tte-surgery/docs/literature/02-claudication-evidence-and-methods.md

Literature review 2: claudication evidence, and what landmark, CCW and sequential trials each estimate

PMIDs were checked through NCBI E-utilities on 2026-10-27. The numbers come from PubMed abstracts. The guideline recommendation wording is from memory and needs checking against the full texts.

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Part A. Clinical evidence

A1. Randomized trials. Every one used walking distance or QoL as the endpoint; none used hard limb outcomes.

Trial	N and comparison	Result	Limitations
CLEVER: Murphy 2012 Circulation (22090168); 18-month results 2015 JACC (25766947); design (18440181); update (19660897)	111 aortoiliac; OMC vs OMC+SE vs OMC+stent	Peak walking time at 6 months: SE better than stent (p=0.04). At 18 months: no difference (p=0.16). QoL better with stent.	Under-recruited: planned 252 in 4 arms, cut to 217 in 3 arms, finished with 111. Only 79 had 18-month data.
ERASE: Fakhry 2015 JAMA (26547465); long-term Klaphake 2022 Ann Surg (33378308)	212; endovascular + SET vs SET	MWD at 12 months +282 m with the combination	At 5.4 years the walking gap had closed (p=0.62). The SET arm had more later revascularizations (HR 2.50) but fewer procedures in total (65 vs 149).
IRONIC: Nordanstig 2014 Circulation (25095886); 5-year Djerf 2020 Circ CV Interv (31937137)	158; revascularization + BMT + exercise vs BMT + exercise	SF-36 better with revascularization at 1 year	No difference at 5 years. Cost about 2× higher.
MIMIC: Greenhalgh 2008 EJVES (19022184)	93 femoropopliteal + 34 aortoiliac; PTA on top of SE + BMT	Walking distance +38% / +78%	Very small. No QoL benefit.
SUPER: Koelemay 2022 EJVES (35151572)	240 iliac; SET vs endovascular	MWD the same at 1 year	Stopped early. 29% of the SET arm crossed over to revascularization within 1 year. Only 50% complied with SET.
Mazari: 2012 BJS (22021102); 2017 BJS (27763685)	178; PTA vs SEP vs both	The same at 12 months and 5.2 years
Spronk: 2009 Radiology (19188327)	151; endovascular vs SET	An early advantage for endovascular was gone by 6–12 months
OBACT: Nylaende 2007 EJVES (17055756)	56; OMT vs OMT + PTA	PTA better at 2 years	434 screened to randomize 56.
Cochrane: Fakhry 2018 (29518253)	10 RCTs, 1,087 patients	Endovascular vs SET: no clear difference	Small, short trials, and no hard limb outcomes.

Across these trials:

• Revascularization improves walking and QoL early, but the advantage fades by 2–5 years.
• Crossover and non-adherence to SET are large.
• No trial was powered for CLTI, amputation or cumulative reintervention.

A2. Observational evidence that intervention is associated with progression

• Madabhushi 2021 JVS (33775749). n = 1,051. Revascularization was associated with CLTI (HR 2.9) and amputation (HR 4.5). The exposure is "ever revascularized", so the result is exposed to immortal time bias.
• Golledge 2018 BJS (29566427). n = 456. Treatment depended on which specialist the patient saw, which is a natural physician-preference contrast. 5-year amputation was 6.2% with early revascularization vs 0.7% with conservative care.
• Sorber 2023 JVS (37276171). aHR 6.89 for late PVI. Patients of outlier physicians had more late PVI and more CLTI.
• Dun 2025 Surgery (40782724). Markov decision model.
• Alabi 2026 JAMA Surg (41405976). VQI–Medicare, 10,012 patients. CLTI within 180 days of revascularization ranged up to 11.8% across subgroups.
• Bose 2025 Ann Surg (38841837) and EJVES (38906366). Infrapopliteal PVI for claudication had poor outcomes.
• Natural history:
  • Sigvant 2016 EJVES (26777541): about 21% progress to CLI.
  • Baubeta Fridh 2017 EJVES (28797662): amputation after revascularization for IC is 0.4% per year.
• Review: Golledge 2022 Nat Rev Cardiol (34997200).

A3. Variation between physicians

• Hicks 2020 JVS (31208940), "Overuse of early PVI for claudication." n = 194,974 patients, 3.2% with early PVI. The median physician's rate was 0%, with a range of 0–58%. 320 physicians (5.6%) were ≥2 SD outliers. Office-based lab (OBL) or ambulatory surgery center (ASC) practice predicted outlier status. This paper is the main empirical source for the physician component of the DGP.
• Dun 2024 JAHA (38958132): the OBL/ASC share of PVI went from 12.4% to 55.7% between 2011 and 2022.
• Dun 2025 Ann Vasc Surg (39419322): market competition.
• Weaver 2023 JVS (37141948).
• Tsou 2024 JVS (38908807).
• Smith 2019 Ann Vasc Surg (30684609).
• Brown 2021 JVS (33617980).
• Iannuzzi 2025 JVS (39824263).

A4. Guidelines

• SVS 2015 (25638515; introduction 25721065)
• ESVS 2024 (37949800)
• ESC 2024 (39210722)
• ACC/AHA 2024 (38743805; JACC 38752899). Advises against revascularizing only to prevent progression to CLTI.

A5. Why there is no RCT of early PVI vs initial conservative therapy on hard outcomes

1. Event rates are low, so the trial would have to be large and long. These are rough two-proportion calculations with 80% power, ≥5-year follow-up and no crossover:
   • Amputation 2% vs 1% at 5 years: about 2,300 per arm.
   • CLTI 8% vs 5%: about 1,050 per arm.
2. Crossover is built into the comparator. The conservative arm includes deferred PVI, so an ITT analysis dilutes the contrast. Examples: SUPER had 29% crossover in year 1; ERASE's SET arm had a revascularization HR of 2.5; CLEVER finished with 111 of 252 planned; OBACT randomized 56 of 434 screened.
3. Equipoise is asymmetric. The guidelines already recommend against early PVI, and the high-use physicians who do most early PVI would not enroll their patients.
4. The hard endpoints are generated by physicians. Reintervention and the coding of CLTI are decisions made by unblinded clinicians, and patients who get early PVI are watched more closely.
5. No sponsor and a lot of heterogeneity. No device company will fund a "fewer devices" hypothesis. Anatomy and devices vary, and Medicare has covered SET only since 2017.

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Part B. Methods: which question each one answers

B1. Immortal time bias

Plain version: if "early PVI" means "had PVI at month 4", that patient had to survive event-free to month 4 to be labelled early PVI. The fix is to line up eligibility, assignment and time zero.

• Suissa 2008 AJE (18056625)
• Lévesque 2010 BMJ (20228141)
• Hernán 2016 J Clin Epidemiol (27237061)
• Hernán 2025 Epidemiology (39494894). Reframes the problem: immortal time is a symptom of misclassification or selection.

B2. Landmark analysis

Estimand: among patients alive and CLTI-free at 6 months, those who happened to have PVI in months 0–6 vs those who did not.

• It is conditional and descriptive.
• The comparator mixes patients who never have PVI with patients who have it at month 7.
• Events in months 0–6 are dropped.
• It conditions on a post-treatment variable.
• Sorber 2023 is effectively a 6-month landmark design.

References:

• Anderson, Cain, Gelber 1983 JCO (6668489); revisited 2008 (18711176)
• Dafni 2011 Circ CV Qual Outcomes (21586725)
• van Houwelingen 2008 (18836831)
• Putter & van Houwelingen 2017 (29225713)

B3. Clone–censor–weight (CCW)

Estimand: the risk if everyone followed strategy A, "PVI within 6 months of diagnosis", vs strategy B, "no PVI in the first 6 months, then usual care (or PVI only for CLTI)". This is a per-protocol effect of sustained strategies starting at diagnosis.

• The 6-month grace period means an event inside the window, before any PVI, counts in both arms.
• The answer depends on how strategy B is written.
• Natural and stochastic grace-period strategies are different estimands (Wanis 2024).

References:

• Hernán 2018 BMJ (29419381)
• Cain 2010 Int J Biostat (21972433)
• Maringe 2020 IJE (32386426); correspondence 33349843, 33524137
• Gaber 2024 Cancer Med (39642890)
• Wanis 2024 JRSS-A (39281783), on grace periods
• Hernán & Robins 2017 NEJM (28976864)
• Cole & Hernán 2008 AJE (18682488)

B4. Sequential trial emulation

Estimand: among patients still eligible this month (no PVI yet, no CLTI, alive), PVI now vs not now.

• "Not now" includes PVI next month, so it is a deferral effect, not an abstention effect.
• The pooled population leans toward slowly progressing patients, because they stay eligible for more trials.

References:

• Hernán 2008 Epidemiology (18854702)
• Danaei 2013 SMMR (22016461)
• Gran 2010 Stat Med (20803557)
• Keogh 2023 Stat Med (37086186)
• Limozin/Seaman 2025 SMMR (40631395): CIs
• Robins 2000 Epidemiology (10955408): MSMs
• The TrialEmulation R package is on CRAN and has no PubMed citation.

B5. Studies comparing methods

• Duchesneau 2022 CEBP (35984990). Surgery in metastatic breast cancer. Compares landmark with CCW against a plasmode known truth. This is the closest template.
• Mi 2016 Stat Med (27350312). Landmark is unbiased under the null but biased when there is an effect.
• Karim 2016 AJE (27455963)
• Zhou 2005 AJE (16192344)
• Pilleron 2023 BJC (36759725). Immortal time bias is larger in older patients.
• Hoffman 2022 JAMA Netw Open (36190729)
• Moreno-Betancur 2026 Epidemiology (41490058). "The Ideal Trial": the estimand you want vs the estimand your data allow.

Gap: we found no simulation that compares landmark, CCW and sequential trials side by side as answers to different estimands.

B6. Physician clustering and unmeasured confounding at the surgeon level

There are two separate problems.

1. Inference. Clustered SEs or random effects fix only the standard errors.

• Panageas 2003 Ann Intern Med (14568854); 2007 Stat Med (17016864)
• Kahan & Morris 2013 Stat Med (23112128)

2. Confounding by physician. Physician style affects both early PVI and the outcome. Here the outcome (late PVI, coding of CLTI) is itself a physician decision.

• Within-physician comparisons (fixed effects, Mundlak, matching within surgeon) remove time-invariant confounding between physicians:
  • Neuhaus & Kalbfleisch 1998 (9629647)
  • Begg & Parides 2003 (12898546)
  • Li Y 2020 SMMR (31694489): closed-form bias results
  • Cafri 2020 Biom J (32419247): matching within surgeon on device data
  • Li/Zaslavsky/Landrum 2013 (23526267)
  • Thoemmes & West 2011 (26735885)
  • Arpino & Cannas 2016 (26833893)
  • Fuentes 2022 (34128730)
  • Austin 2017 (27885709): median HR
• Caveats:
  • A random effect does not remove confounding when it is correlated with PVI use.
  • Frailty HRs are conditional on physician and non-collapsible.
  • Fixed effects need physicians who sometimes do and sometimes do not intervene early (positivity).
• Preference as an instrumental variable:
  • Brookhart 2006 (16617275); Brookhart & Schneeweiss 2007 (19655038)
  • Rassen 2009 (19345561)
  • Brookhart 2010 (20354968)
  • Ertefaie 2017 (28239929)
  • Hutchings 2022 (35588540)
  • The exclusion restriction is doubtful when the same physician also decides on reintervention.
• Bias amplification (Z-bias): Myers 2011 AJE (22025356); Pearl 2011 AJE (22034488).
  • If physician preference is purely instrument-like, conditioning on the physician amplifies remaining unmeasured patient confounding.
  • The simulation can show where the crossover lies.

Gap: we found no paper on unmeasured surgeon-level confounding inside CCW or sequential trial emulation. The nearest are Cafri 2020 and Li 2020.

B7. Simulation methods

Morris, White, Crowther 2019 Stat Med (30652356), the ADEMP framework. Score each method against its own true estimand.

B8. Reporting

TARGET 2025: BMJ 40903028, JAMA 40899949; explanation and elaboration in PLoS Med 41091811.

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Summary table (early PVI ≤6 months)

Method	Estimand	Requires	Failure mode
Naive "ever early PVI"	None that is well defined	—	Immortal time and confounding by indication
Landmark at 6 months	Among patients event-free at 6 months: had PVI in months 0–6 vs not	Confounders measured up to the landmark	Drops early harms. Mixed comparator. Selects on survival after treatment.
CCW with 6-month grace	Everyone follows A vs everyone follows B	Time-varying predictors of PVI timing; positivity; a precise definition of strategy B	Unmeasured symptom progression or physician style. Extreme weights. Sensitive to how B is defined.
Sequential trials (ITT)	PVI now vs not now, among patients eligible this month	Eligibility each month; covariates at each baseline	A deferral effect, not abstention. Leans toward slow progressors.
Physician-clustered models	Clustered SEs: honest SEs. FE: within-physician effect. Frailty: conditional HR	FE needs within-physician variation	RE does not remove confounding. FE can show Z-bias. Conditional vs marginal mismatch.

Read first

1. Hernán 2018 BMJ, CCW (29419381)
2. Hernán 2008 Epidemiology, sequential trials (18854702)
3. Keogh 2023 Stat Med (37086186)
4. Maringe 2020 IJE (32386426)
5. Duchesneau 2022 CEBP (35984990)
6. Morris 2019 Stat Med, ADEMP (30652356)
7. Cafri 2020 Biom J (32419247)
8. Myers 2011 AJE (22025356)