EDITORIAL
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
Renal Angioplasty for Atherosclerotic Renal Artery Stenosis Revisited – Efficacy and Safety of Renal Artery Stenting in the J-RAS Study – Masashi Mukoyama, MD, PhD; Yushi Nakayama, MD, PhD; Masataka Adachi, MD, PhD
R
enal artery stenosis (RAS) leads to renovascular hypertension, a major cause of secondary hypertension, and occurs in approximately 1% of all hypertensive patients in Japan.1 Atherosclerotic RAS (ARAS) is the primary cause in middle-aged and elderly patients, contrasting with fibromuscular dysplasia in younger patients, and usually involves the ostium and proximal one-third of 1 or both renal arteries.2 ARAS is often complicated by other vascular diseases such as peripheral and coronary artery diseases.1 Although many of the patients have normal renal function, hemodynamically significant unilateral or bilateral RAS causes progressive renal failure known as ischemic nephropathy, which may account for 10% of the underlying diseases of endstage renal failure.1,3 In type 2 diabetic patients with suspected severe arteriosclerosis, who represent a major subset of patients with ‘high-risk’ clinical presentations, the presence of ARAS is a significant and independent risk factor for cardiovascular-renal events.4
who were not enrolled in any of the RCTs. In this issue of the Journal, Fujihara et al11 report on clinical outcomes of renal artery stenting in 149 ARAS patients with hypertension and/or renal impairment, revealing a significant BP reduction and stabilization of renal function. Although this is a single-arm study, the results show promise that PTRA may be more beneficial than considered according to the results Table 1. Indications for Percutaneous Transluminal Renal Angioplasty ACCF/AHA Guidelines Class I 1. Hemodynamically significant RAS with unexplained recurrent CHF or sudden pulmonary edema 2. Stent placement for ostial atherosclerotic RAS, and balloon angioplasty (with stent) for FMD Class IIa
Article p 351
1. Hemodynamically significant RAS with accelerated/resistant/malignant hypertension
There are 2 major treatment strategies for ARAS: antihypertensive drug therapy and vascular reconstruction. Medical treatment often requires combination therapy, with a Class I recommendation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers and β-blockers.5 The usefulness of vascular reconstruction using percutaneous transluminal renal angioplasty (PTRA) coupled with medication has long been debated. Two recent, large-scale randomized controlled trials (RCTs), STAR6 and ASTRAL,7 failed to show any further benefit of PTRA in improving renal function as compared with optimal medical therapy. Most recently, the CORAL study also reported negative results of renal revascularization in ‘hard’ endpoints, but with a slight improvement of blood pressure (BP) with stenting.8 These findings may suggest limited benefit and relatively higher risk of stenting for patients with moderate ARAS. In the ACCF/ AHA Practice Guidelines for Management of Patients with Peripheral Artery Disease (revised in 2013),9,10 and also in the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014),1 the indications for PTRA are somehow confined to specific populations of ‘high-risk’ groups, such as those with rapidly declining renal function and/or flash pulmonary edema (Table 1), the types of patients
2. Hemodynamically significant RAS with unstable angina 3. RAS and progressive CKD with bilateral lesion or with a solitary functioning kidney Class IIb 1. Hemodynamically significant RAS with asymptomatic bilateral or a solitary viable kidney 2. Unilateral RAS with chronic renal insufficiency JSH2014 Guidelines 1. Hemodynamically significant RAS and 1) Resistant hypertension to medical therapy alone 2) Exacerbating hypertension 3) Malignant hypertension 4) Hypertension with idiopathic unilateral kidney atrophy 5) Idiopathic pulmonary edema that suddenly develops 6) Repeated heart failure 7) Unstable angina 8) FMD 2. Bilateral RAS 3. Progressive CKD with RAS of a solitary functioning kidney CHF, congestive heart failure; CKD, chronic kidney disease; FMD, fibromuscular dysplasia; RAS, renal artery stenosis. (Modified from references 1 and 10.)
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society. Received December 14, 2014; accepted December 14, 2014; released online December 27, 2014 Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan Mailing address: Masashi Mukoyama, MD, PhD, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-14-1361 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, February 2015
296
MUKOYAMA M et al.
Table 2. Comparison of the Clinical Features of Patients in the Major Clinical Trials for Renal Artery Stenting Study
STAR
ASTRAL
CORAL
J-RAS
2009
2009
2014
2015
64
403
459
149
66.5
70.5
69.3
72.7
Year Patients enrolled (n) Age (years) Male (%)
67.2
63.0
51.0
82.6
Diabetes (%)
25.0
31.3
32.4
40.9
Dyslipidemia (%)
NA
NA
89.4
65.1
Heart failure (%)
9.0
NA
12.0
16.1
43.0
49.6
26.5 (MI)
57.1
SBP (mmHg) (baseline/follow-up)
160/151
148.8/141.2
149.9/133.3
154.2/137.0
DBP (mmHg) (baseline/follow-up)
83/77
76.3/73.0
NA
74.7/73.6
1.74/1.76
2.03/2.37
NA
1.24
45/50 (eCcr)
NA
58.0
40.7/40.8
Coronary artery disease (%)
SCr (mg/dl) (baseline/follow-up) eGFR (ml · min−1 · 1.73 m−2) (baseline/follow-up) CKD (%)
NA
59.6
49.6
79.2
Diameter stenosis (%) (baseline/follow-up)
NA
76.0/NA
72.5/NA
78.7/10.2
Renal function
Renal function
Clinical endpoints
Blood pressure, Renal function
Primary outcome Duration of follow-up (months) No. of antihypertensive drugs (baseline/follow-up)
24
60
43 (median)
12
2.8/2.6
2.79/2.77
2.1/3.3
2.2/2.1 56
NA
NA
NA
Nonfatal myocardial infarction (n)
Responders (%)
3
36
40
0
Mortality (n)
5
103
63
6
10
57
93
7
Chronic heart failure (n)
Renal event (n)
1
47
39
3
Stroke (n)
0
24
16
3
CKD, chronic kidney disease; DBP, diastolic blood pressure; eCcr, estimated creatinine clearance; eGFR, estimated glomerular filtration rate; NA, not available; SBP, systolic blood pressure; SCr, serum creatinine. (Modified from references 6, 7, 8 and 11.)
from the RCTs. The baseline clinical data in the present study were somewhat worse than in the 3 recent RCTs, but the outcomes seemed somewhat better (Table 2). It should be again noted that these clinical trials may not reflect real clinical practice because of their inclusion and exclusion criteria. Elective percutaneous coronary intervention (PCI), for example, is now routine clinical practice, but most clinical studies failed to prove a clear benefit of PCI for ‘hard’ endpoints over optimal medical therapy.12 Most recently, a meta-analysis of revascularization therapy for ARAS, including the aforementioned RCTs, has shown better BP control and less antihypertensive drug use for stenting.13 In conclusion, we should keep in mind that when truly needed, revascularization to restore renal blood flow remains a valuable and essential therapy for high-risk patients with moderate to severe ARAS.14
6.
7. 8. 9.
10.
11.
References 1. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014). Chapter 13: Secondary hypertension. Hypertens Res 2014; 37: 349 – 361. 2. Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001; 344: 431 – 442. 3. Preston RA, Epstein M. Ischemic renal disease: An emerging cause of chronic renal failure and end-stage renal disease. J Hypertens 1997; 15: 1365 – 1377. 4. Ogawa S, Nako K, Okamura M, Senda M, Sakamoto T, Abe T, et al. A decline in glomerular filtration rate rather than renal arterial stenotic lesions, per se, predicts cardiovascular-renal events in type 2 diabetic patients. Circ J 2013; 77: 2816 – 2822. 5. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 Practice Guidelines for the management
12.
13.
14.
of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 2006; 113: e463 – e654, doi:10.1161/CIRCULATIONAHA.106.174526. Bax L, Woittiez AJ, Kouwenberg HJ, Mali WP, Buskens E, Beek FJ, et al. Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: A randomized trial. Ann Intern Med 2009; 150: 840 – 848, W150 – W151. The ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 2009; 361: 1953 – 1962. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, et al. Stenting and medical therapy for atherosclerotic renalartery stenosis. N Engl J Med 2014; 370: 13 – 22. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss L, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline recommendations). J Am Coll Cardiol 2013; 61: 1555 – 1570. Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline recommendations). Circulation 2013; 127: 1425 – 1443. Fujihara M, Yokoi Y, Abe T, Soga Y, Yamashita T, Miyashita Y, et al; on behalf of the J-RAS Study Investigators. Clinical outcomes of renal artery stenting for hypertension and chronic kidney disease up to 12 months in the J-RAS study: Prospective, single-arm, multicenter clinical study. Circ J 2015; 79: 351 – 359. JCS Joint Working Group. Guidelines for elective percutaneous coronary intervention in patients with stable coronary artery disease (JCS 2011) published in 2012: Digest version. Circ J 2013; 77: 1590 – 1607. Caielli P, Frigo AC, Pengo MF, Rossitto G, Maiolino G, Seccia TM, et al. Treatment of atherosclerotic renovascular hypertension: Review of observational studies and meta-analysis of randomized clinical trials. Nephrol Dial Transplant 2014 April 16, doi:10.1093/ ndt/gfu072. Textor SC. Renovascular hypertension 2014: What have we learned from CORAL? J Hum Hypertens 2014 June 26, doi:10.1038/ jhh.2014.51.
Circulation Journal Vol.79, February 2015
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
Renal Angioplasty for Atherosclerotic Renal Artery Stenosis Revisited – Efficacy and Safety of Renal Artery Stenting in the J-RAS Study – Masashi Mukoyama, MD, PhD; Yushi Nakayama, MD, PhD; Masataka Adachi, MD, PhD
R
enal artery stenosis (RAS) leads to renovascular hypertension, a major cause of secondary hypertension, and occurs in approximately 1% of all hypertensive patients in Japan.1 Atherosclerotic RAS (ARAS) is the primary cause in middle-aged and elderly patients, contrasting with fibromuscular dysplasia in younger patients, and usually involves the ostium and proximal one-third of 1 or both renal arteries.2 ARAS is often complicated by other vascular diseases such as peripheral and coronary artery diseases.1 Although many of the patients have normal renal function, hemodynamically significant unilateral or bilateral RAS causes progressive renal failure known as ischemic nephropathy, which may account for 10% of the underlying diseases of endstage renal failure.1,3 In type 2 diabetic patients with suspected severe arteriosclerosis, who represent a major subset of patients with ‘high-risk’ clinical presentations, the presence of ARAS is a significant and independent risk factor for cardiovascular-renal events.4
who were not enrolled in any of the RCTs. In this issue of the Journal, Fujihara et al11 report on clinical outcomes of renal artery stenting in 149 ARAS patients with hypertension and/or renal impairment, revealing a significant BP reduction and stabilization of renal function. Although this is a single-arm study, the results show promise that PTRA may be more beneficial than considered according to the results Table 1. Indications for Percutaneous Transluminal Renal Angioplasty ACCF/AHA Guidelines Class I 1. Hemodynamically significant RAS with unexplained recurrent CHF or sudden pulmonary edema 2. Stent placement for ostial atherosclerotic RAS, and balloon angioplasty (with stent) for FMD Class IIa
Article p 351
1. Hemodynamically significant RAS with accelerated/resistant/malignant hypertension
There are 2 major treatment strategies for ARAS: antihypertensive drug therapy and vascular reconstruction. Medical treatment often requires combination therapy, with a Class I recommendation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers and β-blockers.5 The usefulness of vascular reconstruction using percutaneous transluminal renal angioplasty (PTRA) coupled with medication has long been debated. Two recent, large-scale randomized controlled trials (RCTs), STAR6 and ASTRAL,7 failed to show any further benefit of PTRA in improving renal function as compared with optimal medical therapy. Most recently, the CORAL study also reported negative results of renal revascularization in ‘hard’ endpoints, but with a slight improvement of blood pressure (BP) with stenting.8 These findings may suggest limited benefit and relatively higher risk of stenting for patients with moderate ARAS. In the ACCF/ AHA Practice Guidelines for Management of Patients with Peripheral Artery Disease (revised in 2013),9,10 and also in the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014),1 the indications for PTRA are somehow confined to specific populations of ‘high-risk’ groups, such as those with rapidly declining renal function and/or flash pulmonary edema (Table 1), the types of patients
2. Hemodynamically significant RAS with unstable angina 3. RAS and progressive CKD with bilateral lesion or with a solitary functioning kidney Class IIb 1. Hemodynamically significant RAS with asymptomatic bilateral or a solitary viable kidney 2. Unilateral RAS with chronic renal insufficiency JSH2014 Guidelines 1. Hemodynamically significant RAS and 1) Resistant hypertension to medical therapy alone 2) Exacerbating hypertension 3) Malignant hypertension 4) Hypertension with idiopathic unilateral kidney atrophy 5) Idiopathic pulmonary edema that suddenly develops 6) Repeated heart failure 7) Unstable angina 8) FMD 2. Bilateral RAS 3. Progressive CKD with RAS of a solitary functioning kidney CHF, congestive heart failure; CKD, chronic kidney disease; FMD, fibromuscular dysplasia; RAS, renal artery stenosis. (Modified from references 1 and 10.)
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society. Received December 14, 2014; accepted December 14, 2014; released online December 27, 2014 Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan Mailing address: Masashi Mukoyama, MD, PhD, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-14-1361 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, February 2015
296
MUKOYAMA M et al.
Table 2. Comparison of the Clinical Features of Patients in the Major Clinical Trials for Renal Artery Stenting Study
STAR
ASTRAL
CORAL
J-RAS
2009
2009
2014
2015
64
403
459
149
66.5
70.5
69.3
72.7
Year Patients enrolled (n) Age (years) Male (%)
67.2
63.0
51.0
82.6
Diabetes (%)
25.0
31.3
32.4
40.9
Dyslipidemia (%)
NA
NA
89.4
65.1
Heart failure (%)
9.0
NA
12.0
16.1
43.0
49.6
26.5 (MI)
57.1
SBP (mmHg) (baseline/follow-up)
160/151
148.8/141.2
149.9/133.3
154.2/137.0
DBP (mmHg) (baseline/follow-up)
83/77
76.3/73.0
NA
74.7/73.6
1.74/1.76
2.03/2.37
NA
1.24
45/50 (eCcr)
NA
58.0
40.7/40.8
Coronary artery disease (%)
SCr (mg/dl) (baseline/follow-up) eGFR (ml · min−1 · 1.73 m−2) (baseline/follow-up) CKD (%)
NA
59.6
49.6
79.2
Diameter stenosis (%) (baseline/follow-up)
NA
76.0/NA
72.5/NA
78.7/10.2
Renal function
Renal function
Clinical endpoints
Blood pressure, Renal function
Primary outcome Duration of follow-up (months) No. of antihypertensive drugs (baseline/follow-up)
24
60
43 (median)
12
2.8/2.6
2.79/2.77
2.1/3.3
2.2/2.1 56
NA
NA
NA
Nonfatal myocardial infarction (n)
Responders (%)
3
36
40
0
Mortality (n)
5
103
63
6
10
57
93
7
Chronic heart failure (n)
Renal event (n)
1
47
39
3
Stroke (n)
0
24
16
3
CKD, chronic kidney disease; DBP, diastolic blood pressure; eCcr, estimated creatinine clearance; eGFR, estimated glomerular filtration rate; NA, not available; SBP, systolic blood pressure; SCr, serum creatinine. (Modified from references 6, 7, 8 and 11.)
from the RCTs. The baseline clinical data in the present study were somewhat worse than in the 3 recent RCTs, but the outcomes seemed somewhat better (Table 2). It should be again noted that these clinical trials may not reflect real clinical practice because of their inclusion and exclusion criteria. Elective percutaneous coronary intervention (PCI), for example, is now routine clinical practice, but most clinical studies failed to prove a clear benefit of PCI for ‘hard’ endpoints over optimal medical therapy.12 Most recently, a meta-analysis of revascularization therapy for ARAS, including the aforementioned RCTs, has shown better BP control and less antihypertensive drug use for stenting.13 In conclusion, we should keep in mind that when truly needed, revascularization to restore renal blood flow remains a valuable and essential therapy for high-risk patients with moderate to severe ARAS.14
6.
7. 8. 9.
10.
11.
References 1. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014). Chapter 13: Secondary hypertension. Hypertens Res 2014; 37: 349 – 361. 2. Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 2001; 344: 431 – 442. 3. Preston RA, Epstein M. Ischemic renal disease: An emerging cause of chronic renal failure and end-stage renal disease. J Hypertens 1997; 15: 1365 – 1377. 4. Ogawa S, Nako K, Okamura M, Senda M, Sakamoto T, Abe T, et al. A decline in glomerular filtration rate rather than renal arterial stenotic lesions, per se, predicts cardiovascular-renal events in type 2 diabetic patients. Circ J 2013; 77: 2816 – 2822. 5. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 Practice Guidelines for the management
12.
13.
14.
of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 2006; 113: e463 – e654, doi:10.1161/CIRCULATIONAHA.106.174526. Bax L, Woittiez AJ, Kouwenberg HJ, Mali WP, Buskens E, Beek FJ, et al. Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: A randomized trial. Ann Intern Med 2009; 150: 840 – 848, W150 – W151. The ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 2009; 361: 1953 – 1962. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, et al. Stenting and medical therapy for atherosclerotic renalartery stenosis. N Engl J Med 2014; 370: 13 – 22. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss L, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline recommendations). J Am Coll Cardiol 2013; 61: 1555 – 1570. Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline recommendations). Circulation 2013; 127: 1425 – 1443. Fujihara M, Yokoi Y, Abe T, Soga Y, Yamashita T, Miyashita Y, et al; on behalf of the J-RAS Study Investigators. Clinical outcomes of renal artery stenting for hypertension and chronic kidney disease up to 12 months in the J-RAS study: Prospective, single-arm, multicenter clinical study. Circ J 2015; 79: 351 – 359. JCS Joint Working Group. Guidelines for elective percutaneous coronary intervention in patients with stable coronary artery disease (JCS 2011) published in 2012: Digest version. Circ J 2013; 77: 1590 – 1607. Caielli P, Frigo AC, Pengo MF, Rossitto G, Maiolino G, Seccia TM, et al. Treatment of atherosclerotic renovascular hypertension: Review of observational studies and meta-analysis of randomized clinical trials. Nephrol Dial Transplant 2014 April 16, doi:10.1093/ ndt/gfu072. Textor SC. Renovascular hypertension 2014: What have we learned from CORAL? J Hum Hypertens 2014 June 26, doi:10.1038/ jhh.2014.51.
Circulation Journal Vol.79, February 2015
