# 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. --- ## 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. --- ## 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. --- ## 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)