tte-surgery/docs/literature/drafts/C-pathway-and-tte.md

# Draft C: treatment-pathway challenges, claudication trials, and evidence on TTE itself

Every PMID below was checked with NCBI E-utilities (esummary) on 2026-10-28. Every number comes from the PubMed abstract fetched with efetch; full texts were not read. If a paper has no PubMed abstract, the entry says so and gives no numbers. Papers already in `01-surgical-rct-limitations.md` or `02-claudication-evidence-and-methods.md` are cited by PMID only and are not listed again as new entries, apart from short reminders in the claudication table.

"TTE" here covers emulation in **claims** (e.g., Medicare), **EHR** (e.g., VA, health-system data), and **clinical registries** (e.g., Vascular Quality Initiative [VQI], and VQI linked to Medicare as VQI-VISION). Where the data source changes the answer, the "Can TTE solve it?" paragraphs say so.

---

# Part 1. Treatment-pathway challenges

## Challenge 1. Crossover and contamination

**What it is.** Patients receive the other arm's treatment. In timing trials and conservative-vs-surgery trials, crossover runs mostly one way: the conservative or "watchful waiting" arm later has the operation. The intention-to-treat (ITT) contrast then compares "operate now" with "operate later if needed", not with "never operate", and the difference shrinks toward the null. Naive per-protocol or as-treated analyses (excluding or reclassifying crossovers) remove the dilution but break randomization, because the patients who cross over are the ones who are getting worse.

**How common / how big.**
- Crossover from conservative care to surgery is the norm, not the exception: 39% by about 19 weeks for sciatica, 30% by 6 months for meniscal tear, 43% by 2 years for spinal stenosis, 27–29% within 90 days to 1 year for appendicitis, and two-thirds by 10 years for hernia.
- In cardiac surgery RCTs the median crossover was 7.0% from experimental to control. Trials with more of this crossover had RRs nearer the null (1.01 vs 0.80).
- STICH is the clearest case where crossover changed the conclusion. The ITT result was not significant at 5 years (HR 0.86, P = 0.12). Per-protocol and time-dependent analyses favored CABG. Benefit was significant by ITT only after 10 years of follow-up.
- Per-protocol estimates were on average only 2% larger than ITT across 156 RCTs in general medical journals. The gap grows with non-adherence, and surgical timing trials sit at the high end of non-adherence.

**Vascular / claudication example.**
- SUPER (iliac disease): 29% of the SET arm had endovascular revascularization within 1 year, and 49% had an additional intervention by 5.5 years.
- Swedish SFA stenting trial: 25% of the control arm had crossed over to stenting by 60 months. The authors say this "affected the power of the final analysis".
- ERASE: the exercise arm had a higher hazard of later revascularization (HR 2.50).
- ACST-1 (carotid): the "deferral" arm still had CEA at 4% per year.
- Already listed elsewhere: ADAM 61.6% (12000813) and CAESAR 84.5% at 54 months (20869890).

| Paper | PMID | Takeaway |
|---|---|---|
| Peul WC et al. 2007, *NEJM* (sciatica: early surgery vs prolonged conservative care) | 17538084 | 89% of the early-surgery arm had surgery (mean 2.2 weeks). 39% of the conservative arm had surgery (mean 18.7 weeks). Disability at 1 year was no different by ITT, but recovery was faster with early surgery (HR 1.97). |
| Katz JN et al. 2013, *NEJM* (METEOR) | 23506518 | **30%** of the physical-therapy arm had surgery within 6 months, and 6% of the surgery arm did not have surgery. No ITT difference. |
| Weinstein JN et al. 2008, *NEJM* (SPORT stenosis) | 18287602 | At 2 years, 67% of the surgery arm and **43% of the nonsurgical arm** had surgery. ITT was significant for only 1 of 3 primary outcomes. The as-treated analysis (adjusted, combined with the observational cohort) favored surgery on all of them. |
| CODA Collaborative 2020, *NEJM* | 33017106 | 29% of the antibiotics arm had appendectomy by 90 days (41% of those with an appendicolith). |
| Salminen P et al. 2015, *JAMA* (APPAC) | 26080338 | 27.3% of the antibiotics arm had appendectomy within 1 year. |
| van de Wall BJM et al. 2017, *Lancet Gastroenterol Hepatol* (DIRECT) | 28404008 | Stopped early for poor recruitment (n = 109). 23% of the conservative arm went on to elective resection. |
| Velazquez EJ et al. 2011, *NEJM* (STICH) | 21463150 | 17% of the medical-therapy arm had CABG by a median of 56 months, and 91% of the CABG arm had CABG. ITT on all-cause death: HR 0.86 (0.72–1.04). |
| Velazquez EJ et al. 2016, *NEJM* (STICHES) | 27040723 | At a median of 9.8 years, ITT HR 0.84 (0.73–0.97). The benefit appeared only with long follow-up. |
| Doenst T et al. 2013, *Circ Heart Fail* (STICH crossover) | 23515275 | Crossover in year 1: 10.8% from MED to CABG (driven by worsening symptoms) and 9.0% from CABG to MED (mainly patient or family decision). Per-protocol and time-dependent analyses favored CABG. Crossover "diminished the impact of CABG" in the ITT analysis. |
| **Gaudino M et al. 2019, *JAHA*** | 31663420 | 47 cardiac surgery RCTs. Median crossover was 7.0% from experimental to control and 1.3% from control to experimental. Experimental-to-control crossover was associated with effect estimates nearer the null. |
| Reistrup H et al. 2021, *Hernia* (systematic review) | 32910297 | Watchful waiting for hernia: about one-third crossed over by 3 years and more than two-thirds by 10 years, mainly for pain. |
| Halliday A et al. 2004, *Lancet* (ACST-1) | 15135594 | Immediate-CEA arm: half had CEA by 1 month and 88% by 1 year. Deferral arm: 4% per year had CEA. The authors note that full compliance would have produced "slightly bigger differences". |
| Hernán MA, Hernández-Díaz S 2012, *Clin Trials* | 21948059 | ITT does not guarantee an estimate of clinical effectiveness. With differential adherence, ITT can even overestimate. Adherence-adjusted per-protocol analyses need IPW or g-estimation and time-varying data. |
| Murray EJ, Hernán MA 2016, *Clin Trials* | 26951361 | Coronary Drug Project: placebo adherers vs non-adherers differed by 9.4 percentage points in 5-year mortality. With modern adjustment (IPW for post-randomization covariates) the gap shrank to 2.5 (−2.1 to 7.0). Valid per-protocol estimation is possible. |
| Mostazir M et al. 2021, *J Clin Epidemiol* | 34161805 | Across 156 RCTs, per-protocol estimates were 2% larger than ITT (ratio of ORs 1.02), and the gap grew with non-adherence. |
| Peduzzi P et al. 1993, *Stat Med* (VA CABG trial) | 8210821 | Compares ITT with four naive ways of handling non-adherers (exclude, transfer at randomization, censor, transfer at switch) and describes the bias in each. |
| Morden JP et al. 2011, *BMC Med Res Methodol* | 21223539 | Simulation study (16 scenarios, 1,000 datasets each). Simple switching methods are biased when switchers' prognosis differs. Adjusted (AFT-type) methods do better. |
| Latimer NR et al. 2014, *Med Decis Making* | 24449433 | IPCW relies on no unmeasured confounding of switching. RPSFTM relies on a common treatment effect. Both can be biased, and ITT is sometimes the least biased. |

**Can TTE solve it? Yes, in principle; this is TTE's strongest case.** TTE defines the strategies explicitly ("PVI within 6 months" vs "no PVI for 6 months, then usual care", or "no PVI unless CLTI"). Anyone who deviates is artificially censored, and IPCW corrects for the selection this causes (Hernán 2006, 16611197; Hernán 2018, 29419381). This estimates the per-protocol effect that the RCTs above could only approximate with naive as-treated analyses. The price is that the weights are valid only if the *triggers* for crossover are measured. In timing trials the main trigger is symptom progression (STICH: "progressive symptoms"; hernia: pain).
- **Claims** do not record symptom severity, walking distance or ABI, so the weights miss the main reason patients cross over.
- **EHR and VQI** may record ABI, Rutherford class and symptoms. But VQI records them only at the time of a procedure, so they are missing for patients who stay conservative.
- The same IPCW-with-measured-triggers assumption sinks trial switching adjustments (Latimer 2014). TTE does not escape it.

**Testable in a known-truth simulation? Yes.** Generate deferred PVI driven by a latent progression variable, then vary whether that variable is observed (EHR-like) or not (claims-like), and compare ITT-analogue, naive as-treated, and CCW estimates against the true per-protocol effect.

---

## Challenge 2. Non-adherence and refusal of the assigned surgery (and of SET)

**What it is.** Some patients assigned to surgery never have it: they decline, become unfit, or die waiting. Some patients assigned to a conservative package never start it or drop out. In claudication the conservative package is supervised exercise, which needs about 3 sessions a week for 12 weeks, so adherence is a major problem. Refusal of the assigned operation differs from crossover in both cause and direction: it is often driven by patient preference or frailty, not by disease progression.

**How common / how big.**
- **Refusal or delay of the assigned operation:** ACST-1 managed CEA within 1 month in only half of the immediate-CEA arm. In STICH, 9.0% of the CABG arm received medical therapy only, mainly because of patient or family decision, and that group had higher 5-year mortality (59% vs 33%). SPORT disc herniation: only 50% of the surgery arm had surgery (01 list, 17119140).
- **SET has low uptake and adherence:**
  - Across 23 reports that gave screening numbers, only **24.2%** of screened claudicants were recruited to supervised exercise (Harwood 2016).
  - In a health system with a strong SET program, 773 of 5,320 PAD patients were referred, 415 enrolled, and **49.9%** of those completed (Whipple 2024).
  - Of 51 Chicago PAD patients who had started SET, **9.8% completed 12 weeks** (Cetlin 2023).

**Vascular / claudication example.**
- SUPER: compliance with SET was **50%** at 6 months, and 8% of the endovascular arm never received the intervention.
- CLEVER: only 79 of 111 randomized patients completed the 18-month assessment (attrition, not refusal).
- In US practice, 85.1% of surveyed PAD patients said SET had never been prescribed (Cetlin 2023), and 49% of surveyed vascular physicians had never referred a patient (Dua 2020).

| Paper | PMID | Takeaway |
|---|---|---|
| Doenst T et al. 2013, *Circ Heart Fail* | 23515275 | CABG-to-MED crossover was mostly patient or family choice. These patients had worse prognosis (5-year mortality 59% vs 33%), so they were not a random subset. |
| Halliday A et al. 2004, *Lancet* (ACST-1) | 15135594 | Even in the "immediate" arm, only half had CEA by 1 month. "Immediate" in practice meant a distribution of delays. |
| Koelemay MJW et al. 2022, *EJVES* (SUPER) | 35151572 | SET compliance was 50% at 6 months. 8% of the ER arm did not get ER. |
| **Harwood AE et al. 2016, *Ann Vasc Surg*** | 27126713 | Systematic review: 24.2% of 7,517 screened claudicants were recruited to supervised exercise, and 75.1% of 4,012 completed it. Only one article defined a minimum attendance. About 1 in 3 screened patients was suitable and willing. |
| Whipple MO et al. 2024, *Vasc Med* | 38084864 | One US health system, 2017–2022: of 5,320 PAD patients, 773 were referred to SET, 415 enrolled, and 49.9% completed. |
| Cetlin MD et al. 2023, *J Vasc Surg* | 36150636 | Of 489 people with PAD, 85.1% had never had SET prescribed. Of those willing to travel, 59.9% were unwilling or unable to pay the $11 copay per session. Of 51 who started, 9.8% completed 12 weeks. |
| Dua A et al. 2020, *J Vasc Surg* | 31699514 | Survey of 135 physicians: 54% had no SET program at their facility, 49% had never referred a patient, and 26% did not know CMS covered SET. |
| Kahan BC et al. 2024, *BMJ* (estimands primer) | 38262663 | The ICH E9(R1) estimands framework, worked through on an emergency bowel surgery trial. It names how "intercurrent events" (refusal, switching) are handled: the treatment-policy (ITT) estimand vs the hypothetical (per-protocol) estimand. |

**Can TTE solve it? Partly.** TTE avoids the *consent* step, so trial refusal does not exist. But refusing an *offered* operation still happens in routine care.
- **Claims** cannot separate "offered surgery and declined" from "never offered", so the comparator arm absorbs refusers, who may be frailer or more risk-averse. This is unmeasured confounding.
- **EHR** notes sometimes record refusal or shared-decision documentation.
- **Adherence to SET** is partly visible. SET has been a Medicare-covered, billable service since 2017 (Dua 2020), so claims can count sessions. Home exercise and walking advice cannot be seen in any of these data sources.
- **Adherence to the surgery itself** is easy to observe in all three sources: a procedure either happens or it does not.

**Testable in a known-truth simulation? Yes.** Add a latent "refuser" trait that lowers the chance of PVI and independently raises the risk of the outcome. A claims-like scenario leaves it unobserved; an EHR-like scenario observes it with misclassification.

---

## Challenge 3. Co-interventions and heterogeneous usual care in the comparator arm

**What it is.** The outcome depends on everything else patients receive, not just the index procedure: statins, antiplatelets, smoking cessation, supervised or home exercise, cilostazol, and surveillance. In claudication trials the "conservative" arm ranges from "aspirin plus advice" to "12 weeks of supervised treadmill training plus best medical therapy". Usual care is undefined by design and varies between sites, so the comparator is a moving target. Co-interventions can also differ *by arm* because nobody is blinded: patients who had a procedure get more follow-up visits and more statin prescriptions.

**How common / how big.**
- Usual-care comparators are reported very poorly. In 67 knee-OA exercise RCTs, the median TIDieR score was 1 of 12 for the usual-care arm vs 4 for the exercise arm.
- Exercise arms in claudication RCTs scored on average 10 of 19 on CERT, with adherence and fidelity the least reported items.
- In practice, only **38.1%** of VQI claudicants undergoing elective revascularization had complete optimal medical therapy (antiplatelet, statin, non-smoking). Complete OMT was associated with lower 1-year reintervention (aOR 0.72).
- Preoperative statin-plus-antiplatelet use in VQI held at about 62% from 2013 to 2023.

**Vascular / claudication example: the comparator differs from trial to trial.**
- Whyman: aspirin plus advice on smoking and exercise.
- CLEVER: "optimal medical care" (claudication pharmacotherapy), with or without SE.
- IRONIC: BMT plus a structured *non-supervised* exercise program (Djerf 2018).
- MIMIC: SE plus BMT in both arms.
- Cochrane 2018: "conservative" meant supervised exercise in some trials and cilostazol in others.
- A meta-analysis therefore pools different comparators.

| Paper | PMID | Takeaway |
|---|---|---|
| Thompson BT, Schoenfeld D 2007, *Proc Am Thorac Soc* | 17878473 | Usual care is "the full spectrum of patient care practices". Whether to use it as a control depends on the question and on how uniform usual care is. |
| Freedland KE et al. 2011, *Psychosom Med* | 21536837 | Extrinsic, non-study care has "important but under-recognized" effects on trials with usual-care control groups. |
| Ribeiro da Silva Neto J et al. 2026, *Musculoskeletal Care* | 42366407 | 67 RCTs: median TIDieR score 1 for the usual-care arm vs 4 for the exercise arm. No improvement over time. |
| Ibeggazene S et al. 2023, *Vascular* | 35130092 | 73 claudication exercise RCTs: mean CERT 10/19. Adherence and fidelity were the least reported items. |
| Fakhry F et al. 2018, *Cochrane* | 29518253 | Across 10 RCTs (1,087 patients), "conservative" meant supervised exercise or cilostazol. Effects differed by comparator: ER vs no specific treatment MWD SMD 0.70; ER vs SET −0.42 (not significant). |
| **Jarosinski MC et al. 2025, *J Vasc Surg* (VQI)** | 39208918 | Of 39,088 claudication revascularizations: 38.1% complete OMT, 56.4% partial, 5.4% none. Complete OMT was associated with lower reintervention (aOR 0.72) and MALE (aOR 0.70). |
| Ramkumar N et al. 2026, *J Vasc Surg* (VQI) | 42248488 | Of 257,129 patients, preop statin plus antiplatelet use held at 62%. Postop use rose from 68% to 81%. Lower in women (OR 0.88). |
| Jansen SCP et al. 2020, *EJVES* (Dutch national claims) | 32888779 | 54,504 new IC patients. Primary SET rose from 63% to 87% (2013–2017). **Claims captured SET because it is reimbursed there.** Primary ER was associated with more secondary revascularizations (HR 1.44) and higher mortality (HR 1.38). These are observational associations. |
| Djerf H et al. 2018, *Br J Surg* (IRONIC cost) | 30357819 | Describes the IRONIC control arm as BMT "including a structured, non-supervised exercise programme". |
| Divakaran S et al. 2021, *Circ Cardiovasc Qual Outcomes*; 2024, *Vasc Med* | 34293930; 39129558 | Medicare SET participation 2017–2018, and "underutilization" of SET in Medicare. **No PubMed abstract (research letters), so no numbers are given here.** |

**Can TTE solve it? Partly.** TTE cannot randomize co-interventions. It can either (a) build them into the strategy definition ("PVI plus statin" vs "no PVI plus statin") or (b) treat them as time-varying confounders or mediators. Both need the co-intervention to be measured.
- **Claims.** Part D captures statin and P2Y12 fills, but not OTC aspirin. Medicare SET is billable from 2017. Smoking is captured poorly, and home exercise not at all.
- **EHR.** May record SET referral, smoking status, ABI and symptom class.
- **VQI.** Records OMT and smoking only *at the time of a procedure* (Jarosinski 2025). Patients who are never revascularized are not in the registry, so **VQI alone cannot form a "no PVI" comparator arm**. Linking it to claims or EHR is required.
- **A known advantage over RCTs.** The usual-care comparator in an emulation is real-world usual care, so it is representative. It is just not standardized.

**Testable in a known-truth simulation? Yes.** Add an unmeasured exercise or OMT variable that differs by arm (more OMT after PVI) and affects outcomes. Compare scenarios where it is observed (EHR/Part D) and unobserved (exercise in claims).

---

## Challenge 4. Defining the comparator: "conservative" vs "delayed surgery" vs "never surgery"

**What it is.** "Conservative management" is a *dynamic strategy*: start without the operation, and operate if and when a trigger occurs (symptoms, patient request, progression). It is not "never operate". Trials label it "watchful waiting", "deferral", "surveillance", "initial conservative", or "prolonged conservative treatment with surgery if needed". These labels name different estimands. A TTE has the same problem in sharper form, because the analyst has to write the strategy down: the trigger, the grace period, and what happens after the grace period.

**How common / how big.**
- Nearly every trial in Challenge 1 used a "surgery-if-needed" comparator, and 23–68% of the comparator arm had the operation.
- ISCHEMIA explicitly defined its comparator as "medical therapy alone and angiography if medical therapy failed".
- The same data analysed as a CCW emulation vs a sequential emulation can answer different questions with different numbers. Example (mAb timing): CCW 4-year survival difference 4.3% vs sequential −2.8%. A naive design gave an implausible RR of 0.13.

**Vascular / claudication example.**
- IRONIC and the Gothenburg trial (Nordanstig 2011) allowed patients in the noninvasive arm to "request invasive treatment if they deteriorated".
- SUPER: the authors suggest it is "reasonable to start with SET … and accept a 30% failure rate".
- In PVI-for-claudication terms, three candidate comparators answer different questions:
  - "no PVI within 6 months" (a deferral estimand);
  - "no PVI unless CLTI develops" (a progression-triggered dynamic strategy);
  - "never PVI" (an abstention estimand, hard to emulate because positivity fails once CLTI appears).

| Paper | PMID | Takeaway |
|---|---|---|
| Maron DJ et al. 2020, *NEJM* (ISCHEMIA) | 32227755 | Comparator defined as "medical therapy alone and angiography if medical therapy failed". Early harm from the invasive arm (5.3% vs 3.4% at 6 months) crossed over to a non-significant later benefit (16.4% vs 18.2% at 5 years). The timing of effects depends on the strategy definition. |
| Halliday A et al. 2004, *Lancet* (ACST-1) | 15135594 | Comparator was "indefinite deferral of any CEA", which still produced CEA at 4% per year. |
| Nordanstig J et al. 2011, *EJVES* | 21397530 | n = 201, invasive vs noninvasive. Noninvasive patients could request invasive treatment if they deteriorated. 7% of the invasive arm crossed over. |
| Hernán MA et al. 2006, *Basic Clin Pharmacol Toxicol* | 16611197 | Comparing dynamic regimes by artificial censoring plus IPW. Valid if all joint predictors of survival and of deviating from the regime are measured. |
| Young JG et al. 2011, *Stat Biosci* | 24039638 | Parametric g-formula for "when to start" dynamic regimes, with measured time-varying confounders affected by earlier treatment. |
| Kahan BC et al. 2024, *BMJ* | 38262663 | The estimands language (treatment-policy vs hypothetical strategies) for writing down what "conservative" means. |
| Garcia-Albeniz X et al. 2026, *Cancer Med* | 42321955 | "When to start" emulation: aligning eligibility with time zero, CCW vs sequential trials (4-year differences 4.3% vs −2.8%). Biased designs gave a 6-month RR of 0.13. |
| Ahn J et al. 2026, *JAMA Netw Open* (registry) | 42832200 | Surgical timing TTE: early MV surgery (≤6 months) vs watchful waiting, CCW with a 6-month grace period, n = 802. RMST gain of 66 days at 5 years; HR 0.69. Shows the grace-period comparator in a surgical setting. |
| Cheung LC et al. 2026, *Ann Intern Med* (Kaiser EHR) | 42330497 | "Delayed" was explicitly defined as "after 6 months or no" treatment. Immediate excision gave more unnecessary excisions (36.2% vs 7.8%) and similar 3-year cancer risk. |
| Murray J et al. 2025, *J Clin Epidemiol* (TAA cohort linked to HES) | 39929323 | Repair within 12 months vs no repair within 12 months (CCW), with competing risks. 7-year survival 57.4% vs 49.9%. |
| Yoshiyama T et al. 2026, *Clin Orthop Relat Res* (Japanese administrative data) | 42821763 | Early (≤2 days) vs delayed (3–10 days) surgery by CCW, explicitly to remove the immortal time in "delayed" groups. |

**Can TTE solve it? Yes, and this is where TTE adds most.** A trial chooses one comparator, and crossover then blurs it. A TTE can emulate *several* comparators from the same data: deferral (no PVI for 6 months), progression-triggered PVI, and, where positivity allows, abstention. It reports each as a separate, named estimand.
- **Triggers must be measurable.** "PVI only after CLTI" is emulable in claims because CLTI has codes; ICD-10 discriminates claudication from CLTI with 81.3% agreement (Bose 2025). "PVI only if walking distance deteriorates" needs EHR or registry symptom data.
- **"Never PVI" is hard to emulate.** It may lack positivity once CLTI develops.

**Testable in a known-truth simulation? Yes, and central.** The DGP can produce the true risk under each named comparator by intervening on the simulated data, so landmark, CCW and sequential estimates can each be scored against their own truth (02, B7).

---

# Part 2. RCTs of revascularization vs exercise or medical therapy for intermittent claudication

All rows come from abstracts. "NR" means not reported in the abstract (it may be in the full text). **EXITPAD could not be verified:** searches for "EXITPAD" and "EXIT-PAD" in PubMed returned no trial report or protocol, so it is left out.

| Trial (first report) | PMID(s) | n planned → randomized | Comparison | Primary endpoint | Follow-up | Crossover / non-adherence | Stopped early? | Hard limb outcome reported? |
|---|---|---|---|---|---|---|---|---|
| Lundgren 1989, *Ann Surg* | 2647051 | NR → 75 | Surgery vs surgery + training vs training | Walking performance | ~13 months | NR | NR | No |
| Creasy 1990, *Eur J Vasc Surg* (Oxford) | 2140987 | NR → 36 (20 PTA, 16 exercise) | PTA vs supervised exercise | ABPI and treadmill distances | 12 months (preliminary) | 2 PTA patients later had surgery. 1 exercise patient later had PTA. | NR | No |
| Perkins 1996, *EJVES* (Oxford long term) | 8846172 | NR → 56 | PTA vs exercise training | ABPI, treadmill distances | 15 months and ~6 years (37 reviewed) | NR | NR | 2 amputations (4%) in the whole cohort. Not compared by arm. |
| Whyman 1996 / 1997, *EJVES* / *JVS* (Edinburgh) | 8760978; 9357454 | 600 screened → 62 | PTA + medical (aspirin, advice) vs medical | Walking, ABPI, QoL, duplex | 6 months; 2 years | NR | NR | No. Only 10% of claudicants had lesions suitable for PTA. |
| Gelin 2001 / Taft 2001, *EJVES* (Gothenburg) | 11472042; 11472043 | NR → 264 (HRQL paper: 253) | Invasive (open or endovascular) vs supervised exercise vs observation | Maximum walking power; HRQL | 1 year | NR. HRQL data at 1 year available for 171. | NR | No |
| OBACT, Nylaende 2007, *EJVES* | 17055756 | 434 considered → 56 | OMT + PTA vs OMT | QoL | 2 years | NR | NR | Mortality was a secondary measure. No limb outcome. |
| MIMIC, Greenhalgh 2008, *EJVES* | 19022184 | NR → 93 femoropopliteal + 34 aortoiliac | PTA vs no PTA, on top of SE + BMT | ICD / AWD on treadmill | 24 months | NR | NR | No (ABPI only) |
| Spronk 2009, *Radiology*; long term Fakhry 2013, *BJS* | 19188327; 23842830 | NR → 151 | Endovascular vs hospital-based SET | Rutherford-based clinical success | 12 months; ~7 years | Secondary interventions significantly higher after SET (P = 0.001). Total interventions still higher after ER. | NR | No (secondary interventions only) |
| Nordanstig 2011, *EJVES* (Gothenburg INV vs NON) | 21397530 | NR → 201 | Invasive (endovascular and/or surgical) vs noninvasive. NON could request invasive treatment. | Maximal walking performance | 2 years | 7% of the INV arm crossed over | NR | No |
| CLEVER, Murphy 2012, *Circulation*; 2015, *JACC* | 22090168; 25766947 (design 18440181; update 19660897) | **252 planned (design) → 217 planned (update) → 111** | OMC vs OMC + SE vs OMC + stent (aortoiliac) | Change in peak walking time at 6 months | 6 and 18 months (79 completed at 18 months) | NR | Fewer patients than planned. Abstract does not say whether it was formally stopped. | No |
| Mazari 2012 / 2017, *BJS* (Hull) | 22021102; 27763685 | NR → 178 | PTA vs SEP vs PTA + SEP (femoropopliteal) | Clinical and QoL outcomes | 12 months; median 5.2 years | Withdrawals at 1 year: 8 PTA, 14 SEP, 11 combined | NR | 18 (16.2%) had a major cardiovascular event. Reinterventions: PTA 29, SEP 17, combined 9. No amputation data in abstract. |
| IRONIC, Nordanstig 2014, *Circulation*; Djerf 2020, *Circ CV Interv* | 25095886; 31937137 | NR → 158 | Revascularization + BMT + structured exercise vs BMT + structured exercise | SF-36 at 1 year | 1, 2, 5 years | NR in abstract | No | No. Benefit lost by 5 years; cost about 2× ($13,098 vs $6,965). |
| ERASE, Fakhry 2015, *JAMA*; Klaphake 2022, *Ann Surg* | 26547465; 33378308 | NR → 212 | ER + SET vs SET | MWD at 12 months (+282 m) | 12 months; median 5.4 years | SET arm had higher hazard of later revascularization (HR 2.50). Total procedures 65 (SET) vs 149 (combined). | No | Progression to CLI was a secondary endpoint at long-term follow-up. **The result is not given in the abstract.** |
| Swedish SFA stenting trial, Lindgren 2017, *EJVES*; Gunnarsson 2023, *EJVES* | 28372983; 36642399 (cost 34454817) | NR → 100 | Primary nitinol stent + BMT vs BMT (SFA) | HRQoL (SF-36, EQ-5D) at 12 months | 12, 24, 36, 60 months | **25% control-to-stent crossover by 60 months** | No | **Yes:** no differences in CLTI progression, amputation (2.1% vs 1.9%) or mortality (14.6% vs 15.4%). |
| SUPER, Koelemay 2022, *EJVES* | 35151572 (design 22326696) | **400 planned → 240** | SET vs ER (iliac) | MWD and VascuQol at 1 year | 1 year; mean 5.5 years | **29% of the SET arm had ER within 1 year.** SET compliance 50%. 8% of the ER arm did not get ER. Additional interventions by 5.5 years: 49% (SET) vs 27% (ER). | **Yes, terminated prematurely** | No (interventions only) |
| Cochrane, Fakhry 2018 | 29518253 | 10 RCTs, 1,087 participants | ER vs no treatment, SET, or cilostazol | MWD, PFWD, QoL | Short and long term | — | — | No hard limb outcomes were synthesized. Secondary invasive interventions were reported (e.g., ER + SET vs SET: OR 0.27). |

**Reading across the table.**
1. No trial was designed or powered for CLTI, amputation or death. Only the Swedish SFA trial reports CLTI or amputation by arm in its abstract, with about 2% amputation per arm at 5 years in 100 patients.
2. Under-recruitment is common:
   - CLEVER 252 → 111;
   - SUPER 400 → 240 (stopped);
   - OBACT 56 of 434;
   - Whyman 62 of 600.
3. Crossover from the conservative arm to revascularization is 25–49% wherever it is reported (SUPER, Swedish SFA, ERASE by hazard ratio).
4. "Conservative" means different things across rows (see Challenge 3).

---

# Part 3. Evidence on TTE itself

## 5. How well does TTE or observational analysis reproduce RCT results?

| Paper | PMID | Data source | Agreement metrics (from abstract) |
|---|---|---|---|
| **Wang SV et al. 2023, *JAMA* (RCT-DUPLICATE, 32 trials)** | 37097356 (in 01) | US claims (Optum, MarketScan, Medicare) | Overall Pearson r **0.82** (0.64–0.91). 75% agreed on statistical significance, 66% on the estimate, 75% on standardized difference. **Close emulations (16): r 0.93**, with 94% / 88% / 88% agreement. **Emulations that could not closely match PICOT (16): r 0.53**, with 56% / 50% / 69%. All drug trials, deliberately selected for feasibility. |
| Franklin JM et al. 2021, *Circulation* (first 10 of RCT-DUPLICATE) | 33327727 | US claims | Regulatory conclusion agreed in 6/10. HR inside the RCT 95% CI in 8/10. Standardized difference <2 in 9/10. Worst agreement where a sulfonylurea was used as a stand-in for placebo. |
| **Wang C et al. 2026, *BMJ* (systematic review and meta-analysis)** | 42156120 | Mixed (claims, EHR, registries) | 107 TTE–RCT pairs: r **0.59** (0.45–0.70). Standardized difference agreement 79%. Ratio of ratios 0.96. **Closer emulations (63): r 0.83**, 87% agreement. **Claims-based emulations underestimated effects (ratio of ratios 0.90, 0.82–0.99).** Worse agreement with imbalanced baselines, treatment started in hospital, and poor outcome emulation. |
| Dahabreh IJ et al. 2020, *Epidemiology* | 32740470 | Commentary | "Benchmarking observational methods by comparing randomized trials and their emulations." **No PubMed abstract, so no numbers.** |
| Matthews AA et al. 2022, *Am J Epidemiol* (TASTE benchmark) | 35641151 | Swedish registries (SWEDEHEART) | Procedure (thrombus aspiration). The emulation reproduced the null 1-year trial result (RD 0.7 for death, −0.2 for MI), then extended follow-up to 3 years and to under-represented subgroups. Benchmark first, then extend. |
| Westerberg M et al. 2024, *J Clin Epidemiol* | 39159770 | Swedish prostate cancer registry | Prostatectomy vs radiotherapy (treatment chosen by surgeon and patient). Crude HR 1.94. After Charlson adjustment 1.32. After richer comorbidity indices **1.14 (0.91–1.44), in line with the RCT.** Shows how strong confounding by indication is for procedures and how much depends on comorbidity measurement. |
| Forbes SP et al. 2020, *J Gen Intern Med* | 32193818 | Published PS-based studies | 127 observational-vs-RCT comparisons, **49 in surgery**. Large disagreement (relative RR <0.7 or >1.43) in **54%**. These were not explicit emulations, and the authors call for target-trial-based benchmarking. |
| Soni PD et al. 2019, *J Clin Oncol* | 30897037 | SEER, SEER-Medicare, NCDB | 350 comparisons vs 121 RCTs. **Concordance correlation 0.083**. 40% agreed. No modifiable factor (PS, IV, sensitivity analyses) improved agreement. Not TTE: conventional registry analyses. |
| Kumar A et al. 2020, *JAMA Netw Open* | 32729921 | NCDB (cancer registry) | 141 RCTs emulated by eligibility. HRs concordant in 64% of PS models, P values concordant in 45%. No trial characteristic (including type of intervention) predicted concordance. |
| Keyhani S et al. 2020, *JAMA Neurol* | 32478802 | VA EHR and other VA databases | **Vascular surgery vs initial medical therapy (asymptomatic carotid).** 5-year stroke risk 5.6% vs 7.8% (RD −2.3%). Accounting for competing death: RD −0.8% (not significant). The RCT-eligible subset gave similar numbers. The authors read this as a benefit smaller than in the trials of 20 years earlier, not as a failed replication. |
| Koeppe J et al. 2026, *Sci Rep* | 42711453 | German insurance claims | Replication across insurers (not vs RCT) of a surgical comparison (RTSA vs locked plating for humeral fracture): 7/11 endpoints replicated, Pearson r 0.97. |

**What this says for surgery.**
- **Benchmarks for procedures are scarce.** Every large benchmark of explicit emulations is mostly drug trials (RCT-DUPLICATE, Wang 2026). The procedural benchmarks found are single examples: thrombus aspiration, prostatectomy vs radiotherapy, and carotid endarterectomy against older trials.
- **Conventional registry analyses of procedures agree poorly with RCTs.** Agreement was near zero in Soni 2019 and only 45–64% in Kumar 2020, and in Forbes 2020 more than half of the 127 comparisons (49 in surgery) disagreed by a large margin.
- **Agreement depends on emulating closely, not on the statistical method.** Wang 2023 shows this for claims and Wang 2026 for mixed sources. In Wang 2026, claims-based emulations also tended to underestimate the trial effect (ratio of ratios 0.90).
- **Data-source caveat:** Kumar 2020, Soni 2019 and Westerberg 2024 used cancer registries, which have clinical stage but poor comorbidity data. Westerberg shows that better comorbidity measurement moved the estimate most of the way to the RCT.

## 6. Known limitations of TTE, guidance, and reviews of how it is used

### 6a. Guidance and frameworks (core references, PMIDs verified)

| Paper | PMID | Takeaway |
|---|---|---|
| Hernán MA, Robins JM 2016, *AJE* | 26994063 (in 01) | Foundational TTE paper. |
| Hernán MA et al. 2016, *J Clin Epidemiol* | 27237061 (in 01) | Aligning eligibility, assignment and time zero prevents immortal time bias. |
| Hernán MA et al. 2022, *JAMA* (JAMA Guide) | 36508210 (in 01) | Framework for causal inference from observational data. |
| Matthews AA et al. 2022, *BMJ* | 36041749 | "Target trial emulation: applying principles of randomised trials to observational studies." **No PubMed abstract.** |
| Cashin AG et al. 2025, *JAMA* / *BMJ* (TARGET); Hansford 2025, *PLoS Med* (E&E) | 40899949; 40903028; 41091811 (in 01 and 02) | Reporting guideline. |
| Messinger CJ et al. 2025, *Anesthesiology* | 40067038 | Perioperative and critical care primer: which biases the framework does and does not avoid. |
| Wong KHF et al. 2025, *Br J Surg* | 40893042 | "Harnessing real-world data to evaluate surgery and perioperative care interventions." **No PubMed abstract.** |
| Wanis KN et al. 2024, *JRSS-A* | 39281783 (in 02) | Natural vs stochastic grace-period strategies are different estimands. |
| VanderWeele TJ, Ding P 2017, *Ann Intern Med* | 28693043 | The E-value: how strong an unmeasured confounder would need to be to explain away an estimate. |
| Lipsitch M et al. 2010, *Epidemiology* | 20335814 | Negative control exposures and outcomes for detecting confounding. |

### 6b. Reviews of how TTE is actually done (quality)

| Paper | PMID | Takeaway |
|---|---|---|
| Hansford HJ et al. 2023, *JAMA Netw Open* | 37755828 | 200 TTEs (2012–2022): 43% did not describe all key emulation items, and 57% did not describe the target-trial protocol. |
| **Ren Y et al. 2026, *JAMA Netw Open*** | 41712213 | 237 TTEs in high-impact journals: 56.5% had a prespecified protocol. 15.2% used post-baseline information for eligibility. 16.9% gave a diagram defining time zero. **Only 30.8% addressed unmeasured confounding.** |
| McIntyre M et al. 2025, *J Clin Epidemiol* | 40639692 | 49% of 181 TTEs had misaligned eligibility, time zero and assignment. Of those, 67% did nothing about it, although 78% of these could have fixed it cheaply. |
| Manzanilla A et al. 2026, *J Clin Epidemiol* | 42600711 | 113 CCW studies: **19.5% still had potential immortal time bias**, mostly from excluding patients on post-time-zero criteria. |
| Scola G et al. 2023, *BMC Med Res Methodol* | 37587484 (in 01) | Only 16% of TTEs used cloning to handle immortal time. |

**Surgery- and vascular-specific reviews:** none found that systematically appraises TTE in surgery or vascular surgery (this repeats the gap noted in 01). Wong 2025 *BJS* and Messinger 2025 are narrative primers, and Hoskins 2026 (01) and Hatano 2026 *Int Orthop* (42287372; abstract not read) are orthopaedic primers.

### 6c. Limitations by data source (claims vs EHR vs registry), with vascular evidence

| Paper | PMID | Data source | Takeaway |
|---|---|---|---|
| **Bose S et al. 2025, *Circ Cardiovasc Qual Outcomes*** | 40439664 | VQI-VISION (VQI linked to Medicare) | Using VQI as the gold standard, predefined ICD-10 codes separated claudication from CLTI with 80.9% sensitivity, 81.9% specificity and **81.3% agreement**. Machine learning raised agreement to 84.2%. **About 1 in 5 claims is misclassified on the key indication or outcome.** |
| Appah-Sampong A et al. 2025, *Vasc Med* | 40340584 | Review of EHR and claims PAD studies | 84 studies: **76.2% used a single-code query** to identify PAD, despite its low yield. Only 5 used regression-based phenotypes. |
| **Columbo JA et al. 2019, *J Vasc Surg*** | 29914838 | VQI vs VQI-Medicare vs chart review (EVAR) | **VQI alone found 12 of 30 one-year reinterventions.** VQI-Medicare found all 30 (κ 0.93 vs chart review). At 3 years, sensitivity 92% and specificity 96%. Registry follow-up alone undercounts reinterventions, and linking to claims fixes most of it. |
| Goodney P et al. 2022, *BMJ* | 36283705 | VQI-Medicare | 20,489 EVAR patients with complete follow-up through registry and/or claims. Detected a device-specific reintervention signal (HR 1.61; surgeon-level IV 1.75) in mid-2013, years before the 2017 regulatory warnings. |
| Mao J et al. 2022, *J Vasc Surg* | 35181518 | VQI-Medicare linkage | Indirect linkage (without SSNs) matched 93.0% of patients with 99.4% accuracy. |
| **Mao J et al. 2024, *BMJ Open*** | 39327057 | VQI linked to EHR (INSIGHT CRN, New York) | After PVI, **75.2% were retained in the EHR through year 3.** Older, Medicaid, heart-failure, dialysis and less ambulatory patients were less likely to be retained, so attrition is informative. Amputation-free survival estimates were sensitive to this from 6–12 months onward. |
| Jansen SCP et al. 2020, *EJVES* | 32888779 | Dutch national claims | SET captured in claims where it is reimbursed (63% → 87% primary SET). Shows that SET's visibility in claims depends on the healthcare system. |
| Keyhani S et al. 2020 / 2022, *JAMA Neurol* / *Stroke* | 32478802; 35164531 | VA EHR (carotid imaging reports) | Emulations of carotid surgery vs medical therapy that used **imaging-report stenosis**, an EHR-only variable, for eligibility. 2022 (CAS vs MT): 5-year stroke 6.9% vs 7.1%. The population was 98.8% men (2020 paper), which limits generalizability. |
| Sakowitz S et al. 2025, *Ann Surg* | 40607703 (in 01) | Nationwide Readmissions Database | TCAR vs CEA "national target trial": 90-day composite 4.1% vs 4.1%. Follow-up is limited to 90 days by the database. |
| Wang Z et al. 2026, *J Vasc Surg* | 42448157 | 3-center clinical data | Open- vs closed-cell carotid stents. Median follow-up 26 months. Example of a short-follow-up, single-system emulation in vascular surgery. |
| Heindel P et al. 2024, *Eur Heart J Open* | 39175849 | Medicare linked with academic health-system EHR | PAD drug TTE (colchicine) with a MALE/MACE/death outcome. RD −1.7% (−6.5 to 3.1). Example of a claims-plus-EHR PAD emulation. |
| Westerberg 2024; Wang C 2026 (above) | 39159770; 42156120 | — | Comorbidity measurement drives residual confounding. Claims-based emulations tended to underestimate RCT effects. |

**Summary of data-source trade-offs for an early-PVI TTE.**
- **Claims (Medicare).**
  - Strengths: population-wide, long and nearly complete follow-up for procedures and amputation, procedure dates, operator NPI, Part D fills, and SET billing from 2017.
  - Weaknesses: no ABI, walking distance or symptom severity (the main triggers for crossover and confounding by indication). About 19% misclassification between claudication and CLTI (Bose 2025). Home exercise, smoking, and patient refusal are not recorded.
- **EHR.**
  - Strengths: ABI, imaging, symptom notes, SET referral, smoking, and refusal documentation.
  - Weaknesses: follow-up is fragmented, and patients leave the system informatively (75% retained at 3 years; Mao 2024). Usually a single system, so fewer physicians to compare.
- **Registry (VQI).**
  - Strengths: rich anatomy and indication data, plus OMT and smoking status at the time of the procedure.
  - Weaknesses: **enrolls only patients who have a procedure**, so there is no conservative arm. Long-term outcomes are undercounted unless linked to claims (12 of 30 reinterventions captured; Columbo 2019).
- **Linked data (VQI-Medicare/VISION).** Best for outcomes after a procedure. It still has no comparator arm of patients never treated, unless claims-only patients are added, and those patients then lack registry detail.

### 6d. Unmeasured confounding by indication: the limit that remains

- Every guidance paper above, and every review, names unmeasured confounding as the limitation TTE does not remove. Only 30.8% of published TTEs address it (Ren 2026).
- For procedures, Westerberg 2024 shows that adjustment moved the HR from 1.94 to 1.14, and that most of the bias came from how well comorbidity was measured.
- In the claudication setting the main unmeasured confounders are:
  - symptom severity and walking distance;
  - frailty;
  - patient preference and refusal;
  - physician style (see 02, B6).
- Tools exist for each: E-values (28693043), negative controls (20335814), physician-level designs (02), and linking to EHR or registry data to measure symptoms.

---

## Feed for Table 1 (this draft's rows)

| Challenge | Evidence it is common/important | Vascular/claudication example | Can TTE solve it? | Known-truth simulation? |
|---|---|---|---|---|
| Crossover / contamination | 27–43% crossover in conservative arms within 1–2 years (Peul, Katz, SPORT, CODA, APPAC). Effect estimates nearer the null with more crossover (Gaudino 2019). STICH ITT not significant at 5 years. | SUPER 29% at 1 year. Swedish SFA 25% at 5 years. ERASE HR 2.50. | **Yes** (CCW/IPCW for explicit strategies), if crossover triggers are measured. Claims lack symptoms; EHR/registry partly have them. | Yes: latent progression drives deferred PVI. Observed vs unobserved. |
| Non-adherence / refusal | STICH CABG→MED crossover mainly by patient/family choice, with worse prognosis. ACST only 50% operated by 1 month. SET recruitment 24.2%. | SUPER SET compliance 50%. US SET completion 9.8–49.9%. | **Partly.** No consent step. Refusal is not visible in claims (sometimes in EHR). SET billing is visible in Medicare from 2017. | Yes: latent "refuser" trait. |
| Co-interventions / usual care | Usual care poorly reported (TIDieR median 1/12). Only 38.1% complete OMT before revascularization in VQI. | Comparator differs across trials (aspirin plus advice vs SET plus BMT vs cilostazol). | **Partly.** Part D statins and SET claims are visible. Home exercise and smoking are not. VQI has OMT only at procedure and no conservative arm. | Yes: unmeasured exercise or OMT that differs by arm. |
| Comparator definition | Most "conservative" arms are "surgery-if-needed". ISCHEMIA and ACST define dynamic comparators. CCW and sequential trials give different numbers (Garcia-Albeniz 2026). | "No PVI within 6 months" vs "PVI only for CLTI" vs "never PVI". | **Yes**, and TTE's main gain: several named estimands from one dataset. Triggers must be coded (CLTI codes about 81% accurate). "Never" may lack positivity. | Yes, central: true risk under each strategy. |

## Five-line summary

1. Crossover from conservative care to surgery is common and large: 25–68% across hernia, spine, knee, appendicitis, cardiac surgery and claudication trials. It pulls ITT estimates toward the null, as in STICH and the Swedish SFA trial, and it is the challenge TTE handles best, through explicit dynamic strategies with CCW/IPCW.
2. Non-adherence and refusal (to surgery and especially to SET) are substantial, and patients who refuse have a different prognosis. TTE removes the consent barrier, but refusal of an offered operation is not visible in claims and is only partly visible in EHR.
3. Co-interventions and "usual care" vary widely and are poorly reported. Claims see drugs and Medicare SET but not home exercise or smoking. VQI records OMT only at the time of a procedure and cannot provide a no-PVI arm on its own.
4. Of the 15 claudication revascularization trials checked (plus the Cochrane review), none was powered for hard limb outcomes. Several under-recruited (CLEVER 252 → 111) or stopped early (SUPER 400 → 240). Only the Swedish SFA trial reports CLTI and amputation by arm (about 2% each). EXITPAD could not be found in PubMed.
5. TTE agrees well with RCTs when the emulation is close (r 0.93 in RCT-DUPLICATE; 0.83 in Wang 2026 *BMJ*), but agreement is poor otherwise (r 0.53; and 0.08 for conventional cancer-registry analyses). Procedural benchmarks are scarce, many published TTEs are of low quality (only 30.8% address unmeasured confounding), and no claudication or PVI TTE was found.

---

### Verification notes
- **No PubMed abstract, so cited without numbers:** Divakaran 2021 (34293930), Divakaran 2024 (39129558), Dahabreh 2020 (32740470), Matthews 2022 *BMJ* (36041749), Wong 2025 *BJS* (40893042), Katsoulis 2024 (39024012, in 01).
- **EXITPAD:** not found in PubMed under that name. It may be a non-indexed acronym or a confusion with ERASE or SUPER (both Dutch).
- **Not in the abstracts** (need full text): planned sample sizes for MIMIC, IRONIC and ERASE; crossover rates for IRONIC, CLEVER and MIMIC; ERASE's long-term CLI result; whether CLEVER was formally stopped.
- **ISCHEMIA and COURAGE crossover rates** are not in their abstracts, so they are not quoted.
- **Creasy 1990 and Perkins 1996 are probably the same Oxford trial** (preliminary report with 36 patients, later report with 56). The abstracts do not confirm this.
- **No claudication or PVI target trial emulation** was found by a PubMed search (2026-10-28).