ALTHOUGH MEDICATIONS have an important

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1 Dialysis Outcomes and Practice Patterns Study (DOPPS) Data on Medications in Hemodialysis Patients Vittorio E. Andreucci, MD, Rachel B. Fissell, MD, MS, Jennifer L. Bragg-Gresham, MS, Jean Ethier, MD, Roger Greenwood, MSc, MD, FRCP, Mark Pauly, PhD, Volker Wizemann, MD, and Friedrich K. Port, MD, MS Background: Medications affect many measures of hemodialysis patients well-being. Methods: The Dialysis Outcomes and Practice Patterns Study (DOPPS) has evaluated the use of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), analgesics, antidepressants, and multivitamins. Additionally, DOPPS has reported on the associations between vascular access outcomes and related medications. Results: Prescription of statins varied widely across countries, with the highest use in the United States. Patients prescribed statins had lower risk of cardiac and noncardiac causes of mortality than those who were not prescribed statins. DOPPS data also show that statins are underprescribed relative to recent Kidney Disease Outcomes Quality Initiative guidelines. No guidelines have been established for analgesic use, but high pain levels self-reported by hemodialysis patients suggest opportunities for improved pain management strategies. Guidelines for analgesic use in dialysis patients may help balance improved quality of life against potential side effects of analgesics. Medical and patient questionnaires show that depression in hemodialysis patients is common, frequently underdiagnosed, usually untreated, and associated with increased rates of mortality and hospitalization. Calcium channel blockers were associated with improved primary graft patency, aspirin with improved secondary graft patency, and angiotensinconverting enzyme inhibitors with improved secondary fistula patency. All 3 medications were associated with significantly decreased relative risk for access failure. There is large country variation in multivitamin use, with significantly higher use in the United States compared with Europe and Japan. Patients taking multivitamins had lower mortality risk than patients not taking multivitamins. Conclusion: DOPPS findings on medications indicate that prospective trials are needed before guidelines can be developed for appropriate medication use in these different therapeutic categories. Am J Kidney Dis 44(S2):S61-S by the National Kidney Foundation, Inc. INDEX WORDS: Analgesics; medications; mortality; statins; vascular access outcomes; water-soluble vitamins. ALTHOUGH MEDICATIONS have an important effect on the well-being of hemodialysis patients, the Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines have not specifically addressed their use. The Dialysis Outcomes and Practice Patterns Study (DOPPS) data offer comprehensive information, including not only details on comorbidities and laboratory data but also on all medications prescribed to patients at baseline and during follow-up. This article reviews previous DOPPS findings on the use of hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, analgesics, medications related vascular access, antidepressants, and water-soluble vitamins. STATINS Cardiovascular disease is the most frequent cause of mortality among dialysis patients. HMG- CoA reductase inhibitors (statins) have been shown to affect mortality in the general population. Because minimal data are available on statins efficiency in uremic patients receiving hemodialysis (HD), the DOPPS has evaluated the relationship between statin prescription and clinical outcomes in HD patients. 1 The expanded study has included data on patients undergoing chronic HD treatment in the United States (n 9,846), Europe, France, Germany, Spain, Italy, United Kingdom (n 4,591), and Japan (n 2,784). From Universita Federico II, Naples, Italy; Veterans Administration Medical Center/University of Michigan, Ann Arbor, MI; University Renal Research and Education Association, Ann Arbor, MI; Centre Hospitalier de l Université de Montreal, Montreal, Quebec, Canada; Lister Hospital, Stevenage, United Kingdom; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA; and Georg Haas Dialyzentrum, Giessen, Germany. The Dialysis Outcomes and Practice Patterns Study is supported by research grants from Amgen and Kirin without restrictions on publications. The NKF gratefully acknowledges the support of Amgen, founding and principal sponsor of K/DOQI. The publication of this supplement was supported by the DOPPS. Address reprint requests to Friedrich K. Port, MD, MS, University Renal Research and Education Association, 315 W. Huron Street, Suite 260, Ann Arbor, MI dopps@urrea.org 2004 by the National Kidney Foundation, Inc /04/ $30.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 44, No 5, Suppl 2 (November), 2004: pp S61-S67 S61

2 S62 DOPPS I data from all 7 countries revealed that, in early 2000, statins were prescribed for only 11.8% of all HD patients. However, there was wide variation among the countries, with the prescriptions of statins averaging 16.6% in the United States, 15.7% in France, 11.9% in Germany, 8.1% in the United Kingdom, 7.1% in Japan, 4.9% in Spain, and only 3.5% in Italy. Prescription of statins was relatively higher for patients who had either total serum cholesterol of 200 mg/dl (5.17 mmol/l) (15.7% overall), coronary artery disease (17.5%), or a history of myocardial infarction (22.0%). But even under these 3 conditions, although statin prescription rates were relatively higher in the United States (27.5% in patients with total serum cholesterol 200 mg/dl [5.17 mmol/ L], 22.3% in patients with coronary artery disease, and 27.5% in patients with a history of myocardial infarction) and in France (12.9%, 24.0%, and 26.4%, respectively); they were much lower in all other countries. This low prescription of statins in at-risk HD patients is consistent with other published observations. 2,3 Multivariate analysis showed that patients were less likely to be prescribed statins if they were older (probability of receiving statins was 11% less for each 10-year older age), male (26% less), or on dialysis for longer periods (probability of receiving statins was 5% less for each year of prior dialysis therapy). All else being equal, the likelihood of being prescribed a statin was 45% higher in patients with coronary artery disease, 48% higher in patients with peripheral vascular disease, and 61% higher in diabetic patients. The most commonly used statin agent was simvastatin in France, Italy, and Spain (58% to 72%); pravastatin in Germany (51%) and Japan (58%); and atorvastatin in the United States (45%). Simvastatin (50%) and pravastatin (48%) were equally prescribed in the United Kingdom. 1 Statin prescriptions at the HD unit level indicated that in 16.5% of the units no patients were receiving statins, whereas as many as 37.1% of units prescribed statins to 1% to 10% of their patients. Evaluation of the association of statins use and mortality in DOPPS patients suggest a large opportunity for benefits from greater use of statins. Patients prescribed statins, in fact, had a 31% lower relative risk of death compared with those who were not prescribed statins. Results ANDREUCCI ET AL adjusted for mortality show that statin prescription was also associated with a 23% lower risk of cardiac causes of death (P 0.03). This reduction in cardiac mortality associated with the use of statins occurred in all countries involved in the DOPPS, confirming the data of Seliger et al 2 on incident HD patients in the US Renal Data System Dialysis Morbidity and Mortality Study Wave 2 ( ) and those reported in the general population. 4-6 A 44% lower risk of noncardiac mortality associated with statin prescription was also observed in the DOPPS and suggests a role for statin effects other than through plasma lipids. Statins have pleiotropic effects: they may have favorable effects on endothelial function, coagulation, and plaque stability. 7 Even more clear is their effect on systemic inflammation A strong association has been described between inflammation, nutritional status, and atherosclerosis in chronic kidney disease and the important role of inflammation in enhancing cardiovascular risk and mortality in HD patients These data clearly show that statin prescription is very low in HD patients of all the DOPPS countries, much lower than suggested by the National Kidney Foundation s K/DOQI Guidelines. 7 A K/DOQI workshop has, in fact, estimated that more than 60% of HD patients require treatment of their hyperlipidemia. 7 The DOPPS data indicate high percentages of HD patients with total serum cholesterol of 200 mg/dl (5.17 mmol/l). For example, in Germany 59.2% of HD patients have elevated total cholesterol levels, but only 11.9% have a statin prescribed. In countries with fewer HD patients having elevated total serum cholesterol ( 200 mg/dl [5.17 mmol/l]), such as the United Kingdom (37.2%) and Italy (33.5%), prescriptions of statins were extremely low (8.1% and 3.5%, respectively). Thus, all the DOPPS countries appear to underuse statins. 1 Potential factors for underprescription of statins in HD patients include (1) absence of data from randomized trials conducted in patients with chronic kidney disease, as recognized by the K/DOQI 7 ; (2) statins are expensive; and (3) doctors may be afraid of possible side effects and only recent dissemination of guidelines. Whereas the DOPPS data refer to early 2000, the K/DOQI Guidelines for managing dyslipidemias in chronic

3 MEDICATIONS IN HEMODIALYSIS PATIENTS kidney disease were only published in It is reasonable to expect that statin prescription will greatly increase in HD patients, particularly among those in the high-risk categories. Consistent with this provision are the available DOPPS data in the period of observation going from September 1996 to January 2001, showing that in the United States the proportion of patients prescribed statins was increasing steadily with time. A similar increasing tendency was observed also in France and in Germany from September 1998 to September ANALGESICS Uremic patients undergoing HD frequently suffer from pain due to a variety of factors, including advanced bone disease, peripheral neuropathy, and chronic arthritis. Thus, use of analgesics is quite relevant to the quality of life of HD patients. Pain may lead to sleep deprivation and reduced efficiency and physical functioning during the day. These physical consequences of chronic pain may predispose HD patients to unemployment and depression. 18,19 Nevertheless, little is known about analgesic prescriptions in HD patients, and no guidelines have been established for such prescriptions for this type of patient. Thus, it appeared worthwhile to evaluate analgesic use in the DOPPS. Analgesic prescriptions were evaluated by the DOPPS for 3,749 HD patients distributed across 142 United States facilities (US-DOPPS) during 1996 and Data on aspirin were excluded from consideration because aspirin is commonly used in HD patients as an antiplatelet aggregation drug rather than as an analgesic. The use of analgesics was recorded as part of all medications prescribed at the HD unit. Prescription during hospitalization periods was not recorded in DOPPS. In the US-DOPPS, 50.7% of the patients under narcotic analgesics received propoxyphene either alone or in combination with other analgesics. Narcotics were usually prescribed in combination rather than as single drugs. The most prescribed narcotics were combinations of propoxyphene and acetaminophen (47.2%), whereas the prescription of propoxyphene alone was limited to 3.5% of the patients. Acetaminophen was widely used in combination, being prescribed in 84.1% of patients under narcotic S63 analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most prescribed non-narcotic analgesics; the most prescribed was ibuprofen (33%), followed by naproxen (16.8%) and indomethacin (12.5%). 20 In 1999, cyclo-oxygenase 2 (COX-2) drugs became available. This led to a decline in prescriptions of other NSAIDs and acetaminophen. Thus, from May 1997 (pre COX-2 evaluation) to September 2000 (post COX-2 evaluation) the prescription of any analgesic decreased from 30.2% to 24.3%, that of narcotic analgesics from 18.0% to 14.9%, and that of NSAIDs from 6.4% to 2.3%. Meanwhile, the use of COX-2 agents increased from 0% to 4.9%. In addition to this switch in prescription from NSAIDs and acetaminophen to COX-2 drugs, the DOPPS has also shown a lower use of analgesics with time. However, the duration of analgesic use was usually long: almost half of the patients were still taking these drugs 1 year later, and many of them were taking analgesics for much longer. 20 The DOPPS also evaluated by patient questionnaire self-reported pain status. The findings of a high level of pain in these patients suggested underprescription of analgesics. One may speculate that nephrologists avoid analgesic prescriptions, particularly NSAIDs, in the earlier stages of chronic kidney disease. Although there are no guidelines on the use of analgesics in HD patients, the National Kidney Foundation discourages the prescription of NSAIDs in patients with chronic kidney disease who are not yet on dialysis. 21 The World Health Organization also suggests a limited use of these agents in patients with chronic kidney disease. 22,23 Physicians may want to avoid possible side effects from analgesics. Both NSAIDs and COX-2 agents may impair kidney function. 24,25 HD patients who have residual renal function and are taking NSAIDs or COX-2 agents, are at risk of losing that residual renal function. The role of residual renal function in reducing risk for mortality in HD patients is not yet clear. DOPPS analysis to date has not demonstrated that loss of residual kidney function is a risk factor for mortality in HD patients. 20 For patients requiring chronic dialysis, guidelines for analgesic use in HD patients may help balance an improved quality of life against potential side effects. During the early phase of dialy-

4 S64 sis, it may be wise to avoid NSAIDs while patients have residual renal function. DEPRESSION AND RELATED MEDICATIONS Depression is quite frequent in HD patients. 26 DOPPS II evaluated the prevalence of physician diagnosis of depression and patient-reported symptoms of depression in 6,987 patients in all 12 DOPPS countries. Patient-reported symptoms of depression were assessed by using the short, 10-item version of the Center for Epidemiological Studies Depression (CES-D) Screening Index for depressive symptoms in the past week. CES-D scores can range from 0 to 30, higher scores being indicative of greater depressive symptoms. For comparison purposes, the cutoff value of 10 for symptoms of depression was used. 27 Physician-diagnosed depression was reported in the medical records of 13.9% of patients. The lowest prevalence was observed in Japan (2.0%) and the highest in Sweden (19.8%) and the United States (21.7%). Among all patients with physician-diagnosed depression, however, only 34.9% were prescribed antidepressant medications (eg, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclics). The overall percentage of patients with a CES-D score 10 (43.0%) was approximately 3 times higher than the prevalence of physician-diagnosed depression; yet, overall, only 17.3% of these patients with CES-D score 10 were prescribed antidepressants. Physician-diagnosed depression was reported among only 32.3% of patients with CES-D scores 15, and even fewer (20.8%) were prescribed antidepressants; 39.7% had either physician-diagnosed depression or were prescribed antidepressants. 28 After adjustments for demographic and comorbid conditions, significantly higher relative risks of all-cause mortality (relative risk 1.42), first hospitalization after study start (relative risk 1.12), and withdrawal from dialysis (relative risk 1.55) were observed for patients with CES-D scores 10 (compared with lower CES-D scores). However, the association between self-reported depression and mortality did not differ significantly between patients receiving and not receiving antidepressive drugs. 28 The DOPPS data suggest that depression in HD patients is frequent, often not recorded as a ANDREUCCI ET AL diagnosis, frequently untreated, and associated with an increased rate of mortality, hospitalization, and withdrawal from dialysis. Depression is the most prevalent psychological problem among HD patients. Given its strong correlation with risk of adverse outcomes, the development of specific guidelines to inquire about and identify depression in HD patients may help improve the clinical diagnosis of depression. Additionally, these DOPPS findings indicate the need for clinical trials to investigate the benefits of long-term antidepressive therapy. It appears that correcting depression in HD patients may reduce mortality and greatly improve their quality of life. VASCULAR ACCESS AND RELATED MEDICATIONS Vascular access failure is one of the major problems in HD patients that requires intervention and often hospitalization. 29 Reasons for failure of arteriovenous grafts and fistulae may be a stenosis at the venous anastomosis secondary to neointimal hyperplasia, along with vascular smooth muscle proliferation followed by thrombosis. 30,31 The DOPPS researchers studied, in a large number of HD patients, the association of the use of cardioprotective or antithrombotic drugs with vascular access outcomes, while adjusting for numerous potentially contributing factors. This evaluation, performed in 133 HD units in the United States, included 892 patients with 900 arteriovenous fistulae and 1,511 patients with 1,944 arteriovenous grafts. Primary (unassisted access survival) and secondary (assisted access survival) access patency were considered. (Primary access patency is the time from access creation to first access thrombosis or access salvage procedure; secondary access patency is the time from access creation to its complete failure or the creation of a new access.) The secondary access patency allowed the inclusion of possible benefits of nonpharmacological (eg, surgical and/or radiological) interventions. The association of 11 drugs (angiotensin-converting enzyme [ACE] inhibitors, antianginal agents, calcium channel blockers [CCBs], angiotensin II inhibitors, NSAIDs, aspirin, coagulation modifiers, statins, antiplatelet agents other than heparins, or warfarin) with access (graft and fistula) failure were evaluated.

5 MEDICATIONS IN HEMODIALYSIS PATIENTS The use of CCBs was associated with improved primary graft patency, with a significant 14% decrease of relative risk for failure (P 0.034). 32 This finding appears to agree with a reported lower incidence of neointimal hyperplasia in association with the use of CCBs. 33 The use of aspirin was associated with improved secondary graft patency, with a significant 30% decrease in relative risk for failure (P 0.001). The beneficial effect of aspirin may be the result of its antiplatelet properties, already shown in the prophylaxis of myocardial infarction. 34 However, other antiplatelet drugs were not associated with risk reduction for graft failure, presumably because of the small number of DOPPS patients taking these drugs. 32 The use of ACE inhibitors was associated with improved secondary fistula patency, with a significant 44% decrease of relative risk for failure (P 0.010). 32 Patients receiving warfarin, a well-known anticoagulant, had a higher relative risk of primary graft failure. Patients prescribed this drug, however, are likely to have been predisposed to access thrombosis or are known to be hypercoagulable. 35 This suggests that this finding was confounded by the indication for warfarin prescription. An evaluation of DOPPS data has shown that patients administered warfarin had a greater prevalence of certain risk factors that may be associated with graft failure. 32 These data suggest the need for randomized trials of drug therapies that have been associated in the DOPPS with better access survival. Thus, the DOPPS has been generating new hypotheses that are worth exploring through prospective trials. WATER-SOLUBLE VITAMINS The DOPPS has also evaluated the use of watersoluble vitamins in HD patients and their association with mortality and hospitalization. The study included 16,345 patients randomly selected from 308 HD units in the United States, Japan, and 5 European countries (France, Germany, Italy, Spain, and the United Kingdom). 36 Water-soluble vitamins were usually taken as multivitamins (containing vitamins B 6, B 12, ascorbic acid, and, in 72.2% of US patients, folate). There was large variation in the prescription of water-soluble vitamins in the different countries. Although 71.9% of HD patients in the United States were prescribed these vitamins, S65 this percentage was much lower in Europe, ranging from 37.9% in Spain to 6.4% in Italy. Only 5.6% of Japanese patients were prescribed watersoluble vitamins, and in the majority of Japanese HD units no patients had a prescription of watersoluble vitamins recorded. There are several possible explanations for such a large variation (eg, differences in cost, insurance coverage, patients preferences, and doctors and patients beliefs regarding their efficacy). In fact, several short-term studies have not shown benefits of vitamin supplementation. 37,38 The DOPPS evaluated associations of watersoluble vitamin use and outcomes. Patients taking such vitamins had a 16% lower mortality risk than patients not taking water-soluble vitamins, after adjustment for age, sex, race, comorbid conditions, hemoglobin, serum albumin, body mass index, time on HD, average facility singlepool Kt/V, and average facility normalized protein catabolic rate. 36 How can we explain such associations? Dialysis therapy clearly leads to removal of watersoluble vitamins, particularly when high-flux, high-efficiency dialysis is used It has been shown that uremic patients have elevated serum levels of homocysteine, which is a cardiovascular risk factor Supplementation of watersoluble vitamins (particularly folic acid) reduces serum level of homocysteine in HD patients, 37,46-50 thereby potentially decreasing cardiac complications and mortality. Other factors may also influence the association of reduced patient mortality with the use of water-soluble vitamins, such as more meticulous care at the HD unit, better socioeconomic conditions, and possibly better nutritional status of the patients taking water-soluble vitamins or a greater tendency to take vitamins by patients who do not need as many other medications. It is, however, an interesting hypothesis that the use of watersoluble vitamins may improve longevity in HD patients. Observational studies can describe significant associations that are useful for practicing clinicians. 51 However, particularly with regards to medications, the DOPPS points to areas in which prospective trials are needed before medication guidelines can be developed. Until such trial results become available, clinicians must balance risks against potential benefits. For prescription

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