What Randomized Clinical Trials Are Possible / Necessary In Phlebology

1. What Randomized Clinical Trials Are Possible / NecessaryIn Phlebology Mark H. Meissner, MD Professor of Surgery University of Washington School of Medicine

2. Levels of Evidence for Therapeutic StudiesStraus SE, Evidence-Based Medicine 3rd Ed What Do We Really Care About? • The best available estimate of benefits and harms (estimate of treatment effect) • Application of the evidence to the individual patient (generalizeabilty) • Incorporation of societal values • Societal costs • Comparative effectiveness of different technologies

3. Where Does Clinical Evidence Come From?How Do We Measure the Magnitude of Effect? • Semi – experimental • Comparison with historical controls • Fatally biased • Observational studies (all with concurrent controls) • Cross sectional - Compares proportion with disorder based on exposure at one point in time • Cohort studies – Prospective evaluation of outcome based on exposure • Case - control studies – Retrospective evaluation of exposure based on outcome • Randomized, controlled clinical trials

4. Determinants of Evidence Quality Similarity of treatment effect across studies Appropriateness of groups and outcomes

5. RCTs – The Holy Grail • Require true clinical equipoise (RR 0.4 – 0.9) • Difficult to justify if observational studies show • Large harmful effects • Large (risk ratio < 0.4) beneficial effects • Small beneficial effects (risk ratio 0.9 - 1.0) • Are expensive • May be difficult to generalize (Restrictive inclusion criteria) • Usually not powered to detect harms of treatment • May be better, worse, or complimentary to observational studies • Why are RCTs the holy grail? • Comparison to standard of care • Minimizes bias & confounders • Provides a precise estimate of effect But …

6. Not All Questions Require RCTs This is Nonsense Magnitude of effect is important All or None Phenomenon “We think that everyone might benefit if the most radical protagonists of evidence-based medicine organised and participated in a double blind, placebo controlled, crossover trial of the parachute”

7. Nor Is There An RCT For Every QuestionIoannidis et al: JAMA 2001 • 48 interventions with randomized and observational trials • Results highly correlated (correlation coefficient - 0.83) • Larger treatment effect in nonrandomized trials

8. Trial DesignA Continuum Rather Than A Hierarchy Standard of Care Established Standard of Care Established Case Series Observational Studies Standard of Care Established Case Series RCTs Case Series Observational Studies

9. What Are The Important Questions?Chronic Venous Disease • Is the use of compression prior to intervention cost effective ? • What is the best treatment for C2 & C3 disease? • Interventions • Compression • Pharmacotherapy (HCSE, MPFF) • Ablation (RF, laser, foam) • Outcomes • Patient important benefits – Pain, quality of life, recurrence • Costs to health care system • Perforating veins • The pathological perforator – Which are clinically important? • C5, 6 disease – Healing and recurrence • Is 1st rib resection after a first effort thrombosis warranted? • What is the accuracy of CTV / MRV for iliac obstruction … And Many Others

10. What Are The Important Questions?Chronic Venous Disease • Is there a role for extended prophylaxis other than THR and malignancy? • Are there ANY prophylactic indications for IVC Filters? • The treatment of acute DVT • Pharmacomechanical thrombolysis • Iliofemoral DVT • Femoropopliteal DVT • Isolated calf vein thrombosis • Is there any role for U/S (using US protocols) in determining the duration of anticoagulation? … And Many Others

11. How Do We Answer the Questions?

12. The CLASS Trial • HTA (UK) funded randomized clinical trial • 1000 C 2-6 patients (6 centers) • Saphenous surgery • Foam sclerotherapy • Laser ablation with adjuvant foam sclerotherapy • 1º outcomes (6 months, possible 5 yr) • Disease specific – Aberdeen VV Questionnaire • Generic – EuroQol, SF-36 • 2º outcomes • Validated return to function instrument • Incremental cost effectiveness

13. ATTRACT TRIAL • 692 patients • 28 North American centers • Randomized to • Best medical therapy • Pharmacomechanical lysis • Trellis 8 • Angiojet powerpulse • Iliofemoral & femoropopliteal arms • Clinically relevant endpoints • Objective PTS (Villalta) • Quality of life

14. The DiVeTAS Trial – Specific AimsDIstal VEnous Thrombosis: Anticoagulation vs Surveillance • To compare the short-term efficacy and safety of standard anticoagulation versus duplex ultrasound surveillance for a first episode of acute symptomatic DVT confined to the calf veins. The primary endpoint will be a composite of proximal propagation, symptomatic pulmonary embolism (PE), major bleeding, and all-cause mortality occurring during the first 3 months of treatment.   • To evaluate the relationship between baseline characteristics, including D-Dimer and other biomarkers, and the risk of proximal propagation and other endpoints, with the goal of identifying high risk and low risk sub-groups which may differ in treatment efficacy. •  To compare long-term outcomes of calf DVT after treatment with standard anticoagulation versus duplex ultrasound surveillance with respect to the development of objectively defined PTS and quality of life. • To compare the cost and cost-effectiveness of standard anticoagulation versus duplex ultrasound surveillance for the management of isolated calf vein thrombosis.

15. Comparative Effectiveness ResearchThe “New” Holy Grail • Background • Interventional technology – 50% of healthcare resources (50 million procedures / yr) • Clinical data in < 15% of 510k approvals • Adoption after only 10-20% perceived implementation • Practice integration before value, risks, and costs established • Comparative effectiveness • “a rigorous evaluation of different treatment options” (Congressional Budget Office) • May focus on benefits/risks or cost/benefit • > $1 billion dollars appropriated by Congress

16. CDRH Device Classification • Class I • Low risk devices (tongue depressors, scalpels) • General controls • Good manufacturing practices • Quality systems regulation • Class II • Venous lasers, RF devices • Special controls - Performance standards, registries, postmarket surveillance • Most approved through Premarket Notification (510k) • Safety / effectiveness equivalent to predicate device • Class III • Insufficient information to ensure safety & effectiveness • Most approved through Premarket Application (PMA)

18. Growth in Varicose Vein Treatment Courtesy of John Mauriello

19. Economic Analysis* * All require data from comparative trials

20. The REACTIV TrialRatcliffe , Br J Surg 2006 • 246 patients extensive vv and saphenous reflux randomized to • Conservative measures (n = 122) • Saphenous stripping / phlebectomy (n = 124) • 24 mo cost effectiveness of £4682 per QALY gained • Below NHS threshold of £20,000 per QALY * Incremental cost effectiveness ratio

21. Conclusions • The questions are important and need prioritization • The goals, not the methods, are most important • Precise estimates of harms, risks, and benefits • Minimizing bias and unknown confounders • Every question requires a comparison group • An RCT is not necessary, feasible , or even desirable for every question But …

22. Developing Phlebology as a Clinical Science • Demands for industry • Clinical evidence prior to marketing • Research with patient important endpoints • Demands for ourselves • Avoid herd mentality in the absence of data • Pay attention to costs to the health care system • Consider comparative effectiveness of technology • Demands for phlebology • Raise the bar for presentation / publication • Fellowships in epidemiology & health systems research