Endovascular Stenting in Superior Vena Cava Syndrome: A Systematic Review and Meta-analysis

Two authors (EA, MK) performed the search of MEDLINE, EMBASE and PUBMED online databases to identify articles related to the outcomes of endovascular stenting in the treatment of SVCS. The following search terms were used, alone and in combinations; “superior vena cava syndrome”, “superior vena cava obstruction”, “superior vena cava” and “stent”. All retrieved studies were first screened on title and abstract, then screened studies read in full by both authors to determine eligibility for inclusion. The final search was on 14^th November 2020.

Study selection was performed independently by two authors (EA, MK). The selection criteria were as follows: (1) Full text of the study had to be available in English. (2) Studies had to include 10 or more adult human patients. (3) Where studies concerned interventions in the SVC as well as other vessels, only studies with identified data for technical and clinical outcomes of SVC interventions, with or without involvement of brachiocephalic veins, were included.

The following data were extracted from each included study: (1) details of the study—first author, year, study type (prospective/retrospective), journal of publication, conflict of interests; (2) population demographic data—size of study population, mean age, gender, benign or malignant pathology, pre-intervention chemotherapy or radiotherapy; (3) procedural data—type and make of stent, use of anticoagulation or thrombolysis, technical and clinical success, complications, and (4) follow-up data—primary and secondary patencies, recurrence of symptoms, re-interventions and survival. Data were extracted independently by two authors (EA, MK). Where the reviewers had any disagreement, this was resolved by discussion and where necessary, consensus with the senior author (MH). The methodological quality of the included studies was assessed for risk of bias using the Newcastle–Ottawa scale [14].

Meta-analyses were performed to report technical and clinical success of stenting to relieve SVCS, as well as recurrence of symptoms at 1, 3, 6 and 12 months. Using a random effects model, individual and pooled proportions and 95% confidence intervals were calculated by the Clopper–Pearson estimation method based on the exact binomial distribution. Statistical heterogeneity was assessed using the I² (inconsistency) statistic. SAS software version 9.4 was used for analysis and production of the graphs.

The initial search resulted in 7604 studies (Fig. 1). After removal of duplicates and screening on title and abstract, 78 studies were obtained and read in full text, of which 54 met all inclusion criteria, for a total of 2249 patients. Data extraction and study quality assessment were subsequently performed. The most frequent reasons for exclusion were insufficient sample sizes or undifferentiated reporting of outcomes in the SVC.

The total number of patients reported was 2249. The cumulative mean age of all patients was 58.7 years and the sex ratio (males/females) was 2.6 (1605/612). One study presented no data on patient demographics [15], while two did not present mean age [16, 17].

Characteristics of included studies are summarised in Table 1. Of the 54 studies included, 34/54 were retrospective, 17/54 were prospective, and 3/54 had both prospective and retrospective arms. No randomised controlled trials or multi-centre studies were identified. The risk of conflict of interests in all studies was low. Risk of bias, assessed via the Newcastle–Ottawa scale, is shown in Table 2. All papers scored between 7 and 9, indicating high quality.

All studies relied on clinical criteria to determine need for intervention, as well as pre-operative imaging to denote the nature of the obstruction. Five papers selected only patients presenting with significant stenosis, ranging between 75 and 90% [18‐22]. One study categorised patient population by level of stenosis into high (> 80%), moderate (50–80%), and low grade (30–50%) [23].

Follow-up protocol was heterogenous among the included studies. Where prospectively specified, it involved regular imaging and clinical assessment in 9/54 studies or imaging only in 10/54 studies. The remaining studies relied on patients self-reporting symptoms. Length of follow-up was variable, with mean follow-up lengths ranging from 2 months to 3 years. All studies followed patients up where possible until death or study endpoint.

Malignant or benign pathology was the exclusive cause of SVCS in 39/54 studies and 6/54 studies respectively. The remaining 9 studies did not discriminate by pathology. Of the 2237 patients in which SVCS pathology was reported, 222 had benign and 2015 had malignant pathology. The most frequent malignant pathologies included non-small cell and small cell bronchial carcinoma, as well as lymphadenopathies or invasion from extra-mediastinal primary tumours. Of the 6 studies that reported outcomes in benign SVCS, the primary pathology in 5 of these studies was indwelling medical devices, of which 1 included patients on dialysis. The primary pathology in the remaining study was fibrosing mediastinitis.

The type of stent used was reported in 50/54 studies, comprising 1795 patients. Uncovered stents were exclusively used in 47/50 studies. One study exclusively used covered stents [24], and three studies used both covered and uncovered stents in direct subgroup comparison [25‐27]. The rationale for using covered stents in these papers was their anecdotal use in several published case reports of recurrent SVCS after uncovered stent placement or iatrogenic injury of the SVC [24‐27]. The total number of patients receiving uncovered or covered stents was 1688/1795 and 107/1795.

The use of intra-procedural anticoagulation was documented in 42/54 studies, comprising 1861 patients. Fixed doses of heparin injected before stenting were documented in 34/42 studies, with doses of 2000–5000 IU used. The most common dose used was 5000 IU in 28/34 studies. Use of heparin in the post-operative period at unspecified doses or frequency was documented in 8/42 studies.

The use of long-term anticoagulation was documented in 27/54 studies, comprising 1197 patients. Regimens used were heterogenous in medication and duration of treatment. Where specified, regimens used more than once included 3 months of warfarin in 4 studies [28‐31] or 1 month of dual antiplatelet therapy in 2 studies [32, 33]. Anticoagulation medications used included warfarin, aspirin, heparin, antiplatelets and their combinations. Three studies comprising 142 patients stated that neither intra-procedural nor long-term anticoagulation was attempted [3, 20, 34].

The use of intra-procedural thrombolysis before stenting was documented in 19/54 studies, comprising 727 patients. In 16/19 studies, thrombolysis was only used for cases in which thrombosis above the stent was too severe to navigate across. In 3/19 studies, thrombolysis was used for all patients to prevent intra-stent thrombosis in follow-up [18, 35, 36]. The pharmacological agent used was specified in 16/19 studies, with urokinase, recombinant tissue plasminogen activator and streptokinase used in 8, 5 and 3 studies respectively. Mechanical thrombolysis, relying on thromboaspiration, fragmentation or crushing the thrombus against the vessel wall, was used in 3/19 studies [37‐39].

Stenting was attempted as the first-line procedure for treatment of malignant SVCS in 4/54 studies, comprising 202 patients [17, 20, 22, 40]. One further study retrospectively investigated a cohort of 56 malignant SVCS patients, with 33 patients undergoing stenting at initial presentation before chemoradiotherapy and 23 only after the failure of chemoradiotherapy [41].

The technical success rate was 96.8% (95% CI 96.0–97.5%), with a range of 79.7–100% and I² = 0 indicating no heterogeneity (Fig. 2). The technical success rate for studies investigating benign SVCS alone was 88.8% (95% CI 83.0–93.1%) (Fig. 3). Most studies described technical success as navigation and successful deployment and expansion of the stent across the obstruction or stenosis, with evidence of flow restoration on post-intervention venography. Further requisites for technical success where specified included a final pressure gradient < 10 mmHg in 4 studies [16, 24, 25, 42] and < 50% residual stenosis in 3 studies [22, 43, 44]. Two studies used the Society of Interventional Radiologists (SIR) definition of technical success; complete coverage of the obstruction, with overlapping margins of 1 cm on either side and residual stenosis < 30% [45‐47].

The clinical success rate was 92.8% (95% CI 91.7–93.8%), with a range of 78.3–100% and I² = 0 indicating no heterogeneity (Fig. 2). The clinical success rate for studies investigating benign SVCS alone was 88.8% (95% CI 83.0–93.1%) (Fig. 3). All studies except two described clinical success as acute improvement in symptoms, whether partial or complete, measured through patient description of symptoms or the Kishi scoring system [48]. One study further defined clinical failure as persistence of at least 2 of the cardinal symptoms of SVCS; prominent veins, facial oedema, plethora, dizziness, headaches and dyspnoea [49]. Dyspnoea was exempted from consideration as a symptom of clinical improvement in most studies, as it is a common symptom of underlying pulmonary disease and is frequently found in patients presenting with tumour invasion into the bronchus or pulmonary vessels. The other study defined clinical success as < 10 mmHg pressure gradient between ends of the stent after insertion [27].

Following the CIRSE complication [50], complications are presented in Table 3. The average complication rate was 5.78% (SD = 9.3182), with a range of 0–53.8%. No complications were reported in 25/54 studies. The overall 24-h mortality rate was 0.006%. The most frequent cause of mortality was rupture of the SVC leading to cardiac tamponade. The most frequent complications above Grade 3 reported were bleeding events while on long-term anticoagulation or antiplatelet therapy, pulmonary oedema and thromboembolic events. The most frequent complications below Grade 3 reported were stent migration, localized pain and puncture site haematoma.

Primary patency was reported in 19/54 studies, comprising 906 patients, while secondary patency was reported in 20/54 studies, comprising 1117 patients. Primary and secondary patency ranged from 65 to 92% and 75–100% respectively. Primary patency was defined as continued stent patency without re-intervention at study endpoint, while secondary patency included those requiring re-interventions. Four studies separately defined primary patency as the time interval from procedure to re-intervention, ranging from 83 days to 31.3 months [16, 22, 27, 51].

Recurrence rate of symptoms in follow-up was reported in 29/54, 23/54, 16/54 and 13/54 studies at 1, 3, 6 and 12 months respectively (Fig. 4). From these studies, pooled patency for endovascular stenting in both benign and malignant SVCS remained above 90% for the first year (98.0%, 95.6%, 93.7% and 94.0% at 1, 3, 6 and 12 months respectively). At all timepoints, I² = 0 indicating no heterogeneity. In order of frequency, the cause of recurrence was intra-stent thrombosis, tumour overgrowth above or below the stent, or tumour ingrowth through the stent. The average re-intervention rate was 9.11% (SD = 11.190), with a range from 0 to 60%. No re-interventions were required in 17/54 studies. Re-interventions performed included balloon dilatation, thrombolysis and further stenting.

One study found primary patency to be significantly longer in patients with malignant SVCS compared to SVCS secondary to haemodialysis [38]. Three studies found covered stent use to be significantly associated with lower rates of stent occlusion in follow-up, lower rates of symptom recurrence and longer primary and secondary patencies [25‐27].

Median and mean survival were reported in 12/54 studies and 10/54 studies respectively, of which all but one study comprised patients with malignant pathology. The average median survival was 4.74 months (SD = 3.3602), with a range of 1–13 months. The average mean survival was 4.71 months (SD = 1.4235), with a range of 2.49–6.70 months. One study found survival was significantly longer in patients in whom stenting was attempted as a first-line procedure [41]. Another study found survival was significantly longer in patients who underwent subsequent chemotherapy, or chemoradiotherapy, as compared to patients who did not receive further treatment [21].