than 12 patients was 2.7%, while for practitioners who had included fewer than 12 patients, the figure was 9.8% (8).

4. Patient management: The risk of stroke after one year (10,11,12) could be reduced in the medical therapy section of the SAMMPRIS study by 12.2% (11,12,20). This improvement can be explained with the application of so-called “aggressive” medical therapy (dual antiplatelet therapy and intensive management of the vascular risk factors in combination with strict lifestyle modification). Lifestyle modification was conducted and monitored by a coach who contacted the patients by telephone every fortnight in the first three months after inclusion, and once a month after that (6)(vi). The jury is still out as to how far such a procedure transfers to the requirements of everyday life (5,6).

In summary, it can be said that the SAMMPRIS study shows weaknesses, whereby the clinical data gained would apply to patients who are typically treated with a stent in clinical practice in a way that is very limited (7,9,12).

In Germany, after the publication of the SAMMPRIS data, the Institute for Quality and Efficiency in Healthcare (IQWiG) was commissioned by the German Federal Joint Committee (G-BA) to carry out a benefit assessment. The IQWiG does not conduct any studies itself. Instead, scientific studies (which are generally sponsored by the manufacturers) are the basis for evaluating whether drugs or medical procedures add value to the treatment of patients (Link)(http://www.berliner-zeitung.de/wirtschaft/iqwig-leiter-juergen-windeler--wir-kennen-die-tricks-der-pharmaindustrie--3169370). The IQWiG is financed by premiums for stationary and ambulatory medical treatments. That is to say, the finance comes ultimately from the contributions of members of all of the statutory healthcare insurers (GKV). The premium amount is stipulated annually by the G-BA.
The IQWiG receives orders from the German Federal Joint Committee (G-BA) and the German Federal Ministry for Health (Link)(http://www.bmg.bund.de/glossarbegriffe/i-j/institut-fuer-qualitaet-und-wirtschaftlichkeit-im-gesundheitswesen.html ).
The main task of the G-BA is to determine more closely in guidelines the contents of the provision and to decide which services are paid by the GKV. In so doing, the G-BA fulfils its statutory mandate to ensure that all patients can be well provided for and benefit from medical progress. At the same time, its guidelines serve to guarantee that provision is carried out cost-effectively and does not result in unnecessary expense for policyholders (Link) (http://www.bmg.bund.de/themen/gesundheitssystem/selbstverwaltung/gemeinsamer-bundesausschuss.html). The G-BA is composed of representatives of the organisations of the healthcare insurers and contracted medical professionals, as well as hospitals at a federal level, whereby representatives of patient organisations have a right to take part in discussions (Link) (http://www.bmg.bund.de/themen/gesundheitssystem/selbstverwaltung/selbstverwaltung-im-ueberblick.html).

With regard to the results of the SAMMPRIS study, in 2014 the IQWIG generated a rapid report, which contains the following conclusions, amongst other things:
“In the comparison of PTAS with medical therapy versus medical therapy, the stroke endpoint demonstrated a reference point for worse damage in the PTAS (percutaneous angioplasty and stenting) group. This damage could be attributed, in particular, to the significant increase in periprocedural strokes.“ So, in a temporal context, using existing strokes as a benchmark, there are clues for greater damage in the PTAS group. The other patient-related endpoints show clues neither for damage nor for benefit with regard to stenting by comparison with medical therapy (11).
In addition, the IQWiG points out that the drugs as they were applied in the studies (dual platelet inhibition, consisting of ASS and clopidogrel) are not approved in Germany for the secondary prevention (bow method) of a stroke (11).

However, the professional medical associations in Germany, namely the Professional Association of German Neuroradiologists (BDNR), the German Association for Neuroradiology (DGNR), the German Association for Neurology (DGN) and the German Stroke Association (DSG) took a different, i.e. a differentiated approach, in its joint statement on the SAMMPRIS results (13) (Link) http://www.dgnr.org/de-DE/103/intrakranielle-stents-stellungnahme). The summary of the statement of the professional associations is as follows:
“In summary, we adhere to the view that the data basis on which the benefit assessment of the IQWiG is founded is not sufficient to make a comprehensive and conclusive assessment of the intracranial stenting treatment method. A differentiated approach is required with regard to different clinical constellations, indications and implants. In certain treatment situations, which have been outlined above, there is no other therapeutic alternative to intracranial stenting” (13).

Therefore, the leading clinical practitioners in Germany state clearly that for certain patients who, despite optimal medical therapy, suffer a recurrent stroke, the option of balloon angioplasty and stent implantation as a treatment option of last resort must continue to be covered by the GKV. This is advocated both by representatives of doctors who use the PTAS method themselves and by those who have observed the application in their patients.

 The VISSIT Study

In 2015, the results of a further clinical study, the “Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT), was published (14).
The results of the VISSIT study, in which a balloon-expandable stent was deployed (a self-expandable stent was used in the SAMMPRIS study), were even worse than with SAMMPRIS, so that the inclusion of further patients was stopped by the sponsor of the study.
The interim analysis after the inclusion of 112 patients (initial 250 patients planned) resulted in a worse clinical result in the group of patients who were treated with a stent (13). The design and execution, and therefore also the weaknesses, of the study were comparable with SAMMPRIS.

In response to this, the IGWiG produced another expert report (Stents for The Treatment of Intracranial Arterial Stenoses: VISSIT Study and Acute Treatment in Germany - IQWiG Reports – No. 303) and summed it up as follows:
“The results of the VISSIT study confirm the results of the SAMMPRIS study and therefore support the assessment of Rapid Report N14-01.“ (15)

The professional medical associations authored a new report (the Professional Association of German Neuroradiologists (BDNR), the German Association for Neuroradiology (DGNR), the German Association for Neurology (DGN) and the German Stroke Association (DSG)), a position paper opposing the IGWiG expert report (16), in which it came to the following conclusion:
“Based on medical experience in clinical practice, we regard the non-treatment of patients with progressive neurological symptoms due to acute local atherosclerotic occlusions of cerebral arteries as unacceptable and regard the removal of such treatments from GKV cover as ethically and morally indefensible.”(15)

 
Further Studies

In the following, we mention some studies on the subject of stent application for intracranial stenosis.

The GESICA study:
The GESICA study (17) shows that patients who are resistant to medical therapy are at high risk for the recurrence of ischaemic events. 102 of the patients observed in the natural course of the study manifested (observation period mean: 23.4 months) for a total of 38.2% (n=39) a recurrent ischaemic event (13.7% stroke and 24.5% TIA).  60.7% of the 27.4% of observed patients (n=28) who suffered a haemodynamically significant stenosis manifested another ischaemic event.
This study therefore suggests that clinically significant haemodynamic stenoses are liable to have a high risk of stroke and that these sorts of classifications help to identify high-risk groups (16).

The WEAVE study:
The Wingspan® Stent System Post Market Surveillance Study (Wingspan® Stents) is a prospective, observational study with the indication revised by the FDA. The organisers of the study lay emphasis on the stent being deployed within its approved indication. After inclusion of the first 122 patients (102 of whom were treated within the indication), an interim analysis was carried out. Of these 122 patients, 3 patients (2.9%) suffered a stroke or died within 72 hours of the intervention. Of the 20 patients outside the indication who were treated with the stent, 4 patients (20%) suffered a stroke or died in the same observation period. The complication rate comes well under the complication rate from the SAMMPRIS study (14.7%), which indicates that sensible patient selection as well as optimisation of the application of the medical products within their indication (corresponding, essentially, to usual clinical practice) and of patient management, reduce the periprocedural risks of intracranial stenosis stenting. Due to the positive interim result, this study is continuing (18,19).

The CASSISS study:

In the Asiatic area, the CASSISS study (China Angioplasty & Stenting for Symptomatic Intracranial Severe Stenosis) must be mentioned. In this study, 50% of 380 planned patients are supposed to receive optimal medical therapy, while 50% receive optimal medical therapy in combination with a stent. The organisers of this study also stress the importance of avoiding the weaknesses of the SAMMPRIS study. Clinical practice is taken into account by combining medical therapy with stenting, selecting patients with greater care and selecting participating hospitals based on their experience and capabilities. This study has been running since 2014 (20).

Stroke prevention

To prevent an initial stroke, risk factors must be considered and, if possible, minimised. These factors include raised blood lipid levels, smoking, diabetes and high blood pressure. So, risks can be minimised through healthy nutrition and regular exercise.
Along with optimal medical therapy, the same applies if a stroke has already occurred. Even in the SAMMPRIS study, the patients observed were able to lower the risk of stroke after one year (14,13,21) through drugs and the intensive management of vascular risk factors in combination with strict lifestyle modification (5,6) to 12.2% (11,12). Lifestyle modification was conducted and monitored by a coach who contacted the patients by telephone every fortnight in the first three months after inclusion, and once a month after that (6). The jury is still out as to how far such a procedure transfers to the requirements of everyday life (5,6).

Current developments in Germany

After an intensive advisory process lasting over three years, the German Federal Joint Committee (G-BA) came to a decision in September 2016 on future treatment methods to be covered by statutory insurers.
As a result of this decision, patients who have an intracranial stenosis with a degree of stenosis of at least 70% and have suffered at least one further infarction after a stenosis-induced infarction despite subsequent intensive medical therapy remain unaffected by an exclusion.  Equally, patients with an acute vessel occlusion due to a high degree of stenosis for whom alternative treatments fail or cannot be considered are excepted (see decision).

Summary
When all the arguments mentioned are weighed against each other and the clinical studies are examined closely, the picture appears clearer. No one is arguing with the fact that changing to a healthy lifestyle is the best stroke prevention there is. However, if a stroke or a TIA occurs due to a high degree of intracranial stenosis, it appears to be indisputable that optimal medical therapy represents the method of choice. Nevertheless, these drugs are not sufficient for all patients. In such cases, medical experts maintain that, under quite specific circumstances, the treatment alternative of last resort should be used, which consists of PTA and stenting.
Consideration of the use of medical products from a technical standpoint

Consideration of the use of medical products from a technical standpoint
The SAMMPRIS study has shown clearly that the high percentage of early strokes and haemorrhagic complications are correlated with the procedure of intracranial stenting, which can be put down to the technical limitations of the Wingspan® stent used and can possibly be remedied with new technical developments (5).
An important step in the procedure applied in the SAMMPRIS study is the so-called exchange manoeuvre, which basically can cause a movement in the microwire needed and lead to vessel ruptures and haemorrhaging (5). This manoeuvre serves to remove the balloon catheter from the patient after application in order to widen the vessel and in a second step to navigate the stent conduction system to the site to be treated.
Consequently, at least some complications can be prevented by avoiding the exchange manoeuvre. The implementation of this optimisation in miniaturised, modern medical products is described in (22), whereby the stent can be applied directly using a PTA catheter, making the exchange manoeuvre described superfluous. This modified treatment method consisting of a PTA catheter and stent in “one system” is carried out in selected hospitals in Germany and observed as part of the “AcandiS Stenting of Intracranial STENosis – regisTry“ (ASSISTENT).

Sources
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