Angioplasty and stenting for intracranial stenosis.

Of the patients enrolled in the Japanese Registry of Neuroendovascular Therapy (JR-NET), a surveillance study in Japanese, 1133 patients who underwent intracranial percutaneous transluminal angioplasty (PTA)/stenting for intracranial stenosis during the period from 2005 to 2009 were investigated. A technical success was achieved in 98.3% of the patients, and 70.5% and 7.5% had a residual stenosis of < 30% and ≥ 50%, respectively. The incidence of ischemic complications and hemorrhagic complications was as low as 7.7% and 2.5%, respectively, but tended to increase in patients who underwent stenting. While a significant correlation with ischemic complications was observed in previously untreated patients and patients who underwent stenting followed by post-dilatation, a significant correlation with hemorrhagic complications was observed in patients who received emergency treatment and those treated between 24 hours and 14 days of the onset. Flexible intracranial stents are expected to contribute to improvement in the treatment outcome.

Introduction

Angioplasty has traditionally been used for the treatment of intracranial stenosis, primarily for intracranial stenosis refractory to medical therapy. However, since no stent is specifically designed for intracranial arteries, treatment is usually completed with balloon angioplasty alone, and stenting using a coronary stent is applied only in unavoidable circumstances. While more flexible intracranial stents that are compatible with the characteristics of more tortuous intracranial arteries have been awaited for a long time, the Wingspan (Stryker, Kalamazoo, Michigan, USA) was approved in the United States in 2005, and an investigator-initiated clinical trial is under way in Japan with the aim of gaining coverage by the Japanese National Health Insurance system. In advance of introduction of intracranial stents in Japan, review of previous treatment results in Japan may be essential for the development of endovascular therapy for intracranial stenosis. The Japanese Registry of Neuroendovascular Therapy (JR-NET) was a retrospective registration survey on all neuroendovascular procedures performed in Japan. Procedures performed from 2005 to 2006 were included in JR-NET1, and those from 2007 to 2009 were included in JR-NET2. We report the results of the JR-NET, including analysis and discussion.

Materials

All patients enrolled in JR-NET1 or JR-NET2 who were treated with intracranial percutaneous transluminal angioplasty (PTA)/stenting for intracranial stenosis were included in the present study. Data from a total of 1133 patients who underwent angioplasty/stenting for intracranial stenosis were analyzed: 438 patients in JR-NET1 (2005 to 2006) and 695 patients in JR-NET2 (2007 to 2009).

Methods

Data files from JR-NET were used to determine correlations between differences in the baseline characteristics of patients, procedures, or perioperative management, and the occurrence of hemorrhagic or ischemic complications in a retrospective manner. Data were analyzed for each factor, except for “unknown” data and missing data. For the factors asked about in JR-NET2 but not in JR-NET1 (presence or absence of pre-dilatation and post-dilatation, type of stent, timing of treatment, and presence or absence of general anesthesia), only data from JR-NET2 were used. Statistical analysis was performed by chi-square test using excel statistics.

Results

The baseline characteristics of patients, lesion profile, treatment situation, treatment, treatment outcome, and complications are shown in Table 1. The mean age was 66.7 (19 to 94) years, and the proportion of male subjects was as high as 76.5%. At baseline, the mean modified Rankin scale (mRS) was 0.86, and patients with an mRS of 0 to 2 accounted for 89.1%. Of all patients, 25.0% received treatment under general anesthesia, and 17.0% received emergency treatment. Stenting was performed in 60.6% patients. The most common preoperative antiplatelet treatment was treatment with two agents in 71.6%, followed by treatment with one agent in 14.1%. While the most common postoperative antithrombotic agents were argatroban in 38.9% and heparin in 25.9%, no postoperative antithrombotic treatment was performed in 26.4%. Technical success was achieved in 98.3%, and 70.5% and 7.5% had a residual stenosis of < 30% and ≥ 50%, respectively. The incidence of ischemic complications and hemorrhagic complications was 7.7% (87 patients) and 2.5% (28 patients), respectively, and 1 patient had both ischemic and hemorrhagic complications. As a result, the incidence of hemorrhagic and ischemic complications within 30 days postoperatively was 10.1%. At 30 days postoperatively, the mean mRS was 1.02, and the mRS increased from baseline by 2 points or more in 8.6%. The mortality was 1.9%.

Table 1

Characteristics of 1,133 patients

Patient characteristics
Baseline characteristics of patients	Age	Mean 66.8 (19–94) years
	Sex	Male 76.5%
	mRS at baseline	Mean 0.86
	mRS 0 to 2	89.1%
	Previously untreated	92.7%
Lesion profile	Region	IC (intracranial epidural): 36.0%, IC (intradural): 84.7%, MCA: 22.2%, VA: 16.6%, BA: 14.4%, other: 2.4%
	Symptom at diagnosis	Asymptomatic: 19.9%, amaurosis: 1.4%, TIA (cerebrum): 22.1%, minor stroke: 36.5%, major stroke: 8.7%, progressing: 11.3%
	Timing of treatment (JR-NET2)	Within 24 hr: 13.5%, within 14 days: 20%, after at least 15 days: 66.5%
	Percent diameter stenosis	< 50%: 2.4%, 50% to 60%: 4.5%, 60% to 70%: 9.9%, 70% to 80%: 32.0%, 80% to 90%: 26.7%, 90% to 100%: 22.2%, 100%: 2.3%
	Lesion length	< 5 mm: 25.0%, 5–10 mm: 53.2%, 10–15 mm: 16.3%, ≥ 15 mm: 5.5%
	Normal vascular diameter	< 2 mm: 1.9%, 2–2.5 mm: 16.0%, 2.5–3 mm: 24.1%, 3–3.5 mm: 25.1%, 3.5–4 mm: 19.7%, ≥ 4 mm: 13.2%
	Pathology	Arteriosclerosis: 93%, traumatic dissection 0.3%, iatrogenic dissection 0.7%, idiopathic dissection 1.1%, others 4.7%
	Refractory to medical therapy	44.9%
Treatment situation	Diagnostic cerebral angiography	39.6%
	Emergency treatment	17.0%
	Treatment at another hospital	10.6%
	Investigator	Supervisory physician: 55.0%, specialist: 37.4%, nonspecialist: 7.5%
	Scrub-in of supervisory physician	62.5%
	No. of scrub-in supervisory physicians and specialists	1: 58.0%, 2: 33.0%, ≥ 3: 9.0%
	General anesthesia (JR-NET2)	25.0%
Treatment	Stenting	Yes: 60.6%
	Presence or absence of pre-dilatation (JR-NET2)	Yes: 72.0%
	Use of coronary stent (JR-NET2)	97.9%
	Presence or absence of post-dilatation (JR-NET2)	28.8%
	Preoperative antiplatelet treatment	No: 5.4%, 1 agent: 14.1%, 2 agents: 71.6%, 3 agents: 8.9%
	Postoperative antiplatelet treatment	No: 6.0%, 1 agent: 12.7%, 2 agents: 71.7%, 3 agents: 9.6%
	Postoperative antithrombotic treatment	No: 26.4%, heparin: 25.9%, argatroban: 38.9%, ozagrel: 3.1%, combination: 5.6%
	Other concurrent treatment	12.8%
Treatment outcome	Technical success	98.3%
	Residual stenosis immediately after treatment	< 30%: 70.5%, 30% to 50%: 22.1%, ≥ 50%: 7.5%
	Hemorrhagic complication	2.5%
	Ischemic complication	7.7%
	mRS at 30 days postoperatively	Mean 1.02
	Postoperative increase in mRS ≥ 2 points	8.6%
	Mortality	1.9%

BA: basilar artery, IC: internal cerebral artery, JR-NET: Japanese Registry of Neuroendovascular Therapy, MCA: middle cerebral artery, mRS: modified Rankin scale, TIA: transient ischemic attack, VA: vertebral artery.

Ischemic and hemorrhagic complications are listed in Table 2. The most common ischemic complication was distal embolization in 3.4%, followed by vascular dissection in 1.9%. The most common hemorrhagic complications were vascular rupture in 0.6% and hyperperfusion-related hemorrhage in 0.4% of patients.

Table 2

Details of ischemic complications and hemorrhagic complications

	Total	Incidence(%)
Ischemic complication
Distal embolization	39	3.4
Vascular dissection	21	1.9
Acute obstruction	15	1.3
Other	4	0.4
Unknown	8	0.8
Total	87	7.7
Hemorrhagic complication
Vascular rupture	7	0.6
Hyperperfusion	5	0.4
Vascular dissection	3	0.3
Vessel perforation	2	0.2
Other	5	0.4
Unknown	6	0.5
Total	28	2.5

Correlation between each factor tested and ischemic complications are shown in Table 3. The following factors were significantly correlated with ischemic complications: no previous treatment; not refractory to medical therapy; stenting followed by post-dilatation; postoperative antithrombotic treatment; and supervisory physician who served as the investigator. The incidence of ischemic complications was significantly lower in patients who received postoperative antithrombotic treatment with heparin alone than in those who received no postoperative antithrombotic treatment (Table 4).

Table 3

Correlation between each factor and ischemic complications

Baseline characteristics of patients	Age	≤49 years: 7.0%, 50 to 59 years: 6.9%, 60 to 69 years: 7.1%, 70 to 79 years: 6.7%, ≥ 80 years: 2.7%
	Sex	Male: 6.6%, female: 6.6%
	mRS at baseline	0 to 2: 6.9%, 3 to 5: 5.2%
	Previous treatment	Previously untreated: 8.4%, previously treated: 2.2% (p < 0.05)
Lesion profile	Region	IC (intracranial epidural): 6.2%, IC (intradural): 5.5%, MCA: 7.5%, VA: 9.6%, BA: 11.0%
	Symptom at diagnosis	Asymptomatic: 8.0%, symptomatic: 7.8%
		Nonprogressively symptomatic: 8.1%, progressively symptomatic: 5.8%
	Timing of treatment (only symptomatic patients)	Within 24 hr: 8.8%, between 24 hr and 14 days: 5.9%, after at least 15 days: 7.7%
	Percent diameter stenosis	< 50%: 8.0%, 50% to 60%: 8.7%, 60% to 70%: 8.9%, 70% to 80%: 7.3%, 80% to 90%: 7.3%, 90% to 100%: 8.4%, 100%: 8.7%
	Lesion length	< 5 mm: 8.3%, 5–10 mm: 6.4%, 10–15 mm: 12.2%, ≥ 15 mm: 5.4%
	Normal vascular diameter	< 2 mm: 0%, 2–2.5 mm: 10.4%, 2.5–3 mm: 10.2%, 3–3.5 mm: 5.9%, 3.5–4 mm: 6.5%, ≥ 4 mm: 6.7%
	Pathology	Arteriosclerosis: 7.2%, traumatic dissection 0%, iatrogenic dissection 0%, idiopathic dissection 12.5%, others 3.1%
	Refractory to medical therapy	No: 8.8%, yes: 5.0% (p < 0.05)
Treatment	Stenting	No: 6.6%, yes: 9.7%
	Presence or absence of pre-dilatation (JR-NET2)	No: 10.1%, yes: 6.0%
	Presence or absence of post-dilatation (JR-NET2)	No: 5.7%, yes: 9.8%
	Stent + presence or absence of post-dilatation (JR-NET2)	No: 5.6%, yes: 14.0% (p < 0.05)
	Preoperative antiplatelet treatment	No: 8.9%, 1 agent: 6.2%, 2 agents: 8.2%, 3 agents: 7.6%
	Postoperative antiplatelet treatment	No: 11.2%, 1 agent: 8.3%, 2 agents: 7.0%, 3 agents: 12.0%
	Postoperative antithrombotic treatment	No: 4.9%, heparin: 3.5%, argatroban: 9.7%, ozagrel: 12.9%, combination: 30.3% (p < 0.000000001*)
	Other concurrent treatment	No: 7.3%, yes: 11.0%
Treatment situation	Diagnostic cerebral angiography	No: 8.0%, yes: 7.4%
	Emergency treatment	Planned: 7.2%, emergency: 10.4%
	Treatment facility	Hospital at work: 8.2%, another hospital: 3.3%
	Investigator	Supervisory physician: 10.1%, specialist: 4.5%, nonspecialist: 5.8% (p < 0.01**)
	Scrub-in of supervisory physician	No: 2.7%, yes: 10.0% (p < 0.001)
	No. of scrub-in supervisory physicians and specialists	1: 7.1%, 2: 8.8%, ≥ 3: 3.3%
	General anesthesia	Local anesthesia: 7.7%, general anesthesia: 5.7%
Treatment outcome	Residual stenosis immediately after treatment	< 30%: 7.4%, 30% to 50%: 7.0%, ≥ 50%: 11.7%

Each p-value is shown in Table 4.

Supervisory physician vs. specialist (p < 0.001).

mRS: modified Rankin scale.

Table 4

Correlation between postoperative antithrombotic treatment and ischemic complications

	Ischemic complication (−)	Ischemic complication (+)	Total	Incidence	p value
No postoperative antithrombotic treatment	253	13	266	4.9%	p < 0.000000001	n.s.	p < 0.05	p < 0.01
Heparin	251	9	260	3.5%	p < 0.00000001	n.s.	p < 0.05	*
Argatroban	353	38	391	9.7%	p < 0.001	n.s.	*
Ozagrel	27	4	31	12.9%	n.s.	*
Combination	39	17	56	30.3%	*

control. n.s.: no significant.

Correlation between each factor tested and hemorrhagic complications are shown in Table 5. The following factors were significantly correlated with hemorrhagic complications: progressively symptomatic; treatment between 24 hours and 14 days of the onset; no postoperative antiplatelet treatment; no postoperative antithrombotic treatment; and emergency treatment. In patients with hemorrhagic complications, the mortality was very high at 23.3% (Table 6).

Table 5

Correlation between each factor and hemorrhagic complications

Baseline characteristics of patients	Age	≤49 yrs: 4.2%, 50–59 yrs: 2.8%, 60–69 yrs: 1.6%, 70–79 yrs: 2.2%, ≥ 80 yrs: 4.1%
	Sex	Male: 2.1%, female: 3.1%
	mRS at baseline	0% to 2: 2.2%, 3% to 5: 3.2%
	Previous treatment	Previously untreated: 2.8%, previously treated: 2.2%
Lesion profile	Region	IC (intracranial epidural): 1.8%, IC (intradural): 4.4%, MCA: 2.5%, VA: 3.4%, BA: 4.0%
	Symptom at diagnosis	Asymptomatic: 1.9%, symptomatic: 2.9%
		Nonprogressively symptomatic: 2.2%, progressively symptomatic: 6.6% (p < 0.05)
	Timing of treatment (only symptomatic patients)	Within 24 hr: 2.9%, between 24 hr and 14 days: 5.9%, after at least 15 days: 1.5% (p < 0.05*)
	Percent diameter stenosis	< 50%: 0%, 50% to 60%: 0%, 60% to 70%: 3.0%, 70% to 80%: 1.5%, 80% to 90%: 4.0%, 90% to 100%: 3.5%, 100%: 0%
	Lesion length	< 5 mm: 1.6%, 5–10 mm: 3.0%, 10–15 mm: 3.0%, ≥ 15 mm: 3.6%
	Normal vascular diameter	< 2 mm: 4.8%, 2–2.5 mm: 1.8%, 2.5–3 mm: 2.0%, 3–3.5 mm: 2.3%, 3.5–4 mm: 3.0%, ≥ 4 mm: 5.2%
	Pathology	Arteriosclerosis: 1.9%, traumatic dissection 0%, iatrogenic dissection 20%, idiopathic dissection 0%, others 0%
	Refractory to medical therapy	No: 2.7%, yes: 2.5%
Treatment	Stenting	No: 2.4%, yes: 3.2%
	Presence or absence of pre-dilatation (JR-NET2)	No: 1.6%, yes: 2.5%
	Presence or absence of post-dilatation (JR-NET2)	No: 2.3%, yes: 2.1%
	Stent + presence or absence of post-dilatation (JR-NET2)	No: 3.7%, yes: 5.0%
	Preoperative antiplatelet treatment	No: 5.4%, 1 agent: 4.8%, 2 agents: 2.0%, 3 agents: 3.2%
	Postoperative antiplatelet treatment	No: 10.0%, 1 agent: 6.0%, 2 agents: 1.3%, 3 agents: 1.0% (p < 0.000000001**)
	Postoperative antithrombotic treatment	No: 7.1%, heparin: 1.9%, argatroban: 0.8%, ozagrel: 0%, combination: 1.8% (p < 0.0001***)
	Other concurrent treatment	No: 3.0%, yes: 0.7%
Treatment situation	Diagnostic cerebral angiography	No: 3.1%, yes: 2.2%
	Emergency treatment	Planned: 2.1%, emergency: 5.7% (p < 0.01)
	Treatment facility	Hospital at work: 2.7%, another hospital: 3.3%
	Investigator	Supervisory physician: 3.4%, specialist: 2.4%, nonspecialist: 0%
	Scrub-in of supervisory physician	No: 2.3%, yes: 2.1%
	No. of scrub-in supervisory physicians and specialists	1: 2.0%, 2: 3.1%, ≥ 3: 0.0%
	General anesthesia	Local anesthesia: 1.7%, general anesthesia: 4.0%
Treatment outcome	Residual stenosis immediately after treatment	< 30%: 2.6%, 30% to 50%: 3.1%, ≥ 50%: 0%

Within 24 hr vs. between 24 hr and 14 days: p < 0.05.

Each p-value is not shown.

Each p-value is not shown.

JR-NET: Japanese Registry of Neuroendovascular Therapy.

Table 6

Correlation between complications and mortality

Mortality
	No	Yes
Hemorrhagic complication	1.3%	23.3%	(p < 0.0000001)
Ischemic complication	1.8%	2.3%	n.s.

n.s.: no significant.

Discussion

In this study, the incidence of ischemic complications and hemorrhagic complications was 7.7% and 2.5% in 1,133 patients who underwent angioplasty/stenting, respectively, resulting in an overall incidence of approximately 10%. Nguyen et al. reported that of 74 patients, 5% of patients who underwent angioplasty for symptomatic intracranial stenosis experienced major stroke within 30 days postoperatively.[1)] In the present study, the incidence of ischemic complications and hemorrhagic complications was 6.6% and 2.4%, respectively, in patients who underwent PTA alone. The higher incidence of complications in this study may be because the complications included minor stroke, unlike in Nguyen's study.

When limited to patients who underwent stenting, on the other hand, the incidence of ischemic complications and hemorrhagic complications was relatively high at 9.7% and 3.2%, respectively, in Japan. This outcome was worse compared even with a 30-day stroke rate of 5.7% reported with Wingspan, an intracranial stent approved in the United States, at the time of approval.[2)] This may have been due to the use of inflexible coronary stents in the present study, which was more likely to result in vascular injury at the time of access or stent deployment. In addition, since the incidence of complications was greatly different with or without stenting in this study, it is likely that there may have been problems with the device. On the other hand, the proportion of patients who had a residual stenosis of ≥ 50% postoperatively was significantly lower in the stenting group, showing the usefulness of stenting in maintaining cerebral artery patency and thus warranting quick approval of flexible intracranial stents.

In this study, which had a large sample size (1,133 patients), several factors were found to be correlated with complications, and even multifactorial analysis could have been performed. However, since the data were retrospectively collected and analyzed, it is not doubtful that various biases existed. For instance, hemorrhagic complications may substantially restrict subsequent antithrombotic therapy. For significantly biased data, it may be more important to analyze individual factors correlated with complications carefully, rather than to perform a multifactorial analysis.

In the analysis, first, several factors were correlated with ischemic complications. The incidence of complications was significantly lower in previously treated patients. Patients who experienced complications at the initial treatment often preclude retreatment for medical or social reasons, thus more patients who experienced no complications at the initial treatment might have been included in the previously treated group. In many previously treated patients, angioplasty may have been more suitable in terms of plaque characteristics or position of penetrating branches in the lesion. In addition, the intima formed after the initial treatment may have been histopathologically stable. In this study, an unexpected negative correlation was observed in patients unresponsive to medical therapy, although such patients generally have an increased risk of ischemic complications. Many of the patients enrolled with the disease refractory to medical therapy may have received not only adequate antiplatelet treatment, but also medical therapy such as statins or intensive antidiabetic treatment that can contribute to plaque stabilization. It may be hypothesized that medical therapy contributing to plaque stabilization reduced ischemic complications and is thus useful in enhancing the safety of angioplasty although this is a matter of speculation since non-antithrombotic drugs were not investigated. Additional post-dilatation following placement of balloon-expandable coronary stent was also significantly correlated with ischemic complications. Plaques excluded by repeated PTA may have impaired blood flow in the penetrating branches. As for postoperative antithrombotic therapy, the incidence of ischemic complications was significantly lower in heparin-treated patients than in untreated patients, indicating the usefulness of heparin. On the other hand, treatment with multiple antithrombotics was also positively correlated with ischemic complications. This may be because ischemic complications occurred in many of the patients who received multiple antithrombotics for the treatment of intraoperative ischemic symptoms.

In addition, some factors were found to be correlated with hemorrhagic complications. Progressively symptomatic disease, which is complicated by so-called misery perfusion, may have resulted in cerebral hemorrhage due to hyperperfusion syndrome. The higher incidence of hemorrhagic complications in patients treated between 24 hours and 14 days of the onset may be explained by the assumption that hemorrhagic changes were caused by reperfusion of brain tissue that had just undergone irreversible ischemic changes, although there was no data on cerebral blood flow, such as single photon emission computed tomography (SPECT) or positron emission tomography (PET), in our study. Likewise, postoperative hemorrhagic complications were more likely to occur in patients who received emergency treatment, because such patients often develop acute cerebral infarction. In addition, inadequate preoperative assessment or equipment may have resulted in vascular injury during catheter manipulation or PTA in patients who received emergency treatment. A positive correlation with hemorrhagic complications was observed in patients who received no postoperative antiplatelet or antithrombotic treatment, but this may be explained by the fact that hemorrhagic complications precluded the use of these drugs.

As mentioned above, the data were retrospectively collected and analyzed in this study, requiring prospective confirmatory studies to determine whether each factor found to be correlated with complications is actually a risk factor for complications. This procedure is associated with more complications than other neuroendovascular procedures, and unfortunately the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, a randomized controlled study in the United States, failed to show the effectiveness of stenting and abandoned.[3)] The final result of this study also showed that the early benefit of aggressive medical management over aggressive medical management plus stenting with the Wingspan stent persists during a median follow-up of 32.4 months.[4)] It may be important to not only use intracranial stents, which are expected to be introduced in Japan in the near future, but also to seek to improve the treatment outcome in a multidimensional manner based on the findings of the present study.

Conclusion

Angioplasty for intracranial stenosis in Japan is almost as safe as that in the West. On the other hand, stenting using a coronary stent is associated with a higher incidence of complications, warranting quick introduction of intracranial stents.