Raising the stakes for acute deep vein thrombosis care: understanding the catheter-directed venous thrombolysis study

Abstract

The catheter-directed venous thrombolysis (CAVENT) study is an open-label multicentre randomized controlled trial (RCT) that was conducted in 20 centres in southern Norway from 2006 to 2009, and subsequently reported in The Lancet in December 2011.^1,2

In this important study, 209 patients with acute deep vein thrombosis (DVT) involving the femoral, common femoral and/or iliac vein were randomized to receive either standard DVT therapy (anticoagulant therapy and elastic compression stockings) or standard DVT therapy plus additional catheter-directed thrombolysis (CDT). The study's two co-primary endpoints were: (a) iliofemoral venous patency at six-month follow-up; and (b) the frequency of the post-thrombotic syndrome (PTS) at 24-month follow-up, using the validated Villalta scale.³ From the study's published outcome data (Table 1), two very important points can be gleaned.

Table 1

Major findings of the CAVENT study

Outcome	CDT %	Control %	P value
PTS (24 months)	41.1	55.6	0.047
Iliofemoral patency (six months)	65.9	47.4	0.012
Major bleeds	3.2*	0.0	not presented
Recurrent VTE	11.1	18.2	ns

*One major bleed required surgery to address, and one required a blood transfusion

PTS, post-thrombotic syndrome; VTE, venous thromboembolism; CDT, catheter-directed thrombolysis

First, the study provides strong support for the contention that PTS occurs with high frequency in patients with anatomically extensive DVT. In judging the need for aggressive approaches to DVT treatment, different physician subspecialists have expressed very different perceptions of the importance of PTS to patients. A belief among most medical physicians that anticoagulation and compression are sufficient to prevent PTS in the vast majority of patients has been rooted in data from contemporary prospective trials that found two-year PTS rates of 25–30% in patients with first-episode proximal DVT.^4,5 However, other studies strongly suggest that ‘all proximal DVT is not equal’ in terms of PTS risk.^6,7 But the proof is in the pudding – in the control arm of the CAVENT study, which included only those proximal DVT patients in whom thrombus extended above the popliteal vein, fully 56% of randomized patients developed PTS. Taken together with data from the venous thrombosis outcomes (VETO) study, a large prospective multicentre Canadian cohort study that found PTS to be significantly more frequent in patients with extensive DVT, there should no longer be any doubt that patients with femoral, common femoral, or iliac vein DVT are at very high risk for PTS.⁷

Second, the CDT outcomes observed in CAVENT indeed support endovascular thrombolytic therapy as a potentially important adjunct to anticoagulation and compression in patients with proximal DVT that extends above the popliteal vein. Specifically, CDT conferred a 28% relative reduction in the two-year risk of PTS. Although there was more bleeding in the CDT arm, major bleeds occurred in just 3.2% of CDT-treated patients. There was no intracranial bleeding or CDT-related pulmonary embolism, and the bleeding complications did not affect the patients’ ultimate outcome. Given the strong methodological design (multicentre RCT with blinded outcome assessors) and scientific rigor, CAVENT provides the strongest available assessment of the validity of the ‘open vein hypothesis’ which posits that early thrombus removal and restoration of venous patency will improve long-term DVT outcome.

That said, the immediate impact CAVENT will exert upon DVT practice is difficult to predict: (1) the study reported outcomes on just 189 patients (of whom only 90 received CDT) and consequently, its treatment effect estimates are imprecise; (2) some physicians may argue that the degree of benefit observed (a 14.4% absolute PTS risk reduction) may not justify the risks and costs of CDT. No ulcers, and just one case of severe PTS (in the control arm), were observed in the study population; as the distributions of PTS severity in the two cohorts were not detailed, some physicians may question whether the effect of CDT was just to prevent mild PTS cases; and (3) while statistically significant, the gain in iliofemoral venous patency with use of CDT was not particularly impressive, and clot removal scores did not correlate with two-year PTS.

With respect to the latter two issues, it should be noted that CAVENT evaluated a CDT protocol that consisted of 1–4-day infusions of recombinant tissue plasminogen activator (rt-PA) without use of mechanical thrombectomy devices. In contrast, ‘pharmacomechanical’ CDT (PCDT) methods are commonly used in contemporary practice, particularly in the USA, and are hypothesized to be more effective (due to more complete thrombus removal) and safer (due to reduced dose and duration of rt-PA exposure) compared with drug-only CDT.^8–10

An ongoing NIH-sponsored multicentre RCT, the acute venous thrombosis: thrombus removal with adjunctive catheter-directed thrombolysis (ATTRACT) trial, should address many of these issues. The ATTRACT investigators plan to enroll 692 patients (to date, 263 are enrolled), reducing statistical imprecision. The study intervention is PCDT, delivered with physician-directed use of subsequent thrombectomy, angioplasty and stent placement, per typical United States practice. ATTRACT also features careful assessments of quality of life and cost-effectiveness, enabling a rigorous assessment of PCDT's incremental benefits, risks and costs.

The CAVENT investigators should be congratulated for accomplishing what seemed impossible – completing a multicentre RCT to evaluate an endovascular thrombolytic therapy for the treatment of acute DVT. Undoubtedly, a great deal of collaborative skill and persistence were needed to accomplish this feat. The CAVENT study should rightly be recognized as the most rigorous completed study of interventional DVT therapy, and its findings should encourage clinicians to consider the use of adjunctive CDT for the treatment of selected patients with acute proximal DVT. The findings of CAVENT highlight the strong potential of interventional DVT therapy to benefit patients and transform DVT treatment paradigms, and raise the stakes for the completion of larger, more definitive studies. In particular, it is hoped that CAVENT will serve as a call to action that spurs US physicians to refer their DVT patients to local sites that are participating in the NIH-sponsored ATTRACT trial (www.attract.wustl.edu) that will obtain more precise estimates of the effect of interventional DVT therapy upon patient outcomes.

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