Effetti dell'angioplastica renale transluminale percutanea della stenosi dell'arteria renale aterosclerotica nei pazienti ad alto rischio. (DAN-PTRAII)

Percutaneous transluminal renal angioplasty with stent placement

Catheter-based angiography performed in accordance with the study protocol.

Measurement of translesional pressure gradients performed in accordance with the study protocol.

Optimal medical therapy, including maximally tolerated renin-angiotensin system blockade with either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker.

Renal artery stenting performed in accordance with the study protocol.

Sham procedure

Catheter-based angiography performed in accordance with the study protocol.

Measurement of translesional pressure gradients performed in accordance with the study protocol.

Optimal medical therapy, including maximally tolerated renin-angiotensin system blockade with either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker.

Sham procedure performed in accordance with the study protocol.

Defined as the between-group difference in the change in 24-hour ambulatory systolic blood pressure from baseline to 6 months.

Defined as the between-group difference in the change in estimated glomerular filtration rate (eGFR) from baseline to 6 months.

Defined as the between-group difference in the change in urine albumin-to-creatinine ratio from baseline to 3 and 6 months.

Defined as the between-group difference in the change in attended automated office systolic blood pressure from baseline to 3 and 6 months.

Defined as the between-group difference in the change in unattended automated office systolic blood pressure from baseline to 3 and 6 months.

Defined as the between-group difference in the change in defined daily dose (DDD) of antihypertensive medications from baseline to 3 and 6 months.

Defined as the between-group difference in the change in the number of antihypertensive medications from baseline to 3 and 6 months.

Defined as the between-group difference in the change in 24-hour ambulatory systolic blood pressure from baseline to 3 and 6 months, corrected for changes in antihypertensive medication burden (1 DDD = 5 mmHg).

Between-group comparison of the number of participants with clinical events from baseline to 6 months.

Clinical events are defined using the same criteria as in the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, except for progressive renal insufficiency (defined in CORAL as a reduction from baseline of 30% or more in estimated GFR).

Clinical events included in the composite endpoint from baseline to 6-month follow-up are:

1. Death from cardiovascular causes
2. Death from renal causes
3. Stroke
4. Myocardial infarction
5. Hospitalization for congestive heart failure
6. Progressive renal insufficiency (a reduction from baseline of 50% or more in estimated GFR)
7. Permanent renal-replacement therapy

Only the first event per participant is included in the composite.

Between-group comparison of the number of participants with death from any cause from baseline to 6 months.

Defined as the between-group difference in the change in 12-item Short Form Health Survey (SF-12) scores from baseline to 3 and 6 months.

Scores range from 0 to 100, with higher scores indicating better physical and mental health functioning.

All SAEs occurring from baseline to 6 months, as well as procedure-related adverse events (≤24 hours) and postoperative adverse events (>24 hours) occurring within 30 days after the procedure, will be systematically recorded. Events include, but are not limited to:

1. Death from any cause
2. Rupture, dissection, occlusion, or perforation of the renal artery
3. Stent thrombosis of the PTRA-treated renal artery
4. Embolic complications affecting the kidney or peripheral circulation (upper or lower extremity depending on access site)
5. Bleeding requiring transfusion
6. Embolization or nephrectomy due to bleeding or other complications
7. Access-related complications requiring treatment: bleeding, thrombosis, or pseudoaneurysm
8. Need for acute dialysis
9. Clinical events as defined above

Defined as the between-group difference in the change in intrarenal resistive index (unitless) of the affected kidney from baseline to 6 months, measured by Doppler ultrasound.

Additional renal ultrasound and Doppler parameters (kidney length, peak systolic velocity, acceleration time, renal-renal ratio, and pulsatility index) will be assessed at baseline and 6 months and compared between groups. In exploratory analyses, the association between baseline intrarenal resistive index (≥0.80 vs <0.80) and the change in 24-hour ambulatory systolic blood pressure and eGFR from baseline to 6 months will be evaluated, and the diagnostic accuracy (sensitivity and specificity) of baseline Doppler ultrasound for identifying hemodynamically significant renal artery stenosis will be assessed using invasive pressure measurement as the reference standard.

Defined as the between-group difference in the change in left ventricular mass index (g/m²) from baseline to 6 months, assessed by transthoracic echocardiography.

Additional transthoracic echocardiographic parameters of cardiac systolic and diastolic function and cardiac chamber dimensions and volumes will be assessed at baseline and 6 months and compared between groups.

Defined as the between-group difference in the change in split renal function (%) of the affected kidney from baseline to 6 months, assessed by renography.

The change in renogram configuration (renogram grade) of the affected kidney from baseline to 6 months will be compared between groups as the proportion of participants with improvement in renogram grade. In exploratory analyses, the diagnostic accuracy (sensitivity and specificity) of baseline renography for identifying hemodynamically significant renal artery stenosis will be assessed using invasive pressure measurement as the reference standard, and the association between baseline renography with intermediate/high probability of renovascular hypertension and the change in 24-hour ambulatory systolic blood pressure and eGFR from baseline to 6 months will be evaluated.

Defined as the distal-to-aortic pressure ratio (Pd/Pa, unitless) across the target renal artery stenosis, measured by intra-arterial pressure assessment during the endovascular procedure.

Systolic, diastolic, mean, and pulse pressure gradients (mmHg) across the target renal artery stenosis will be measured invasively during the procedure. In exploratory analyses, the association between baseline Pd/Pa and mean and systolic translesional pressure gradients and the change in 24-hour ambulatory systolic blood pressure and eGFR from baseline to 6 months will be evaluated, and whether the effect of PTRA differs according to baseline Pd/Pa will be explored.

Defined as the mean difference (Bland-Altman bias, unitless) between Pd/Pa derived non-invasively from CT angiography using computational fluid dynamics (CFD) and Pd/Pa measured invasively during the endovascular procedure.

Agreement between CFD-derived and invasively measured mean and systolic translesional pressure gradients will be assessed correspondingly. In exploratory analyses, the association between CFD-derived Pd/Pa and mean and systolic translesional pressure gradients and the change in 24-hour ambulatory systolic blood pressure and eGFR from baseline to 6 months will be evaluated.

Defined as the between-group difference in the change in plasma renin concentration (mIU/L) from baseline to 3 and 6 months.

In exploratory analyses, the association between baseline plasma renin and the change in 24-hour ambulatory systolic blood pressure and eGFR from baseline to 6 months will be evaluated.

Defined as the between-group difference in the change in plasma aldosterone concentration (pmol/L) from baseline to 3 and 6 months.

In exploratory analyses, the association between baseline plasma aldosterone and the change in 24-hour ambulatory systolic blood pressure and eGFR from baseline to 6 months will be evaluated.

Defined as the between-group difference in the change in plasma NT-proBNP concentration (ng/L) from baseline to 3 and 6 months.

In exploratory analyses, the association between changes in echocardiographic parameters, including left ventricular mass index, and the change in NT-proBNP from baseline to 6 months will be evaluated to assess whether changes in NT-proBNP reflect changes in cardiac structure and function.

Defined as the proteomic profile in blood and in material retrieved from the angioplasty balloon after dilation during PTRA. In exploratory analyses, the association between the proteomic profile and the change in 24-hour ambulatory systolic blood pressure and eGFR from baseline to 6 months, and the need for reintervention due to restenosis, will be evaluated. Proteomic analyses will be described in a separate analysis plan.