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Journal Club

The SWEDEPAD Trials: One Program, Two Trials, Same Answer

Two massive Swedish trials put paclitaxel-coated devices to the test in PAD - and the answer is the same for both

Falkenberg M, et al. SWEDEPAD 1. Lancet 2025;406:1103-14.
Nordanstig J, et al. SWEDEPAD 2. Lancet 2025;406:1115-27.

Section 1: One Program, Two Trials, One Answer

A vascular surgeon in Sweden sees two patients back-to-back. Both need endovascular revascularisation. The surgeon reaches for a paclitaxel-coated balloon. Should they?

The Clinical Scenario

Patient A: A 68-year-old man with severe intermittent claudication (Rutherford 3). He can't walk 100 metres without stopping. His ankle-brachial index is 0.55. He wants to get back to gardening.

Patient B: A 79-year-old woman with critical limb-threatening ischaemia (CLTI). She has rest pain and a non-healing ulcer on her right foot (Rutherford 5). Her ABI is 0.3. Without revascularisation, she may lose her leg.

Different patients. Different goals. Same question: does the drug-coating on the balloon matter?

The SWEDEPAD Program

SWEDEPAD - the Swedish Drug-Elution Trial in Peripheral Arterial Disease - was not one trial but a coordinated program of two parallel randomised controlled trials.

  • Same 22 Swedish centres
  • Same Swedvasc registry platform
  • Same enrollment period: November 2014 to September 2023
  • Published simultaneously in The Lancet, August 31, 2025

SWEDEPAD 1 (CLTI)

2,355

Rutherford 4-6
Primary endpoint:
Major amputation

SWEDEPAD 2 (Claudication)

1,136

Rutherford 1-3
Primary endpoint:
Quality of life (VascuQoL-6)

Why two separate trials? Because the goals of treating CLTI and claudication are fundamentally different. In CLTI, you're trying to save the limb. In claudication, you're trying to improve how the patient walks and lives. Different questions need different primary endpoints.

Section 2: The Design - A Registry-Based RCT

SWEDEPAD used a powerful but underappreciated design: the registry-based randomised controlled trial, embedding research into routine clinical care.

The Swedvasc Registry

Swedvasc captures >95% of all vascular procedures in Sweden. By embedding randomisation directly into this registry, SWEDEPAD achieved:

  • Pragmatic, real-world enrollment at the point of care
  • High external validity (study patients matched the national Swedish PAD population)
  • Cross-linkage with national death registries for near-complete mortality follow-up
  • Minimal disruption to clinical workflow

How Randomisation Worked

Patients were randomised after successful guidewire crossing of the target lesion. This is a critical detail: it means only patients who could actually undergo balloon angioplasty were randomised.

  • Allocation: 1:1, stratified by centre
  • Participant-masked but operator-unmasked (pragmatic necessity - operators must know which device to use)
  • Drug-coated devices: >99% used paclitaxel as the coating agent
  • Investigators chose device brands from commercially available options

SWEDEPAD 1 (CLTI)

2,400

Randomised
1,206 drug-coated vs 1,194 uncoated
ITT: 1,180 vs 1,175

SWEDEPAD 2 (Claudication)

1,155

Randomised
577 drug-coated vs 578 uncoated
ITT: 565 vs 571

The Largest RCT Ever for Drug-Coated Devices in PAD

Combined, SWEDEPAD enrolled approximately 3,500 patients across the two trials. No prior RCT of paclitaxel-coated devices in PAD comes close to this size. And unlike most prior trials, these were government-funded and independent from industry.

Registry-based RCT advantages: The population studied closely mirrors real clinical practice. There are no restrictive exclusion criteria creating a "trial population" that doesn't exist in your clinic. And because Swedvasc links to the Swedish national death registry, virtually no patients are lost to follow-up for the mortality endpoint.

Section 3: The Patients

Understanding WHO was enrolled in each trial is essential for interpreting the results - especially the mortality data.

SWEDEPAD 1 - CLTI Population

Median age 77 years
Male 55.9%
Diabetes 52.6%
Rutherford 5 or 6 74.9%
Baseline ABI 0.6
VascuQoL-6 baseline 10
Femoropopliteal 52.7%
Infrapopliteal 22.8%

Both femoropopliteal + infrapopliteal: 23.8%. TASC distribution: ~17% A, 33% B, 30% C, 19% D.

SWEDEPAD 2 - Claudication Population

Median age 73 years
Male 53.9%
Diabetes 33.7%
Rutherford 3 59.6%
Baseline ABI 0.6
VascuQoL-6 baseline 10
Femoropopliteal 96.1%
Actual stenting rate 42.8%

Planned primary stenting 18.8% but actual 42.8% (many needed supplementary stenting). TASC: ~24% A, 40% B, 24% C, 12% D.

CLTI patients are sicker. Older (77 vs 73), more diabetes (52.6% vs 33.7%), more tissue loss (74.9% Rutherford 5-6), more multi-level disease. This matters hugely when we get to interpreting the mortality data - their background death rate is roughly 4-5 times higher than the claudication cohort.
The stenting gap: In SWEDEPAD 2, planned primary stenting was only 18.8% but actual stenting reached 42.8%. This reflects real-world decision-making: many initially planned balloon-only cases needed supplementary stenting after suboptimal results. Crucially, stenting rates were similar between groups, so it didn't bias the comparison.

Section 4: SWEDEPAD 1 - Did Drug-Coating Save Limbs?

In 2,355 patients with CLTI, the question was simple: does a paclitaxel-coated device reduce major amputation?

PRIMARY ENDPOINT: IPSILATERAL MAJOR AMPUTATION AT 5 YEARS

HR 1.05 (95% CI 0.87-1.27), p=0.61

NO DIFFERENCE

Drug-Coated

6.17

amputations per
100 person-years

Uncoated

5.96

amputations per
100 person-years

Secondary Endpoints

Endpoint Drug-Coated Uncoated Result
All-cause mortality (5yr) 15.01/100py 13.99/100py HR 1.04
p=0.54
Amputation-free survival - - HR 1.01
p=NS
TVR at 1 year Lower Higher HR 0.81
p=0.031
TVR at 5 years - - HR 0.97
p=0.71
VascuQoL-6 at 1yr 13 13 Diff -0.05
p=0.84

The Reintervention Story

Drug-coating reduced target vessel reintervention at 1 year: HR 0.81 (0.66-0.98), p=0.031. But by 5 years: HR 0.97 (0.83-1.14), p=0.71.

The cumulative reintervention curves converged by year 2. The uncoated group had more reinterventions early, but then the rate dropped as those lesions were treated. The drug-coated group's reintervention rate stayed constant.

The Key Interpretation

Drug-coating delayed rather than prevented reinterventions. At 1 year there appeared to be a benefit, but it vanished as the uncoated group caught up. And crucially, this reintervention delay translated into zero improvement in amputation, survival, or quality of life.

Rutherford improvement at 1 year: 65.2% vs 64.7% - identical. ABI at 1 year: 0.9 vs 0.9 - identical. By every patient-centred measure, drug-coated devices provided no benefit in CLTI.

Section 5: SWEDEPAD 2 - Did Drug-Coating Improve Quality of Life?

In 1,136 claudicants, the primary question was about what patients care about most: can they walk better and live better?

PRIMARY ENDPOINT: VascuQoL-6 AT 1 YEAR

Mean difference -0.02 (95% CI -0.66 to 0.62), p=0.96

NO DIFFERENCE

Drug-Coated

10 → 15

VascuQoL-6 improvement
72.9% improved at 1yr

Uncoated

10 → 15

VascuQoL-6 improvement
73.7% improved at 1yr

Both groups had massive QoL improvement - the procedure itself works. The coating adds nothing.

Secondary Endpoints

Endpoint Drug-Coated Uncoated Result
TVR at 1 year - - HR 0.86
p=0.37
TVR at 5 years - - HR 0.96
p=0.71
Rutherford improvement 1yr 70.1% 71.4% Identical
ABI change at 30 days +0.3 +0.3 Identical
Amputation at 5yr - - HR 1.58
p=0.24

MORTALITY SIGNAL

All-cause mortality at 5 years: HR 1.47 (95% CI 1.09-1.98), p=0.010

4.57 vs 3.28 deaths per 100 person-years

The Mortality Curves

The mortality curves began to diverge at approximately 2 years, with the drug-coated group experiencing progressively more deaths. The separation persisted through the 5-year landmark.

Per-protocol analysis confirmed: HR 1.56 (1.15-2.13), p=0.0042

Over full follow-up (median 7.1 years): HR 1.18 (0.94-1.48), p=0.16

The mortality signal was strongest at 5 years but attenuated over the full follow-up period, suggesting a time-limited effect of paclitaxel exposure.

No benefit AND a safety signal. Drug-coating did not improve QoL, did not reduce reinterventions, did not improve ABI or Rutherford class - and was associated with increased mortality at 5 years. In claudication patients, where the condition itself rarely threatens the limb, this risk-benefit equation is clearly unfavourable.

Section 6: Head-to-Head - Why Mortality in One But Not the Other?

This is the central epidemiological question of the SWEDEPAD program. The same drug, the same device types, the same country - but a mortality signal in claudicants and not in CLTI. Why?

Side-by-Side Comparison

SWEDEPAD 1 (CLTI) SWEDEPAD 2 (Claud.)
ITT population 2,355 1,136
Primary endpoint Major amputation QoL (VascuQoL-6)
Primary result HR 1.05, p=0.61 Diff -0.02, p=0.96
TVR at 1yr HR 0.81, p=0.031 HR 0.86, p=0.37
TVR at 5yr HR 0.97, p=0.71 HR 0.96, p=0.71
Mortality at 5yr HR 1.04, p=0.54 HR 1.47, p=0.010

The Signal-to-Noise Explanation

This is a classic epidemiological concept. Consider the background mortality rates:

CLTI Background Mortality

~15

deaths per 100 person-years

Claudication Background Mortality

~3.3

deaths per 100 person-years

The Math of Detection

If paclitaxel adds approximately 1 extra death per 100 person-years:

  • In CLTI: 15 → 16 per 100py = 7% relative increase → virtually undetectable, even in 2,355 patients
  • In Claudication: 3.3 → 4.6 per 100py = 39% relative increase → easily detectable in 1,136 patients

The CLTI cohort was TWICE as large (2,355 vs 1,136) and STILL couldn't detect it. The problem wasn't sample size - it was signal-to-noise ratio.

Think of it this way: Trying to detect a small excess mortality from paclitaxel in CLTI patients is like trying to hear a whisper in a hurricane. In claudicants, it's like hearing a whisper in a quiet room. A small absolute harm is easier to detect in a low-risk population because there's less background noise to mask it.
The absence of a signal in CLTI does NOT mean the absence of harm. It may simply mean the harm is undetectable against the high background mortality. Both trials showed point estimates above 1.0 for mortality with drug-coating.

Section 7: The Bigger Picture - What SWEDEPAD Means for Claudication

SWEDEPAD tells us drug-coating doesn't help. But the data also tell us something important about what DOES work for claudication patients.

Background Event Rates in SWEDEPAD 2 (Both Groups Combined)

Event Rate at 1yr Rate at 5yr
Reintervention ~13-15/100py ~8/100py
Death ~3-5/100py ~3-5/100py
Major amputation ~0.5-0.7/100py ~0.5-0.7/100py

Late Amputation: The Fear That Didn't Materialise

A common worry with claudication is progression to limb loss. SWEDEPAD 2 puts hard numbers on this: the major amputation rate was only ~0.5-0.7 per 100 person-years over 5 years. That's about 1-2% at 5 years - and it stayed flat, with no late spike.

This is actually reassuring for the intervention strategy. These patients were revascularised and they kept their limbs. The late-amputation bogeyman didn't show up.

The QoL Win Is Real

Both groups improved from a baseline VascuQoL-6 of ~10 to ~15 at 1 year. That's a 50% improvement in disease-specific quality of life. The procedure works - the drug coating just doesn't add anything on top of it.

This is an important distinction: SWEDEPAD does not argue against intervention for claudication. It argues against drug-coating the devices.

What Guidelines Recommend

Both the ESVS 2024 and ESC 2024 guidelines recommend supervised exercise therapy FIRST for claudication, before considering endovascular intervention. But when patients fail or can't access supervised exercise, intervention is a reasonable next step.

Exercise therapy improves walking distance, QoL, and cardiovascular fitness. But in practice, access to structured supervised programs varies enormously - and many patients end up in the cath lab regardless.

A generalisability note: This is a Swedish population with universal healthcare, lower comorbidity burdens, and generally better baseline health than many US cohorts. The 1-year amputation rate of ~15% in the CLTI arm and the low background mortality in claudicants may not map directly to American practice, where patients tend to present later and sicker. Keep this in mind when applying these numbers to your own patients.
The bottom line for claudication: Intervention works - QoL improved dramatically. Drug-coating doesn't add benefit and may add harm. If you're reaching for a balloon, an uncoated one does the job.

Section 8: The Paclitaxel Mortality Saga

The SWEDEPAD results land in the middle of a controversy that has been simmering for seven years. Here is the timeline.

2018: Katsanos Meta-Analysis (JAHA)

Pooled data from RCTs suggested increased late mortality with paclitaxel-coated devices. Critically, 89% of included patients were claudicants, only 11% CLTI. This meta-analysis shook the vascular world.

2018-2019: FDA Safety Letters

The FDA issued safety communications. SWEDEPAD paused enrollment for 15 months while safety was assessed.

2020: SWEDEPAD Interim Analysis (NEJM)

Published interim safety analysis showed no mortality difference at mean 2.49 years of follow-up. Enrollment resumed March 2020. But as we now know, the signal appears between years 2-5.

2020: Rocha-Singh IPD Meta-Analysis

Industry-sponsored individual patient data meta-analysis found no increased mortality. But follow-up was limited.

2023: Parikh IPD Meta-Analysis (Lancet)

Updated individual patient data meta-analysis: no increased mortality detected. But again, mix of CLTI and claudicants, limited long-term follow-up.

2024: BASIL-3 Trial

UK trial in CLTI: no differences with drug-coated devices. Consistent with SWEDEPAD 1's CLTI finding.

2025: SWEDEPAD Final Results

CLTI (SWEDEPAD 1): No mortality signal (HR 1.04, p=0.54).
Claudication (SWEDEPAD 2): Mortality signal at 5 years (HR 1.47, p=0.010).

The Pattern Matches

The SWEDEPAD 2 mortality signal follows the same pattern as the 2018 Katsanos meta-analysis: divergence at approximately 2 years, persisting through 5 years. And remember, 89% of Katsanos patients were claudicants.

The 2020 SWEDEPAD interim analysis found nothing at 2.49 years - because the signal hadn't emerged yet. This is why long-term follow-up matters.

Why Was This So Hard to Settle?

Most prior individual RCTs of drug-coated devices were:

  • Small: Typically 100-400 patients (vs SWEDEPAD's 3,500)
  • Industry-sponsored: With potential reporting bias
  • Surrogate-focused: Using patency and TLR, not patient-centred endpoints
  • Short follow-up: 1-2 years (the signal appears at 2-5 years)
  • Mixed populations: CLTI and claudicants pooled together

SWEDEPAD 2 is the first adequately-powered individual trial with pre-specified mortality analysis and sufficient follow-up to detect this signal in a pure claudication population.

The lesson for evidence-based medicine: Meta-analyses can generate hypotheses, but they cannot definitively answer them. Large, well-designed trials with patient-centred endpoints and long follow-up are what ultimately settle questions. SWEDEPAD did what no prior trial could.

Section 9: Strengths & Limitations

Every trial has trade-offs. Understanding them helps you weigh the evidence appropriately.

Strengths

  • Largest RCT ever for drug-coated devices in PAD (~3,500 patients combined across two trials)
  • Registry-based design: High external validity. SWEDEPAD patients closely matched the national Swedish PAD population.
  • Patient-centred endpoints: Amputation and quality of life, not surrogate endpoints like patency or binary restenosis
  • Independent from industry: Government-funded. Investigators chose device brands from commercially available options.
  • Long follow-up: Up to 10 years for some patients, with a pre-specified 5-year landmark analysis
  • Cross-linkage with national registries: Near-complete mortality data via the Swedish national death registry. Virtually no loss to follow-up for the mortality endpoint.

Limitations

  • Operator not masked: Pragmatic necessity (operators must know which device to deploy), but participants WERE masked. Could introduce bias in reintervention decisions.
  • Multiple device brands used: Reflects real-world practice but prevents device-specific conclusions. We cannot say whether one brand is safer than another.
  • VascuQoL-6 missing for ~5% at 1 year: A small but non-trivial amount of missing primary endpoint data in SWEDEPAD 2.
  • No routine duplex ultrasound follow-up: Patency could not be assessed directly. This is a limitation for understanding mechanism but not for patient-centred endpoints.
  • 15-month enrollment pause: After the Katsanos meta-analysis. Could introduce era effects (different devices available, different operator experience over time).
  • 5-year follow-up cap applied post-hoc: The primary analysis was capped at 5 years. Full follow-up analysis was also presented but with less statistical power per time point.
  • Target vessel reintervention (not target lesion): Registry limitation. TVR captures all reinterventions in the treated vessel, which may overestimate restenosis-related procedures.
  • No mechanistic explanation: The trial cannot explain WHY paclitaxel might cause late mortality in claudicants. The mechanism remains unknown.
  • Swedish population may not generalise: Sweden has universal healthcare, lower comorbidity burdens, and patients who may present earlier than US cohorts. The ~15% 1-year CLTI amputation rate and low claudicant mortality are lower than what many American centres see. Apply these numbers cautiously to non-Scandinavian populations.
The pragmatism trade-off: SWEDEPAD sacrificed some internal validity (no operator blinding, multiple device brands, registry-level data) in exchange for massive gains in external validity and sample size. For the clinical question "should I use drug-coated devices in my practice?" - this pragmatic design gives you a more relevant answer than a tightly controlled efficacy trial ever could.

Test Your Understanding

Apply what you've learned about both SWEDEPAD trials.

Key Takeaways

  • 1
    Largest RCT ever for drug-coated devices in PAD

    ~3,500 patients across 2 parallel trials in 22 Swedish centres, with up to 10 years of follow-up.

  • 2
    SWEDEPAD 1 (CLTI): No reduction in major amputation

    HR 1.05 (0.87-1.27), p=0.61. Drug-coated devices did not save limbs.

  • 3
    SWEDEPAD 2 (Claudication): No improvement in quality of life

    Mean difference -0.02 (-0.66 to 0.62), p=0.96. Both groups improved from 10 to 15 on VascuQoL-6.

  • 4
    Drug-coating delayed reinterventions at 1 year in CLTI but did NOT prevent them long-term

    1-year TVR HR 0.81 (p=0.031) converged to HR 0.97 (p=0.71) at 5 years. Delayed, not prevented.

  • 5
    No reintervention benefit at all in claudication patients

    1-year TVR HR 0.86 (p=0.37), 5-year TVR HR 0.96 (p=0.71). Not even a temporary benefit.

  • 6
    5-year mortality signal in claudicants

    HR 1.47 (1.09-1.98), p=0.010. Death rate 4.57 vs 3.28 per 100 person-years. Confirmed on per-protocol analysis (HR 1.56, p=0.0042).

  • 7
    No mortality signal in CLTI (high background mortality masks the signal)

    HR 1.04 (0.92-1.17), p=0.54. Background mortality of ~15/100py makes a small excess undetectable.

  • 8
    Low amputation rate in claudicants is reassuring - intervention works, but consider carefully whether you need the drug-coating

    ~0.5-0.7 amputations per 100py with no late spike. QoL improved 50% (10→15) in both arms. The procedure helps; the coating doesn't.

The Bottom Line

Drug-coating didn't add benefit in either population. In claudication, intervention itself works well (QoL improved 50%), but the paclitaxel adds nothing except a concerning 5-year mortality signal. Consider carefully whether drug-coated devices are worth the trade-off when uncoated ones achieve the same outcomes.

Before You Go: A Quick Poll

Your hospital's vascular lab currently defaults to paclitaxel-coated balloons for all femoropopliteal interventions. Based on SWEDEPAD, what do you recommend?