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What Randomized Clinical Trials Are Possible / Necessary
In Phlebology
Mark H. Meissner, MDMark H. Meissner, MDProfessor of SurgeryProfessor of Surgery
University of Washington School of MedicineUniversity of Washington School of Medicine
Levels of Evidence for Therapeutic StudiesLevels of Evidence for Therapeutic StudiesStraus SE, Evidence-Based Medicine 3rd EdStraus SE, Evidence-Based Medicine 3rd Ed
Level of Level of EvidenceEvidence
Studies of therapy, prevention, etiology, harmStudies of therapy, prevention, etiology, harm
1a1a Systematic review with homogeneity of RCTsSystematic review with homogeneity of RCTs
1b1b Individual RCT with narrow confidence intervalsIndividual RCT with narrow confidence intervals
1c1c All or noneAll or none
2a2a Systematic review with homogeneity of cohort studiesSystematic review with homogeneity of cohort studies
2b2b Individual cohort study or low quality RCTIndividual cohort study or low quality RCT
3a3a Systematic review with homogeneity of case-control studiesSystematic review with homogeneity of case-control studies
3b3b Individual case-control studyIndividual case-control study
44 Case seriesCase series
55 Expert opinion without explicit critical appraisalExpert opinion without explicit critical appraisal
What Do We Really Care About?What Do We Really Care About?
Incorporation of societal valuesIncorporation of societal values Societal costsSocietal costs Comparative effectiveness of different technologiesComparative effectiveness of different technologies
The best available estimate of benefits and harms The best available estimate of benefits and harms (estimate of treatment effect)(estimate of treatment effect)
Application of the evidence to the individual patient Application of the evidence to the individual patient (generalizeabilty)(generalizeabilty)
Where Does Clinical Evidence Come From?Where Does Clinical Evidence Come From?How Do We Measure the Magnitude of Effect?How Do We Measure the Magnitude of Effect?
Semi – experimentalSemi – experimental
Comparison with historical controlsComparison with historical controls
Fatally biasedFatally biased
Observational studies (all with concurrent controls)Observational studies (all with concurrent controls)
Cross sectional - Compares proportion with disorder based Cross sectional - Compares proportion with disorder based on exposure at one point in timeon exposure at one point in time
Cohort studies – Prospective evaluation of outcome based on Cohort studies – Prospective evaluation of outcome based on exposureexposure
Case - control studies – Retrospective evaluation of Case - control studies – Retrospective evaluation of exposure based on outcomeexposure based on outcome
Randomized, controlled clinical trialsRandomized, controlled clinical trials
Determinants of Evidence QualityDeterminants of Evidence Quality
DeterminantDeterminant DefinitionDefinition QualityQuality BiasBiasTreatment Treatment
EffectEffect
Systematic Review of RCTsSystematic Review of RCTs HighHigh LowLow PrecisePrecise
Randomized Clinical TrialsRandomized Clinical Trials
Observational StudiesObservational Studies
MethodologyMethodology Cohort StudiesCohort Studies
Case-Control StudiesCase-Control Studies
Case SeriesCase Series UnknownUnknown
Expert OpinionExpert Opinion LowLow HighHigh UnknownUnknown
ConsistencyConsistency
Directness
Similarity of treatment effect across studiesSimilarity of treatment effect across studies
Appropriateness of groups and outcomes
RCTs – The Holy GrailRCTs – The Holy Grail
Require true clinical equipoise (RR 0.4 – 0.9)Require true clinical equipoise (RR 0.4 – 0.9) Difficult to justify if observational studies showDifficult to justify if observational studies show
Large harmful effectsLarge harmful effects Large (risk ratio < 0.4) beneficial effectsLarge (risk ratio < 0.4) beneficial effects Small beneficial effects (risk ratio 0.9 - 1.0)Small beneficial effects (risk ratio 0.9 - 1.0)
Are expensiveAre expensive May be difficult to generalize (Restrictive inclusion criteria)May be difficult to generalize (Restrictive inclusion criteria) Usually not powered to detect harms of treatmentUsually not powered to detect harms of treatment May be better, worse, or complimentary to observational May be better, worse, or complimentary to observational
studiesstudies
Why are RCTs the holy grail?Why are RCTs the holy grail? Comparison to standard of careComparison to standard of care Minimizes bias & confoundersMinimizes bias & confounders Provides a precise estimate of effectProvides a precise estimate of effect
But …But …
Not All Questions Require RCTsNot All Questions Require RCTs
““We think that everyone We think that everyone might benefit if the most might benefit if the most radical protagonists of radical protagonists of
evidence-based medicine evidence-based medicine organised and participated in organised and participated in
a double blind, placebo a double blind, placebo controlled, crossover trial of controlled, crossover trial of
the parachute”the parachute”
This is NonsenseThis is Nonsense
Magnitude of effect is Magnitude of effect is importantimportant
All or None PhenomenonAll or None Phenomenon
Nor Is There An RCT For Every QuestionNor Is There An RCT For Every QuestionIoannidis et al: JAMA 2001Ioannidis et al: JAMA 2001
48 interventions with randomized and observational trials48 interventions with randomized and observational trials Results highly correlated (correlation coefficient - 0.83)Results highly correlated (correlation coefficient - 0.83) Larger treatment effect in nonrandomized trialsLarger treatment effect in nonrandomized trials
Trial DesignTrial DesignA Continuum Rather Than A HierarchyA Continuum Rather Than A Hierarchy
Treatment Effect
Example
Huge (All or None)
ParachutesEpinephrine/AnaphylaxisUFH/DVT
Large Bypass for CLI
ModerateStatinsHCSE
Case SeriesCase Series
Case SeriesCase Series
Observational Observational StudiesStudies
Case SeriesCase Series
Observational Observational StudiesStudies
RCTRCTss
Standard of Care Established
Standard of Care Established
Standard of Care Established
What Are The Important Questions?What Are The Important Questions?Chronic Venous DiseaseChronic Venous Disease
Is the use of compression prior to intervention cost effective ?Is the use of compression prior to intervention cost effective ? What is the best treatment for C2 & C3 disease?What is the best treatment for C2 & C3 disease?
InterventionsInterventionsCompressionCompression
Pharmacotherapy (HCSE, MPFF)Pharmacotherapy (HCSE, MPFF)
Ablation (RF, laser, foam)Ablation (RF, laser, foam) OutcomesOutcomes
Patient important benefits – Pain, quality of life, recurrencePatient important benefits – Pain, quality of life, recurrence
Costs to health care systemCosts to health care system Perforating veinsPerforating veins
The The pathologicalpathological perforator – Which are clinically important? perforator – Which are clinically important? C5, 6 disease – Healing and recurrenceC5, 6 disease – Healing and recurrence
Is 1Is 1stst rib resection after a first effort thrombosis warranted? rib resection after a first effort thrombosis warranted? What is the accuracy of CTV / MRV for iliac obstructionWhat is the accuracy of CTV / MRV for iliac obstruction
… … And Many OthersAnd Many Others
What Are The Important Questions?What Are The Important Questions?Chronic Venous DiseaseChronic Venous Disease
Is there a role for extended prophylaxis other than THR Is there a role for extended prophylaxis other than THR and malignancy?and malignancy?
Are there ANY prophylactic indications for IVC Filters?Are there ANY prophylactic indications for IVC Filters?
The treatment of acute DVTThe treatment of acute DVT
Pharmacomechanical thrombolysisPharmacomechanical thrombolysis
Iliofemoral DVTIliofemoral DVT
Femoropopliteal DVTFemoropopliteal DVT
Isolated calf vein thrombosisIsolated calf vein thrombosis
Is there any role for U/S (using US protocols) in Is there any role for U/S (using US protocols) in determining the duration of anticoagulation?determining the duration of anticoagulation?
… … And Many OthersAnd Many Others
How Do We Answer the Questions?How Do We Answer the Questions?
Clinical Question RCT Observational Outcomes
Value of Compression (C2) √ √ QoL, Cost (ICER)
Comparative effectiveness of different technologies
√ QoL, Cost (ICER, cost-consequence)
Definition of the pathologic perforator
√ Ulcer healing / recurrence
Extended prophylaxis √ Recurrent DVT, Bleeding
Pharmacomechanical lysis √ QoL, Bleeding, Cost
Calf vein thrombosis √ Recurrent thrombosis,
Bleeding, cost
U/S & anticoagulation √ Recurrent thrombosis
Role of 1st rib resection in effort thrombosis
√ Recurrent thrombosis
The CLASS TrialThe CLASS Trial
HTA (UK) funded randomized clinical trialHTA (UK) funded randomized clinical trial 1000 C 1000 C 2-6 2-6 patients (6 centers)patients (6 centers)
Saphenous surgerySaphenous surgery Foam sclerotherapyFoam sclerotherapy Laser ablation with adjuvant foam sclerotherapyLaser ablation with adjuvant foam sclerotherapy
1º outcomes (6 months, possible 5 yr)1º outcomes (6 months, possible 5 yr) Disease specific – Aberdeen VV QuestionnaireDisease specific – Aberdeen VV Questionnaire Generic – EuroQol, SF-36Generic – EuroQol, SF-36
2º outcomes2º outcomes Validated return to function instrumentValidated return to function instrument Incremental cost effectivenessIncremental cost effectiveness
ATTRACT TRIALATTRACT TRIAL 692 patients692 patients
28 North American centers28 North American centers
Randomized toRandomized to
Best medical therapyBest medical therapy
Pharmacomechanical lysisPharmacomechanical lysis
Trellis 8Trellis 8
Angiojet powerpulseAngiojet powerpulse
Iliofemoral & femoropopliteal armsIliofemoral & femoropopliteal arms
Clinically relevant endpointsClinically relevant endpoints
Objective PTS (Villalta)Objective PTS (Villalta)
Quality of lifeQuality of life
The DiVeTAS Trial – Specific AimsThe DiVeTAS Trial – Specific AimsDIDIstal stal VEVEnous nous TThrombosis: hrombosis: AAnticoagulation vs nticoagulation vs SSurveillanceurveillance
To compare the short-term efficacy and safety of standard anticoagulation To compare the short-term efficacy and safety of standard anticoagulation versus duplex ultrasound surveillance for a first episode of acute symptomatic 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 DVT confined to the calf veins. The primary endpoint will be a composite of proximal propagation, symptomatic pulmonary embolism (PE), major bleeding, proximal propagation, symptomatic pulmonary embolism (PE), major bleeding, and all-cause mortality occurring during the first 3 months of treatment. and all-cause mortality occurring during the first 3 months of treatment.
To evaluate the relationship between baseline characteristics, including D-Dimer To evaluate the relationship between baseline characteristics, including D-Dimer and other biomarkers, and the risk of proximal propagation and other 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 endpoints, with the goal of identifying high risk and low risk sub-groups which may differ in treatment efficacy. may differ in treatment efficacy.
To compare long-term outcomes of calf DVT after treatment with standard To compare long-term outcomes of calf DVT after treatment with standard anticoagulation versus duplex ultrasound surveillance with respect to the anticoagulation versus duplex ultrasound surveillance with respect to the development of objectively defined PTS and quality of life. development of objectively defined PTS and quality of life.
To compare the cost and cost-effectiveness of standard anticoagulation versus To compare the cost and cost-effectiveness of standard anticoagulation versus duplex ultrasound surveillance for the management of isolated calf vein duplex ultrasound surveillance for the management of isolated calf vein thrombosis. thrombosis.
Comparative Effectiveness ResearchComparative Effectiveness ResearchThe “New” Holy GrailThe “New” Holy Grail
BackgroundBackground Interventional technology – 50% of healthcare resources Interventional technology – 50% of healthcare resources
(50 million procedures / yr)(50 million procedures / yr) Clinical data in < 15% of 510k approvalsClinical data in < 15% of 510k approvals Adoption after only 10-20% perceived implementationAdoption after only 10-20% perceived implementation Practice integration before value, risks, and costs establishedPractice integration before value, risks, and costs established
Comparative effectivenessComparative effectiveness ““a rigorous evaluation of different treatment options”a rigorous evaluation of different treatment options”
(Congressional Budget Office)(Congressional Budget Office) May focus on benefits/risks or cost/benefitMay focus on benefits/risks or cost/benefit > $1 billion dollars appropriated by Congress> $1 billion dollars appropriated by Congress
CDRH Device ClassificationCDRH Device Classification Class IClass I
Low risk devices (tongue depressors, scalpels)Low risk devices (tongue depressors, scalpels) General controlsGeneral controls
Good manufacturing practicesGood manufacturing practicesQuality systems regulationQuality systems regulation
Class IIClass II Venous lasers, RF devicesVenous lasers, RF devices Special controls - Performance standards, registries, Special controls - Performance standards, registries,
postmarket surveillancepostmarket surveillance Most approved through Premarket Notification (510k)Most approved through Premarket Notification (510k) Safety / effectiveness equivalent to predicate deviceSafety / effectiveness equivalent to predicate device
Class IIIClass III Insufficient information to ensure safety & effectivenessInsufficient information to ensure safety & effectiveness Most approved through Premarket Application (PMA)Most approved through Premarket Application (PMA)
Growth in Varicose Vein TreatmentGrowth in Varicose Vein Treatment
Courtesy of John Mauriello
Economic Analysis*Economic Analysis*
ModelModel DescriptionDescription Pros / ConsPros / Cons
EconomicEconomicQuantitative, statistical Quantitative, statistical analysis of economics analysis of economics
onlyonly
Simple, but neglects Simple, but neglects clinical outcomesclinical outcomes
Cost-Cost-consequenceconsequence
Economic & clinical Economic & clinical outcomes evaluated in outcomes evaluated in
commoncommon
Allows evaluation of Allows evaluation of “trade offs”“trade offs”
Model-basedModel-basedPreviously reported Previously reported data used as model data used as model
inputinput
Flexible, but relies Flexible, but relies on high quality dataon high quality data
* All require data from comparative trials* All require data from comparative trials
The REACTIV TrialThe REACTIV TrialRatcliffe , Br J Surg 2006Ratcliffe , Br J Surg 2006
246 patients extensive vv and saphenous reflux randomized to246 patients extensive vv and saphenous reflux randomized to Conservative measures (n = 122)Conservative measures (n = 122) Saphenous stripping / phlebectomy (n = 124)Saphenous stripping / phlebectomy (n = 124)
24 mo cost effectiveness of £4682 per QALY gained24 mo cost effectiveness of £4682 per QALY gained Below NHS threshold of £20,000 per QALYBelow NHS threshold of £20,000 per QALY
ConservativeConservative SurgerySurgery Mean DifferenceMean Difference
Mean NHS CostMean NHS Cost £344.53£344.53 £733.10£733.10 £388.57£388.57
AUC SF-6DAUC SF-6D 1.421.42 1.501.50 0.0830.083
ICER *ICER * £4682£4682
* Incremental cost effectiveness ratio
ConclusionsConclusions
The questions are important and need prioritizationThe questions are important and need prioritization
The goals, not the methods, are most importantThe goals, not the methods, are most important Precise estimates of harms, risks, and benefitsPrecise estimates of harms, risks, and benefits Minimizing bias and unknown confoundersMinimizing bias and unknown confounders
Every question requires a comparison groupEvery question requires a comparison group An RCT is not necessary, feasible , or even desirable An RCT is not necessary, feasible , or even desirable
for every questionfor every question
But …But …
Developing Phlebology as a Clinical ScienceDeveloping Phlebology as a Clinical Science
Demands for industryDemands for industry
Clinical evidence prior to marketingClinical evidence prior to marketing
Research with patient important endpointsResearch with patient important endpoints
Demands for ourselvesDemands for ourselves
Avoid herd mentality in the absence of dataAvoid herd mentality in the absence of data
Pay attention to costs to the health care systemPay attention to costs to the health care system
Consider comparative effectiveness of technologyConsider comparative effectiveness of technology
Demands for phlebologyDemands for phlebology
Raise the bar for presentation / publicationRaise the bar for presentation / publication
Fellowships in epidemiology & health systems researchFellowships in epidemiology & health systems research