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Literature reviews and decisions log (rounds 1-5) for the early-PVI TTE simulation

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Co-Authored-By: Claude Opus 5.5 <[email protected]>
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# Literature review 1: limitations of RCTs in surgery, mapped to TTE on claims data
All citations were checked against PubMed through NCBI E-utilities, 2026-10-27. The numbers come from PubMed abstracts; full texts were not read. Papers with no PubMed abstract are described only in general terms.
**Corrections and caveats**
- Chapman 2014 was published in *BMJ*, not *Surgery*.
- The page numbers for McCulloch 2002 are from memory, not from PubMed.
- BASIL-3 recruited 481 of the planned 861 patients. That the paclitaxel signal caused the shortfall is a guess, not a verified finding.
---
## 1. Classic critiques and the IDEAL framework
| Paper | PMID | Takeaway |
|---|---|---|
| McCulloch P et al. 2002, *BMJ* "Randomised trials in surgery: problems and possible solutions" | 12065273 | The founding critique. Barriers: equipoise, learning curve, quality control, blinding, surgeon preference. |
| McLeod RS 1996, *Surgery* 119:483 | 8619200 | Problems specific to RCTs in surgery. |
| Solomon MJ, McLeod RS 1995, *Surgery* | 7652679 | Many surgical questions could be randomized but are not. |
| Solomon MJ, McLeod RS 1998, *Med J Aust* | 9803252 | Overview of RCTs in surgery: past, present and future. |
| Barkun JS et al. 2009, *Lancet* 374:1089 | 19782874 | IDEAL series, paper 1: the stages of surgical innovation. |
| Ergina PL et al. 2009, *Lancet* 374:1097 | 19782875 | Few of the challenges are unique to surgery, but in surgery they occur together: complexity, surgeon factors, and the range of outcomes. |
| McCulloch P et al. 2009, *Lancet* 374:1105 | 19782876 | IDEAL recommendations: registries and prospective databases, with RCTs "whenever possible". |
| McCulloch 2013 / Ergina 2013 / Cook 2013, *BMJ* (IDEAL series) | 23778427, 23778426, 23778425 | Observational studies in the Exploration and Assessment stages; RCTs and long-term registry evaluation. |
| Hirst A et al. 2019, *Ann Surg* | 29697448 | IDEAL update: adds a Pre-IDEAL stage and covers devices. |
| Cook JA 2009, *Trials* 10:9 | 19200379 | Checklist for the design, conduct and analysis of surgical RCTs. |
| Pronk AJM et al. 2023, *Br J Surg* 110:1300 | 37379487 | Of 1,188 surgical RCTs, only **22.1%** published in 2019 were at low risk of bias (14.7% in 2009). |
| Ahmed Ali U et al. 2018, *J Surg Res* 228:1 | 29907196 | Of 228 negative surgical RCTs, the median sample size was about 76–80, so most were underpowered. |
## 2. Recruitment failure, discontinuation, and equipoise
| Paper | PMID | Takeaway |
|---|---|---|
| **Chapman SJ et al. 2014, *BMJ* 349:g6870** | 25491195 | Of 395 surgical RCTs, **21% stopped early**. The main reason was poor recruitment (44% of stopped trials). Of completed trials, 34% were unpublished at a median of 4.9 years. |
| **Rosenthal R et al. 2015, *Ann Surg* 262:68** | 24979608 | Discontinued: **43%** of surgical vs **27%** of medical RCTs. Stopped for slow recruitment: 18% vs 11%. Discontinuation predicted non-publication (OR 4.18). |
| Kasenda B et al. 2014, *JAMA* 311:1045 | 24618966 | Across all fields, **24.9%** of RCTs were discontinued, most often for poor recruitment. |
| Cook JA et al. 2008, *Contemp Clin Trials* 29:631 | 18397843 | **Trials of surgery vs medical treatment recruited about 2× slower** than trials of surgery vs surgery (median 68 vs 35 days per recruit). This applies directly to PVI vs exercise. |
| Donovan J et al. 2002, *BMJ* 325:766 (ProtecT) | 12364308 | Qualitative work on how recruiters presented the options made an "impossible" trial feasible. |
| Donovan JL et al. 2014, *J Clin Epidemiol* 67:912 | 24811157 | Clinicians' "hunches" undermined equipoise, and **surgeons felt this most intensely**. |
| Rooshenas L et al. 2016, *PLoS Med* 13:e1002147 | 27755555 | In recorded consultations, the equipoise clinicians stated differed from how they actually presented the options. |
| Donovan JL et al. 2022, *Trials* 23:258 (QRI-Two) | 35379301 | A rapid recruitment intervention for trials that are failing to recruit. |
| Hamdy FC et al. 2023, *NEJM* 388:1547 (ProtecT at 15 years) | 36912538 | A monitor-vs-intervene trial can be completed. |
## 3. Surgeon skill, learning curve, expertise-based trials, and clustering
| Paper | PMID | Takeaway |
|---|---|---|
| **Devereaux PJ et al. 2005, *BMJ* 330:88** | 15637373 | Proposes expertise-based RCTs: each surgeon performs only the procedure they are expert in, to avoid differential-expertise bias. |
| Cook JA et al. 2015, *Trials* 16:241 | 26025450 | Review of 43 expertise-based RCTs: 92% compliance, but expertise criteria were poorly reported. |
| Cook JA et al. 2004, *Clin Trials* 1:421 | 16279280 | Statistical methods for learning curves in surgical trials. |
| Ramsay CR et al. 2000 / 2001 | 11155830, 11319991 | Assessing learning curves in health technology. |
| **Lee KJ, Thompson SG 2005, *BMJ* 330:142**; *Clin Trials* 2:163 | 15649931, 16279138 | Outcomes cluster by clinician even under individual randomization. Ignoring it makes the estimates look more precise than they are. |
| Roberts C, Roberts SA 2005, *Clin Trials* 2:152 | 16279137 | Clustering induced by treatment, which can differ between arms (partially nested designs). |
| Walters SJ 2010, *J Clin Nurs* 19:1102 | 20492055 | Therapist effects: cluster-level, random-effects, and marginal models compared. |
| **Birkmeyer JD et al. 2013, *NEJM* 369:1434** | 24106936 | Peer ratings of surgical skill from video: the bottom quartile vs the top had **14.5% vs 5.2%** complications and **0.26% vs 0.05%** mortality. |
| Birkmeyer JD et al. 2003, *NEJM* 349:2117 | 14645640 | Surgeon volume and mortality. |
## 4. Blinding and sham surgery
| Paper | PMID | Takeaway |
|---|---|---|
| **Wartolowska K et al. 2014, *BMJ* 348:g3253** | 24850821 | Across 53 placebo-controlled surgical RCTs, the placebo arm improved in 74%. Surgery was **no better than placebo in 51%**. |
| Wartolowska K et al. 2016, *BMJ Open* | 27008687 | Placebo-controlled surgical trials are feasible but recruit slowly. |
| Boutron I et al. 2017, *Ann Intern Med* 167:40 | 28630973 | CONSORT extension for non-pharmacologic treatments: expertise, blinding, and standardization. |
## 5. Standardization, crossover, and contamination
| Paper | PMID | Takeaway |
|---|---|---|
| **Garas G et al. 2018, *Ann Surg Oncol* 25:221** | 29110271 | Across 40 RCTs of minimally invasive vs open surgery, crossover averaged **12.6% (0–45%)** and worsened the ITT results. |
| **Weinstein JN et al. 2006, *JAMA* 296:2441 (SPORT)** | 17119140 | **Only 50%** of the surgery arm had surgery, and **30%** of the nonoperative arm did, so the ITT comparison could not be interpreted. |
| Hernán MA, Robins JM 2017, *NEJM* 377:1391 | 28976864 | Per-protocol effects in pragmatic trials. |
## 6. Generalizability and external validity
| Paper | PMID | Takeaway |
|---|---|---|
| **Rothwell PM 2005, *Lancet* 365:82** | 15639683 | "To whom do the results of this trial apply?" |
| Rothwell PM 2006, *PLoS Clin Trials* | 16871331 | Factors that affect external validity. |
| Cutteridge J et al. 2025, *BJS Open* | 40105904 | Patients in 307 vascular RCTs were **younger** than those in the UK National Vascular Registry. |
| Jones HG et al. 2026, *EJVES* | 42526742 | Endovascular lower-limb revascularization is under-researched relative to how often it is done. Its trials are 72% efficacy trials and 39% industry-funded. |
| Loudon K et al. 2015, *BMJ* (PRECIS-2) | 25956159 | Tool for rating how pragmatic or explanatory a trial is. |
## 7. Trials of timing, "when to operate" (the key analogue)
| Paper | PMID | Takeaway |
|---|---|---|
| **Fitzgibbons RJ et al. 2006, *JAMA* 295:285** | 16418463 | Hernia watchful waiting: 23% of the waiting arm crossed over to surgery, and 17% of the surgery arm crossed the other way. |
| **Fitzgibbons RJ et al. 2013, *Ann Surg* 258:508** | 24022443 | Long-term crossover was **68%** (79% in men over 65). "Watchful waiting" works out as "delayed surgery". |
| O'Dwyer PJ et al. 2006, *Ann Surg* | 16858177 | UK hernia trial: crossover was higher than predicted. |
| **UK Small Aneurysm Trial 1998, *Lancet*** | 9853436 | HR 0.94. Operative mortality of 5.8% caused an early deficit in survival. |
| **Lederle FA et al. 2002, *NEJM* (ADAM)** | 12000813 | **61.6% of the surveillance arm were eventually repaired.** Surveillance is a dynamic strategy, not "no treatment". |
| Cao P et al. 2011, *EJVES* (CAESAR) | 20869890 | Delayed repair under surveillance: 59.7% by 36 months and 84.5% by 54 months. One in six aneurysms became unsuitable for EVAR, a harm of delay that the ITT effect on mortality does not capture. |
| Ouriel K et al. 2010, *JVS* (PIVOTAL) | 20304589 | 31% of the surveillance arm were repaired by 20 months. HR 1.01. |
| Ulug P et al. 2020, *Cochrane* | 32609382 | Early repair of small AAAs has no advantage. |
## 8. Pragmatic trials, registry trials, and TTE
| Paper | PMID | Takeaway |
|---|---|---|
| **Hernán MA, Robins JM 2016, *AJE* 183:758** | 26994063 | The foundational TTE paper. |
| **Hernán MA et al. 2016, *J Clin Epidemiol* 79:70** | 27237061 | Specifying the target trial avoids self-inflicted biases such as immortal time. |
| Hernán MA et al. 2022, *JAMA* 328:2446 | 36508210 | JAMA Guide to TTE. |
| Cain LE et al. 2010, *Int J Biostat* | 21972433 | "When to start treatment?": dynamic regimes. |
| **Maringe C et al. 2020, *Int J Epidemiol* 49:1719** | 32386426 | CCW tutorial on surgery in older patients with lung cancer. The naive 22% benefit fell to 11%. |
| Wang SV et al. 2023, *JAMA* 329:1376 (RCT-DUPLICATE) | 37097356 | Of 32 RCTs emulated in claims data, agreement was r = 0.93 when the emulation was close and r = 0.53 when it was not. All were drug trials. |
| Cashin AG et al. 2025, *JAMA* / *BMJ* (TARGET) | 40899949 / 40903028 | Reporting guideline for TTE. |
| Scola G et al. 2023, *BMC Med Res Methodol* | 37587484 | Only 16% of TTEs used cloning to handle immortal time. |
| Katsoulis M et al. 2024, *Epidemiology* 35:730 | 39024012 | TTE of bariatric surgery. |
| Hoskins W et al. 2026, *JBJS Rev* | 42896011 | Orthopaedic primer. TTE **does not** address unmeasured confounding. |
| Lauer MS, D'Agostino RB 2013, *NEJM* | 23991657 | The randomized registry trial. |
| Zwarenstein M et al. 2008, *BMJ* | 19001484 | CONSORT extension for pragmatic trials. |
| Brookhart MA et al. 2006, *Epidemiology* 17:268 | 16617275 | Physician preference as an instrumental variable. |
**Gap:** we found no surgery-specific systematic review of TTE methods (JAMA Surg / Ann Surg, 2022–2026). Applied examples: Sakowitz 2025, *Ann Surg* (TCAR vs CEA), PMID 40607703; Talathi 2026, *Surgery* (STRASS 2 emulated), PMID 41936769.
## 9. Vascular surgery
| Paper | PMID | Takeaway |
|---|---|---|
| Farber A et al. 2022, *NEJM* (BEST-CLI) | 36342173 | Cohort 1: MALE or death 42.6% with surgery vs 57.4% with endovascular (HR 0.68). Whether a vein conduit was available decided which cohort a patient entered. |
| Bradbury AW et al. 2023, *Lancet* (BASIL-2) | 37116524 | n = 345. Vein bypass first was worse (aHR 1.35), which conflicts with BEST-CLI. |
| Hunt 2017 *Trials*; Bradbury 2025 *BMJ* (BASIL-3) | 28526046, 39993822 | **481 of 861 planned** randomized. No benefit from drug-coated balloons or drug-eluting stents. |
| **Katsanos K et al. 2018, *JAHA*** | 30561254 | Paclitaxel: 5-year mortality 14.7% vs 8.1% (RR 1.93). Only 3 RCTs had 5-year data. |
| Rocha-Singh KJ et al. 2020, *Circulation* | 32370548 | Individual patient data: **23–24% lost to follow-up or withdrew**. After recovering vital status, HR 1.38 → 1.27. |
| Secemsky EA et al. 2019, *JAMA Cardiol* | 30747949 | Medicare: no excess mortality. |
| Freisinger E et al. 2020, *Eur Heart J* | 31593987 | German claims data: no excess mortality. |
| Nordanstig J et al. 2020, *NEJM* (SWEDEPAD, interim) | 33296560 | Registry RCT: HR 1.06. |
| **Nordanstig J et al. 2025, *Lancet* (SWEDEPAD 2, claudication)** | 40902614 | No benefit in quality of life. 5-year mortality HR 1.47 (1.09–1.98). |
| Falkenberg M et al. 2025, *Lancet* (SWEDEPAD 1, CLTI) | 40902617 | The CLTI companion trial. |
| Fakhry F et al. 2015, *JAMA* (ERASE) | 26547465 | Revascularization plus exercise beat exercise alone at 12 months. |
| Murphy TP et al. 2012, *Circulation* (CLEVER) | 22090168 | Exercise was better for walking time and stenting for quality of life. n = 111. |
| Nordanstig 2014, *Circulation*; Djerf 2020, *Circ CV Interv* (IRONIC) | 25095886, 31937137 | The quality-of-life benefit seen at 1 year was **lost by 5 years**, at about twice the cost. |
| **Sorber R et al. 2023, *JVS*** | 37276171 | Medicare. Early PVI 3.2%. Late PVI 22.5% vs 3.6% (aHR 6.89). High-use physicians. |
| Dun C et al. 2025, *Ann Vasc Surg* 110:424 | 39419322 | Market competition predicts early PVI. |
| Weaver ML et al. 2023, *JVS* | 37141948 | Market competition and claudication management in the VQI. |
| Madabhushi V et al. 2021, *JVS* | 33775749 | Revascularizing claudicants: CLTI HR 2.9, amputation HR 4.5. |
| Conte MS et al. 2025, *JVS* (SVS focused update) | 40316185 | Major evidence gaps for claudication. |
---
## Taxonomy: RCT limitations in surgery → what TTE on claims can do
IV = internal validity, EV = external validity, F = feasibility.
| # | Limitation | Threatens | Can TTE on claims fix it? | Can it go in the simulation DGP? |
|---|---|---|---|---|
| 1 | Recruitment failure and discontinuation | F (and EV) | **Yes.** No consent is needed. The price is confounding instead of randomization. | Indirectly: compare a "would-consent" subset with the whole population. |
| 2 | Patient and surgeon equipoise and preference | F, EV, IV | **Partly.** Preference is what makes treatment vary in practice, and can serve as an IV (high-use physicians). Patient preference is unmeasured. | **Yes.** A latent physician "intervention propensity". |
| 3 | Surgeon skill and learning curve | IV, EV | **Partly.** Skill is not in claims, but the operator NPI is, so random or fixed effects are possible. Skill and preference cannot be separated if they are correlated. | **Yes.** Latent skill, correlated with preference. |
| 4 | Clustering and provider heterogeneity | IV (precision), EV | **Mostly.** Mixed models, cluster-robust SEs. | **Yes.** Random intercepts and random slopes by physician. |
| 5 | Blinding and sham | IV | **No.** No patient-reported outcomes in claims, and outcome ascertainment is not blinded. | Optional: differential ascertainment of CLTI. |
| 6 | Standardization and co-interventions | IV, EV | **Partly.** Procedure type and Part D fills are visible. Exercise, smoking, and adherence are not. | **Yes.** Unmeasured exercise uptake. |
| 7 | Crossover and deferral | IV | **Yes, TTE's strongest case**, using dynamic strategies with CCW or sequential trials. It needs the triggers for crossover to be measured. | **Yes, central.** |
| 8 | Immortal time and misaligned time zero | IV | **Yes, by design.** | **Yes.** The naive design as a comparator. |
| 9 | Selected surgeons, centers, and patients | EV | **Yes, largely.** Population-based data, plus transportability. | **Yes.** A "trial of high-skill operators" vs the whole population. |
| 10 | Long horizon, rare outcomes, changing technology | F, IV | **Partly.** Follow-up is long and complete, but device codes are coarse and calendar time confounds. | **Yes.** Time-varying effect (early benefit, late harm). |
**In one line:** TTE fixes feasibility, generalizability, and (with dynamic strategies) crossover. It cannot fix unmeasured confounding by indication or the lack of patient-reported outcomes. Surgeon skill sits in between: it cannot be measured, but its structure can be modelled through the NPI.
## Read first
1. Sorber 2023 *JVS* (37276171)
2. ADAM 2002 *NEJM* (12000813) and CAESAR 2011 (20869890)
3. Fitzgibbons 2006 *JAMA* and 2013 *Ann Surg* (16418463, 24022443)
4. Hernán & Robins 2016 *AJE*; Hernán 2016 *J Clin Epidemiol* (26994063, 27237061)
5. Maringe 2020 *Int J Epidemiol* (32386426)
6. McCulloch 2002 *BMJ*; Ergina 2009 *Lancet* (12065273, 19782875)
7. Chapman 2014 *BMJ*; Rosenthal 2015 *Ann Surg* (25491195, 24979608)
8. Katsanos 2018; Nordanstig 2020 and 2025 (30561254, 33296560, 40902614)
docs/literature/02-claudication-evidence-and-methods.md
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# 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)