Statins Possess a Dose-responsive Effect of Protecting AVF from

The study demonstrates that statins are associated with an overall 21% risk reduction for recreation of vascular access for long term hemodialysis. The risk reduction effect of statins was found in the autogenous AVF group (HR 0.74, 95% CI, 0.74 to 0.84), but not generally in the AVG group (HR 0.94, 95% CI, 0.83 to 1.07). The protective effect in AVF was found to respond to a dose-index, surrogated by days of prescription. While a significant protective effect was found in the AVG patients with the highest range of prescription days. It is reasonable to assume that statins could also exert a milder beneficial effect on vascular access in AVG patients than in AVF patients. The finding of such a beneficial effect of statins is first reported on the basis of a large scale nation-wide population study.

The randomized controlled clinical trial is the gold standard for confirming the efficacy of an intervention. However, a large observational study provides a unique opportunity to study possible effects of a pharmacological intervention, often without the sample size and ethical limitations of a clinical trial. The potential confounding factors are usually problematic and should be collected and adjusted in such an analysis. In the present study, we further recruited a propensity score matched cohort and re-calculated the hazard ratios by multivariate Cox regression to minimize the potential bias resulting from baseline differences. The results indicate that statins prevent AVF

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from permanent HD access recreation. Mortality and renal transplantation cases were censored in our survival analysis of permanent HD access, which could result in potential bias from these competing risks. The results of competing risk analysis also approve the protective effect of statins on AVF. Furthermore, the statin users are more frequently co-morbid with peripheral vascular disease and diabetes, which may increase risk of AVF failure. The protective effect is thus potentially underestimated in this non-intentional study. Taken these findings together, we conclude that statin users had a lower permanent HD access recreation hazard for AVF.

Statins have been repeatedly shown to possess beneficial effects on the prevention of AVF stenosis in animal and cellular studies.

Simvastatin had been shown to reduce venous neo-intimal hyperplasia and vascular smooth muscle proliferation by decreasing the expression of vascular endothelial growth factor A (VEGF-A) and matrix metalloproteinase 9 (MMP-9)¹³. Rosuvastatin had been demonstrated to increase the blood flow in the venous limb of AVF in diabetic rats, which was associated with the anti-inflammatory effect and resulting from endothelial function improvement¹². Atovastatin has been shown to decrease proliferation, migration, and the passage of human smooth muscle cells (HSMC) across a matrix barrier³⁸. Pravastatin was reported to reduce intimal hyperplasia in mice that was associated with decreased vascular smooth muscle cell (VSMC) proliferation and platelet-derived growth factor-induced VSMC migration and inhibited macrophage migration³⁹. Statins have been almost uniformly

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demonstrated to be beneficial for vascular access patency in basic research but surprisingly this has not been supported by clinical studies.

The present study provides a pharmaco-epidemiologic link between basic research and clinical evidence.

Several previous studies have debated the relationship between statins and outcomes of VA for hemodialysis. Righette et al showed that statins possess a beneficial effect on AVF survival but it was not clear about the generalizability of this small-scale study which was conducted in a single center ¹⁷. Saran et al evaluated the association between specific medicines and AVF outcomes ⁸. The study concluded that statins are not associated with better VA outcomes based on Dialysis Outcomes and Practice Patterns Study (DOPPS), but the study was confined to United States patients. Another study by Andreucci et al based on DOPPS using US, European and Japanese data found the futility of statins on VA patency ⁴⁰. Yevzlin et al evaluated the relationship between medication use and VA patency using the cohort of US Renal Data System Dialysis Mortality and Morbidity Wave II study, and also reported that statins were not associated with better vascular access patency ¹⁰. These hemodialysis cohort studies had similar design to the present study but failed to demonstrate the beneficial effect of statins. Apart from the ethnic and sampling differences, the critical difference between the current study and others is the definition of statin users. Contradictory to previous studies, the current study is based on a national, large population dataset and defines statin users by post VA creation statin prescription. By

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demonstrating a significant risk reduction effect and dose responsive relationship between post VA statin use and VA recreation, our findings provide solid evidence that statins exert a beneficial effect on AVF patency and suggest the needs of further clarification of the target patients who would benefit most.

Four out of six statins investigated in the current study demonstrated a significant risk reduction effect on the AVF failure rate.

Meanwhile, lovastatin and fluvastatin showed a risk lowering trend but not one that was statistically significant. Both of them are categorized as moderate to low potency ⁴¹. This finding suggests that the beneficial effect on VA outcomes is a universal but that the effect depends on the statin’s potency categorization. The differential effects among individual statin should be clarified in future studies.

Older age and being female are demographic features associated with increased VA recreation for AVF in this study. Older age was uniformly recognized as one risk factor of unassisted and assisted VA failure in the previous studies ^42-44. Female patients were shown to have higher AVF failure rates in several recent studies ⁴⁵, but not in other studies ^4,8,14,16. One meta-analysis reported that female gender was not a significant risk factor of VA failure ⁴⁶. We found that peripheral vascular disease was associated with increased VA recreation, which is compatible with previous studies ^4,43-45. However, congestive heart failure, cerebral vascular disease and diabetes were not identified as significant risk factors of AVF or AVG failure in this analysis. These results may indicate that only the more severe cardiovascular disease is

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an important risk factor of vascular access stenosis. Future application of statins for AVF protection should take age, gender and the severity of cardiovascular disease into consideration.

Regarding to VA protection, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) are also drugs of choice for their pleiotrophic effects. Saran’s study based on DOPPS reported that ACEIs were associated with better assisted patency in AVFs, that calcium channel blockers (CCBs) were associated with better unassisted patency in AVGs and that aspirin was associated with better assisted patency in AVGs ⁸. Our findings suggest a benefit of ARBs in AVF patients. No other antihypertensive agents including ACEI and CCB were found to be beneficial for reducing VA failure. In another retrospective study, ARB was also noted to be beneficial for AVF patency in ACE DD genotype patients ⁴⁷. Anti-platelets were reported by a meta-analysis to increase the short term patency of AVFs and AVGs ⁴⁸. In our analysis, neither aspirin nor clopidogrel was related to a decreased risk of VA recreation. To elucidate the relationships between these medications and long term VA outcomes mandates further laboratory and clinical studies.

In summary, the findings suggest that statins possess a dose-responsive effect of protecting AVF from stenosis for patients undertaking long term hemodialysis. The beneficial effect on VA outcomes is a universal class effect but the effect size is dependent on the statins’ potency. Prescribing statin therapy for the hemodialysis patients may be one of the most convenient interventions to prevent

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their vascular access from failure, which will greatly promote the patients’ quality of care and reduce health cost. These results have important therapeutic implications for future prospective randomized control studies. Further investigations towards exploring anti-inflammatory and anti-oxidative effect of statins on the prevtion of AVF stensosis should be addressed.

4.2 Hypoxic Preconditioning Promote the Ability of Stem Cell to