1. Behandeling van laag-gradige nierarteriestenosen PROTAGORAS studie
A.A. (Bram) Kroon
Afd. Interne Geneeskunde
Maastricht UMC+

2. A.A. Kroon none Research contracts: - Consulting:
Employment in industry:
Stockholder of a healthcare company:
Owner of a healthcare company:
Other:

3. Acronym
PROTAGORAS
PROspective Trial of treating Atherosclerotic low-Grade Occlusion in Renal Artery Stenosis

4. The burden of renal artery stenosis: cardiovascular mortality
Hoog CV risico en leidt tot secundaire hypertensie, ischemische nephropathy en cardiale events.
Uzu et al. Hypertens Res, 2002

5. Treatment options in ARAS
Medical
antihypertensive treatment
lipid lowering
other anti-atherosclerotic measures
Mechanical
PTRA
stenting
surgery

6. Outcome trials with stenting
STAR (n=140): PTRA(S) vs med; no difference in renal function (RF)
Astral (n=806): PTRA(S) vs med; no clinical benefit both on BP and RF
Coral (n=947): PTRA(S) vs med; no difference in major cardiovascular and renal adverse events
So, we are confronted with the situation that ARAS is a severe CV condition not improved with stenting; but slowly progressive irrespective of optimal medical therapy.

7. Renal hemodynamics in renal artery stenosis
Haimovici et al. J Cardiovasc Surg 1962;3:259

8. Relationship between severity of RAS and renal blood flow: unilateral ARAS

9. Relationship between severity of stenosis and renin release: unilateral RAS
A meta-analysis of these trials did show an advantage of stent placement in the sense that less antihypertensive medication was required ( 35 Kumbhani 2011). Altogether, the various studies do not support benefit of PTRA with stenting. From a pathophysiological point of view, however, the outcome of restoration of the patency of the renal arteries is not only determined by the direct effects of an improved flow but also and probably to an even larger extent by pre-existing intrarenal pathological changes. If intrarenal parenchymatous changes already occur with lower grades of stenoses, it is conceivable that interventions at an earlier stage when there are less irreversible changes in the kidney may be associated with a greater benefit.
It may thus be possible that with a lower degree of stenosis and at an earlier stage of the disease, i.e. before the intrarenal changes are too far advanced, these processes might still be halted or delayed by restoration of renal artery patency. Although we do not have pilot data, we have experience in about 20 patients with low-grade renal artery stenosis in whom blood pressure became less difficult to control after stent placement.

10. Study summary HYPOTHESIS
Angioplasty with stenting on top of optimal medical treatment is better in terms of blood pressure control and preservation of renal function than medical treatment alone in hypertensive patients with LOW-grade ARAS
STUDY DESIGN
Randomized, controlled, prospective trial in hypertensive patients with ARAS
INTERVENTION
Optimal medical treatment in one group and optimal medical treatment plus angioplasty/stenting in the other group
OUTCOME MEASURES
Blood pressure control and renal function

11. Inclusion criteria
A. proven atherosclerotic renal artery stenosis with a luminal reduction of less than 70% but more than 20%, as shown by MR-angiography
and
B. potentially treatable stenosis in a dominant or accessory renal artery
C. despite adequate treatment resistent hypertension, i.e. blood pressure >140/90 mmHg
D. mild-to-moderate renal insufficiency (estimated GFR between 45 – 90 ml/min/1.73 m2) as estimated by the CKD-EPI formula.

12. Exclusion criteria 1. age <18 jaar or >75 jaar
2. non-atherosclerotic renal artery stenosis
3. cerebrovascular accident or acute coronary syndrome in the past 6 months
4. heart failure, NYHA class III-IV
5. reduced life expectancy due tot comorbidity
6. previous PTRA and/or stent placement for renal artery stenosis
7. affected kidney size <9 cm, corrected for height
8. renal parenchymal disease and proteinuria >2gr/24 uur
9. renal impairment (eGFR]<45 ml/min) and/or rapidly progressing renal insufficiency (eGFR<45 ml/min)

13. Outcome measures
1. Improved blood pressure control (main outcome measure)
which is defined as a reduction in blood pressure with an equal or a reduced Defined Daily Dose (DDD) of antihypertensive medication and is reached when either of the two following situations is achieved:
a. DBP <90 mmHg and/or SBP <140 mmHg, or
b. Reduction in SBP or DBP of ≥10%.
2. Preservation of renal function (secondary outcome measure)

14. Flow scheme
Centra: 10-15; n=312 patients. Utrecht, Nijmegen, AMC, Erasmus, Maastricht

15. Uitspraak Protagoras
“Over elke zaak bestaan er twee opvattingen, die tegenover elkaar staan”