Is Renal Artery Stenting Still Relevant? A Cohort Analysis

Is Renal Artery Stenting Still Relevant? A Cohort Analysis Sunil Naik, MD*, Brijesh Patel, DO, Anas Souqiyyeh, MD, Marc Zughaib, David Eastes, MPH, Marcel Zughaib, MD Abstract Atherosclerotic renal artery stenosis (ARAS) is a process that can lead to a decrease in renal perfusion pressure with subsequent activation of the renin-angiotensin-aldosterone system. The potential deleterious effects of renal function, uncontrolled hypertension and elevated levels of angiotensin II serve as the stimulus for pursuing renal artery stenting as a therapeutic option. The results from the previous studies have led to equivocal results and skepticism about this treatment modality. This is a retrospective cohort analysis of patients with uncontrolled blood pressure and severe renal artery lesions that underwent renal artery stenting from 2007-2011 with up to 18 month follow up. Systolic and diastolic blood pressure showed a mean post-stenting reduction of 34 mmhg (p<0.05) and 13 mmhg (p<0.05) respectively. Renal function and the number of antihypertensive agents did not show a statistically significant difference. Appropriate patient and lesion selection with experienced operators can improve blood pressure reduction in patients with significant renovascular hypertension. Keywords Renovascular artery stenosis, Atherosclerotic renal artery stenosis, Renovascular hypertension, Cite this article as: Sunil Naik S, Patel B, Souqiyyeh A, Zughaib M, Eastes D, Zughaib M. Is Renal Artery Stenting Still Relevant? A Cohort Analysis. JCvD 2015;3(2): 320-324. R I. INTRODUCTION enovascular hypertension caused by renal artery stenosis is a disease process with two distinct etiologies. Atherosclerotic renal artery stenosis (ARAS) and fibromuscular dysplasia (FMD) both cause renal artery stenosis and have vastly different treatment modalities. The beaded, aneurysmal appearance of FMD is best treated with balloon angioplasty and medical therapy while the therapeutic options [1, 2] for ARAS remain unresolved. Atherosclerotic disease of the renal arteries can lead to significant stenosis and a decrease in renal perfusion pressure. The subsequent activation of the renin-angiotensin aldosterone Received on 11 February 2014. No conflict of interest declared. From: Providence Hospital, Cardiology Department: Heart institute 16001 West Nine Mile Road. Southfield, Michigan, 48075 USA. *Corresponding Author - E-mail: Sunil.Naik@providence-stjohnhealth.org system (RAAS) and increase in plasma angiotensin II has several deleterious effects. Sodium retention, vasoconstriction, generation of reactive oxygen species, production of aldosterone, sympathetic nerve activity, intrarenal prostaglandin concentration and cardiac/vascular remodeling are among the most common. [3-5] Significant ARAS has three well recognized systemic complications: resistant renovascular hypertension, renal ischemia and flash pulmonary edema. [6] A review of published reports that evaluated progression of atherosclerotic disease to complete occlusion of the renal artery found that the primary determinant was initial stenosis. [7] Thus, multiple therapeutic modalities have been explored to treat this condition including medical therapy, surgical revascularization and percutaneous intervention. In this study, our goal was to examine whether renal artery intervention in appropriately selected patients and performed by experienced operators is a viable and clinically useful strategy for the treatment of renovascular hypertension. Patients with uncontrolled blood pressure on two or more agents with significant renal artery stenosis of 70%, in whom secondary causes of hypertension had been ruled out, were targeted in this study. We performed a retrospective evaluation of 65 patients who underwent renal artery intervention. Blood pressure, number of antihypertensive agents and renal function were studied at particular time intervals. The study population is from a tertiary care, moderate sized hospital with a busy endovascular program between 2007 and 2011. II. METHODS Study Design: This study is a retrospective, single center, cohort analysis performed at Providence Hospital in Southfield, Michigan, USA. It was funded by the research department at our institution and approved by the institutional review board at Providence Hospital. Members of the writing committee take responsibility of the accuracy, interpretation and completeness of the data and integrity of this manuscript. Patients were searched in the Horizon Cardiology reporting system at Providence Hospital from 2007 to 2011. The query was performed using the words renal + visceral + PTA in order to encompass all possible renal artery interventions. All charts and angiographic data were analyzed individually to determine inclusion in the study. The predetermined exclusion criteria included stenoses < 70%, angioplasty alone, end stage renal disease on hemodialysis, inadequate baseline blood pressure recordings and visceral interventions not involving the renal 320

arteries. The severity of renal stenosis was evaluated angiographically by an operator, but reviewed before including the patient in the study by an interventional cardiologist and cardiology fellow. The baseline demographics and characteristics were collected and adjusted to rule out any confounding variables. Blood pressure, renal function, medications and comorbid conditions were collected at baseline and follow-up intervals of discharge, 0-6 months and 6-18 months. These were obtained from the Providence Hospital electronic medical record as well as records from two separate outpatient clinics where many of these patients followed up. The goal of this study was to determine the effectiveness of renal artery stenting in appropriately selected patients with severe uncontrolled hypertension on multiple medications. These patients all had significant ARAS of one or both renal arteries. This unique cohort was followed to show the true effectiveness of this seemingly controversial intervention. Statistical Analysis: The statistical tests performed were the paired t-test and the Wilson-cox sign test. Data was analyzed using the following methods for matched pairs presenting data with normal distribution. The paired t-test was used to test the likelihood Table 1: Baseline patient characteristics Baseline Characteristics Treated lesions (N) Treated Patients (n) Mean Age Race Caucasians African Americans Asian Unknown Sex Value 70 65 73 68% 22% 2% 8% Female 65% Male 35% No. of Medications* 2.8 Past medical history DM 37% CVA 8% PAD 52% CAD 78% Smokers 46% Renal Artery Stenosis 70-79% 25% 80-89% 51% >90% 22% Stenosis Side Right 40% Left 58% Creatinine Levelψ 1.3 mg/dl BP (mm Hg) Systolic Diastolic 172 ±7 83 ±4 DM=Diabetes, CVA=Cerebrovascular accident, PAD=Peripheral artery disease, CAD=Coronary artery disease. *The number of medications before the procedure was performed and averaged across 53 lesions where data was available. Past medical history relevant to hypertension risk and reported as percentage of the whole patients used. Percentage stenosis of the artery was divided into three categories 70-79, 80-89, and >90%. Side of stenosis. ψ Serum creatinine levels averaged from all patients used. that the mean values were statistically different from one another. For data sets where the distribution of points presented as non-normal, the Wilson-cox sign test was used with a 95% confidence interval and a power of 80%. Necessary sample size was calculated using a power of 80% and confidence of 95%. All calculations were conducted using STATA 12.1 [8]. Endpoints: The primary endpoints for this study included change in mean systolic and diastolic blood pressure at predetermined intervals. Blood pressure was recorded prior to the procedure, at discharge, 0-6 months and 6-18 months. Variable follow up times in this retrospective study required the use of intervals for analysis. Secondary endpoints included the number of antihypertensive medications and renal function. These data points were evaluated prior to the procedure and at the time intervals assigned above. The operators were allowed to adjust medications at their discretion. Treatment complications and serious adverse events were also reported in the results. III. RESULTS During this study of 70 lesions and 65 patients, 3 patients died of non-procedure related causes. They were analyzed with data and follow up information available prior to their death. The average age of the cohort was 73 years. Nearly 60% of all patients were female, and 62% were Caucasian. Baseline characteristics are detailed in Table 1 and indicated that 37% were diabetics, 8% had a history of cerebrovascular accident, 78% had coronary artery disease, 52% had peripheral artery disease, and 46% were smokers. On average, they were taking 2.80 anti-hypertensive medications of any class at baseline. The majority of lesions were 80-89% stenosed (~ 51%). The left and right renal artery involvement was 58% and 42%, respectively. The average systolic and diastolic blood pressures (n=65) at baseline were 172 mmhg (CI 95%, 164 to 179), and 83 mmhg (CI 95%, 78 to 87) (Table 2). We defined follow-up periods as discharge, (0 to 6 months), and (6 to 18 months). There were missing data on 18% (12 patients), 28% (18 patients) and 26% (17 patients) for each follow up period, respectively. Rather than comparing them to the cohort s average, we compared the patients mean SBP and DBP using paired t-test or Wilson-cox to their baseline pressure for each follow up interval so the cohorts served as their own control. 321

Table 2: Post-intervention follow up trends Post intervention data Severity of Renal Artery Follow up Trend data: mean BP (mm Hg), medications and creatinine Pre-procedure At Discharge 0-6 mo. 6-18 mo. SBP from the baseline (mm Hg) 172 ±7 142 ±5* 143 ±6* 138 ±6* 70-79% 164 ±14 136 ±7* 142 ±14* 138 ±11* 80-89% 170 ±10 144 ±8* 142 ±9* 137 ±8* >90% 183 ±12 144 ±9* 147 ±11* 147 ±9* DBP from the baseline (mm Hg) 83 ±4 70 ±3* 71 ±3* 70 ±4* 70-79% 77 ±9 66 ±7* 72 ±6* 74 ±8* 80-89% 85 ±6 71 ±5* 70 ±5* 68 ±4* >90% 84 ±6 71 ±4* 71 ±8* 73 ±12* Number of Medications 2.8 (n=55) 3.10 (n=53) 2.88 (n=34) 2.88 (n=33) Creatinine 1.30 (±0.14) 1.18 (±0.13)* 1.3 (±0.28) 1.2 (± 0.24) Complications 0 0 0 *All averages were statistically significant from the pre-procedure Blood pressure calculated at confidence intervals of 95% corresponding to p value of 0.05. Data were analyzed for the patients at each time interval and significant statistical differences were noted for each. At discharge, a total of 56 lesions were analyzed. The blood pressure measurements were SBP of 142 mmhg (CI 95%, 137 to 147 mmhg; p<0.05) and DBP of 70 mmhg (CI 95%, 67 to 73, p<0.05). Similarly, a total of 45 and 48 lesions were analyzed for (0 to 6 month), and (6 to 18 month) intervals, respectively. The mean SBP and DBP during the 0 to 6 month period were 143 mmhg (CI 95%, 137 to 146 mmhg; p<0.05) and 71 mmhg (CI 95%, 68 to 74; p<0.05). The (6 to 18 month) interval had mean SBP and DBP of 138 mmhg (CI 95%, 132 to 144 mmhg; p<0.05) and 70 mmhg (CI 95%, 66 to 74 mmhg; p<0.05). All reductions in blood pressure throughout the follow up intervals were statistically significant after the intervention (figure 1-2). The severity of stenosis marked by percentage and ranged from (70%-79%), (80%-89%) and (>90%) had a similar reduction trend post procedure for both systolic and diastolic blood pressure per time interval (Figure 3-4). The number of antihypertensive agents was also evaluated. At baseline a mean of 2.8 agents were used. This changed from 2.8 to 3.1, 2.88 and 2.88 at the aforementioned follow up intervals (table 2). This trend showed no difference in the mean number of antihypertensives in this cohort throughout the study. Similarly, renal function was measured using mean creatinine for each follow up interval period. Data showed a baseline mean creatinine value of 1.3. Subsequent levels were 1.18, 1.3 and 1.2 respectively for each follow up endpoint (Table 3). The p value for the 6-18 month time point was 0.24, but strong statistical conclusions are difficult to draw secondary to a small number of appropriate lab follow up. However, a trend from the available data suggested that there was no significant difference in renal function from pre-procedure to 6-18 months of follow-up. When we analyzed patients with co-morbid conditions, we found that the patients who did not have diabetes, coronary artery disease and/or peripheral artery disease have greater reduction in SBP from the baseline compared to the patients with these co-morbidities. These findings were based on trends in the data, but statistical analysis was not feasible secondary to small numbers for subgroup study (Table 3). IV. DISCUSSION Conclusive statements on the treatment of ARAS are lacking. Surgical revascularization has been performed in the past with improvement in renal function and blood pressure; however, this was associated with high procedural morbidity and mortality. The mortality associated with all renal reconstruction and renal bypasses was 5.5% and 5.2% respectively in a 1999 Table 3: Subgroup analysis post renal artery intervention. Follow-up BP post procedure per-time interval group analysis (mm Hg) Pre-procedure BP (mm Hg) (± MR) At Discharge 0-6 mo. 6-18 mo. Risk factor Total n* SBP DBP SBP DBP SBP DBP SBP DBP DM Present 24 173 ±9 80 ±6 145 ±8 67 ±10 154 ±35 70 ±16 142 ±27 68 ±14 Absent 41 172 ±7 86 ±5 140 ±17 72 ±8 136 ±27 72 ±13 136 ±22 72 ±11 CAD Present 51 170 ±13 83 ±7 142 ±8 70 ±4 144 ±10 72 ±5 139 ±9 70 ±5 Absent 14 185 ±13 83 ±10 143 ±10 71 ±16 138 ±23 68 ±17 136 ±16 76 ±16 PAD Present 34 166 ±13 82 ±7 141 ±8 69 ±4 143 ±9 71 ±4 137 ±11 69 ±6 Absent 31 181 ±16 86 ±9 144 ±6 72 ±6 145 ±14 72 ±8 141 ±11 72 ±7 Smoking Present 30 169 ±20 82 ±11 143 ±8 71 ±6 139 ±9 71 ±5 134 ±7 66 ±5 Absent 35 177 ±8 85 ±6 143 ±6 69 ±4 150 ±10 72 ±6) 144 ±11 75 ±7 CVA Present 5 185 ±29 87 ±10 162 ±13 71 ±11 147 ±20 84 ±15 136 ±27 73 ±17 Absent 60 171 ±13 83 ±7 141 ±9 70 ±5 143 ±10 70 ±5 139 ±11 70 ±6 DM=Diabetes, CVA=Cerebrovascular accident, PAD=Peripheral artery disease, CAD=Coronary artery disease, MR=Margin of Error. Figure 4: Diastolic blood pressure trend for all patients treated, for *Total (n) refers to 65 patients used. patient with 70-79%, 80-89%, and >90% initial stenosis at baseline and at discharge up to 18 months follow up. Calculated at p<0.05. 322

crossover rates, low patient numbers, intervention on [3, 4, 10] non-critical lesions and balloon angioplasty alone. These short-comings have resulted in skepticism in the medical community regarding this treatment modality. We feel that these circumstances have led to reluctance in adopting percutaneous stenting of the renal arteries as a viable and effective treatment modality for uncontrolled hypertension in this patient population. Figure 1: A comparison of baseline systolic blood pressure at baseline to three post procedure intervals (At discharge, by 6 months and by 18 months) calculated at p<0.05. The intent of this study was to evaluate the effect of renal artery stenting on a select cohort of patients with significant stenosis 70% and uncontrolled hypertension on at least two antihypertensive medications. The primary endpoint of mean blood pressure showed a statistically significant reduction at all 3 follow up time intervals up to 18 months. This illustrates the efficacy of renal artery stenting as well as its durability. The marked reduction in systolic blood pressure at discharge, 0-6 months and 6-18 months time intervals was 30, 25 and 29mmHg respectively (figure 1). This level of blood pressure reduction is not matched by any currently available single agent Figure 2: A comparison of baseline Diastolic blood pressure at baseline to three post procedure intervals (AT Discharge, by 6 months and by 18 months) calculated at p<0.05. article reviewing 600 operations. [9] Three of the major trials evaluating medical therapy and percutaneous intervention are DRASTIC, STAR, and ASTRAL. [3, 4, 10] Unfortunately, these studies remained inconclusive because of small sample size, treatment of hemodynamically insignificant stenoses, and high crossover rates. In the DRASTIC trial and a number of other studies in the early 1990 s, it was consistently noted that angioplasty alone had a high rate of procedural failures, complications, and restenosis. Subsequently, ASTRAL utilized PTA and stenting to improve these outcomes, but high crossover rates and treatment of insignificant stenoses led to equivocal results. [10] In a recently published trial, CORAL, demonstrated that systolic blood pressure was modestly decreased in stent group vs. medical therapy group and lasted throughout the follow-up period, though it showed that there was no benefit in preventing clinical event. [11] This trend was observed in our study. The treatment of renovascular hypertension and atherosclerotic renal artery stenosis with percutaneous interventions has been controversial, despite a reasonable patho-physiologic justification for it. Negative trials in the past have been inconclusive because of the high Figure 3: Systolic blood pressure trend for all patients treated, for patient with 70-79%, 80-89%, and >90% initial stenosis at baseline and at discharge up to 18 months follow up. Calculated at p<0.05. drug therapy. The results of our study are consistent with a recently published positive study, the HERCULES trial. [12] In the latter study, appropriately selected patients with significant stenosis 60% and uncontrolled blood pressure were included. A reduction of 17mmHg was noted out to 9 months of follow up. This well designed positive study reiterates the importance of patient selection as a primary determinant of therapeutic effectiveness of renal artery stenting. [12] Statistical evaluation of the secondary endpoint of renal function was compromised due to a lack of data in this retrospective cohort analysis and varying practice patterns of the physicians. However, the absolute mean creatinine at each interval showed no statistically significant change in renal function from the analysis that was performed. Despite improving renal perfusion, the overall kidney function did not improve. This may be due to distal embolization during the procedure and progressive renal parenchymal disease in 323

patients with multiple comorbidities. The benefit of distal embolic protection devices has been studied in a small trial. [13] A retrospective study showed no difference in GFR but a consistent reduction in blood pressure. [14] Conversely, another study showed improvement in GFR at 6 weeks post intervention. [13] These inconsistencies have reduced the use of distal embolic protection in renal artery interventions as a standard practice. Difficulty in placing these devices and having a sufficient landing zone are also some of the obstacles faced when using embolic protection devices. These devices were not used in any of our patients in the study. The number of antihypertensive agents was also analyzed and showed no reduction throughout the study period despite improvement in blood pressure control. One explanation may be that despite the substantial improvement in blood pressure, the subjects were not always at goal. Thus, providers may not have been inclined to reduce medical therapy despite better control. Finally, during subgroup analysis it was found that a greater reduction in blood pressure was noted in patients without coronary artery disease (CAD) than those with it. The number of patients in our study without CAD was only nine, thus a statistical analysis was not feasible but a trend was noted. We think that it could indicate the primary etiology of hypertension in patients without CAD is truly renal hypoperfusion and activation of the RAAS. Endovascular treatment of the lesion led to dramatic results in this situation. V. CONCLUSIONS Renal artery stenting is a viable option in the treatment of uncontrolled renovascular hypertension in appropriately selected patients with truly significant lesions. The marked and long-term improvement in hypertension seen in our study is consistent with other positive renal stenting trials performed. [12, 15] There is no clear evidence of improved renal function or a reduction in the number of antihypertensive agents with this intervention. The results of this study suggest that further investigation with large randomized controlled trials is needed to help determine the efficacy of percutaneous intervention for appropriately selected patients with renovascular atherosclerosis. These studies should compare current evidence-based optimal medical therapy to intervention performed on the appropriate patient cohort by experienced operators. The major limitation of this study was the retrospective cohort design. This design resulted in a non-standardized approach to medical therapy during the study period and inconsistencies in follow up. Evaluation of renal function and medication titration was left up to the operators making complete data collection difficult. 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