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Renal revascularization in resistant hypertension
Journal Pre-proof Renal revascularization in resistant hypertension
Marloe Prince, Aashish Gupta, Tamunoinemi Bob-Manuel, Jose Tafur PII:
S0033-0620(19)30161-6
DOI:
https://doi.org/10.1016/j.pcad.2019.12.001
Reference:
YPCAD 1028
To appear in:
Progress in Cardiovascular Diseases
Received date:
3 December 2019
Accepted date:
3 December 2019
Please cite this article as: M. Prince, A. Gupta, T. Bob-Manuel, et al., Renal revascularization in resistant hypertension, Progress in Cardiovascular Diseases(2019), https://doi.org/10.1016/j.pcad.2019.12.001
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof
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Renal Revascularization in Resistant Hypertension
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No relationships with industry
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Marloe Prince MD, Aashish Gupta MD, Tamunoinemi Bob-Manuel MD, Jose
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Tafur MD
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Email addresses:
[email protected], [email protected],
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[email protected], [email protected], From the Department of Cardiology at Ochsner Clinic Foundation Corresponding author: Marloe Prince MD. Address: 1514 Jefferson Hwy, New Orleans, LA 70121. Phone: 281-687-0008. Disclosures/Conflict of Interest: None
Journal Pre-proof Keywords: Renal Artery Stenting Renal Artery Stenosis Resistant Hypertension
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Abbreviations:
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ACC: American college of cardiology AHA: American heart association AHRQ: agency for healthcare research and quality ARAS: Atherosclerotic Renal Artery Stenosis AUC: Appropriate Use Criteria BP: Blood Pressure CIN: contrast-induced nephropathy CKD: Chronic Kidney Disease CTA: Computed Tomographic Angiography DSA: Digital subtraction angiography EFD: embolic protection devices FMD: Fibromuscular dysplasia GDMT: guideline directed medical therapy HSG: hyperemic systolic gradient HTN: Hypertension MRA: Magnetic Resonance Angiography PSV: Peak systolic velocity RAAS: renin-angiotensin aldosterone system RAS: renal artery stenosis RCT: Randomized controlled trial RFC: renal frame count RFFR: renal fractional flow reserve RH : resistant hypertension SCAI: Society of Cardiovascular Angiography and Interventions
Journal Pre-proof ABSTRACT Renal artery stenosis (RAS) is a common cause of secondary hypertension ( HTN) and may lead to resistant (refractory) HTN despite guideline directed medical therapy . Although randomized controlled trials comparing medical therapy to medical therapy and renal artery stenting have shown no benefit with renal artery stenting, according to comparative effectiveness reviews by the Agency for Healthcare Research and Quality, the trials did not
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enroll patients with the most severe RAS who would be more likely to benefit from renal
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stenting. Because of limitations of conventional angiography, it is important to assess the
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hemodynamic severity of moderate (50%-70%) RAS lesions with a hemodynamic
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measurement. We review techniques to optimize patient selection, to minimize procedural complications, and to facilitate durable patency of renal stenting. We also review the
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current ACC/AHA Guidelines and SCAI Appropriate Use Criteria as they relate to renal
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Background
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stenting.
Resistant hypertension ( HTN; RH), defined as a systemic blood pressure (BP) that remains above goal despite maximally tolerated doses of three or more BP medications, including a diuretic, is a common issue that many clinicians face. The prevalence of RH is estimated at about 9% of all US adults with HTN and about 13% of all US adults being treated for HTN, although in clinical trials it is estimated to be about 15-30%[1-5]. Among patients with RH, renal artery stenosis (RAS) is the most common secondary cause with an estimated prevalence of about 2-5%[6, 7]. Although prospective clinical trials suggest
Journal Pre-proof percutaneous transluminal renal artery stenting is safe and efficacious [8-10], randomized controlled trials (RCT) have suggested that there is no difference in outcomes with guideline-directed medical therapy (GDMT) and percutaneous transluminal renal artery stenting compared to GDMT alone[11-14]. Even though these RCTs were negative they were plagued with many design flaws (variability in inclusion and exclusion criteria, inconsistent definitions of improvement, mixtures of HTN and renal function endpoints)
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which has made the selection of patients for renal artery stenting a disputable topic as
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acknowledged by the Comparative Effectiveness Review of Management Strategies for
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Renal Artery Stenosis by Agency for Healthcare Research and Quality AHRQ)[15, 16].
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Despite the controversy, identifying which patients are most likely to reap a benefit from
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renal artery stenting and optimizing the safety and durability of the procedure are what we believe to be the best strategy to treat RAS. Since the patients most likely to clinically
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benefit from renal artery revascularization were not well represented in RCTs, our
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discussion will focus on this subset of patients. We additionally review the current
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American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines [17] and Society of Cardiovascular Angiography and Interventions (SCAI) Appropriate Use Criteria (AUC) [18] as they relate to renal artery stenting. Etiologies of RAS The two causes of RAS are atherosclerotic disease and fibromuscular dysplasia. In the adult population RAS is primarily due to atherosclerotic disease (>90%) and fibromuscular dysplasia (FMD) is more common in younger females [19].
Journal Pre-proof Atherosclerotic RAS (ARAS) typically involves the ostium to proximal 1/3 of the main renal artery. The prevalence ARAS varies depending on the population that is assessed. Among patients with HTN, ARAS is the most common (2% -5%) etiology of secondary HTN [6, 7]. In 834 Medicare-age individuals there was a 6.8% prevalence of ARAS >60% determined by renal duplex screening. In a post mortem series of patients > 50 years old, ARAS > 50% was found in 27% of patients, rising to 53% if severe diastolic HTN ( diastolic
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BP> 100 mmHg) was present [20]. About 25% of elderly patients with chronic kidney
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disease (CKD) and 10% -15% of patients entering dialysis treatment will have ARAS [21].
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ARAS is more common in patients who have atherosclerosis involving other vasculature
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with a prevalence of 25% - 30% in patients undergoing angiography for suspected coronary artery disease and 30% - 40% in patients with peripheral arterial disease [22-
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29].
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FMD, which is caused by fibroplasia and not atherosclerosis, is a congenital condition
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that can cause flow limiting lesions affecting carotid arteries, femoral arteries, and visceral
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(renal) arteries [30]. In contrast to ARAS, which involves the proximal renal artery, FMD involves the mid to distal portion of the renal artery and is characterized by a “string of pearls” angiographically. FMD is more commonly seen in females with an estimated prevalence of 2% - 6% [31-34] and is often found incidentally in asymptomatic individuals but can lead to RH, which is treated with balloon angioplasty [35] . Pathophysiology of HTN in RAS Although there is very little data in humans, in patients with hemodynamically significant RAS, the renin-angiotensin aldosterone system (RAAS) is thought to be activated
Journal Pre-proof leading to HTN. In some patients there is background essential HTN compounded with renovascular HTN. Unilateral RAS results in vasoconstrictor mediated HTN, while bilateral or solitary kidney RAS results in HTN with volume overload. Resistant HTN is defined when BP is not at goal despite three or more different classes of maximally tolerated BP medications, including a diuretic [12, 14]. Predicting which patients with RH and ARAS are most likely to respond to renal artery stenting with improved BP has been controversial [8,
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36-38].
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Clinical Clues and Diagnosis
Patients with HTN before the age of 30 or severe HTN after the age of 55,
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accelerated, resistant, malignant HTN, or worsening renal function after administration of
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an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker agent
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should all be clues that warrant work up for RAS [17]. Non-invasive assessment for RAS: For the diagnosis for RAS, renal doppler
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ultrasound (duplex) is a great initial step. A peak systolic velocity (PSV) of > 200 cm/sec
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correlates to a 95% sensitivity and a 90% specificity for > 50% stenosis. A ratio of the renal artery PSV to the aortic PSV of > 3.5 has a 92% sensitivity for > 60% diameter stenosis [18, 39]. The downfall of duplex imaging is that it is dependent on the body habitus of the patient, the presence of bowel gas, and the skill of the sonographer. If ultrasound is unable to accurately determine the hemodynamic severity of RAS, then non-invasive crosssectional imaging with Computed Tomographic Angiography (CTA) or Magnetic Resonance Angiography (MRA) is the best next step.
Journal Pre-proof CTA has been shown to have a sensitivity and specificity of 90%-100% and 97% for measuring a stenosis greater than 50%. MRA has a sensitivity of 92%-97% and a specificity of 73%-93% [39]. CTA and MRA are very useful for the assessment of accessory arteries, branching patterns, and orientation of vessels. Heavily calcified arteries pose a challenge for CTA, so MRA is the preferred modality. The disadvantages of these tests are that CTA requires iodinated contrast with the associated potential risk of contrast-induced
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nephropathy (CIN)[40, 41] and MRA often uses gadolinium-based contrast, which has been
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associated with nephrogenic systemic fibrosis [42] which may be unattractive for patients
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with poor renal function.
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Invasive Lesion Assessment: Digital subtraction angiography (DSA) has often been
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thought of as the golden standard for lesion assessment, however, with this modality it is difficult to determine severity of lesions because stenosis typically occur in tortuous
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arteries. Subtotal stenotic lesions are easy to identify but more frequently there is a mild to
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moderate stenosis, whose hemodynamic severity remains in question. Angiography lesion
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severity has been determined by a consensus of experts to be severe if ARAS is > 70% diameter stenosis and moderately severe if the diameter stenosis is 50%-70%. For severe lesions no further testing is needed but for moderately severe lesions confirmation of hemodynamic severity is recommended prior to intervention[18]. Confirmation of hemodynamic severity can be done by obtaining a resting or hyperemic translesional systolic gradient of ≥ 20 mmHg, a resting or hyperemic mean translesional gradient of ≥ 10 mmHg or a renal fractional flow reserve (RFFR) < 0.8[18]. A non-obstructive catheter or a 0.014-inch pressure wire should be used to obtain translesional pressure gradients to prevent a false reading from a semi-occlusive catheter. Hyperemia may be provoked with
Journal Pre-proof an intrarenal bolus of papaverine at a dose of 40 mg[43] or 50 µg/kg dopamine[36]. It is very important to keep in mind that papaverine will precipitate in heparinized solutions which are used for flush solutions in the catherization laboratory. Conventional angiography has been compared to RFFR and to translesional pressure gradients to determine severity of ARAS stenosis. There was poor correlation between angiographic stenosis and RFFR (r = -0.18; P = 0.54) as well as to the translesional pressure gradient (r =
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0.22; P = 0.44). However, the correlation between RFFR and the resting translesional
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pressure gradient was excellent (r = 0.76; P = 0.0016)[43].
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The limitations to conventional angiography are similar to CTA imaging which
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include radiation exposure and iodinated contrast use, which poses potential decreased
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renal function. In attempt to prevent CIN, adequate hydration prior to the procedure and limiting contrast volume are helpful [44]. CO2 angiography may be a safer option for
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patients who are unable to receive iodinated contrast [45] but one must keep in mind that
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quality [45, 46].
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since CO2 is a negative contrast agent, motion artifact and bowel gas can distort image
Management of RH in RAS
When evaluating a patient with ARAS, it is important to determine whether their symptoms are caused by renal hypoperfusion, or if ARAS is an innocent bystander. ARAS may be found on routine abdominal imaging when evaluating a patient for other problems. However, if ARAS is not causing a clinical problem, there is no role for revascularization. For symptomatic RAS the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, has demonstrated that the initial management of symptomatic RAS is
Journal Pre-proof GDMT[12]. The ACC/AHA Guidelines and SCAI Appropriate Use Criteria have determined who is likely to benefit and who is unlikely to benefit from revascularization. Patients most likely to benefit from revascularization are those with hemodynamically significant RAS and resistant hypertension who fail or are intolerant of GDMT (Class IIa, LOE B) (AUC – Appropriate)[18]. Patients not likely to benefit from revascularization are those with RAS who are asymptomatic and those that have uncontrolled BP but are not on maximally
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tolerated GDMT, including a total of three antihypertensives, one being a diuretic[18].
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Predicting BP improvement: BP improvement following revascularization has been a
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controversial topic, but some small studies have suggested improvement. Translesional
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resting or hyperemic mean gradients with threshold of > 10 mmHg have been used to
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predict BP improvement following renal artery stenting [36]. BP improvement following renal artery stenting has also be noted in patients with a hyperemic systolic gradient (HSG)
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of ≥ 21 mmHg. 84% patients with a HSG ≥ 21 mmHg had significantly improved BP,
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whereas only 36% of the patients with HSG ≤ 21 mmHg had a significant change in BP at 12
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months (P<0.01). Also of note patients with a HSG ≥ 21 were controlled on fewer BP medications after renal artery stenting, 2.30 +/- 0.90 vs. 3.40 +/- 0.50 for patients with a HSG ≤ 21 mmHg (P<0.01) [47]. Renal blush grade and abnormal renal frame count (RFC) have been reported to predict BP improvement after renal artery stenting [48, 49]. A RFFR of < 0.8 has also been associated with improvement in BP after renal artery stenting [37, 38] (Figure 1). In a meta-analysis of 678 patients who underwent renal stenting procedure, success rate was 98%, however, clinical improvement in HTN was only about 70% and improvement in renal function occurred in 30% of patients, with stabilization in 38%[50].
Journal Pre-proof This discordant data suggests that either non-severe ARAS lesions were treated, or their symptom of HTN or CKD was unrelated to the ARAS. (Table 1.) Modern Trials Observational Trials: Several non-randomized clinical trials have been performed to determine the outcomes of renal artery stenting in ARAS. In the ASPIRE-2 (Evaluation of
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the Safety and Effectiveness of Renal Artery Stenting after Unsuccessful Balloon
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Angioplasty) study, in patients with aorto-ostial ARAS and HTN, balloon expandable stents
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were used as revascularization strategy after balloon angioplasty failed to achieve <50% stenosis. There was a significant decrease in systolic and diastolic BPs from 168 +/- 25/82
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+/-13 mmHg to 149 +/- 25/77 +/- 12 mmHg at 24 months; (P< 0.001) [9, 51]. Significant
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BP improvement has also been noted by A Safety and Effectiveness Study of the Herculink
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Elite Renal Stent to Treat Renal Artery Stenosis (HERCULES) Trial in which systolic BP in patients with significant ARAS and uncontrolled HTN (mean 3.4 HTN medications) who
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underwent renal artery stenting. It was noted that BP pre procedure was 162.3 +/-
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18.5/77.7 +/- 11.5 mmHg and decreased to 145.7 +/- 20.7/75.4 +/- 11.0 mmHg over 36 months P< 0.0001) [8].
Randomized trials: Renal artery stenting for ARAS has been evaluated by three recent RCTs. Stent Placement in Patients with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function: A Randomized Trial (STAR) enrolled patients with ARAS with stenoses >50% and a creatinine clearance < 80 mL/min per 1.73m2 and GDMT alone was compared with GDMT and renal artery stenting. Renal artery stenting had no effect on progression of CKD and BP improved in both groups; however, a major limitation of this
Journal Pre-proof study was that 30% of the patients randomized to the revascularization arm had ARAS <50% and were not candidates for revascularization [11]. Perhaps a better protocol would have confirmed severe stenosis prior to randomization. Revascularization was also deemed non-beneficial over medical therapy per The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL), in regard to BP, renal
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function, cardiovascular events, or mortality. The major criticisms include that only 60% of the patients had a >70% ARAS, employing only ultrasound as the modality used to measure
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the severity of stenosis, so that many of the patients in the trial did not have significant
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stenoses and were unlikely to benefit in the first place. Also notable was that the
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revascularization group was on less antihypertensive medications than the medical group
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(2.77 vs. 2.97, p = 0.03) making comparison of the groups difficult. There was also a 9% complication rate in the revascularization group which is much higher than has been
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[13, 14].
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reported in other studies and suggests that many of these operators were inexperienced
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The most recent RCT was the CORAL trial which enrolled patients without RH by including patients with a systolic BP of ≥ 155 mmHg despite taking ≥2 antihypertensive medications so it’s no surprise that GDMT out performed renal revascularization. Since the hemodynamic lesion severity of moderate (50-70% diameter stenosis) lesions was not hemodynamically confirmed it is very likely that patients with non-obstructive ARAS were enrolled in the trial [12]. Additionally, it is important to note that patients in the medical arm group had significant improvement in their BP once started on the trial medications, suggesting that they did not truly have uncontrolled HTN to begin with.
Journal Pre-proof Despite the negative results of the trials, in 2016 a comparative effectiveness analysis concluded that there was low strength of evidence for the relative benefits and harms of percutaneous transluminal renal artery balloon angioplasty and renal artery stenting versus GDMT alone in patients with ARAS[16]. The ASTRAL trial as well as the CORAL trial demonstrated that in patients with moderate ARAS (50%-70% diameter stenosis) and unconfirmed hemodynamic severity of RAS and HTN (not RH), there was no benefit of
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revascularization over GDMT alone. As stated by the AHRQ Comparative Effectiveness
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Statement on Renal Artery Stenting, selection bias may have prevented enrollment of
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patients who would have likely benefited from revascularization, i.e. those with very severe
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stenoses and uncontrolled BP, recurrent sudden onset, “flash” pulmonary edema, or refractory HTN [12, 14, 16]. There was likely equipoise for patients with borderline or
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unclear ARAS allowing their randomization, but there was likely not equipoise for patients
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with the most severe ARAS. In many RCTs this remains a common limitation, which can
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2).
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often times be addressed with a parallel registry, however in this case was not [12]. (Table
Renal Revascularization Technique Renal artery stenting is the preferred technique to treat severe ARAS. Since ARAS is usually due to bulky aorto-ostial plaque, balloon angioplasty alone is frequently ineffective due to the associated recoil, making renal artery stenting the treatment of choice [52]. When performed by experienced operators, the complication rate approaches 2%, with the most common complications related to femoral access (hematoma, pseudoaneurysm, AV fistula) however, atheroembolism, retroperitoneal hematoma, renal artery rupture, aortic and
Journal Pre-proof renal artery dissection, contrast nephropathy, renal infarction and death have also been reported [18, 51]. In order to reduce complications some procedural considerations to consider include radial artery vascular access, embolic protection devices (EPD), catheterin-catheter technique, no-touch technique, stent sizing with IVUS, and hydration before and after angiography.
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Conclusions
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Patients with hemodynamically significant RAS causing refractory RH despite GDMT are
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reasonable candidates for renal artery stenting. Initial screening with duplex ultrasound, CTA, or MRA is recommended. Hemodynamic significance should be confirmed for a
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moderately severe (indeterminate) ARAS stenosis (50%-70%). Optimally sized renal artery
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stenting is the revascularization procedure of choice. Overall this is a safe procedure with
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complication risk of approximately 2% in experienced hands and highly effective treatment for patients that actually need it. Better BP control and better clinical outcomes can be
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obtained by treating hemodynamically significant ARAS. Even though, this hypothesis has
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not been demonstrated in any RCT due to limitations in trial design [15, 16, 53]. Current data suggests that the decision to revascularize should be based on objective evidence of end-organ ischemia and we believe the renal vasculature should be treated no differently.
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Caridi, J.G., S.W. Stavropoulos, and I.F. Hawkins, Jr., CO2 digital subtraction angiography for renal artery angioplasty in high-risk patients. AJR Am J Roentgenol, 1999. 173(6): p. 1551-6. Caridi, J.G. and I.F. Hawkins, Jr., CO2 digital subtraction angiography: potential complications and their prevention. J Vasc Interv Radiol, 1997. 8(3): p. 383-91. Leesar, M.A., et al., Prediction of hypertension improvement after stenting of renal artery stenosis: comparative accuracy of translesional pressure gradients, intravascular ultrasound, and angiography. J Am Coll Cardiol, 2009. 53(25): p. 2363-71. Mahmud, E., et al., Renal frame count and renal blush grade: quantitative measures that predict the success of renal stenting in hypertensive patients with renal artery stenosis. JACC Cardiovasc Interv, 2008. 1(3): p. 286-92. Naghi, J., et al., Renal frame count: a measure of renal flow that predicts success of renal artery stenting in hypertensive patients. Catheter Cardiovasc Interv, 2015. 86(2): p. 304-9. Leertouwer, T.C., et al., Stent placement for renal arterial stenosis: where do we stand? A metaanalysis. Radiology, 2000. 216(1): p. 78-85. Rocha-Singh, K., et al., Evaluation of the safety and effectiveness of renal artery stenting after unsuccessful balloon angioplasty: the ASPIRE-2 study. J Am Coll Cardiol, 2005. 46(5): p. 776-83. Dorros, G., C. Prince, and L. Mathiak, Stenting of a renal artery stenosis achieves better relief of the obstructive lesion than balloon angioplasty. Cathet Cardiovasc Diagn, 1993. 29(3): p. 191-8. Balk, E.M., et al., Renal Artery Stenosis Management Strategies: An Updated Comparative Effectiveness Review. Comparative Effectiveness Review No. 179. (Prepared by the Brown Evidence-based Practice Center under Contract No. 290-2015-00002-I.) AHRQ Publication No. 16EHC026-EF. Rockville, MD: Agency for Healthcare Research and Quality. Renal Artery Stenosis Management Strategies: An Updated Comparative Effectiveness Review, 2016.
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45.
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Chart showing sensitivity and specificity among invasive measurements to determine hemodynamic significance and improvement of blood pressure after stenting(37).
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Table 1. Current Appropriate Use Criteria SCAI and AHA/ACC Recommendations (12,36,40).
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Scenario
Appropriate Use Criteria SCAI
AHA/ACC Recommendations
Cardiac Disturbance Syndromes (Flash Pulmonary Edema,
Appropriate
Class I, LOE B Class IIa, LOE B (unstable angina)
Appropriate
Class IIa, LOE B
unstable angina or acute coronary syndrome (ACS)) with hypertension with moderate RAS with a resting translesional mean gradient of ≥ 10 mm Hg and/or severe RAS CKD IV with bilateral moderate RAS with a resting
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translesional mean gradient of ≥ 10 mm Hg with a kidney size > 7cm in pole-to-pole length.
Appropriate
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CKD IV and global renal ischemia (unilateral severe RAS with a
explanation.
failed maximally tolerated doses of at least three
Appropriate
Class IIa, LOE B
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Resistant Hypertension (uncontrolled hypertension having
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solitary kidney or bilateral severe RAS) without another
Class IIb, LOE B
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antihypertensive agents, one of which a diuretic) and bilateral or solitary severe RAS
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Recurrent CHF with unilateral moderate RAS with a resting
May be appropriate
Class I, LOE B
May be appropriate
Class IIa, LOE B
Rarely appropriate
Class IIb, LOE C
translesional mean gradient of ≥ 10 mm Hg
Resistant Hypertension (uncontrolled hypertension having
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failed maximally tolerated doses of at least three
unilateral severe RAS
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antihypertensive agents, one of which a diuretic) and
Asymptomatic, unilateral, bilateral, or solitary kidney with hemodynamically significant RAS
Table 2.
Summary of recent trials
Trial
STAR
ASTRAL
CORAL
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2009
2014
140
806
947
Impaired renal function (CrCl < 80) Ostial ARAS of 50% or more (CTA, MRA, DSA) Controlled Blood pressure less than 140/90
Renal artery atherosclerotic disease in ≥ 1 renal artery amenable to revascularization Clinician unsure if revascularization would provide clear benefit
Exclusion Criteria
Renal size less than 8 cm Renal artery less than 4 mm CrCl < 15 Diabetes with proteinuria > 3 g/d Malignant hypertension
Primary End Point
Worsening renal function > 20% decrease of CrCl
Disease needing surgical revascularization High likelihood of needing revascularization in 6 months Non- atheromatous disease Prior RAS revascularization Lack of informed consent Slope of the reciprocal of Cr over 5 years
Severe RAS (angiograpically defined as > 80% but < 100%, OR > 60% but < 80% with systolic pressure gradient of > 20 mmHg AND Hypertension with systolic BP ≥ 155 on two or more agents OR CKD defined as GFR < 60 FMD CKD from causes other than ischemic nephropathy Cr > 4 Kidney size < 7cm Lesions that could not be treated with one stent
Limitations
Patients had controlled blood pressure Considerable amount of participants had less than 50% stenoses
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Year Number of Patients Inclusion Criteria
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Rate of complications much higher than reported Lower number of antihypertensives used in intervention group Diagnosis of RAS made with non-invasive imaging without functional studies Patients with kidney size < 6 cm included in study Patients with insignificant lesions included
Time to major renal or cardiovascular event (stroke, heart attack, CHF hospitalization, progressive renal insufficiency, need for dialysis Patients were not optimized on anti-hypertensive therapy Inclusion of patients with mild stenosis Only moderate correlation between angiography and hemodynamically significant stenoses.
Marloe Prince, Aashish Gupta, Tamunoinemi Bob-Manuel, Jose Tafur PII:
S0033-0620(19)30161-6
DOI:
https://doi.org/10.1016/j.pcad.2019.12.001
Reference:
YPCAD 1028
To appear in:
Progress in Cardiovascular Diseases
Received date:
3 December 2019
Accepted date:
3 December 2019
Please cite this article as: M. Prince, A. Gupta, T. Bob-Manuel, et al., Renal revascularization in resistant hypertension, Progress in Cardiovascular Diseases(2019), https://doi.org/10.1016/j.pcad.2019.12.001
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
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Renal Revascularization in Resistant Hypertension
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No relationships with industry
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Marloe Prince MD, Aashish Gupta MD, Tamunoinemi Bob-Manuel MD, Jose
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Tafur MD
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Email addresses:
[email protected], [email protected],
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[email protected], [email protected], From the Department of Cardiology at Ochsner Clinic Foundation Corresponding author: Marloe Prince MD. Address: 1514 Jefferson Hwy, New Orleans, LA 70121. Phone: 281-687-0008. Disclosures/Conflict of Interest: None
Journal Pre-proof Keywords: Renal Artery Stenting Renal Artery Stenosis Resistant Hypertension
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Abbreviations:
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ACC: American college of cardiology AHA: American heart association AHRQ: agency for healthcare research and quality ARAS: Atherosclerotic Renal Artery Stenosis AUC: Appropriate Use Criteria BP: Blood Pressure CIN: contrast-induced nephropathy CKD: Chronic Kidney Disease CTA: Computed Tomographic Angiography DSA: Digital subtraction angiography EFD: embolic protection devices FMD: Fibromuscular dysplasia GDMT: guideline directed medical therapy HSG: hyperemic systolic gradient HTN: Hypertension MRA: Magnetic Resonance Angiography PSV: Peak systolic velocity RAAS: renin-angiotensin aldosterone system RAS: renal artery stenosis RCT: Randomized controlled trial RFC: renal frame count RFFR: renal fractional flow reserve RH : resistant hypertension SCAI: Society of Cardiovascular Angiography and Interventions
Journal Pre-proof ABSTRACT Renal artery stenosis (RAS) is a common cause of secondary hypertension ( HTN) and may lead to resistant (refractory) HTN despite guideline directed medical therapy . Although randomized controlled trials comparing medical therapy to medical therapy and renal artery stenting have shown no benefit with renal artery stenting, according to comparative effectiveness reviews by the Agency for Healthcare Research and Quality, the trials did not
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enroll patients with the most severe RAS who would be more likely to benefit from renal
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stenting. Because of limitations of conventional angiography, it is important to assess the
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hemodynamic severity of moderate (50%-70%) RAS lesions with a hemodynamic
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measurement. We review techniques to optimize patient selection, to minimize procedural complications, and to facilitate durable patency of renal stenting. We also review the
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current ACC/AHA Guidelines and SCAI Appropriate Use Criteria as they relate to renal
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Background
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stenting.
Resistant hypertension ( HTN; RH), defined as a systemic blood pressure (BP) that remains above goal despite maximally tolerated doses of three or more BP medications, including a diuretic, is a common issue that many clinicians face. The prevalence of RH is estimated at about 9% of all US adults with HTN and about 13% of all US adults being treated for HTN, although in clinical trials it is estimated to be about 15-30%[1-5]. Among patients with RH, renal artery stenosis (RAS) is the most common secondary cause with an estimated prevalence of about 2-5%[6, 7]. Although prospective clinical trials suggest
Journal Pre-proof percutaneous transluminal renal artery stenting is safe and efficacious [8-10], randomized controlled trials (RCT) have suggested that there is no difference in outcomes with guideline-directed medical therapy (GDMT) and percutaneous transluminal renal artery stenting compared to GDMT alone[11-14]. Even though these RCTs were negative they were plagued with many design flaws (variability in inclusion and exclusion criteria, inconsistent definitions of improvement, mixtures of HTN and renal function endpoints)
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which has made the selection of patients for renal artery stenting a disputable topic as
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acknowledged by the Comparative Effectiveness Review of Management Strategies for
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Renal Artery Stenosis by Agency for Healthcare Research and Quality AHRQ)[15, 16].
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Despite the controversy, identifying which patients are most likely to reap a benefit from
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renal artery stenting and optimizing the safety and durability of the procedure are what we believe to be the best strategy to treat RAS. Since the patients most likely to clinically
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benefit from renal artery revascularization were not well represented in RCTs, our
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discussion will focus on this subset of patients. We additionally review the current
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American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines [17] and Society of Cardiovascular Angiography and Interventions (SCAI) Appropriate Use Criteria (AUC) [18] as they relate to renal artery stenting. Etiologies of RAS The two causes of RAS are atherosclerotic disease and fibromuscular dysplasia. In the adult population RAS is primarily due to atherosclerotic disease (>90%) and fibromuscular dysplasia (FMD) is more common in younger females [19].
Journal Pre-proof Atherosclerotic RAS (ARAS) typically involves the ostium to proximal 1/3 of the main renal artery. The prevalence ARAS varies depending on the population that is assessed. Among patients with HTN, ARAS is the most common (2% -5%) etiology of secondary HTN [6, 7]. In 834 Medicare-age individuals there was a 6.8% prevalence of ARAS >60% determined by renal duplex screening. In a post mortem series of patients > 50 years old, ARAS > 50% was found in 27% of patients, rising to 53% if severe diastolic HTN ( diastolic
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BP> 100 mmHg) was present [20]. About 25% of elderly patients with chronic kidney
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disease (CKD) and 10% -15% of patients entering dialysis treatment will have ARAS [21].
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ARAS is more common in patients who have atherosclerosis involving other vasculature
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with a prevalence of 25% - 30% in patients undergoing angiography for suspected coronary artery disease and 30% - 40% in patients with peripheral arterial disease [22-
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29].
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FMD, which is caused by fibroplasia and not atherosclerosis, is a congenital condition
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that can cause flow limiting lesions affecting carotid arteries, femoral arteries, and visceral
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(renal) arteries [30]. In contrast to ARAS, which involves the proximal renal artery, FMD involves the mid to distal portion of the renal artery and is characterized by a “string of pearls” angiographically. FMD is more commonly seen in females with an estimated prevalence of 2% - 6% [31-34] and is often found incidentally in asymptomatic individuals but can lead to RH, which is treated with balloon angioplasty [35] . Pathophysiology of HTN in RAS Although there is very little data in humans, in patients with hemodynamically significant RAS, the renin-angiotensin aldosterone system (RAAS) is thought to be activated
Journal Pre-proof leading to HTN. In some patients there is background essential HTN compounded with renovascular HTN. Unilateral RAS results in vasoconstrictor mediated HTN, while bilateral or solitary kidney RAS results in HTN with volume overload. Resistant HTN is defined when BP is not at goal despite three or more different classes of maximally tolerated BP medications, including a diuretic [12, 14]. Predicting which patients with RH and ARAS are most likely to respond to renal artery stenting with improved BP has been controversial [8,
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36-38].
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Clinical Clues and Diagnosis
Patients with HTN before the age of 30 or severe HTN after the age of 55,
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accelerated, resistant, malignant HTN, or worsening renal function after administration of
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an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker agent
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should all be clues that warrant work up for RAS [17]. Non-invasive assessment for RAS: For the diagnosis for RAS, renal doppler
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ultrasound (duplex) is a great initial step. A peak systolic velocity (PSV) of > 200 cm/sec
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correlates to a 95% sensitivity and a 90% specificity for > 50% stenosis. A ratio of the renal artery PSV to the aortic PSV of > 3.5 has a 92% sensitivity for > 60% diameter stenosis [18, 39]. The downfall of duplex imaging is that it is dependent on the body habitus of the patient, the presence of bowel gas, and the skill of the sonographer. If ultrasound is unable to accurately determine the hemodynamic severity of RAS, then non-invasive crosssectional imaging with Computed Tomographic Angiography (CTA) or Magnetic Resonance Angiography (MRA) is the best next step.
Journal Pre-proof CTA has been shown to have a sensitivity and specificity of 90%-100% and 97% for measuring a stenosis greater than 50%. MRA has a sensitivity of 92%-97% and a specificity of 73%-93% [39]. CTA and MRA are very useful for the assessment of accessory arteries, branching patterns, and orientation of vessels. Heavily calcified arteries pose a challenge for CTA, so MRA is the preferred modality. The disadvantages of these tests are that CTA requires iodinated contrast with the associated potential risk of contrast-induced
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nephropathy (CIN)[40, 41] and MRA often uses gadolinium-based contrast, which has been
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associated with nephrogenic systemic fibrosis [42] which may be unattractive for patients
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with poor renal function.
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Invasive Lesion Assessment: Digital subtraction angiography (DSA) has often been
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thought of as the golden standard for lesion assessment, however, with this modality it is difficult to determine severity of lesions because stenosis typically occur in tortuous
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arteries. Subtotal stenotic lesions are easy to identify but more frequently there is a mild to
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moderate stenosis, whose hemodynamic severity remains in question. Angiography lesion
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severity has been determined by a consensus of experts to be severe if ARAS is > 70% diameter stenosis and moderately severe if the diameter stenosis is 50%-70%. For severe lesions no further testing is needed but for moderately severe lesions confirmation of hemodynamic severity is recommended prior to intervention[18]. Confirmation of hemodynamic severity can be done by obtaining a resting or hyperemic translesional systolic gradient of ≥ 20 mmHg, a resting or hyperemic mean translesional gradient of ≥ 10 mmHg or a renal fractional flow reserve (RFFR) < 0.8[18]. A non-obstructive catheter or a 0.014-inch pressure wire should be used to obtain translesional pressure gradients to prevent a false reading from a semi-occlusive catheter. Hyperemia may be provoked with
Journal Pre-proof an intrarenal bolus of papaverine at a dose of 40 mg[43] or 50 µg/kg dopamine[36]. It is very important to keep in mind that papaverine will precipitate in heparinized solutions which are used for flush solutions in the catherization laboratory. Conventional angiography has been compared to RFFR and to translesional pressure gradients to determine severity of ARAS stenosis. There was poor correlation between angiographic stenosis and RFFR (r = -0.18; P = 0.54) as well as to the translesional pressure gradient (r =
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0.22; P = 0.44). However, the correlation between RFFR and the resting translesional
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pressure gradient was excellent (r = 0.76; P = 0.0016)[43].
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The limitations to conventional angiography are similar to CTA imaging which
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include radiation exposure and iodinated contrast use, which poses potential decreased
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renal function. In attempt to prevent CIN, adequate hydration prior to the procedure and limiting contrast volume are helpful [44]. CO2 angiography may be a safer option for
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patients who are unable to receive iodinated contrast [45] but one must keep in mind that
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quality [45, 46].
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since CO2 is a negative contrast agent, motion artifact and bowel gas can distort image
Management of RH in RAS
When evaluating a patient with ARAS, it is important to determine whether their symptoms are caused by renal hypoperfusion, or if ARAS is an innocent bystander. ARAS may be found on routine abdominal imaging when evaluating a patient for other problems. However, if ARAS is not causing a clinical problem, there is no role for revascularization. For symptomatic RAS the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, has demonstrated that the initial management of symptomatic RAS is
Journal Pre-proof GDMT[12]. The ACC/AHA Guidelines and SCAI Appropriate Use Criteria have determined who is likely to benefit and who is unlikely to benefit from revascularization. Patients most likely to benefit from revascularization are those with hemodynamically significant RAS and resistant hypertension who fail or are intolerant of GDMT (Class IIa, LOE B) (AUC – Appropriate)[18]. Patients not likely to benefit from revascularization are those with RAS who are asymptomatic and those that have uncontrolled BP but are not on maximally
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tolerated GDMT, including a total of three antihypertensives, one being a diuretic[18].
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Predicting BP improvement: BP improvement following revascularization has been a
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controversial topic, but some small studies have suggested improvement. Translesional
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resting or hyperemic mean gradients with threshold of > 10 mmHg have been used to
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predict BP improvement following renal artery stenting [36]. BP improvement following renal artery stenting has also be noted in patients with a hyperemic systolic gradient (HSG)
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of ≥ 21 mmHg. 84% patients with a HSG ≥ 21 mmHg had significantly improved BP,
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whereas only 36% of the patients with HSG ≤ 21 mmHg had a significant change in BP at 12
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months (P<0.01). Also of note patients with a HSG ≥ 21 were controlled on fewer BP medications after renal artery stenting, 2.30 +/- 0.90 vs. 3.40 +/- 0.50 for patients with a HSG ≤ 21 mmHg (P<0.01) [47]. Renal blush grade and abnormal renal frame count (RFC) have been reported to predict BP improvement after renal artery stenting [48, 49]. A RFFR of < 0.8 has also been associated with improvement in BP after renal artery stenting [37, 38] (Figure 1). In a meta-analysis of 678 patients who underwent renal stenting procedure, success rate was 98%, however, clinical improvement in HTN was only about 70% and improvement in renal function occurred in 30% of patients, with stabilization in 38%[50].
Journal Pre-proof This discordant data suggests that either non-severe ARAS lesions were treated, or their symptom of HTN or CKD was unrelated to the ARAS. (Table 1.) Modern Trials Observational Trials: Several non-randomized clinical trials have been performed to determine the outcomes of renal artery stenting in ARAS. In the ASPIRE-2 (Evaluation of
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the Safety and Effectiveness of Renal Artery Stenting after Unsuccessful Balloon
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Angioplasty) study, in patients with aorto-ostial ARAS and HTN, balloon expandable stents
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were used as revascularization strategy after balloon angioplasty failed to achieve <50% stenosis. There was a significant decrease in systolic and diastolic BPs from 168 +/- 25/82
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+/-13 mmHg to 149 +/- 25/77 +/- 12 mmHg at 24 months; (P< 0.001) [9, 51]. Significant
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BP improvement has also been noted by A Safety and Effectiveness Study of the Herculink
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Elite Renal Stent to Treat Renal Artery Stenosis (HERCULES) Trial in which systolic BP in patients with significant ARAS and uncontrolled HTN (mean 3.4 HTN medications) who
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underwent renal artery stenting. It was noted that BP pre procedure was 162.3 +/-
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18.5/77.7 +/- 11.5 mmHg and decreased to 145.7 +/- 20.7/75.4 +/- 11.0 mmHg over 36 months P< 0.0001) [8].
Randomized trials: Renal artery stenting for ARAS has been evaluated by three recent RCTs. Stent Placement in Patients with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function: A Randomized Trial (STAR) enrolled patients with ARAS with stenoses >50% and a creatinine clearance < 80 mL/min per 1.73m2 and GDMT alone was compared with GDMT and renal artery stenting. Renal artery stenting had no effect on progression of CKD and BP improved in both groups; however, a major limitation of this
Journal Pre-proof study was that 30% of the patients randomized to the revascularization arm had ARAS <50% and were not candidates for revascularization [11]. Perhaps a better protocol would have confirmed severe stenosis prior to randomization. Revascularization was also deemed non-beneficial over medical therapy per The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL), in regard to BP, renal
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function, cardiovascular events, or mortality. The major criticisms include that only 60% of the patients had a >70% ARAS, employing only ultrasound as the modality used to measure
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the severity of stenosis, so that many of the patients in the trial did not have significant
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stenoses and were unlikely to benefit in the first place. Also notable was that the
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revascularization group was on less antihypertensive medications than the medical group
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(2.77 vs. 2.97, p = 0.03) making comparison of the groups difficult. There was also a 9% complication rate in the revascularization group which is much higher than has been
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[13, 14].
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reported in other studies and suggests that many of these operators were inexperienced
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The most recent RCT was the CORAL trial which enrolled patients without RH by including patients with a systolic BP of ≥ 155 mmHg despite taking ≥2 antihypertensive medications so it’s no surprise that GDMT out performed renal revascularization. Since the hemodynamic lesion severity of moderate (50-70% diameter stenosis) lesions was not hemodynamically confirmed it is very likely that patients with non-obstructive ARAS were enrolled in the trial [12]. Additionally, it is important to note that patients in the medical arm group had significant improvement in their BP once started on the trial medications, suggesting that they did not truly have uncontrolled HTN to begin with.
Journal Pre-proof Despite the negative results of the trials, in 2016 a comparative effectiveness analysis concluded that there was low strength of evidence for the relative benefits and harms of percutaneous transluminal renal artery balloon angioplasty and renal artery stenting versus GDMT alone in patients with ARAS[16]. The ASTRAL trial as well as the CORAL trial demonstrated that in patients with moderate ARAS (50%-70% diameter stenosis) and unconfirmed hemodynamic severity of RAS and HTN (not RH), there was no benefit of
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revascularization over GDMT alone. As stated by the AHRQ Comparative Effectiveness
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Statement on Renal Artery Stenting, selection bias may have prevented enrollment of
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patients who would have likely benefited from revascularization, i.e. those with very severe
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stenoses and uncontrolled BP, recurrent sudden onset, “flash” pulmonary edema, or refractory HTN [12, 14, 16]. There was likely equipoise for patients with borderline or
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unclear ARAS allowing their randomization, but there was likely not equipoise for patients
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with the most severe ARAS. In many RCTs this remains a common limitation, which can
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2).
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often times be addressed with a parallel registry, however in this case was not [12]. (Table
Renal Revascularization Technique Renal artery stenting is the preferred technique to treat severe ARAS. Since ARAS is usually due to bulky aorto-ostial plaque, balloon angioplasty alone is frequently ineffective due to the associated recoil, making renal artery stenting the treatment of choice [52]. When performed by experienced operators, the complication rate approaches 2%, with the most common complications related to femoral access (hematoma, pseudoaneurysm, AV fistula) however, atheroembolism, retroperitoneal hematoma, renal artery rupture, aortic and
Journal Pre-proof renal artery dissection, contrast nephropathy, renal infarction and death have also been reported [18, 51]. In order to reduce complications some procedural considerations to consider include radial artery vascular access, embolic protection devices (EPD), catheterin-catheter technique, no-touch technique, stent sizing with IVUS, and hydration before and after angiography.
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Conclusions
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Patients with hemodynamically significant RAS causing refractory RH despite GDMT are
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reasonable candidates for renal artery stenting. Initial screening with duplex ultrasound, CTA, or MRA is recommended. Hemodynamic significance should be confirmed for a
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moderately severe (indeterminate) ARAS stenosis (50%-70%). Optimally sized renal artery
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stenting is the revascularization procedure of choice. Overall this is a safe procedure with
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complication risk of approximately 2% in experienced hands and highly effective treatment for patients that actually need it. Better BP control and better clinical outcomes can be
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obtained by treating hemodynamically significant ARAS. Even though, this hypothesis has
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not been demonstrated in any RCT due to limitations in trial design [15, 16, 53]. Current data suggests that the decision to revascularize should be based on objective evidence of end-organ ischemia and we believe the renal vasculature should be treated no differently.
1.
2. 3.
4. 5. 6. 7.
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Cushman, W.C., et al., Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich), 2002. 4(6): p. 393-404. de la Sierra, A., et al., Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension, 2011. 57(5): p. 898-902. Gupta, A.K., et al., Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens, 2011. 29(10): p. 2004-13. Jamerson, K., et al., Benazepril plus amlodipine or hydrochlorothiazide for hypertension in highrisk patients. N Engl J Med, 2008. 359(23): p. 2417-28. Persell, S.D., Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension, 2011. 57(6): p. 1076-80. de Mast, Q. and J.J. Beutler, The prevalence of atherosclerotic renal artery stenosis in risk groups: a systematic literature review. J Hypertens, 2009. 27(7): p. 1333-40. Hansen, K.J., et al., Prevalence of renovascular disease in the elderly: a population-based study. J Vasc Surg, 2002. 36(3): p. 443-51.
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19. 20. 21. 22. 23. 24. 25. 26.
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Caridi, J.G., S.W. Stavropoulos, and I.F. Hawkins, Jr., CO2 digital subtraction angiography for renal artery angioplasty in high-risk patients. AJR Am J Roentgenol, 1999. 173(6): p. 1551-6. Caridi, J.G. and I.F. Hawkins, Jr., CO2 digital subtraction angiography: potential complications and their prevention. J Vasc Interv Radiol, 1997. 8(3): p. 383-91. Leesar, M.A., et al., Prediction of hypertension improvement after stenting of renal artery stenosis: comparative accuracy of translesional pressure gradients, intravascular ultrasound, and angiography. J Am Coll Cardiol, 2009. 53(25): p. 2363-71. Mahmud, E., et al., Renal frame count and renal blush grade: quantitative measures that predict the success of renal stenting in hypertensive patients with renal artery stenosis. JACC Cardiovasc Interv, 2008. 1(3): p. 286-92. Naghi, J., et al., Renal frame count: a measure of renal flow that predicts success of renal artery stenting in hypertensive patients. Catheter Cardiovasc Interv, 2015. 86(2): p. 304-9. Leertouwer, T.C., et al., Stent placement for renal arterial stenosis: where do we stand? A metaanalysis. Radiology, 2000. 216(1): p. 78-85. Rocha-Singh, K., et al., Evaluation of the safety and effectiveness of renal artery stenting after unsuccessful balloon angioplasty: the ASPIRE-2 study. J Am Coll Cardiol, 2005. 46(5): p. 776-83. Dorros, G., C. Prince, and L. Mathiak, Stenting of a renal artery stenosis achieves better relief of the obstructive lesion than balloon angioplasty. Cathet Cardiovasc Diagn, 1993. 29(3): p. 191-8. Balk, E.M., et al., Renal Artery Stenosis Management Strategies: An Updated Comparative Effectiveness Review. Comparative Effectiveness Review No. 179. (Prepared by the Brown Evidence-based Practice Center under Contract No. 290-2015-00002-I.) AHRQ Publication No. 16EHC026-EF. Rockville, MD: Agency for Healthcare Research and Quality. Renal Artery Stenosis Management Strategies: An Updated Comparative Effectiveness Review, 2016.
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Chart showing sensitivity and specificity among invasive measurements to determine hemodynamic significance and improvement of blood pressure after stenting(37).
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Table 1. Current Appropriate Use Criteria SCAI and AHA/ACC Recommendations (12,36,40).
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Scenario
Appropriate Use Criteria SCAI
AHA/ACC Recommendations
Cardiac Disturbance Syndromes (Flash Pulmonary Edema,
Appropriate
Class I, LOE B Class IIa, LOE B (unstable angina)
Appropriate
Class IIa, LOE B
unstable angina or acute coronary syndrome (ACS)) with hypertension with moderate RAS with a resting translesional mean gradient of ≥ 10 mm Hg and/or severe RAS CKD IV with bilateral moderate RAS with a resting
of
translesional mean gradient of ≥ 10 mm Hg with a kidney size > 7cm in pole-to-pole length.
Appropriate
ro
CKD IV and global renal ischemia (unilateral severe RAS with a
explanation.
failed maximally tolerated doses of at least three
Appropriate
Class IIa, LOE B
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Resistant Hypertension (uncontrolled hypertension having
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solitary kidney or bilateral severe RAS) without another
Class IIb, LOE B
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antihypertensive agents, one of which a diuretic) and bilateral or solitary severe RAS
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Recurrent CHF with unilateral moderate RAS with a resting
May be appropriate
Class I, LOE B
May be appropriate
Class IIa, LOE B
Rarely appropriate
Class IIb, LOE C
translesional mean gradient of ≥ 10 mm Hg
Resistant Hypertension (uncontrolled hypertension having
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failed maximally tolerated doses of at least three
unilateral severe RAS
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antihypertensive agents, one of which a diuretic) and
Asymptomatic, unilateral, bilateral, or solitary kidney with hemodynamically significant RAS
Table 2.
Summary of recent trials
Trial
STAR
ASTRAL
CORAL
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2009
2014
140
806
947
Impaired renal function (CrCl < 80) Ostial ARAS of 50% or more (CTA, MRA, DSA) Controlled Blood pressure less than 140/90
Renal artery atherosclerotic disease in ≥ 1 renal artery amenable to revascularization Clinician unsure if revascularization would provide clear benefit
Exclusion Criteria
Renal size less than 8 cm Renal artery less than 4 mm CrCl < 15 Diabetes with proteinuria > 3 g/d Malignant hypertension
Primary End Point
Worsening renal function > 20% decrease of CrCl
Disease needing surgical revascularization High likelihood of needing revascularization in 6 months Non- atheromatous disease Prior RAS revascularization Lack of informed consent Slope of the reciprocal of Cr over 5 years
Severe RAS (angiograpically defined as > 80% but < 100%, OR > 60% but < 80% with systolic pressure gradient of > 20 mmHg AND Hypertension with systolic BP ≥ 155 on two or more agents OR CKD defined as GFR < 60 FMD CKD from causes other than ischemic nephropathy Cr > 4 Kidney size < 7cm Lesions that could not be treated with one stent
Limitations
Patients had controlled blood pressure Considerable amount of participants had less than 50% stenoses
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Year Number of Patients Inclusion Criteria
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Rate of complications much higher than reported Lower number of antihypertensives used in intervention group Diagnosis of RAS made with non-invasive imaging without functional studies Patients with kidney size < 6 cm included in study Patients with insignificant lesions included
Time to major renal or cardiovascular event (stroke, heart attack, CHF hospitalization, progressive renal insufficiency, need for dialysis Patients were not optimized on anti-hypertensive therapy Inclusion of patients with mild stenosis Only moderate correlation between angiography and hemodynamically significant stenoses.