Clinical efficacy of percutaneous renal revascularization with stent placement in hypertension among patients with atherosclerotic renovascular diseases.

AIM: The aim was to assess the effect of renal angioplasty with stent on systolic, diastolic, and mean arterial blood pressure (MAP) in awake and sleep time with ambulatory blood pressure (ABP) monitoring (Holter monitoring).
MATERIALS AND METHODS: Patients with angiographically proven atherosclerotic renal artery stenosis (RAS) were referred to the Angiography Department of Imam Hospital for intervention during a 1-year period from June 2008 to December 2009. Primary stent placement was attempted by a single operator in 27 severe RAS cases although 1 case was omitted from the study because of technical failure. Pre- and postprocedure creatinine levels, ejection fraction (EF), history of diabetes mellitus (DM), and ABP were obtained. Twenty-six (17 men, 9 women; average age, 62.6 years; age range, 90-21 years) consecutive patients participated in the study.
RESULTS: All patients had severe hypertension resistant to multiple medications; 10 patients had impaired renal function (serum creatinine level greater than 130 µmol/L). A total of 3 (11.5%) patients had congestive heart failure, and 10 (37.7%) were diabetic. Hypertension was cured in 1 (4%) patient, had improved in 23 (88.4%) patients, and had failed to respond to treatment in 2 (7.6%). Serum creatinine decreased significantly from 1.46 ± 0.89 to 1.35 ± 0.61 mg/dL (P<0.05).
CONCLUSION: Percutaneous transluminal angioplasty for atheromatous RAS rarely cures hypertension, but improved blood pressure control is often achieved.

INTRODUCTION

Renal artery stenosis (RAS), mostly caused by atherosclerosis, can causeboth renovascular hypertension and renal insufficiency.[12] . Treatmentof RAS by surgery or balloon angioplasty aims at avoiding lifelong antihypertensive treatment and progressive renal ischemia.[1-3] The frequency of documented RAS varies from 0.5% to >20%, according to age[4] and the thoroughness of investigation,[5-7] and will probably increase with the increasing population ageand the widespread use of noninvasive screening tests.[13-8] Attempts at revascularization will also increase because angioplasty reported to be as effective as surgery[9] allows treatmentof older and more fragile patients. The efficacy and safety ofangioplasty in hypertension among these patients should be objectively evaluated.[9] With the exceptionof a randomized trial reported in an abstract form,[10] only information based on retrospective analyses is available.[2101213] We compared the 1-month blood pressure (BP) outcome and the incidence of complications afterdiagnostic angiography plus angioplasty (angioplasty group)in patients with hypertension and unilateral atherosclerotic RAS. The number of antihypertensive agents required to obtain targetBP was determined, and the BP outcome was documented with the useof 24-h ambulatory BP monitoring (ABPM), an observer-independent assessmentthat improves the repeatability of BP measurement.[14]

MATERIALS AND METHODS

Patients were referred to the participating centers for hypertensionand unilateral atherosclerotic RAS documented with intravenoussubtraction angiography or a previous arteriography. Eligiblepatients were men and women younger than 90 years of age, with diastolic blood pressure (DBP) readings >90 mmHg on at least three occasions and/orreceiving antihypertensive treatment; patients with a history of stroke, pulmonary edema, or myocardialinfarction in the previous 6 months were not included. Anatomicinclusion criteria were determined from the qualifying angiographyimmediately before randomization. They comprised(1) the atherosclerotic nature of the RAS, as inferred fromrenal artery and aortic views; (2) a reduction in arterial diameterof either 70% without thrombosis; (3) a stenosis affecting themain renal artery, which had not been previously dilated; and(4) a functional kidney on the opposite side exhibiting a normalmain artery or an arterial diameter reduction of <50%. Patients gave written informed consent before the qualifyingangiography.

Clinical evaluation

The creatinine clearance was estimated from the serum creatinine (sCR) concentration with the Cockcroftformula[15] and ABP was monitored over the 24 h before hospitalization. Patients were hospitalized for qualifying catheter angiography. Before randomization and at termination, 24-hABP was measured with SpaceLabs 5300 or 90207 (SpaceLabs, Inc.) orColin ABPM 630 (Colin Medical Instruments) monitoring devices programmedto record BP every 15 min during the day and every 30 minduring the night. The same monitor was used on the same arm ofeach patient before randomization and at termination. SittingBP was also measured with a mercury sphygmomanometer duringeach visit to compare DBP readings with oscillometric and ambulatory determinations.

Technique

The femoral approach was used in all cases less than 1 month after selective angiography. The standard technique involved the placement of a 7-F introducer sheath into the femoral artery and negotiation of the stenosis by using a wire, and stents (EXPRESS (Boston Scientific Co), HERCULING (Abbot Vascular Co), and HIPPOCAMPUS (Invatec Co)) were positioned coaxially through a 7-F guiding catheter (RDC), with its tip in the renal ostium. Then 10–15 mL of the contrast material (Iopramide [150 mg of iodine per milliliter] was injected into the guiding catheter by using a side-arm adaptor to obtain fine adjustment of the stent position before deployment. In ostial lesions, stents were deliberately deployed so that they projected 1 mm into the aortic lumen. The optimal final stent diameter was determined by measuring the caliber of a normal segment of the same renal artery. Stenosis was not routinely predilated. The immediate technical result was evaluated with angiography. Technical success was defined as a residual stenosis of less than 10%. All patients received 5000 units of heparin that was administered intra-arterially during the procedure, and antiplatelet therapy (aspirin, 325 mg daily, and plavix, 450 mg loading and 75 mg daily for 2 months). No patients formally received anticoagulation therapy following this procedure. Intra-arterial angiographic follow-up was not performed routinely in this high-risk patient group. Clinical follow-up for 6–12 months was used to guide management. If patients showed clinical evidence of relapse following the initial favorable outcome, angiography was performed. Age, gender, pre- and postprocedure creatinine levels and ejection fraction, systolic and diastolic blood pressure recording, and history of DM were recorded. All patients were examined once within 3 weeks of the procedure. In most patients, blood pressure and sCr values were also available for as many as 3 months prior to the procedure. Renal impairment was classified as improved if the sCr level decreased by 10% or more and stable if it was within 10% of the preprocedure level. Renal impairment with an increase of more than 10% was classified as a failure. Hypertension was classified as cured if all antihypertension medication was stopped and diastolic blood pressure returned to less than 90 mmHg. Criteria for improvement were either diastolic blood pressure less than 90 mmHg without the increased medication dose or between 90 and 110 mmHg with a decrease greater than 15 mmHg and no increase in the medication dose. All other possibilities constituted a failure. Complications were evaluated by reviewing the renal angiography reports for immediate procedural complications and the case notes for delayed procedure-related and clinical complications.

Data analysis

We intended to enroll 27 patients. This sample size would have allowed85% power to detect a 10 mmHg difference in diastolic ABP attermination between the two groups, with a type I error of 5%. SPSS software was usedfor statistical analysis. Proportions were compared by the Proc Freq procedure and quantitative variables by theProc T-test procedure.

RESULTS

Patients

Twenty-seven (18 men, 9 women; average age, 62.6 years; age range, 90–21 years) consecutive patients with angiographically proven atherosclerotic RAS were referred to the Angiography Department of Imam Hospital for renal arterial stenting treatment during a 1-year period from June 2008 to December 2009.

All patients had a history of severe hypertension with poor response to drug therapy; 10 (37.7%) patients had an impaired renal function (sCr level greater than 130 µmol/L or 1.4 mg/dL), 3 (11.5%) had congestive heart failure, and 10 (37.7%) were diabetic. Primary stent placement was attempted by a single operator (there is one peripheral interventionalist in our center) in 27 severe RAS cases [Table 1].

Table 1

Baseline clinical characteristics in patients before renal angioplasty

Technical results

Technical success (primary patency) was achieved in 26 (96.2%) patients. Reasons for technical failure were failure to cross the stenosis with a guide wire in one patient.

Clinical outcome

One case was omitted from the study because of technical failure. Hypertension was cured in one (3.8%) patient, had improved in 23 (88.4%) patients, and had failed to respond to treatment in 2 (7.8%) immediately after stenting clinically. Mean arterial systolic and diastolic blood pressures measured with Holter monitoring that recorded awake time, sleep time, and overall blood pressure for all patients who underwent stent placement for their hypertension (including no responders) are shown in Table 2. All blood pressure parameters (systolic/diastolic/mean, for overall, awake time, and sleep time) decreased significantly immediately after the intervention. After intervention in the female group, there was no significant difference for the decrease in mean/diastolic pressure especially in awake and sleep time (P > 0.05). In 46.1% of the patients, the mean arterial blood pressure control was improved after mean follow-up; it remained unchanged in 43% and deteriorated in 11% patients. Patients with diabetes also had improved blood pressure control [Table 3].

Table 2

Holter monitoring of overall, awake, and sleep systolic blood pressure, diastolic blood pressure, and mean arterial pressure, before and after stenting in patients with renal artery stenosis

Table 3

Holter monitoring of systolic, diastolic, and mean arterial pressure before and after renal artery stenting in patients with and without diabetes

Renal impairment

Serum creatinine decreased significantly from 1.46 ± 0.89 to 1.35 ± 0.61 mg/dL (P<0.05). Renal impairment improved in 12 (46.1%) patients (>10% decrease in the Cr concentration from baseline), stabilized in 12 (46.1%; 0–9% change in the Cr concentration), and failed to respond to treatment in 2 (7.8%; 10% increase in the Cr concentration). However, some important subgroup changes were noted.

Four (11%) patients had a deterioration of the renal function during 3 months after stenting, leading to chronic renal failure without leading to dialysis. Subgroup analysis in the improved renal function showed no significant change in sCr in patients with a normal renal function at baseline, but there was a significant (P < 0.05) decrease in sCr in patients with moderate and severe renal dysfunction, respectively [Table 4]. The more severe the renal dysfunction at baseline, the more the patients benefited from the intervention: improved mean sCr concentrations were seen in 43.6% of patients with a normal renal function, 44.6% of patients with moderate impairment, and 100% of those with a severely impaired renal function. Patients without diabetes mellitus had higher sCr concentrations at baseline compared with patients with diabetes mellitus (1.58 ± 1.08 mg/dL versus 1.25 ± 0.3 mg/dL; P < 0.05). The decrease in sCr was significant in the subgroup of patients without diabetes mellitus (1.58 ± 1.08 to 1.41 ± 0.7 mg/dL; P < 0.05), whereas the sCr decrease was not significant in diabetic patients (1.25 ± 0.32 to 1.23 ± 0.38 mg/dL; P > 0.05).

Table 4

Mean range of serum creatinine improvement before and after renal artery stenting

Patients with severe nephrosclerosis and diabetes mellitus needed the greatest number of antihypertensive drugs and had the highest blood pressure levels at baseline. Procedure-related complications occurred in 2 (7.7%) of the 26 cases. The major complications included one femoral artery false aneurysm that was successfully treated with compression, and one patient had acute renal failure.

DISCUSSION

In patients with hypertension and RAS, renal artery angioplastyshould ideally provide a cure for hypertension, that is, normal BP without treatment. Angioplasty allows hypertension cure in 50% of patients with fibromuscular RAS, and complications arenot frequent in this group. However, the cure rate is lowerand the incidence of complications higher among patients withatherosclerotic RAS.[1316] Atherosclerotic patients more frequentlysuffer from technical failures or subsequent restenosis than thosewith fibromuscular RAS.[1317] They frequently have preexistingprimary hypertension, structural changes in large arteries,or an impaired renal function that limit the efficacy and safetyof angioplasty.[2371316] Retrospective series report thatthe usual BP outcome after angioplasty for atherosclerotic RASis improvement, that is, a reduction in BP levels and/or inthe required number of antihypertensive agents.[213] There are no uniform criteria for assessing the improvement, however, and it may be spontaneous or a consequence of alterations in the drugchoice and dosage.[3913] There is therefore a need for more trials to assess risks and benefits associated withangioplasty in atherosclerotic RAS. The "Scottish and Newcastle Renal Artery Stenosis Collaborative Group" reported in an abstract form a trial of angioplastyversus medical therapy in patients with bilateral or unilateralatherosclerotic RAS.[10] In the bilateral RAS group (n = 28), thedrop in systolic BP was significantly greater after angioplastythan after medical therapy, but diastolic BP and creatininelevels did not differ between the two groups after 24 months. In the unilateral RAS group (n = 27), there was no significantdifference in BP levels after angioplasty or medical therapy. The main outcome variable used was OBP, and no detail was providedconcerning treatment standardization.

In our study on percutaneous stent-supported angioplasty of severe atherosclerotic RAS, we observed the stabilization of the renal function and substantial improvement in the blood pressure control at a mean follow-up of 1 month. The observed 11% deterioration of the renal function during follow-up is comparable to previous reports.[18-39] However, in contrast to Dorros et al.’sstudy,[242531] which found a deteriorated renal function in 47% of patients with a baseline sCr concentration of >2 mg/dL, and like Zeller et al.,[26] we saw a higher proportion of patients with improved or unchanged sCr among those with the worst renal function at baseline.

The 11% rate of the deteriorated blood pressure control during follow-up was remarkably low, which may be explained by the blood pressure acquisition method in this study. Blood pressure data were exclusively obtained using ambulatory 24-h blood pressure recordings. In our opinion, this type of blood pressure data is more reliable compared to the incidental blood pressure measurements used in all other published studies.[40-47]

We found an improved renal function that was similar to that reported by van de Ven et al.,[2228] Iannone et al.,[25] Dorros et al.,[242531] and Zeller et al.[39] The US Multicenter Registry[25] demonstrated a significant decrease in the sCr concentration in an unselected study population comparable to ours (1.7 ± 1.1 to 1.3 ± 0.8 mg/dL after 4 years), which is similar to our data.

The present trial was targeted toward patients with unilateralRAS because such cases are more frequent and revascularizationis easier, safer, and more likely to result in a favorable BPoutcome than in cases with bilateral RAS or RAS affecting asolitary kidney.[21] Patients with fibromuscular RAS were notincluded because good evidence is already available that thebenefits of angioplasty outweigh the risks in such patients.[13] It is difficult to differentiate patients with primary hypertensionassociated with RAS from those having hypertension secondaryto RAS, that is, renovascular hypertension.[13] To increase the likelihood of our patients having renovascular hypertension,they were selected on the basis of high-grade stenosis (renalartery diameter reduction 75%) or a stenosis of 60% plus a positive lateralizingtest. Patients had been screened for RAS on the basis of poorefficacy and/or tolerance of previous antihypertensive regimenand referred to the participating centers because a unilateral atheroscleroticRAS was present. Although those with refractory hypertensionwere not included for safety reasons, patients in this trialare representative of the population of cases with unilateralatherosclerotic RAS in whom renal revascularization may be considered.[13] In real life, the early use of a combination of diuretics andangiotensin-converting enzyme inhibitors might have resultedin adequate BP in a larger number of patients. To avoid the biases, poor repeatability,and lack of precision associated with Office Blood Pressure(OBP) determination, therapeuticdecisions were based on the average of three measurements, usinga semiautomatic device, and the outcome was assessed by 24-hABP monitoring. Mean ABP levels, including sleep time BP readings,were lower than mean OBP levels, as expected. The differencebetween ABP and OBP levels was 150/70 mmHg (systolic/diastolic)at randomization in our patients, a difference comparable tothat reported at the first visit (120/90 mmHg) in the 50 hypertensivepatients analyzed by Bottini et al.[14] The mean ABP levels inthe two groups were similar at termination, although the dropin diastolic OBP levels was higher in the control group than inthe angioplasty group. These results emphasize the need foran outcome assessment made independent of investigators whenblinding is not possible.

Although mean ABP levels were very similar in both groups at termination,angioplasty allowed an easier BP control than medication alone. Treatment scores were higher in the control group than in the angioplastygroup, antihypertensive agents being required at terminationfor all control patients but not for 6 of the 23 allocated toangioplasty (26%). Moreover, 7 of 25 (28%) patients in the controlgroup developed refractory hypertension leading to secondary angioplastywithin 6 months. The high BP levels and treatment scores thatthese seven patients exhibited immediately before secondary angioplastywere included in the analysis. Guidelines for early interruptionwere established at the design stage of the study and statedthat patients should be withdrawn for safety reasons if hypertensionwere refractory or there were intolerable drug-induced sideeffects. These guidelines necessitated an on-treatment analysis,with seven patients in the control group having a follow-up of <6 months. We did not perform an intention-to-treat analysis at6 months because this would have overestimated the drop in BPin the control group, the BP effects of angioplasty being addedto those of medication in the seven patients developing refractory hypertensionand switching to angioplasty. It is possible that their 6-monthABP levels and treatment score would have been even higher if earlytermination had not been allowed, raising the possibility that theBP difference between control and angioplasty groups was underestimatedbecause of safety dispositions. The BP effects of the randomizedtherapeutic regimen, medication, and angioplasty were only comparedin the short term, the experimental period lasting for 6 monthsor less. However, mean OBP levels and the proportion of patients givenantihypertensive treatment were similar 1 year after randomizationin the control and angioplasty groups, confirming that the BP-loweringeffect of angioplasty in the short and medium terms is limitedin atherosclerotic RAS. Although the patients were selected on the basisof high-grade stenosis (>75%) and/or a positive lateralizingtest, only a minority of them had true renovascularhypertension, that is, a form of hypertension fully reversibleafter revascularization.[13] In addition to frequently associatedprimary hypertension and an impaired renal function, individualswith atherosclerotic RAS lose the ability, with increasing age,to reverse the structural vascular changes associated with secondaryhypertension.[45] This underlines the need for the early detectionof RAS to allow angioplasty in patients with a short durationof hypertension.[3423]

The complication rate in our group of patients undergoing angioplasty was substantial (6 of 23, or 26%) and higher than that in many retrospectiveseries.[1316] Clinicians involved in the present trial might haveused a low threshold to define the presence of a complication. However, they probably applied the same criteria to patientsin both treatment groups, and angioplasty was more frequentlyassociated with complications than diagnostic angiography alone. It is also possible that complication rates have been underestimatedin some series because they were not documented prospectivelyin a standardized clinical report form. In the largest retrospectiveseries of angioplasty for atherosclerotic RAS, mechanical complicationsand acute renal failure (generally reversible) occurred in 26%and 14% of procedures, respectively.[21] In a prospective randomizedtrial comparing angioplasty with surgery in atheroscleroticRAS,[9] there were major and minor complications in 5 and 11of the 29 patients in the angioplasty group (17% and 48%), respectively. In the present trial, most immediate complications were mildand transient.

CONCLUSION

In summary, previous uncontrolled and unblinded assessmentsof angioplasty overestimated its potential for lowering BP [Table 5]. Using a prospective, randomized, open, blinded outcome (PROBE)design, we found that angioplasty made the BP control easier inthe short term but was more frequently associated with complicationsthan conservative management in patients with unilateral atheroscleroticRAS. Most patients undergoing angioplasty still needed antihypertensiveagents 6 or 12 months after the procedure. The reduction intreatment required by patients undergoing angioplasty shouldtherefore be weighed against the risks of complications andrestenosis. Previously reported data and this evidence suggestthat patients with RAS and little or no renal insufficiencyshould be offered angioplasty if the underlying disease is fibromusculardysplasia,[13] in cases with recurrent pulmonary edema,[47] andin those with refractory hypertension. Patients with atheroscleroticRAS also have or develop atherosclerotic plaques or stenosison extrarenal arteries. In such patients with a stable renal functionand controllable hypertension, the effects of angioplasty onthelong-term cardiovascular outcome should be compared with thoseof conservative treatment by using antihypertensive and lipid-lowering agents. Until such a comparison becomes available, the immediate risks andthe potential long-term benefits of angioplasty should be weighed foreach individual patient, possibly by including patient preference.

Table 5

Summary