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Keywords:

  • Allograft vasculopathy;
  • Cardiac transplant;
  • Cholesterol;
  • Hyperlipidemia;
  • Statins

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Despite widespread statin therapy, 91% of cardiac transplant patients have hyperlipidemia within 5 years from cardiac transplantation. The implications of this are profound, particularly given that coronary allograft vasculopathy is a leading cause of death. Unfortunately the solution is not easy, with problems of toleration at higher statin doses and a lack of good quality evidence for second line agents. We review the literature and discuss some of the key issues transplant physicians are faced with when considering alternatives to statin therapy.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Data from the 2010 annual registry of the International Society of Heart and Lung Transplantation (ISHLT) demonstrates that posttransplant hyperlipidemia has an incidence of 74% within the first year and 91% by 5 years [1]. This is despite the current widespread use of statins. There are a multitude of pathophysiological processes leading to the derangement of the lipid profile in cardiac transplant (CT) recipients. The most important of these is long-term immunosuppression. For example, cyclosporine inhibits cholesterol 21 hydroxylase and binds to the LDL receptor resulting in an increase in circulating LDL-C of up to 31%[2]. Corticosteroids induce peripheral insulin resistance and an ensuing inability to activate lipid storage, which stimulates a reflex increase in total cholesterol [3–5].

Cardiac graft vasculopathy (CGV) is a multifaceted process, contributed to by immunological (including inflammatory Th17 cell-mediated damage and neutrophilia) and nonimmunological (such as ischemia and hypertension) factors. Infiltrating neutrophils and macrophages release potent reactive oxygen species, which induce a state of oxidative stress, causing progressive graft damage. The damaged graft will, in addition, upregulate and secrete damage associated molecular patterns, which initiate the activation of important leukocyte subsets, including dendritic cells via toll-like receptor signaling. Dendritic cell activation is an integral process in the stimulation of an allospecific immune response, mediating the clonal expansion of T cells. Inflammatory Th17 cells cause direct damage to the graft and are a major contributor to CGV [6]. Importantly, upregulated expression of cell adhesion molecules (such as ICAM-1) is observed on the damaged vascular endothelium, which aids immune cell infiltration into the graft [7].

Nonspecific damage by innate immune cells, such as macrophages and neutrophils, as well as direct damage by allospecific Th17 cells will significantly decrease endothelial integrity, enhancing vascular smooth muscle cell (VSMC) proliferation. In addition, the immune cell infiltrate is able to promote CGV humorally, via the release of cytokines, such as vascular endothelial growth factor (VEGF) [8,9]. This effect is augmented by tissue secretion of VEGF. VEGF mediates elevated endothelial permeability, promoting lipid insudation [10]. The disruption of endothelial tight junctions by VEGF provides gaps through which VSMC will proliferate, resulting in significant intimal hyperplasia, a hallmark of CGV. In addition, medial smooth muscle cell apoptosis contributes significantly to intimal thickening, and promotes vessel remodeling via proliferation of the remaining viable adjacent VSMC and progenitors [11]. The failure to remove necrotic or apoptotic VSMC as a result of hyperlipidemia results in a significant inflammatory response, which may be pertinent in inducing progressive arterial injury [12]. Persistent damage to the graft will also necessitate significant reparative myocardial and adventitial fibrosis and induce extracellular matrix deposition by adventitial fibroblasts, deleteriously reducing arterial elasticity, and expediting vascular occlusion. This process can be mediated by cytokine release, including transforming growth factor-beta and IL-6 [13,14] (Figure 1).

image

Figure 1. Cardiac graft Vasculopathy is a multifaceted process, contributed to by immunological and nonimmunological factors.

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The link between cholesterol and CGV has long been recognized in animal models of cardiac transplantation [15–17]. Further evidence is seen in retrospective clinical data, identifying hyperlipidemia as an independent risk factor for the development and progression of CAV [18,19]. In the setting of renal transplantation, hyperlipidemia is an established risk factor for the occurrence of vascular lesions seen in renal allograft rejection [20–23]. Moreover, histological examination of vascular lesions in this setting demonstrate the composition of oxidized LDL and foam cells, which are both accepted byproducts of disordered intravascular cholesterol metabolism [24]. Translation of this evidence into the heart transplant setting was provided by a landmark paper that studied the effect of pravastatin or placebo in a cohort of 97 CT patients [25–27]. After 12 months of follow up, the pravastatin group had significantly lower mean total cholesterol and a corresponding lower occurrence of CGV (as determined by angiography or autopsy). Interestingly, the collaborators also demonstrated that there was a reduced incidence of cardiac rejection accompanied by hemodynamic compromise (3 vs. 14 patients, P= 0.005) and a better overall survival rate (94% vs. 78%, P= 0.025) in the statin treated group. An additional intracoronary ultrasound substudy of the same cohort also showed benefits of pravastatin on coronary intimal thickness (0.11 ± 0.09 mm, vs. 0.23 ± 0.16 mm, respectively, P= 0.002). The overwhelming benefits of pravastatin shown in this study pioneered the acceptance of statins in CT patients for lipid lowering. Yet it is widely accepted that with the use of statins (particularly at high doses) there is a greater risk of myopathy and rhabdomyolisis after transplantation. Statins are also associated with other adverse effects. The underlying pathophysiology for these unwanted effects are not fully understood but are thought to involve mitochondrial dysfunction. They include include cognitive loss, neuropathy, pancreatic, and hepatic dysfunction, however there are few reports in the literature of these effects occurring in the transplant setting [28–31]. Cyclosporine inhibits enzymes MRP2 and CYP3A4 [32,33] and both of these enzymes play a key involvement in the metabolism of statins. A pharmacokinetic analysis reveals that cyclosporine causes an increase in the bio-availability of atorvastatin by approximately 6-fold, lovastatin by 20-fold, pravastatin up to 23-fold, and simvastatin by 3-fold [34]. As a result, concomitant statin use in the transplant setting accounts for a disproportionate 8% of the reported cases of statin associated myopathy [35]. It is, therefore, often difficult to achieve optimum lipid levels in CT recipients with statin therapy alone, which presents a treatment dilemma to the transplant physician. The combination with a second type of lipid lowering pharmacotherapy would theoretically negate some of the difficulties encountered with high dose statins. However, evidence demonstrating the efficacy, safety, and outcomes of secondary lipid lowering agents is unfortunately lacking in the transplant setting. Therapies that are typically considered include fish oils, ezetimibe, fibrates, niacin, and plant sterols (Table 1). Under the conclusion that it is difficult to repudiate the assumption that hyperlipidemia is a crucial component in the propagation of CGV, we aim to review the literature in other to discuss the current best options for second line antilipid therapy.

Table 1. Second line drug therapy for hyperlipidemia treatment. A comparison of evidence after and before cardiac transplantation
TreatmentEvidence after transplantationLevelEvidence in native heart diseaseLevel
  1. Level A evidence is derived from multiple randomized clinical trials or meta-analyses. Level B evidence is from a single randomized clinical trial or large nonrandomized studies. Level C evidence is the consensus of opinion of experts and/or small studies, retrospective studies, or registries.

Fish oils 1–10 gReduction in triglycerides [39, 40]CReduces all cause mortality and cardiovascular hospitalization versus placebo after MI [95] and in heart failure [96]A
 Antihypertensive and reno-protective [41, 42]C  
Ezetimibe 10 mg odReduction in total cholesterol, LDL, and triglycerides [66, 97, 98]BCompared with placebo, Ezetimibe added to Simvastatin therapy significantly reduces LDL [102]B
 Concomitant statin use, reduction in total cholesterol, LDL, and Trigylcerides [67, 68, 99–101]CEzetimibe added to statin therapy significantly reduces LDL-C levels by 25.8% [60]B
Fibrates Gemfibrozil 600 mg–1.2 g od Bezafibrate 400 mg odConflicting evidence on total cholesterol reduction by Gemfibrozil [75, 76] Gemfibrozil reduced the incidence of coronary heart disease by 34% versus placebo in dyslipidemic patients [103]B
 Reduction in total cholesterol, LDL, trigycerides and an increase in HDL by bezafibrate [39]BFenofibrate did not reduce the risk of coronary events in patients with Type 2 Diabetes [104]B
   Gemfibrozil reduced the risk of major cardiovascular events versus placebo in men with coronary heart disease [105]B
   Bezafibrate did not reduce the risk of myocardial infarction or sudden death versus placebo in patients with a previous myocardial infarct or stable angina [106]B
Niacin 50–500 mg bdReduction in total cholesterol [85]CReduces all cause mortality versus lipid-influencing drugs in patients with previous myocardial infarct [80]B
 65% of patient discontinued due to side effects [86]C  
Cholestyramine 4 g bdNo proven benefit on lipid profile [75]CSignificant reduction in death or myocardial infarction [107]B
DietReduction in triglycerides [90]CSignificant reduction in cardiovascular events [108]B
 Reduction in total cholesterol and LDL [94]C  

Methodology

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

We performed an extensive MEDLINE search, using combinations of the key words “transplant,”“lipids,”“cholesterol,” and each of the discussed therapies. Search criteria was limited to articles printed in English. Cross-referencing was performed wherever possible.

Fish Oils

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Omega-3 fatty acids, namely eicosapentenoic acid (EPA) and docosahexenoic acid (DHA) are thought to confer a cardio-protective effect at least in part by inhibiting the synthesis of V-LDL and reducing circulating triglycerides [36,37]. In the nontransplant setting, a large multicenterd trial of 11,324 postmyocardial infarct patients, demonstrated a significant 15% reduction of the composite primary endpoint of death, nonfatal myocardial infarction or stroke using fish oils [38]. Studies after transplantation are naturally limited to much smaller cohorts. The largest study of fish oils in hyperlipidemic CT recipients was performed by Barbir et al., who conducted an open randomized study of 87 patients [39]. Of these, 44 received 10 g a day of fish oil (Maxepa) over a 3-month follow-up period, and 43 received bezafibrate. Fish oils demonstrated both safety and efficacy via the reduction of triglycerides by 36%, which was comparable to the 31% seen in the bezafibrate group. No significant effect on total cholesterol, low-density lipoprotein (LDL), or apolipoprotein B was seen, whereas bezafibrate significantly reduced these—albeit at the expense of an unexpected rise in creatinine. A smaller study was conducted in 15 heart transplant patients with sirolimus or everolimus induced hypertriglyceridemia [40]. Treatment with omega-3 fatty acids after 4 months resulted in a significant decrease of triglyceride concentration from a pretreatment mean triglyceride of 354 ± 107–226 ± 74 mg/dL (P < 0.001). All patients showed a reduction of at least 20%. Similarly, there was no significant reduction in LDL-cholesterol. Although the study had a short follow up and few participants, it suggested that omega-3 fatty acids show no concerning interaction with sirolimus and everolimus.

Although significant effects of fish oils on triglyceride levels have been demonstrated after transplantation, it is perhaps the identification of other nonlipid lowering effects that stimulates a special interest in their use. A beneficial effect on blood pressure was noted in a double blind randomized study of fish oil treatment (vs. placebo) in transplant recipients [41]. Over the 12-month follow-up period, the treatment group showed no significant rise in SBP in contrast to placebo, which saw an increase of SBP by 8 ± 3 mmHg (P < 001). Interestingly, the placebo group also developed worsening renal function—detected by a decline in the GFR (74 ± 5–68 ± 4 mL/min, P= 002). The treatment group benefited from no such decline. In a similar study, 6 month treatment with fish oils lead to a reduction in SBP by 2 ± 4 mmHg compared to an increase of 17 ± 4 mm in the placebo group (P < 0.01) [42]. After renal transplantation, a meta-analysis of 16 trials unfortunately did not show evidence for a benefit of fish oils on total cholesterol reduction or graft survival [43]. Yet by the authors own conclusion, the numbers involved were not sufficient to power an accurate analysis on graft survival and of interest, a significant (albeit modest) benefit of diastolic blood pressure reduction was noted.

The reported potential for immunomodulation makes fish oils of particular interest to the transplant physician. Both EPA and DHA have been shown to suppress the production of inflammatory cytokines and modulate T cell function [44–46]. Animal models of organ transplantation have repeatedly demonstrated increase graft survival in groups treated with dietary omega-3 fatty acids. Iwami et al. showed in a murine mismatched cardiac allograft model that intraperitoneal administration of EPA improved median survival time of the allograft from 8 days to >100 days (P < 0.01) [47]. Animal models of intestinal transplantation have demonstrated many potential benefits of omega-3 fatty acids including a decrease in the rate of graft tissue apoptosis [48], a reduction in rejection grade [49], and a decrease in graft atherosclerosis [46].

There is also a growing body of in vivo and in vitro evidence demonstrating that fish oils reduce heart rate and prevent tachyarrhythmias [50,51]. Mechanisms are possibly through an inhibitory effect on the parasympathetic innervation of the heart [52] or even a direct effect on the myocardium, through stabilization of membrane ion channels [53]. Indeed, Harris et al. [54] demonstrated that fish oil after cardiac transplantation resulted in a reduction of the resting heart rate, which suggests that this effect is independent of cardiac innervation. There remains a great deal of uncertanity if fish oils actually provide an antiarrhythmogenic benefit in the native setting. A large epidomological study demonstrated consumption of n-3 fatty acids from fish had no affect on the incidence of atrial fibrillation [55]. This, however, was contradicted in a prospective population-based study, which demonstrated after an average follow up of 17.7 years, that an increased concentration of long-chain n-3 polyunsaturated fatty acids (PUFAs) in serum was associated with a lower incidence of atrial fibrillation [56]. This has led to much debate on whether or not fish oils do have an antiarrhythmogenic effect, a review of the subject is provided in the reference [57]. Although the implications of heart rate reduction after cardiac transplantation are at present undefined, the recent appreciation that heart rate is adversely associated with cardiovascular outcome in the setting of native coronary disease [58] will hopefully stimulate further research in this potentially beneficial property.

In summary, fish oils are proven to safely treat hypertriglyceridemia after cardiac transplantation, yet they unfortunately have no documented effect on the primary concern of LDL cholesterol. Although this may be seen as a weakness, alternative properties such as blood pressure reduction, immunomodulation, and heart rate reduction have been suggested.

Ezetimibe

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Ezetimibe has emerged as an alternative to increasing the dose of statins in patients whom low dose statin monotherapy is not enough to achieve optimal lipid levels [59–63]. However its use in the transplant setting might be met with scepticism after many reports of immunosuppressant interaction, malignancy, and hepatic derangement. Concerns about ezetimibe administration after cardiac transplantation was first reported in a case study that demonstrated a supra-therapeutic response of ezetimibe during its concomitant use with cyclosporine and atorvastatin [64]. A small pharmacokinetic study of 13 healthy individuals by Bergman et al. also reported a 15% increase of cyclosporine exposure after administration of high dose ezetimibe (20 mg) [65]. In the setting of renal transplantation, a small open label study of ezetimibe in eight renal transplant recipients was reported. By comparison to a prespecified database of healthy volunteers, the authors demonstrated that maximum plasma concentration of ezetimibe was 3.9-fold higher in renal transplant patients on concomitant cyclosporine [32]. However, it is important to take into account the inherent weaknesses in each of these studies, including the low numbers and design flaws including the lack of placebo control groups and open label administration. Subsequent larger and better-designed datasets have since offered reassuring conclusions about the use of ezetimibe after cardiac transplantation. A placebo controlled, randomized double blind study of ezetimibe was performed in 59 cardiac transplant recipients taking cyclosporine [66]. At baseline, the mean total cholesterol level in the cohort was 5.4 mmol/L (209 mg/dL) despite over 91% of patients already being treated with a statin. After 6 months of concomitant ezetimibe, LDL levels reduced by an average of 26.1% (P < 0.001). Triglyceride levels were reduced by 13.5% (P= 0.020). Cyclosporine trough levels were monitored at multiple time points during follow up and no significant effect was identified. Over the 6-month follow-up period, an equal number of patients (three) withdrew from each arm because of perceived side effects and just one patient death (from a noncardiac cause) occurred in the placebo group. Corroborative findings have also been shown in other clinical studies [67,68].

There has been a reported link between the use of ezetimibe and an increase in the risk of malignancy. This is naturally a concern to the transplant physician, given that malignancy accounts for 20% of deaths after the first 3 years of cardiac transplantation [1]. The association arose from a surprise finding of a trial that was designed to assess the effect of combination ezetimibe plus simvastatin in 1873 patients with aortic valve stenosis. After a median follow up of 52.2 months, patients in the active treatment arm appeared to have a greater collective incidence of any type of cancer (101 vs. 65 cases, respectively, P= 0.01). The safety concerns led to an independent analysis by pooling the data from other large ongoing ezetimibe trials [69]. Of 20,617 patients analyzed there was an insignificant 313 cancer cases recorded in ezetimibe patients compared to 326 cases in the placebo arm (P= 0.61). Furthermore there was no increase in the relative risk of death from cancer over time (P= 0.54). The authors concluded that the results provided no credible evidence of any adverse effect on the incidence of cancer with the addition of ezetimibe to statin therapy. Other findings from in depth in silico and in vitro analyses have revealed ezetimibe shows no evidence of inducing precancerous proliferative cellular changes [70].

For some physicians, the current absence of an ezetimibe clinical outcome study after transplantation and the high profile negative publicity over recent years may result in a continuing question over its merits in a transplant setting. Yet perhaps the overriding concern should be the consequences of suboptimal dyslipidemia management, which continues to be a major contributory cause for mortality and morbidity after transplantation. So, though there is no overwhelming evidence for clinical outcome for ezetimibe after cardiac transplantation, at the same time there does not appear to be a robust justification in withholding ezetimibe for enhanced LDL control in this setting.

Fibrates

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Conflicting evidence exists for the use fibrates after transplantation. As previously discussed, Barbir et al. [39] reported that bezafibrate use over a 3-month period caused effective reductions of total cholesterol by 12% (P= 0.0003), LDL cholesterol by 18% (P= 0.0001), and an increase of HDL cholesterol by 30% (P= 0.0002). A small but significant deterioration of creatinine was identified however, although it was not clear if this was a detrimental effect of bezafibrate or a beneficial effect of fish oils, given the lack of a placebo control. Fibrates have been shown to decrease plasma insulin, fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in hyperlipidemic heart transplant recipients [71]. Hyperfibrinogenemia is thought to contribute to a prothromobotic state increasing the risk of intravascular events postcardiac transplant [72]. By abating thrombosis through reducing circulating components of the clotting cascade, fibrates may, therefore, have the potential to reduce cardiovascular complications [73,74]. This is a theoretical point, however, rather than solid evidence. Other clinical trials have reported only modest effects of fibrates on lipid parameters in the transplant setting. A prospective study conducted over 12 months of follow up compared the effects of gemfibrozil 600 mg twice daily (17 patients), simvastatin 10 mg daily (13 patients), or cholestyramine 4 gm twice daily (18 patients) on lipid parameters. In this study, gemfibrozil reduced triglyceride levels (P < 0.01) but did not reduce either total cholesterol or increase circulating HDL [75]. Peters et al. [76] performed a retrospective analysis of the stepwise use gemfibrozil at two doses in posttransplant dyslipidemia (600 and 1200 mg daily, respectively). In all 52 patients (treated with gemfibrozil), there was a modest total cholesterol reduction of 7.4–7.0 mmol/l (287–272 mg/dL) after a mean treatment period of 5.4 months. Only 7 patients (13.5%) achieved “effective” lipid lowering (defined as a reduction ≥10% of baseline total cholesterol) with 600 mg dose. This rose to 22 patients (42%) after being switched to high dose (1200 mg a day). The authors concluded that gemfibrozil was effective only in a small group of patients. There was no biochemical abnormality or significant alteration in cyclosporine blood levels. However, as this was a short-term retrospective study with no control it is difficult to ascertain the strength of this finding.

Finally, in the native setting the combination of a stain and fibrate is associated with a possible greater risk of myopathy [77]. However with dual therapy the overall 0.12% incidence of myopathy is lower than in some studies using statin mono-therapy [78]. In conclusion, the merits of fibrate use after cardiac transplantation remain under question with perhaps the exception of hypertriglyceridemia management.

Niacin

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Nicotinic acid reduces total cholesterol and prevents the progression of atherosclerosis [79]. It has also been shown to significantly reduce the incidence of all cause mortality in patients with previous myocardial infarction [80]. It affects a wide array of lipid parameters, namely a reduction in total cholesterol and LDL-C and a rise in HDL-C. How niacin exerts its beneficial effect is not fully understood, but increasing evidence suggests that it may be through a cholesterol-independent pathway [81]. Niacin may prevent atherothrombotic events in part by lowering prothrombotic factors [82] and its antiinflammatory effects on the vascular endothelium [83]. This was supported by an animal model which suggested that niacin prevents endothelial dysfunction independent of plasma lipid levels [84]. However, its clinical use has been limited by toleration issues particularly due to the side effect of flushing. Unfortunately there is also very little evidence of its efficacy, tolerability, or benefit in the transplant setting. One pediatric study in five heart transplant recipients who were treated with niacin therapy, the dose ranging from 50 mg twice a day to 500 mg twice a day, demonstrated that after 6 months niacin caused a significant decrease in serum cholesterol (mean reduction 73 mg/dL, P < 0.01) and only one child complained of facial flushing, which was subsequently resolved [85]. Henkin et al. [86] conducted a retrospective analysis of 82 patients treated with niacin who attended a dyslipidemia clinic, they included a subgroup of 17 heart transplant recipients. Sadly 10 of these 17 patients had to discontinue the drug; some due the development of hyperglycemia. Three patients developed drug-induced hepatitis. Overall, these studies shed little light on the clinical benefits of niacin use. There is also no experience documented for the use of a new compound containing niacin and laropiprant after transplantation. Of note, one report highlighted that an unusually high 28% of patients (n = 18) taking the combination of niacin, lovastatin, and cyclosporine-developed myopathy [87]. Although this finding was not seen in an alternative study in renal transplantation [88], it may be wise to avoid niacin use in patients who are taking cyclosporine until safety data can be demonstrated.

Cholestyramine

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Cholestyramine or bile acid sequestrants are a recognized therapy for the treatment of persistent hyperlipidemia in the nontransplant setting. Its lack of immunosuppressant drug interactions [89] and potential beneficial immunomodulatory properties [90] make it first appear like a viable option in the transplant setting. However, its use will continue to be limited by the high incidence of gastrointestinal upset, which results in high discontinuation rates (up to 41% after a year) [91]. Furthermore, the only randomized trial in heart transplant recipients concluded that after 12 months, cholestyramine did not result in a reduction of total cholesterol or serum triglyceride [75]. With this limited clinical data, it is difficult to clarify the role of bile acid sequestrants in transplant associated hyperlipidemia.

Diet and Exercise

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

Dietary advice is the first step in the treatment of hypercholesterolemia and many transplant recipients receive dietary counseling from a dietician. Perrino et al. [92] conducted a prospective observational study of 42 heart transplant recipients. All participants were given a diet and exercise plan. The level of compliance was assessed with an interview after 3 months. At interview those patients who described 90% compliance with the plan were placed in the active arm, patients who did not score so highly in the interview were followed as the control arm. After 12 months the patients in the compliant arm had a significant reduction in triglyceride level (P < 0.05) but not total cholesterol level. The study design had several weakness; both arms of the study were given the same dietary and exercise advice and the control group was only differentiated based on an interview which itself was a subjective assessment. Nevertheless it does suggest that although beneficial, dietary change is merely an adjunct to lipid lowering drug treatment after transplantation.

Sterol and stanol esters are a well-established dietary adjuvant in managing dyslipidemia [93]. A study compared 17 heart transplant recipients of which 16 were already stabilized on statins, who altered their diet to include sterol or stanol containing margarine with 11 control patients [94]. After 12 weeks the active treatment group demonstrated a significant reduction of total cholesterol and LDL cholesterol (total cholesterol −17%, P= 0.003; LDL-C −22%, P < 0.005). There were no reported side effects with mean cyclosporine blood concentrations not altering significantly. This study had a short follow up and was neither randomized nor blinded, but as preliminary data, it suggests that plant sterols might prove to be a safe and effective adjunctive strategy in the transplant setting.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References

The importance of treating dyslipidemia in the CT setting cannot be over emphasized, given the high incidence of CGV, which is regarded as a leading cause of mortality. The first line approach should be dietary advice in conjunction with a HMG-CoA-Reductase inhibitor (statin) which is effective in reducing total cholesterol, LDL-C and all cause mortality. However, at present, patients remain hyperlipidemic despite the widespread use of statins. A review of the literature reveals that all other second line therapy options have a paucity of clinical trial data to support their use. Studies in transplant cohorts tend to have short follow-up periods, low patient numbers, and few have placebo controls. This makes it difficult to derive absolute conclusions based on their findings alone and often forces the extrapolation of data from nontransplant evidence. This clearly creates a dilemma for the transplant physician and opinions may be divided on what is the correct management decision in the setting of hyperlipidemia despite statin therapy.

For evidence of tolerability and safety after transplantation, fish oils and ezetimibe arguably have the strongest backing in the literature as second line agents. It is likely that plant sterols will also prove tolerable without drug interaction, based on preliminary data. The efficacy of each of these agents on the lipid profile is, however, very different, underscoring the importance of individualizing the approach to lipid management after transplantation [95–108].

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methodology
  5. Fish Oils
  6. Ezetimibe
  7. Fibrates
  8. Niacin
  9. Cholestyramine
  10. Diet and Exercise
  11. Conclusion
  12. References
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