Christopher J. Cooper

Embolic Protection and Platelet Inhibition During Renal Artery Stenting

Background— Preservation of renal function is an important objective of renal artery stent procedures. Although atheroembolization can cause renal dysfunction during renal stent procedures, whether adjunctive use of embolic protection devices or glycoprotein IIb/IIIa inhibitors improves renal function is unknown. Methods and Results— One hundred patients undergoing renal artery stenting at 7 centers were randomly assigned to an open-label embolic protection device, Angioguard, or double-blind use of a platelet glycoprotein IIb/IIIa inhibitor, abciximab, in a 2×2 factorial design. The main effects of treatments and their interaction were assessed on percentage change in Modification in Diet in Renal Disease–derived glomerular filtration rate from baseline to 1 month using centrally analyzed creatinine. Filter devices were analyzed for the presence of platelet-rich thrombus. With stenting alone, stenting and embolic protection, and stenting with abciximab alone, glomerular filtration rate declined (P<0.05), but with combination therapy, it did not decline and was superior to the other allocations in the 2×2 design (P<0.01). The main effects of treatment demonstrated no overall improvement in glomerular filtration rate; although abciximab was superior to placebo (0±27% versus −10±20%; P<0.05), embolic protection was not (−1±28% versus −10±20%; P=0.08). An interaction was observed between abciximab and embolic protection (P<0.05), favoring combination treatment. Abciximab reduced the occurrence of platelet-rich emboli in the filters from 42% to 7% (P<0.01). Conclusions— Renal artery stenting alone, stenting with embolic protection, and stenting with abciximab were associated with a decline in glomerular filtration rate. An unanticipated interaction between Angioguard and abciximab was seen, with combination therapy better than no treatment or either treatment alone.

Renal artery angioplasty and stent placement: Predictors of a favorable outcome ☆ ☆☆

BACKGROUND Renal artery stenosis is a common disorder and is an established cause of hypertension and renal insufficiency. Although treatment with renal artery stents has been shown to improve blood pressure and renal function for some patients, the patient population most likely to benefit is unknown. The current study was designed to determine which factors are predictive of improved blood pressure and renal function when patients with renal artery stenosis are treated with renal artery angioplasty and stent placement. METHODS In a prospective evaluation 127 consecutively enrolled patients with renal artery stenosis in 171 vessels were treated with angioplasty and intravascular stents. Blood pressure and serum creatinine concentration were measured before stent placement and during the follow-up period. RESULTS The mean length of the follow-up period was 15 +/- 14 months. Mean systolic blood pressure improved among patients with hypertension (from 177 +/- 26 mm Hg before stent placement to 151 +/- 24 mm Hg 6 months after stent placement (P <.001). The greatest improvement occurred among those with the highest baseline systolic blood pressure. This beneficial effect on blood pressure was sustained for 3 years. Sex, age, diastolic blood pressure, number of vessels into which stents were placed, serum creatinine concentration, presence of bilateral disease, race, and severity of stenosis were not predictive of improved blood pressure. Mean creatinine concentration was not significantly changed for the group as a whole. A significant decrease in serum creatinine concentration occurred among 43% of patients with baseline renal insufficiency. None of the examined variables was predictive of improvement. CONCLUSIONS Renal artery angioplasty and stent placement produced a significantly greater reduction in systolic blood pressure among patients with the highest baseline systolic blood pressure. Other examined variables were not predictive of a significant improvement in blood pressure. No examined variable was predictive of improved renal function. We concluded that management of renal artery stenosis with renal artery angioplasty and stent placement is most likely to result in significant improvement in systolic blood pressure among patients with the highest baseline systolic blood pressure.

Renal-Artery Stenosis

A 73-year-old former smoker with a history of hypertension and dyslipidemia presents to the emergency department with shortness of breath. His blood pressure is 160/75 mm Hg, heart rate 60 beats per minute, and respiratory rate 24 breaths per minute. Chest auscultation reveals diffuse rales, and there is 1+ pitting edema. The serum creatinine level is 1.4 mg per deciliter (124 µmol per liter) (estimated glomerular filtration rate, 52 ml per minute), and urinalysis shows 1+ protein. His condition improves after treatment with intravenous diuretics, but his systolic blood pressure remains elevated, at 170 mm Hg. Magnetic resonance angiography (MRA) reveals a diseased aorta, a high-grade ostial lesion of the left renal artery that is consistent with atherosclerotic stenosis, and a normal right renal artery. How should he be further evaluated and treated?

Guidelines for the Reporting of Renal Artery Revascularization in Clinical Trials

Although the treatment of atherosclerotic renal artery stenosis with use of percutaneous angioplasty, stent placement, and surgical revascularization has gained widespread use, there exist few prospective randomized controlled trials (RCTs) comparing these techniques to each other or against the standard of medical management alone. To facilitate this process as well as help answer many important questions regarding the appropriate application of renal revascularization, well-designed and rigorously conducted trials are needed. These trials must have clearly defined goals and must be sufficiently sized and performed so as to withstand intensive outcomes assessment. Toward this end, this document provides guidelines and definitions for the design, conduct, evaluation, and reporting of renal artery revascularization RCTs. In addition, areas of critically necessary renal artery revascularization investigation are identified. It is hoped that this information will be valuable to the investigator wishing to conduct research in this important area.

The influence of basal nitric oxide activity on pulmonary vascular resistance in patients with congestive heart failure

Increased pulmonary resistance may reduce survival and treatment options in patients with congestive heart failure. Nitric oxide (NO) is a determinant of normal pulmonary resistance vessel tone. We tested the hypothesis that loss of NO function contributes to increased pulmonary vascular resistance index (PVRI) in congestive heart failure. Pulmonary arterial resistance vessel function was studied in 25 conscious adults. Three groups were studied: 8 controls, 9 patients with congestive heart failure and normal PVRI, and 8 patients with congestive heart failure and raised PVRI. Segmental arterial flow was determined with a Doppler wire and quantitative angiography. NG-monomethyl-L-arginine (L-NMMA) was used to inhibit NO, whereas phenylephrine was used as an endothelium-independent control. The response to inhibition of NO with L-NMMA was less in patients with congestive heart failure and elevated PVRI than in patients with congestive heart failure and normal PVRI (p <0.05). The difference in response between the congestive heart failure groups was specific to NO-dependent regulation because the response to the endothelium-independent constrictor phenylephrine was not different (p = 0.92). There was no difference in response to L-NMMA between controls and patients with congestive heart failure and normal PVRI. The response to L-NMMA correlated to PVRI. In adults with congestive heart failure, NO appears to play an important role in maintaining normal pulmonary resistance.

Spironolactone Attenuates Experimental Uremic Cardiomyopathy by Antagonizing Marinobufagenin

Spironolactone has been noted to attenuate cardiac fibrosis. We have observed that the cardiotonic steroid marinobufagenin plays an important role in the diastolic dysfunction and cardiac fibrosis seen with experimental renal failure. We performed the following studies to determine whether and how spironolactone might ameliorate these changes. First, we studied rats subjected to partial nephrectomy or administration of exogenous marinobufagenin. We found that spironolactone (20 mg/kg per day) attenuated the diastolic dysfunction as assessed by ventricular pressure-volume loops and essentially eliminated cardiac fibrosis as assessed by trichrome staining and Western blot. Next, we examined the effects of spironolactone and its major metabolite, canrenone (both 100 nM), on marinobufagenin stimulation of rat cardiac fibroblasts. Both spironolactone and canrenone prevented the stimulation of collagen production by 1 nM marinobufagenin but not 100 nM marinobufagenin, as assessed by proline incorporation and procollagen 1 expression, as well as signaling through the sodium-potassium-ATPase, as evidenced by protein kinase C isoform &dgr; translocation and extracellular signal regulated kinase 1/2 activation. Both spironolactone and canrenone also altered ouabain binding to cultured porcine cells in a manner consistent with competitive inhibition. Our data suggest that some of the antifibrotic effects of spironolactone may be attributed to antagonism of marinobufagenin signaling through the sodium-potassium-ATPase.

Utility of a 0.014" pressure-sensing guidewire to assess renal artery translesional systolic pressure gradients.

Renal ischemia due to renal artery stenosis (RAS) is an important cause of secondary hypertension and renal insufficiency. Several methods are available to diagnose RAS; however, the identification of clinically significant lesions remains problematic. We measured the translesional systolic pressure gradient (TSPG) with a 4 Fr catheter and a 0.014″ pressure‐sensing guidewire and compared these data to angiographic findings. The TSPG obtained by pressure‐sensing guidewire correlated more strongly with angiographic minimal lumen diameter (r2 = 0.801) than those obtained by 4 Fr catheter (r2 = 0.360). The relationship of TSPG with percent stenosis was not strong, regardless of the method used (r2 = 0.228 with pressure‐sensing guidewire, 0.358 with 4 Fr catheter). Using a 0.014″ pressure‐sensing guidewire is effective for assessing TSPG and provides a more reliable indication of stenosis significance than use of a 4 Fr catheter. Cathet Cardiovasc Intervent 2003;59:372–377.

Is adjunctive balloon postdilatation necessary after coronary stent deployment? Final results from the POSTIT trial

Early‐generation balloon‐expandable stents required postdilatation with noncompliant balloons at high pressure to optimize stent deployment. The need for adjunctive balloon postdilatation with modern stent delivery systems is unknown. Patients undergoing elective stenting were randomized to Boston Scientific NIR, Guidant Tri‐Star/Tetra, and Medtronic AVE S670 stents. The primary endpoint was optimum stent deployment defined as a minimal stent diameter (MSD) ≥ 90% of the average reference lumen diameter assessed by intravascular ultrasound (IVUS) performed immediately following stent deployment. If, by operator assessment, the primary endpoint was not achieved with the stent delivery system, adjunctive postdilatation with noncompliant balloons was performed. Of 256 patients with IVUS studies adequate for core laboratory analysis, only 29% achieved optimum stent deployment with the stent delivery system. None of the baseline clinical or angiographic variables predicted optimum stent deployment. Of the procedural variables, the type of stent and nominal stent size were not predictors, but higher deployment pressures were associated with a higher frequency of optimum stent deployment (< 12 atm 14% vs. ≥ 12 atm 36%; P = 0.007). The inability to achieve optimum stent deployment was not due to undersizing the stent delivery balloon, but rather to an inability of the stent delivery balloon to expand fully the stent to nominal size. In patients who underwent postdilatation, the frequency of achieving optimum stent deployment increased from 21% to 42%, minimal stent area increased from 6.6 ± 2.2 to 7.8 ± 2.3 mm2, and MSD increased from 2.6 ± 0.5 to 2.8 ± 0.4 mm. These data stress the continued need for adjunctive balloon postdilatation with modern stent delivery systems. Cathet Cardiovasc Intervent 2003;59:184–192.

Efficacy and Safety of Carvedilol in Treatment of Heart Failure with Chronic Kidney Disease A Meta-Analysis of Randomized Trials

Background—The safety and efficacy of different types of &bgr;-blocker therapy in patients with non–dialysis-dependent chronic kidney disease (CKD) and systolic heart failure (HF) are not well described. We assessed whether treatment of systolic HF with carvedilol is efficacious and safe in adults with CKD. Methods and Results—We performed a post hoc analysis of pooled individual patient data (n=4217) from 2 multinational, double-blinded, placebo-controlled, randomized trials, CAPRICORN (Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction Study) and COPERNICUS (Carvedilol Prospective Randomized, Cumulative Survival study). Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, HF mortality, first HF hospitalization, the composite of cardiovascular mortality or first HF hospitalization, and sudden cardiac death. Non–dialysis-dependent CKD was defined by estimated glomerular filtration rate ⩽60 mL/min/1.73 m2, using the abbreviated Modification of Diet in Renal Disease equation. CKD was present in 2566 of 4217 (60.8%) of the cohort, 50.4% of whom were randomly assigned to carvedilol therapy. Within the CKD group, treatment with carvedilol decreased the risks of all-cause mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63 to 0.93; P=0.007), cardiovascular mortality (HR, 0.76; 95% CI, 0.62 to 0.94; P=0.011), HF mortality (HR, 0.68; 95% CI, 0.52 to 0.88; P=0.003), first hospitalization for HF (HR, 0.74; 95% CI, 0.61 to 0.88; P=0.0009), and the composite of cardiovascular mortality or HF hospitalization (HR, 0.75; 95% CI, 0.65 to 0.87; P<0.001) but was without significant effect on sudden cardiac death (HR, 0.76; 95% CI, 0.56 to 1.05; P=0.098). There was no significant interaction between treatment arm and study type. Carvedilol was generally well tolerated by both groups of patients, with an increased relative incidence in transient increase in serum creatinine without need for dialysis and other electrolyte changes in the CKD patients. However, in a sensitivity analysis among HF subjects with estimated glomerular filtration rate <45 mL/min/1.73 m2 (CKD stage 3b), the efficacy of carvedilol was not significantly different from placebo. Conclusions—This analysis suggests that the benefits of carvedilol therapy in patients with systolic left ventricular dysfunction with or without symptoms of HF are consistent even in the presence of mild to moderate CKD. Whether carvedilol therapy is similarly efficacious in HF patients with more advanced kidney disease requires further study.

Atherosclerotic Peripheral Vascular Disease Symposium II Intervention for Renal Artery Disease

The primary goal of this American Heart Association renal intervention writing group was to discuss current controversies related to renal interventions and to recommend important areas of clinical research and advocacy initiatives in this peripheral arterial bed. The 4 areas covered in this section include (1) management of asymptomatic renal artery disease, (2) treatment of ischemic nephropathy, (3) prevention and treatment of atheroembolism in renal artery interventions, and (4) treatment of renal in-stent restenosis (ISR). Atherosclerotic renal artery disease is an often unrecognized contributor to refractory hypertension, renal insufficiency, and increased risk of cardiovascular death.1,2 Renal artery disease is associated with increased cardiovascular events (myocardial infarction, stroke, and death), and when associated with symptomatic coronary artery disease, it independently doubles the risk of death.3 Additionally, the presence of bilateral renal artery stenoses is associated with a reduced 4-year survival rate when compared with unilateral disease (47% versus 59%, P <0.001).3 Hypertension, renal insufficiency, and multisystem atherosclerosis are common entities, and the independent occurrence of these conditions is frequent. Thus, the physician must distinguish between association and causation in the evaluation of patients with atherosclerotic renal artery disease and critically appraise the potential for clinical improvement in selecting patients for renal artery intervention. In contrast to other regional manifestations of atherosclerosis, it is impractical to classify patients with atherosclerotic renal artery disease into symptomatic or asymptomatic categories. Two of the cardinal manifestations of renal artery disease, hypertension and renal insufficiency, are frequently “silent” with regard to clinical manifestations until end-organ damage or uremia occurs. Thus, the majority of patients may be deemed asymptomatic. A more appropriate classification of patients with atherosclerotic renal artery disease may be to classify them in relation to potential clinical consequences. We propose the following classification scheme in patients with renal artery disease: