Dose-Related Effect of Statins in Venous Thrombosis Risk Reduction

Abstracts Gregory L. Moneta, MD, Section Editor

Arteriovenous Graft Placement in Predialysis Patients: A Potential Catheter-Sparing Strategy Shingarev R, Maya ID, Barker-Finkel J, et al. Am J Kidney Dis 2011;58: 243-7. Conclusion: Arteriovenous grafts placed predialysis have primary failure rates and cumulative survival rates that are similar to grafts placed after starting dialysis therapy. Summary: The fistula first initiative (www.fistulafirst.org) strongly encourages dialysis access via arteriovenous fistulas. Some patients, however, have anatomy more suitable for a graft. In such cases the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) suggests grafts be placed three to six weeks prior to the need for dialysis therapy. It is difficult to predict the onset of time for the need of dialysis in patients not undergoing dialysis. Some surgeons postpone graft creation until after the initiation of hemodialysis reasoning graft placement prior to dialysis therapy may result in diminished time of patent access when the patient actually needs the access. However, postponing initiation of graft placement until after beginning dialysis therapy exposes the patient to the risk of catheter related bacteremia, central vein stenosis and decreased overall survival. The authors reasoned, that if outcomes of dialysis access grafts placed prior to dialysis initiation are similar to those placed after dialysis initiation then one should argue for early graft placement in this patient subpopulation to avoid the potential complications of venous catheters. They compared their outcomes of patients whose grafts were placed before and after dialysis therapy initiation. This was a retrospective analysis of a prospective computerized vascular access data base. There were 248 patients who received their first arteriovenous graft at a single large institution. Most patients were African American reflecting the demographic distribution of the author’s institution. The first graft was placed predialysis in 62 patients and post dialysis in 186 patients. More than half of the post dialysis patients had a least one previous fistula and of the pre dialysis patients, nearly 1/3 had at least one prior access and 10% had had two or more fistulas. Primary graft failure was similar for pre and post dialysis graft placement (20% vs 24%; P ⫽ .5) median culamative graft survival was similar for pre and post dialysis graft placement (365 vs 414 days; HR, 1.22; 95% CI, 0.81-1.98; P ⫽ .3). Median duration of catheter dependence after graft placement in the post dialysis group was 48 days and was associated with 0.63 (95% CI, 0.48-0.79) episodes of catheter related bacteremia per patient. Comment: This study demonstrates similar graft related outcomes between grafts placed for hemodialysis access predialysis and those created after the initiation of hemodialysis. Predialysis graft placement appears to be a reasonable strategy in selected patients. In this study 86% of predialysis patients started hemodialysis therapy with a permanent access. In contrast when a graft was placed after initiation of dialysis therapy, catheter dependence was for a mean of 4 months. Given all the problems with venous catheters, the placement of arteriovenous grafts in selected patients prior to initiation of hemodialysis therapy should be considered a viable cathetersparing strategy.

Association of Body Mass Index With Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study Ix JH, Biggs ML, Kizer JR, et al. Am J Epidemiol 2011;174:1036-43. Conclusion: Greater body mass index (BMI) is associated with peripheral arterial disease (PAD) in healthy older patients who never smoked. Summary: Novel and traditional cardiovascular disease risk factors are associated with PAD. One important cardiovascular risk factor previously not associated with PAD is BMI. Epidemiologic studies have either not demonstrated a relationship between PAD and BMI (Murabito JM. Am Heart J 2002;143:961-5, and Meijer WT et al. Arch Inter Med 2000;160: 2934-8) or demonstrated an inverse association (Criqui MH. Circulation 2005;112:2703-7). Such studies have had cross sectional designs. In this study the authors hypothesize poor health and smoking status might simultaneously be associated with a lower BMI and greater PAD prevalence obscuring a positive association that might exist if adiposity itself leads to development of PAD. For this study the authors evaluated the association of BMI and PAD in adults age ⬎65 years at baseline who are participating in The Cardiovascular Health Study (The Cardiovascular Health Study is a community based study of older adults with the goal to evaluate risk factors for development and progression of vascular disease). The authors also evaluated the association of BMI with subsequent incident clinical PAD events during follow up. They used self-reported recalled weight at age 50 to estimate mid-life BMI and evaluate its association with PAD prevalence at

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baseline. The analysis was repeated in a subset of participants who reported good health status and who had never smoked. There were 5419 non institutionalized residents of four communities who were more than 65 years of age who entered in the study. Each participant had their ankle brachial index measured at baseline and each participant recorded their history of PAD procedures. They were followed longitudinally for incident PAD events. At baseline mean BMI was 26.6 (SD, 4.6) and 776 participants (14%) had PAD at entrance into the study. During a median follow up of 13.2 years incident PAD events occurred in 276 patients. Each 5 unit increase in BMI was inversely associated with PAD prevalence ratio (PR ⫽ 0.92; 95% CI, 0.85 -1.00). The opposite relationship, however, was found in patients in good health who had never smoked (PR ⫽ 1.20; 95% CI, 0.94-1.52). Findings were similar when PAD prevalence was correlated with weight at age 50 years (PR ⫽ 1.3; 95% CI, 1.11-1.51). Similar results were also reserved between BMI baseline and incident PAD events during follow up (HR ⫽ 1.32; 95% CI, 1.00-1.76). Comment: This study indicates the previous lack of a demonstrated relationship between BMI and PAD was due to the design of previous studies. While these studies showed inverse, U-shaped, or absent association of BMI with PAD prevalence they did not evaluate association stratified according to health status or smoking status thus likely obscuring the relationship between BMI and PAD. This is the first major epidemiologic study to indicate an independent association between BMI and prevalence of PAD. The study provides yet another reason to avoid weight gain as one grows older.

Asymptomatic Carotid Artery Stenosis and Cognitive Outcomes After Coronary Artery Bypass Grafting Norkienë I, Samalavièius R, Ivaèius J, et al. Scandinavian Cardiovascular Journal 2011;45:169-73. Conclusion: Asymptomatic ⬎ than 50% carotid stenosis is a risk factor for cognitive decline following coronary artery bypass grafting (CABG). Summary: Patients anticipate CABG will improve their quality of life (Koch CG et al. Semin Cardiothorac Vasc Anesth 2008;12:203-17). Preservation and improvement of psycho- emotional well-being enhances quality of life. Neuropsychological disorders are being more frequently addressed in the care of the postoperative patient. Cerebrovascular disease and coronary artery disease potentionally put patients at risk for cognitive decline. In this paper the authors correlate asymptomatic carotid stenosis with cognitive decline following coronary artery bypass grafting (CABG). They sought to detect the incidence of cognitive decline following CABG, identify risk factors associated with such cognitive decline and to investigate a possible link between cognitive performance and asymptomatic carotid stenosis. The authors studied 127 patients who underwent CABG. The patients underwent a neuropsychological examination that included seven cognitive tests and two scales for evaluation of mood disorders. The patients were tested the day before surgery and before discharge from the hospital. Testing revealed that early postoperative decline was common and was detected in 46% of patients. Post operative cognitive decline was associated with low cardiac output syndrome perioperatively (P ⬍ .05), postoperative bleeding (P ⫽ .03), longer duration of surgery (P ⫽ .02), and longer intensive care unit stay and post operative mechanical ventilation time (P ⬍ .05). Multivariate regression analysis indicated carotid artery stenosis of more than 50% was a strong independent predictor of postoperative cognitive decline (OR, 26.9; 95% CI, 6.44-112.34). Comment: The striking finding here is a very strong relationship between asymptomatic carotid stenosis and cognitive performance following CABG. The author’s data suggest screening for carotid artery disease in patients undergoing CABG may help identify patients at risk of neurocognitive damage following CABG. Such information could possibly be of use in counseling patients regarding their overall quality of life following CABG. It is, however, unclear whether correction of carotid stenosis, either before CABG, or concurrent with CABG, can serve as a mechanism to diminish cognitive decline associated with CABG and carotid artery stenosis.

Dose-Related Effect of Statins in Venous Thrombosis Risk Reduction Khemasuwan D, Chae YK, Gupta S, et al. Am J Med 2011;124:852-9. Conclusions: Antiplatelet therapy and statin therapy are associated with reductions in the occurrence of venous thromboembolisim (VTE) with a dose related effect of statins. Summary: Many of the same inflammatory mediators are elevated in patients with atherosclerosis and venous thrombosis (van Aken BE et al.

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Thromb Haemost 2000;83:536-9, and Sorensen HT. Lancet 2007;370: 1773-9). Patients with a diagnosis of deep venous thrombosis and pulmonary embolism have higher risk of cardiovascular events over the next 20 years. In addition, patients with myocardial infarction or stroke have an increased risk of VTE within 3 months of diagnosis (Sorensen HT et al. J Thromb Haemost 2009;7:521-528) and patients with the metabolic syndrome and those with elevated levels of low density lipoprotein are also at increased risk of VTE (Ageno W et al. Circulation 2008;117:93-102). This emerging relationship between atherosclerosis and VTE with respect to biochemical etiologic factors led the authors to hypothesize statins and antiplatelet therapy could possibly have a role in preventing VTE in patients at high risk for atherosclerosis. This was a retrospective cohort study reviewing 1795 consecutive patients with atherosclerosis admitted to a teaching hospital between 2005 and 2010. Patients treated with anticoagulation therapy were excluded. Patients who were statin naive or who had used statins for less than two months were allocated to the non statin user group. After exclusions, the final analysis included 1100 patients with an overall incidence of VTE of 9.7 %. 6.3% (54/861) of the statin users developed VTE while 22.2 % of the non users (53/239) developed VTE (HR, 0.24; P ⬍ .001). Even after controlling for compounding factors, statin use was still associated with a decreased risk of developing VTE (HR, 0.29; P ⬍ .001). There was a greater reduction in VTE events in patients with high does stain use compared to those with standard statin use. High dose statin use was an average 50.9 mg per day with a HR for VTE reduction of 0.25 (P ⬍ .01. Standard statin use was 22.2 mg per day with a VTE reduction HR of 0.38 (P ⬍ .001). The combination of aspirin and clopidogrel also decreased of VTE (HR, 0.19; P ⬍ .001). The combination of statins and antiplatelet therapy further reduced occurrence of VTE (HR, 0.16; P ⬍ .001). Comment: There are potentially huge implications in this paper. There may be more than just coincidental sharing of biochemical risk factors for VTE and atherosclerosis. In addition the paper questions the popular perception aspirin is ineffective in prevention of VTE. Finally, it is the first paper to suggest a possible dose response relationship of statins in preventions of VTE.

Late Follow-up of a Randomized Trial of Routine Duplex Imaging Before Varicose Vein Surgery Blomgren L, Johansson G, Emanuelsson L, et al. Brit J Surg 2011;98:112-6. Conclusion: Preoperative duplex imaging prior to varicose vein surgery reduces recurrence and need for reoperation over 7 years of post operative follow-up. Summary: Inadequate surgery secondary to in adequate preoperative investigation may contribute to recurrence following surgery for primary varicose veins (Blomgren L et al. Br J Surg 2005;92:688-94). The authors previously reported recurrence and reoperation 2 years after varicose vein surgery were lower with preoperative duplex examination (Blomgrin L et al. Br J Surg 2005;92:688-94). It has also been suggested groin surgery associated with saphenous vein open surgery induces recurrence through neovascularization. The aim of the current study was to evaluate the impact of preoperative duplex imaging after seven years with respect to recurrence of varicose veins, performance of reoperation and neovascularization as a source of recurrence. Patients with primary varicose veins undergoing saphenous surgery were randomized to two groups. Group one underwent preoperative duplex imaging and group two did not. Patients were invited for follow up with interviews, clinical examination and duplex imaging. Quality of life was measured with the short form SF 36 questionnaire. Initially, there were 293 patients (343 legs) included. After seven years, 227 were interviewed or their records were reviewed. There were 114 patients in group one and 113 patients in group two. Ninety-five legs in group one and 99 legs in group two were examined clinically and with duplex imaging. Fourteen percent of the legs in group one and 46% of the legs in group two exhibited incompetence at the saphenofemoral junction and/or saphenopopliteal junction (P ⬍.001). Seventy-five legs were without initial surgery at the saphenofemoral junction and there was no incompetence at the saphenofemoral junction after two months. Of these, 20% developed reflux in saphenofemoral junction after 7 years. Corresponding values with the saphenopopliteal were 1.6% of 253 legs. 163 legs had showed no reflux of the saphenofemoral junction two months after surgery. Of these, 14% had incompetence of the saphenofemoral junction 7 years after surgery. At the saphenopopliteal junction 4 of 11 legs developed incompetence following surgery. After a mean follow up of 7 years, 15 legs in group 1 underwent reoperation and 38 in group (P ⫽ .001). There were no differences in quality of life in group 1 or group 2 at 7 years. Comment: The study demonstrates preoperative duplex imaging prior to primary varicose vein surgery results, even after 7 years, in lower recurrence and reoperation rates. The study also addresses a controversial topic in varicose vein treatment, that of neovascularization. In this study, at 7 years, neovascularization did not appear to cause recurrence with symptoms that required reoperation. The current thought that catheter based techniques provide better long term results than open surgery because of decreased

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neovascularization associated with non operative obliteration of the greater saphenous vein may not be true. In this study, within seven years, neovascularization did not cause recurrence with symptoms that required reoperation.

Long-Term Results of Vascular Graft and Artery Preserving Treatment With Negative Pressure Wound Therapy in Szilagyi Grade III Infections Justify a Paradigm Shift Mayer D, Hasse B, Koelliker J, et al. Ann Surg 2011;254:754-60. Conculsion: Szilagyi III infections are safely and effectively treated both short and long term with negative pressure wound therapy (NPWT). Summary: Wound infections with prosthetic graft or arterial involvement (Szilagyi grade III infections) can be associated with high morbidity and mortality (Kikta MJ et al. J Vasc Surg 1987;5:566-71). Traditional treatment for Szilagyi III infections is graft excision, radical debridement and secondary vascular reconstruction. NPWT was introduced in 1997 by Argenta and Morykwas (Morykwas MJ et al. Ann Plast Surg 1997;33:553-62). There have been small series of patients with vascular graft infections treated by NPWT without graft excision with apparently good short term results (Dosluoglu HH et al. J Vasc Surg 2010;51:1160-6). In this paper the author’s report their short and long term results of NPWT for treatment of vascular infections with a mean follow up of 43 months. There were 44 patients (mean age 62 years) with Szilagyi III infections treated with NPWT from 2002 to 2009 and 13 of the 44 required intensive care unit admission. There were 40 grafts (prosthetic , 24; vein, 3; biologic, 13) and 9 native arteries involved with infection. NPWT (VAC; KCI International, Amstelveen, The Netherlands) was applied directly to grafts and arteries using negative pressures from 50 to 125 mm Hg. VAC therapy was instituted after radical debridement of infected tissue. Antibiotics were used according to culture information. The median duration of NPWT was 33 days (IQR, 20-78). Median hospitalization was 32 days (IQR, 20-82) days. There were no deaths within 30 days and one-year mortality was 16%. After a mean follow up of 43 months long term mortality was 41% (18/44). Only one of the 18 deaths was related to graft infection. Complete wound healing was achieved in 91% and 37 of 44 grafts were preserved without long term reinfection. There were no significant positive predictors for mortality. Patients presenting with early infection had a negative association for reinfection (OR, 0.17; 95% CI, 0.03-1.07; P ⫽ .03). Patients presenting with late infection had a positive association with reinfection (OR, 5.73; 95%CI, 0.93-39.1; P ⫽ .03). Amputation was also a strong predictor of reinfection (OR, 7.94; 95%CI, 1.02-72.5; P ⫽ .24). Comment: There is no universally accepted management for wound infection that involves prosthetic grafts, vein grafts, or native arteries. The results here using NPWT therapy are encouraging. There was only one graft related death. VAC therapy has revolutionized care of open wounds in recent years. Through a combination of antimicrobial activity, stimulation of granulation tissue, and increased local perfusion, it appears VAC therapy can create an environment suitable to combat infection. The author’s implication that the results of NPWT for Szilagyi III infections justify a paradigm shift in the management of vascular graft infections just may be true.

Lower Extremity Vascular Injuries: Increased Mortality for Minorities and the Uninsured? Crandall M, Sharp D, Brasel K, et al. Surgery 2011;150:656-64. Conclusion: There are mortality disparities associated with race and insurance status in patients with penetrating lower extremity vascular injury. Summary: Outcome disparities for Medicaid patients, people of color and the uninsured may be partially attributable to differences in baseline healthcare characteristics and/or hospital performance (Osborne NH et al. J Vasc Surg 2009;50:709-13). The author’s considered that in trauma patients heterogeneity of injury, difficulties in injury measurement and a lack of standardized care may contribute to potential disparities in trauma outcomes, including vascular injury. Their hypothesis was that mortality rate disparities by socioeconomic status and race could be explained by injury heterogeneity. They therefore limited analysis of vascular injury to a group with homogenous injuries; those with lower extremity vascular injuries. They postulated disparities in outcome would be diminished or eliminated by such stratification. They used the National Trauma Data Bank version 7.0 of the American College of Surgeons to identify patients with lower extremity vascular injury. Univariate and multivariate analyses were performed using Stata software (version 11; StataCorp, LP, College Station, Tex). There were 4928 patients with lower extremity vascular injury identified. There were 2452 blunt injuries and 2452 penetrating injuries, with 24 cases where mechanism was unknown. Mortality was 7.6 % overall and did not differ by mechanism. Regression analysis, using mechanism as a covariate, revealed worse mortality for people of color (OR, 1.45; 95%CI, 1.03-2.02; P ⫽ .03) and worse mortality for the uninsured (OR, 1.62; 95%CI, 1.152.23; P ⫽ .006). When a separate analysis was performed stratified by mechanism there was no significant mortality disparity for blunt trauma; for people of color (OR, 1.28; 95%CI, 0.85-1.96; P ⫽ .23) or for the uninsured