Cardiovascular disease (CVD) is the most common cause of mortality and morbidity after kidney transplantation (1, 2). In the general population, many studies have resulted in guidelines for the prevention and management of CVD (3, 4). However, despite high rates of CVD in renal transplant patients, few studies have examined the effects of CVD medications in this patient population and most have focused on use of statins (5). Moreover, analyses of registries have been limited by lack of CVD medication data. Hence, there are few guidelines for the prevention and management of CVD after renal transplantation, and the guidelines that exist have largely been extrapolated from studies of the general population (6), or they focus on blood pressure management (7).
The Patient Outcomes in Renal Transplantation (PORT) study was a large, multicenter, international study of kidney transplant outcomes (8). The PORT database includes comprehensive CVD medication data. In this retrospective observational study, we used the PORT database to examine use of CVD medications after renal transplant and the relationship of medication use to coronary heart disease risk.
Medication data were available for 15,410 patients from 10 centers. After excluding patients who died in the first 4 months posttransplant, we analyzed data on the medication use of 14,236 patients. Only a small proportion of patients had a history of CVD pretransplant; 27.9% were diabetic at the time of transplant and more than 70% reported a history of hypertension (Table 1). Approximately 50% of patients with detailed medication data underwent transplant in the most recent era, 2000 to 2006.
Medication Use Time Posttransplant
Use of CVD medications was high; 87% of patients who underwent transplant between 2000 and 2006 were using an antihypertensive or antiplatelet agent, and more than 40% a lipid-lowering agent, within the first 4 months posttransplant. For patients who underwent transplant in 1990 to 2006, the most common CVD medication class prescribed early in the posttransplant period was calcium channel blockers, with 42.7% of patients using this class of medication in the first 4 months.
Use of almost all medications increased in the first 4 months posttransplant (Fig. 1A), but use became static for most CVD and lipid-lowering medications after that time. In contrast, use of angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) declined in the first 3 months posttransplant. This was followed by a steady increase in use of these medications up to 5 years posttransplant, when 36.3% of patients were using ACE/ARBs. Similarly, use of statins continued to increase over the first 4 years posttransplant and then leveled off; only 17% of patients used a statin during the first 30 days, increasing to 39.6% at 5 years.
Medication Use Transplant Era
Use of all CVD medications in the first 4 months posttransplant significantly increased in more recent years (Fig. 1B). The odds ratios (OR) for any CVD medication use were significantly increased in both the 1995 to 1999 and 2000 to 2006 time periods compared with the earliest period examined (Fig. 1C), and the most marked increase was in use of medications in the statin class. The exception was use of diuretics, which did not change over the period examined. Despite an increase in more recent eras, use of ACE/ARBs remained low, with only 25% of patients using an ACE inhibitor or ARB in the first 4 months posttransplant in 2006.
Use of CVD Medications in High-Risk Patients
In patients who underwent transplant between 2000 and 2006, use of at least one CVD medication was high; more than 90% of patients used at least one of the medications studied. The reported use of each class of medication in patients with and without the CVD risk factors of diabetes, previous myocardial infarction, or coronary artery revascularization is shown in Figure 2(A).
In patients with no CVD risk factors, use of most medications was less than 50%. In patients with a previous myocardial infarction, use of β-blockers, ACE/ARBs, antiplatelet agents, and statins was significantly higher compared with patients with no history of myocardial infarction (Fig. 2B). Results were similar for patients who were reported to have undergone revascularization. Use of ACE/ARBs, however, was significantly lower in patients with a reported history of coronary artery revascularization compared with those with no revascularization history (OR 0.72, 95% confidence interval 0.55–0.95). In comparison, there was no significant difference in use of most CVD medications in patients with and without diabetes. The exception was use of lipid-lowering agents; use of statins and nonstatin lipid-lowering agents was significantly higher among diabetic patients. Adjusted ORs for use of CVD medications, 2000 to 2006, in patients with versus without CVD risk factors are shown in the Appendix.
Factors Associated With Use of CVD Medications
By logistic regression analysis, the factor most significantly associated with use of all classes of CVD medications was transplantation in the most recent era. Use of any CVD medication increased nearly 4-fold in 2000 to 2006 compared with the early 1990s, and use of statins increased 12-fold (Table 2). Other factors associated with use of CVD medications were increasing age, which was associated with increased use of diuretics and antiplatelet and lipid-lowering agents, and male sex, which was associated with increased use of all antihypertensive agents except antiplatelet agents but reduced use of diuretics and statins. In a model adjusted for history of diabetes or hypertension, neither diabetes nor hypertension, as a primary cause of renal failure, was associated with increased medication use.
Risk Factors for Major Adverse Cardiac Events Posttransplant
Several factors were associated with increased risk of a major adverse cardiac event at 12 months and 5 years posttransplant. The most significant risk factors at either time point were older age at the time of transplant and a major adverse cardiac event occurring posttransplant (Table 3).
Medication Use and Major Adverse Cardiac Events
In a univariate analysis, use of β-blockers, diuretics, antiplatelet agents, statins, and other lipid-lowering agents in the first 4 months posttransplant was associated with an increased risk of major adverse cardiac events at 12 months, and use of β-blockers, calcium channel blockers, statins, and other lipid-lowering agents at 12 months was associated with an increased risk at 5 years. With adjustment for comorbid factors, however, there was no significant increase in risk for major adverse cardiac events at 12 months with use of any CVD medication. Use of antiplatelet medications in the first year posttransplant was associated with a 27% lower risk of major adverse cardiac events at 5 years (Table 3).
This is the first description of CVD medication use in a large international observational renal transplant study with a long duration of follow-up. The primary finding was the significant increase in use of all CVD medications in more recent years, but despite this, the low use of many CVD medications in patients with known risk factors for coronary heart disease.
Demonstrating the substantial increase in use of all CVD medications is consistent with a general increase in awareness of CVD in renal transplant patients (9). In addition, the last decade has seen practice guidelines for primary and secondary prevention of coronary artery disease in both the general population (10, 11) and the kidney disease population (6, 12). Few randomized controlled trials have examined most CVD medications after transplantation. The Assessment of Lescol in Renal Transplantation (ALERT) study demonstrated a significant reduction in low-density lipoprotein cholesterol levels with use of fluvastatin after renal transplant, but no significant reduction in major CVD events (5). Although a subsequent analysis demonstrated a 35% reduction in incidence of cardiac death and definite nonfatal myocardial infarction (13) with use of fluvastatin, this was a post hoc analysis of endpoints that were not prespecified. Despite this negative study, practice guidelines now recommend treatment of hypercholesterolemia with statins in renal transplant patients (14, 15).
While use of all CVD medications except diuretics increased from 1990 to 2006, use of the statin class of medications increased most strikingly, with a 12-fold increase from the early 1990s. Use of statins continued to increase after publication of the ALERT trial in 2003 and the development of practice guidelines, but this trend was significant from the mid-1990s. Possibly, the increased use of CVD medications that we have demonstrated is due to more stringent reporting in more recent years. However, the trend observed in use of diuretics would suggest that this is not the case, as different reporting practice for one particular class of medications is unlikely.
Use of all types of CVD medication was lower than expected in patients at high risk for coronary heart disease. Fewer than 50% of patients with preexisting diabetes mellitus before transplant were given prescriptions for statins in the first 4 months posttransplant, and only 27% were recorded to be using ACE/ARBs. Notably, use of ACE/ARBs was lower in patients with than without preexisting diabetes. The only medications administered with significantly greater frequency to diabetic versus nondiabetic patients were lipid-lowering agents, despite guidelines for use of aspirin and ACE/ARBs in the general diabetic population (16). Although use of most CVD medications was significantly greater in patients with ischemic heart disease, only three fourths of patients with a previous myocardial infarction were using aspirin and only 62% were using a statin. These results are similar to results described in the Deterioration of Kidney Allograft Function study (17), and suggest a lack of certainty regarding use of CVD medications in this population. In contrast to the general population (18), the use of CVD medications in the PORT group was not higher in those patients who had undergone revascularization compared to those who had a previous myocardial infarction; rates of CVD medication use were lower than in the general population.
We also demonstrated that use of most CVD drugs did not increase after 4 months posttransplant, suggesting that physicians are less likely to institute new CVD medications later in the posttransplant period. Exceptions to this were ACE/ARBs and statins. The prevalence of ACE/ARB use decreased in the first 3 months posttransplant, but then continued to increase for up to 5 years posttransplant, from a prevalence of 13% at 3 months to 36% by 5 years. The low use of these medications in the early posttransplant period is not unexpected, due to concerns about renal artery stenosis and hyperkalemia (19). Little in the literature, however, demonstrates a deleterious effect of this class of drug, even when used in the early posttransplant period (20). Similarly, use of statins increased over time posttransplant. Reasons for this cannot be determined in this study; however, this trend may be due to the increase in serum cholesterol levels associated with immunosuppressive agents. Unfortunately, there were insufficient records of serum lipid levels in our data to accurately evaluate the efficacy of statins on cholesterol levels in this study.
This is the first study to associate a reduction in major adverse cardiac events with CVD medications after renal transplantation. Use of antiplatelet agents in the first year posttransplant was associated with a 27% lower incidence of major adverse cardiac events at 5 years among patients with a functioning graft at 1 year. However, these data must be interpreted with caution. While a reduction in CVD events with use of aspirin is plausible, and has been demonstrated in high-risk groups in the general population (21, 22), a cause-effect relationship cannot be established in this retrospective observational study. Only a proportion of the PORT population was examined in this study due to lack of medication data from some centers, and doses were not recorded. Additionally, while the ALERT study demonstrated a reduction in some CVD end points with use of fluvastatin, no such association was demonstrated with statins in this analysis. Nevertheless, the associations of risk factors such as preexisting CVD events, increasing age, diabetes, and nonfatal major adverse cardiac events in the first 4 months posttransplant with cardiac events at 1 and 5 years in this study are consistent with previous reports (1, 2, 8). Randomized controlled trials are necessary to determine the effects of CVD medications on cardiac events in the transplant population, and are crucial to confirm the findings of observational studies such as this.
This study is limited in several ways. Only 55% of the total PORT population was included in the analysis due to incomplete or nonexistent collection of medication data from some centers. The accuracy of medication reporting was checked by each unit after initial analyses of medication use were collated. Collection of drug dosing data would have added useful information; however, these data were rarely recorded and were therefore unsuitable for analysis. Similarly, blood pressure measurements and lipid levels at a number of time points were documented for a small proportion of patients. Thus, these variables were not analyzed in this study. Descriptions of patient subgroups according to CVD risk (23), as in the general population, would have been useful; however, blood pressure and lipid measures were unavailable for a substantial number of patients, and family history was not recorded. Patients who died or returned to dialysis within 4 months of transplant were excluded from the study; an additional analysis was performed to assess use of CVD medications in this group. Despite these patients being older and more likely to have underlying CVD, CVD medication use was even lower.
All CVD medications recorded were analyzed in this study. In the general population, evidence supports use of only aspirin, β-blockers, statins, and ACEs (18). Unfortunately, no such evidence exists in the renal transplant population. Calcium channel blocker use is commonplace posttransplant, and this is the only class of agent shown to affect patient and graft survival (24). Because of the lack of evidence for the benefits of CVD medications in the renal transplant setting, we included all classes of medications in the analyses. Findings of analyses including only ACEs, β-blockers, aspirin, and statins were very similar.
In summary, this is the first study to comprehensively analyze use of CVD medications in a large international registry of more than 14,000 patients, and to examine use of these medications in patients at high risk for CVD events. We demonstrated a substantial increase in use in recent years, suggesting increased acceptance of guidelines and confidence in the use of these agents. However, despite the high risk of coronary heart disease after renal transplant, use of CVD medications was lower than anticipated, even in high-risk groups, and use of most CVD medications did not increase after the first 4 months posttransplant. These data suggest the need for clinical trials to examine the effects of CVD medication in renal transplant patients and assess the potential for reducing cardiac events.
MATERIALS AND METHODS
The PORT study examined outcomes and CVD risk in 23,575 renal transplant patients from 14 centers worldwide. Methods for the data collection have been reported previously (8). Comprehensive data, including use of CVD medications, were collected from 10 centers for patients who underwent transplants from 1990 through 2006. Eight centers reported data on nonlipid-lowering CVD medications, and 10 centers reported on CVD medications including lipid-lowering agents. Four centers did not report data on CVD medications and were excluded from this analysis. Data were analyzed at multiple time points up to 5 years posttransplant. Patients were classified as using a particular class of medication if they had a record of taking that medication at any time during the month. For most analyses, patients were considered to be using CVD medication if use had been recorded in the first 4 months posttransplant. Additional analyses were performed examining medication use at 12 months.
Results from each individual center were reviewed locally to ensure accurate data collection. In addition, site visits were made to audit data and data collection procedures, as described previously (8).
Medications were categorized by mechanism of action. Any CVD medication included β-blockers, ACEs or ARBs, calcium channel blockers, and diuretics. The antiplatelet category included aspirin, clopidogrel, dipyridamole, and other antiplatelet agents, but excluded anticoagulants. The other antihypertensive category included α-antagonists, clonidine, nitrates, and minoxidil.
Transplant patient data elements included age, sex, race, body mass index, cytomegalovirus and hepatitis C serostatus, smoking history, cause of end-stage renal failure, and time from commencement of dialysis to transplantation. In addition, data regarding pretransplant diabetes mellitus, hypertension, cancer, and CVD events (myocardial infarction, cerebrovascular accident, peripheral vascular disease, coronary revascularization, and congestive heart failure) were included. Transplant-related variables included panel reactive antibodies, human leukocyte antigen mismatches, and cold ischemia time. Other factors analyzed were donor status (living vs. deceased), transplant era, and year of transplant. Transplant era was divided into cohorts, 1990 to 1994, 1995 to 1999, and 2000 to 2006. Posttransplant data included delayed graft function (defined as need for dialysis in the first week posttransplant).
We analyzed associations of CVD medications and major cardiac adverse events. Medication use at 4 months posttransplant was included in the analyses of adverse events at 1 year, and medication use at 1 year was included in the analyses of adverse events at 5 years. Patients who died within the first 4 months posttransplant were not included in the study.
Logistic regression analysis was used to determine ORs of medication use at 4 months posttransplant by transplant era, adjusted for age, sex, race, and primary cause of renal failure. The reference era was 1990 to 1994. In a subset of patients who underwent transplant in 2000 to 2006, logistic regression was used to determine ORs for medication use at 4 months posttransplant, adjusted for the following risk factors: age, race, body mass index, primary cause of renal failure, history of hypertension, time on dialysis, donor type, cold ischemia time, and transplant center. Cox proportional hazards analysis was used to quantify hazard ratios of medication use on 1- and 5-year major cardiac adverse events, adjusted for age, sex, race, body mass index, primary cause of renal failure, time on dialysis, panel reactive antibodies, and history of CVD risk factors. SAS version 9.1 (SAS Institute, Cary, NC) was used for all analyses.
The authors thank Chronic Disease Research Group colleagues Shane Nygaard for manuscript preparation and Nan Booth, MSW, MPH, for manuscript editing.
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