Management of Mixed Dyslipidemia: Knowledge and Practice

Transcription

1 Management of Mixed Dyslipidemia: Knowledge and Practice U. Shanette Granstaff, MPH, Farrokh Sohrabi, MD, Hamidreza Doroodchi, MD, Nancy Roepke, MBA, Maziar Abdolrasulnia, PhD Outcomes, Inc., Birmingham, Alabama, USA Abstract Background: Despite the beneficial effects of lowering low-density lipoprotein cholesterol (LDL-C) to Adult Treatment Panel (ATP) III guideline recommended levels, major statin trials have revealed a two-thirds residual cardiovascular event risk in high-risk populations. This study was designed to explore how clinicians address residual cardiovascular risk. Methods: Case-vignette surveys were distributed to a representative set of 4 US provider groups to investigate perceptions and practice patterns in the management of high-risk patients with mixed dyslipidemia. Results: Ninety-three percent of cardiologists, 96% of endocrinologists, and 97% of primary care practitioners (PCPs) and nurse practitioners (NP) and physician assistants (PAs) underestimated residual risk in a patient achieving LDL-C goal. Sixty-nine percent of cardiologists, 61% of endocrinologists, 66% of PCPs and 70% of NP/PAs would not focus on LDL-C and non high-density lipoprotein cholesterol (HDL-C) levels for lipid-lowering therapy in a high-risk patient, and 69% of cardiologists, 59% of endocrinologists, 57% of PCPs, and 68% of NP/PAs did not identify appropriate lipid profile management goals. Sixty-four percent of cardiologists would not initiate treatment targeting both LDL-C and non HDL-C in a very high-risk patient with mixed dyslipidemia; 50% of endocrinologists would not add niacin in a patient with atherogenic dyslipidemia; and 64% of PCPs and 55% of NP/PAs would not treat with combination statin and fenofibrate in a patient with mixed dyslipidemia. Conclusion: Although many clinicians report familiarity with National Cholesterol Education Program (NCEP) guideline recommendations, there is low concordance with recommendations when managing high-risk patients with mixed dyslipidemia. Educational initiatives and practice tools that enhance understanding of non HDL-C and improve clinicians skills in using combination therapies to optimally manage mixed dyslipidemia in high-risk patients may reduce variability in practice and improve patient outcomes. CE Meas. 2009;3: doi: /cem Carden Jennings Publishing Co., Ltd. Introduction Mixed, or atherogenic, dyslipidemia is characterized by a high proportion of low-density lipoprotein cholesterol (LDL-C) particles, elevated triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C). In prior studies, each of these abnormalities has been associated with increased rates of cardiovascular (CV) risk [1-5]. Mixed dyslipidemia is common in type 2 diabetes, obesity, and the metabolic syndrome [6]. Findings from the National Health and Nutrition Examination Surveys (NHANES) indicated that 17% of adults have a total cholesterol level of at least 240 mg/dl [7] a level that is considered high by the National Cholesterol Education Program (NCEP) criteria [8]. Although serum total cholesterol and LDL-C levels have steadily declined in the United States over the last 40 years, most recently, this decline has occurred primarily among older men and women and is largely attributed to the increased use of lipid-lowering medications [7]. The 2001 publication of NCEP Adult Treatment Panel III (ATP III) guidelines heralded significant increases in both the reach and intensity of LDL-lowering therapy [9]. Nonetheless, despite the beneficial effects of lowering LDL-C to ATP III guideline recommended levels, CV events continue to occur, especially among high-risk populations, including those with the metabolic syndrome and type 2 diabetes [10]. The ATP III guidelines define high-risk patients as those with coronary heart disease (CHD) or CHD risk equivalents (noncoronary forms of clinical atherosclerotic disease, diabetes, or multiple 2 or more CHD risk factors with 10-year risk for CHD >20%) [9]. High-risk patients classified as very high-risk are those who have had a recent myocardial infarction or those who have cardiovascular disease combined with either diabetes or severe or poorly controlled risk factors (such as continued smoking) or the metabolic syndrome. Major statin trials, some of which were published after the release of ATP III guidelines, have revealed up to a two-thirds residual CV event risk in such high-risk or very high-risk patients despite therapy with statins [10,11]. Abnormalities in LDL-C particle size and number, very lowdensity lipoprotein (VLDL) remnants, TGs, and HDL-C that characterize mixed dyslipidemia are thought to play a role along with other known and unknown factors in maintaining this residual risk of CV disease. Treating these additional lipid abnormalities has proven beneficial in risk reduction in certain high-risk populations particularly those with type 2 diabetes or the metabolic syndrome [12-14]. In 2004, a detailed assessment of the newly published statin trial data was designed in order to provide recommendations for Correspondence: U. Shanette Granstaff, MPH, Outcomes, Inc., 107 Frankfurt Circle, Birmingham, AL 35211, USA; ; fax: ( shanette.granstaff@ceoutcomes.com). 65

2 66 Granstaff et al Table 1. Provider Demographics and Characteristics Related to Dyslipidemia Management* Parameter Cardiologists (n = 149) Endocrinologists (n = 141) PCPs (n = 149) NP/PAs (n = 143) Years in practice (mean ± SD) ± ± ± ± 8.43 Degree type, n (%) MD 144 (96.6) 135 (95.7) 145 (97.3) N/A DO 5 (3.4) 6 (4.3) 4 (2.7) N/A Practice Type, n (%) Private 138 (93.2) 114 (87.7) 134 (90.5) 115 (87/1) Hospital 3 (2.0) 8 (6.2) 6 (4.1) 15 (11.4) Academic 7 (4.7) 8 (6.2) 8 (5.4) 2 (1.5) Number of patients seen per week (mean ± SD) ± ± ± ± Percent of patients seen per week with ± ± ± ± dyslipidemia (mean ± SD) Number of patients seen per week with dyslipidemia (mean ± SD) ± ± ± ± *PCP indicates primary care physician; NP/PA, nurse practitioner/physician assistant; SD, standard deviation; DO, doctor of osteopathic medicine; N/A, not applicable. patients at high risk and very high risk for CV disease. The NCEP Update reinforced previous statements made in ATP III and recommended considering low HDL-C and elevated TGs as independent predictors for CV risk, assessing non HDL-C as a secondary target of therapy in persons with high TGs (3200 mg/dl), and considering the addition of a fibrate or nicotinic acid to current LDL-C lowering therapy in high-risk or very high-risk patients [9]. Non HDL-C equates to VLDL + LDL-C. The non HDL-C goal is 30 mg/dl higher than the LDL-C goal. Non HDL-C was added as a secondary target of therapy to take into account the atherogenic potential associated with remnant lipoproteins in patients with hypertriglyceridemia [9]. Once target LDL-C goals have been achieved with statins, combination therapy with nicotinic acid or a fibrate should be considered to optimize TG and HDL-C levels [9]. The most recent national survey of compliance with NCEP ATP III treatment guidelines was conducted in 2003 and surveyed 4,885 patients. Of the 1,447 patients with CV disease, the largest treatment gaps were found for features new to ATP III, including goal achievement for patients with CHD risk equivalents and for non HDL-C targets. Attainment of combined LDL-C and non HDL-C targets among patients with CHD or CHD risk equivalents and TG level 200 mg/dl was only 27%, indicating potential under-treatment of patients with hypertriglyceridemia [15]. As part of an educational needs assessment, this study sought to examine current practice patterns and guideline concordance, as well as the uptake of recent recommendations by practicing US cardiologists, endocrinologists, primary care physicians (PCPs), and nurse practitioners and physician assistants (NP/PAs) in the management of high-risk and very high-risk patients with mixed dyslipidemia. Methods Survey Development Three parallel surveys were developed in order to investigate practice patterns of US cardiologists, endocrinologists, PCPs, and NP/PAs in the management of high-risk and very high-risk patients with mixed dyslipidemia. A review of the scientific literature was first conducted in order to examine gaps between NCEP ATP III guidelines, NCEP Update recommendations, and actual clinical practice. As a second step, focus groups were conducted with practicing clinicians from each specialty to identify issues that are most challenging in managing high-risk and very high-risk patients with mixed dyslipidemia. Based on the information from the literature and focus groups, a series of dyslipidemia-based case vignettes were created, each with multiple choice questions that examined how clinicians approach atherogenic dyslipidemia in high-risk and very high-risk patients with respect to NCEP ATP III guidelines. Questions specifically explored targets and goals of lipid lowering therapy, choice of therapeutic agents, and understanding of residual CV risk the risk of CV events remaining after reducing LDL-C to goal. In order to determine validity, all cases and questions were reviewed by experts from each targeted specialty group. Survey questions revolved around case vignettes because this approach has proven to be a valid and comprehensive way to assess clinicians actual practice choices [16-18]. Additional questions addressing perceptions, attitudes, and demographics were included in each of the surveys.

3 CE MEasure Volume 3, Issue Table 2. Provider Perceptions Related to Dyslipidemia Management* Parameter Cardiologists (n = 149) Endocrinologists (n = 141) PCPs (n = 149) NP/PAs (n = 143) P Familiar or extremely familiar, n (%) Combination therapies targeting total lipid profile Side effects of combination therapies targeting total lipid profile Treating residual risk in patients at LDL-C goal NCEP ATP III guidelines for TG and HDL-C Agree or strongly agree, n (%) 126 (85.1) 125 (90.6) 119 (80.4) 86 (61.4) < (88.4) 131 (93.6) 127 (85.8) 99 (69.2) < (84.8) 115 (82.7) 102 (69.9) 76 (53.9) < (83.1) 117 (84.2) 96 (64.4) 70 (49.3) <.001i Low HDL-C level is an independent 139 (93.3) 126 (89.4) 134 (91.2) 116 (81.7).01# risk factor for CHD *PCP indicates primary care physician; NP/PA, nurse practitioner/physician assistant; LDL-C, low-density lipoprotein cholesterol; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease. Values of 4 or 5 on a scale of 1 to 5, with 1 being not at all familiar and 5 being extremely familiar. Significant differences exist between NP/PAs and all other groups. Significant differences exist between all groups except cardiologists and endocrinologists and endocrinologists and PCPs. isignificant differences exist between all groups except cardiologists and PCPs and NP/PAs. Values of 4 or 5 on a scale of 1 to 5 with 1 being strongly disagree and 5 being strongly agree. #Significant differences exist between NP/PAs and cardiologists. Case Characteristics The patients described in the case vignettes were considered high-risk or very high-risk for the development of CV events (based on NCEP ATP III guidelines definitions) and are summarized in Table 3. Each patient presented with a combination of conditions including type 2 diabetes, hypertension, and the metabolic syndrome. Other risk factors portrayed included smoking, personal or family history of CV disease, and a sedentary lifestyle. Cholesterol levels and treatment histories varied. Case vignettes and questions were not identical for each specialty group; rather, they were parallel in order to represent patient types and treatment histories commonly encountered in each group s practice setting. Survey Distribution A random sample of practicing clinicians was drawn from the American Medical Association Master file. Between July 26 and August 15, 2007, surveys were distributed by and fax to practicing US cardiologists, endocrinologists, PCPs, and NP/PAs. Individuals who did not respond to the survey after 3 contacts were replaced by others drawn randomly until a sample size of approximately 150 for each group was obtained. A professionally appropriate incentive was offered for completing the survey. Statistical Analysis All analyses were performed using the Statistical Package for Social Sciences (SPSS) v (Chicago, IL). Results Respondent Characteristics A total of 600 health care provider (HCP) responses were collected. For analysis, the sample was restricted to practicing US cardiologists, endocrinologists, PCPs, and NP/PAs currently engaged in direct patient care (N = 582). The usable sample included cardiologists (n = 149), endocrinologists (n = 141), PCPs (n = 149), and NP/PAs (n = 143). Demographic data regarding this sample are presented in Table 1. On average, cardiologists, endocrinologists, and PCPs had 19, 17, and 16 years of practice experience, respectively. NP/PA respondents were less experienced, reporting an average of 11 years of practice experience. Cardiologists and endocrinologists estimated seeing, on average, 62 and 49 patients per week with dyslipidemia, respectively, and PCPs and NP/PAs estimated lower numbers (40 and 36 patients per week, respectively). The majority of physician respondents were MDs and practiced in private offices; NP/PA respondents were also primarily involved in private practice. Provider Perceptions Related to Dyslipidemia Management Several survey questions addressed provider familiarity and agreement with issues related to dyslipidemia management; these perceptions are summarized in Table 2. Eighty-five percent of cardiologists, 83% of endocrinologists, 70% of PCPs, and 54% of NP/PAs stated that they

4 68 Granstaff et al Table 3. Clinical Decision-Making Patterns of Cardiologists and Endocrinologists in Dyslipidemia Management* Parameter Cardiologists (n = 149) Endocrinologists (n = 141) P Patient 1: A high-risk, middle-aged type 2 diabetic and hypertensive patient with mixed dyslipidemia and metabolic syndrome who is currently taking a statin and at LDL-C goal. Lipid profile: TC, 190 mg/dl; TGs, 288 mg/dl; HDL-C, 34 mg/dl; LDL-C, 98 mg/dl. Focus of lipid-lowering therapy LDL-C and non HDL-C 47 (31.5) 55 (39.3).17 Total cholesterol and LDL-C 11 (7.4) 4 (2.9) LDL-C 23 (15.4) 34 (24.3) Non HLD-C and TGs 68 (45.6) 47 (33.6) Lipid profile management goal LDL-C <130mg/dL, non HDL-C <160 mg/dl, TGs <150 mg/dl 3 (2.0) 2 (1.4) LDL-C <100mg/dL, non HDL-C <130 mg/dl, TGs <150 mg/dl 46 (30.9) 57 (40.7).08 LDL-C <70mg/dL, non HDL-C <130 mg/dl, TGs <150 mg/dl 62 (41.6) 50 (35.7) LDL-C <70mg/dL, non HDL-C <100 mg/dl, TGs <100 mg/dl 38 (25.5) 31 (22.1) Continue statin at same dose 6 (4.0) 2 (1.4) Add fenofibrate 59 (39.6) 71 (50.4).07 Add ezetimibe 24 (16.1) 18 (12.8) Switch to fenofibrate 0 (0.0) 2 (1.4) Increase statin dose and add fenofibrate 60 (40.3) 48 (34.0) Patient 2: A very high-risk, middle-aged, type 2 diabetic and hypertensive man with atherogenic dyslipidemia who is taking a statin and has had improvements, but is not yet at lipid goal. Lipid profile: TC, 214 mg/dl; TGs, 280 mg/dl; HDL-C, 32 mg/dl; LDL-C, 125 mg/dl. Focus of lipid-lowering therapy LDL-C 39 (26.4) 46 (32.6) TGs 3 (2.0) 2 (1.4) HDL-C 4 (2.7) 2 (1.4) LDL-C and non HDL-C 93 (62.8) 74 (52.5).08 HDL-C and TGs 9 (6.1) 17 (12.1) Lipid profile management goal LDL-C <130 mg/dl, non HDL-C <100 mg/dl, TG <150 mg/dl 1 (.7) 3 (2.2) LDL-C <100 mg/dl, non HDL-C <130 mg/dl, TG <100 mg/dl 9 (6.0) 8 (5.8) LDL-C <70 mg/dl, non HDL-C <100 mg/dl, TG <150 mg/dl 115 (77.2) 96 (69.6).14 LDL-C <70 mg/dl, non HDL-C <130 mg/dl, TG <100 mg/dl 24 (16.1) 31 (22.5) Increase statin dose 40 (27.0) 47 (33.6) Add ezetimibe 19 (12.8) 21 (15.0) Increase statin dose and add niacin 86 (58.1) 70 (50.0).17 Table 3 continues to page 69

5 CE MEasure Volume 3, Issue Table 3. Clinical Decision-Making Patterns of Cardiologists and Endocrinologists in Dyslipidemia Management* (CONT.) Parameter Cardiologists (n = 149) Endocrinologists (n = 141) P Switch to ezetimibe only 0 (0.0) 1 (0.7) Switch to niacin 3 (2.0) 1 (0.7) Patient 3: A high-risk, middle-aged woman with metabolic syndrome, mixed dyslipidemia, and a family history of diabetes and coronary heart disease. Lipid profile: TC, 254 mg/dl; TGs, 190 mg/dl; HDL-C, 40 mg/dl; LDL-C, 165 mg/dl. Primary target of therapy for risk-reduction LDL-C and non HDL-C 58 (38.9) 57 (40.4) LDL-C 85 (57.0) 80 (56.7).96 TGs 1 (0.7) 0 (0.0) Total Cholesterol 5 (3.4) 4 (2.8) Initial dyslipidemia treatment selection Statin 141 (94.6) 133 (94.3).91 Niacin 7 (4.7) 6 (4.3) Fenofibrate 0 (0.0) 2 (1.4) Omega-3 fatty acid 1 (0.7) 0 (0.0) Patient adhered to treatment regimen. New lipid profile: LDL-C at goal; TGs, 200 mg/dl; HDL-C, 44 mg/dl. Despite LDL-C at goal, residual risk is: 20% 79 (53.0) 59 (42.1) 33% 43 (28.9) 63 (45.0) 50% 16 (10.7) 13 (9.3) 66% 11 (7.4) 5 (3.6).16 Optimal HDL-C target >40 mg/dl 16 (10.7) 12 (8.6) >45 mg/dl 35 (23.5) 22 (15.7) >50 mg/dl 73 (49.0) 81 (57.9).13 >55 mg/dl 9 (6.0) 12 (8.6) >60 mg/dl 16 (10.7) 13 (9.3) If statin was initial treatment, would now: Continue current medication 14 (9.5) 9 (6.5) Add niacin 56 (37.8) 46 (33.1) Add fenofibrate 60 (40.5) 64 (46.0).35 Add omega-3 fatty acid 18 (12.2) 20 (14.4) Patient 4: A very high-risk, elderly, obese, and poorly controlled hypertensive female smoker with previous cardiovascular disease and mixed dyslipidemia. Lipid profile: TGs, 290 mg/dl; HDL-C, 34 mg/dl; LDL-C, 184 mg/dl. Statin only 55 (36.9) Table 3 continues to page 70

6 70 Granstaff et al Table 3. Clinical Decision-Making Patterns of Cardiologists and Endocrinologists in Dyslipidemia Management* (CONT.) Parameter Cardiologists (n = 149) Endocrinologists (n = 141) P Patient 4: A very high-risk, elderly, obese, and poorly controlled hypertensive female smoker with previous cardiovascular disease and mixed dyslipidemia. Lipid profile: TGs, 290 mg/dl; HDL-C, 34 mg/dl; LDL-C, 184 mg/dl. Statin only 55 (36.9) Fenofibrate only 2 (1.3) Combination therapy of statin and ezetimibe 38 (25.5) Combination therapy of statin and niacin 54 (36.2) N/A Patient 4: A middle-aged, obese, hypertensive and pre-diabetic male smoker with mixed dyslipidemia. Lipid profile: TC, 253 mg/dl; TGs, 340 mg/ dl; HDL-C, 39 mg/dl; LDL-C,146 mg/dl. Statin only 52 (37.1) N/A Fenofibrate only 15 (10.7) Combination therapy of statin and ezetimibe 28 (20.0) Combination of therapy of statin and niacin 45 (32.1) *LDL-C indicates low-density lipoprotein cholesterol; TC, total cholesterol; TGs, triglycerides; HDL-C, high-density lipoprotein cholesterol; N/A, not applicable. P values test preferred versus non-preferred responses; level of significance set at <.05. Evidence-based preferred answer. were familiar or extremely familiar with treating residual risk in patients at their LDL-C goal. Accordingly, 93% of cardiologists, 89% of endocrinologists, 91% of PCPs, and 82% of NP/PAs agreed or strongly agreed that low HDL-C is an independent risk factor for CHD, and 83% of cardiologists, 84% of endocrinologists, 64% of PCPs, and 49% of NP/PAs stated that they were familiar with NCEP ATP III guideline recommendations regarding HDL-C and TG. Similarly, 85% of cardiologists, 91% of endocrinologists, 80% of PCPs, and 61% of NP/PAs reported familiarity or extreme familiarity with combination drug therapies targeting a patient s total lipid profile and even higher proportions of all groups reported being familiar or extremely familiar with the side effects of these therapies (88% of cardiologists, 94% of endocrinologists, 86% of PCPs, and 69% of NP/PAs). Clinical Decision Making Residual Cardiovascular Risk. Eighty-five percent of cardiologists stated that they were familiar or extremely familiar with treating residual risk in patients at LDL-C goal, yet 93% underestimated residual risk in a patient at LDL-C goal (Table 3, Patient #3). Similarly, 83% of endocrinologists stated that they were familiar or extremely familiar with treating residual risk in patients at LDL-C goal, but 96% underestimated residual risk in a patient at LDL-C goal. Finally, 70% of PCPs and 54% of NP/PAs stated being familiar or extremely familiar with treating residual risk in patients at LDL-C goal, but 97% in both groups underestimated the residual risk in a patient at LDL-C goal (Table 4, Patient #3). Focus of Lipid-Lowering Therapy and Goal Setting. When presented with a patient with type 2 diabetes, mixed dyslipidemia, and the metabolic syndrome (Patient #1), 69% of cardiologists, 61% of endocrinologists, 66% of PCPs, and 70% of NP/PAs would not focus on LDL-C and non HDL-C levels for lipid-lowering therapy. Rather, 46% of cardiologists, 34% of endocrinologists, 37% of PCPs, and 39% of NP/PAs would focus on non HDL-C and TGs. Further, 69% of cardiologists, 59% of endocrinologists, 57% of PCPs, and 68% of NP/PAs did not identify appropriate lipid profile goals for this patient. Forty-two percent, 36%, 30%, and 42% respectively selected a non HDL-C goal that was 60 mg/dl higher than the LDL-C target goal. Dual Therapy for Mixed Dyslipidemia. When faced with 2 very high-risk patients with prior CV events, 64% of cardiologists would not initiate dual therapy with both a statin and niacin to manage mixed dyslipidemia (Patient #4), and 42% would not add niacin to a statin for atherogenic dyslipidemia (Patient #2) to bring both LDL-C and non HDL-C to goal. Further, 20% of cardiologists would not add fenofibrate to the current statin treatment regimen in a high-risk patient with mixed dyslipidemia whose LDL-C is below 100 mg/dl (Patient #1). Similarly, 50% of endocrinologists would not simultaneously increase statin dose and add niacin in a very high-risk patient with elevated LDL-C and TGs with

7 CE MEasure Volume 3, Issue Table 4. Clinical Decision-Making Patterns of Primary Care Providers in Dyslipidemia Management* Parameter PCPs (n = 149) NP/PAs (n = 143) P Patient 1. A high-risk, postmenopausal, type 2 diabetic woman with metabolic syndrome and mixed dyslipidemia. Lipid profile: TC, 190 mg/dl; TGs, 248 mg/dl; HDL-C, 32 mg/dl; LDL-C, 108 mg/dl. Focus of lipid-lowering therapy LDL-C and non HDL-C 50 (33.6) 42 (29.6).47 Total cholesterol and LDL-C 14 (9.4) 13 (9.2) LDL-C 30 (20.1) 32 (22.5) Non HDL-C and TGs 55 (36.9) 55 (38.7) Lipid profile management goal LDL-C <130 mg/dl, non HDL-C <160 mg/dl, TGs <150 mg/dl 6 (4.0) 3 (2.1) LDL-C <100 mg/dl, non HDL-C <130 mg/dl, TGs <150 mg/dl 64 (43.0) 46 (32.4).06 LDL-C <70 mg/dl, non HDL-C <130 mg/dl, TGs <150 mg/dl 45 (30.2) 60 (42.3) LDL-C <70 mg/dl, non HDL-C <100 mg/dl, TGs <100 mg/dl 34 (22.8) 33 (23.2) Statin only 48 (32.2) 36 (25.2) Combination statin and fenofibrate 53 (35.8) 65 (45.5).09 Fenofibrate only 20 (13.5) 14 (9.8) Combination statin and ezetimibe 27 (18.2) 28 (19.6) Patient 2: A very high-risk, middle-aged, type 2 diabetic and hypertensive man with atherogenic dyslipidemia who is taking a statin and has had improvements, but is not yet at lipid goal. Lipid profile: TC, 214 mg/dl; TGs, 280 mg/dl; HDL-C, 32 mg/dl; LDL-C, 125 mg/dl. Focus of lipid-lowering therapy LDL-C 31 (20.9) 28 (19.6) TGs 4 (2.7) 5 (3.5) HDL-C 1 (.7) 4 (2.8) LDL-C and non HDL-C 85 (57.4) 74 (51.7).33 HDL-C and TGs 27 (18.2) 32 (22.4) Lipid profile management goal LDL-C <130 mg/dl, non HDL-C <100 mg/dl, TG <150 mg/dl 2 (1.4) 2 (1.4) LDL-C <100 mg/dl, non HDL-C <130 mg/dl, TG <100 mg/dl 14 (9.5) 10 (7.1) LDL-C <70 mg/dl, non HDL-C <100 mg/dl, TG <150 mg/dl 94 (63.5) 88 (62.4).85 LDL-C <70 mg/dl, non HDL-C <130 mg/dl, TG <100 mg/dl 38 (25.7) 41 (29.1) Increase statin dose 34 (23.0) 32 (22.5) Add ezetimibe 31 (20.9) 28 (19.7) Increase statin dose and add niacin 79 (53.4) 80 (56.3).61 Switch to ezetimibe only 1 (.7) 2 (1.4) Table 4 continues to page 72

8 72 Granstaff et al Table 4. Clinical Decision-Making Patterns of Primary Care Providers in Dyslipidemia Management* (CONT.) Parameter PCPs (n = 149) NP/PAs (n = 143) P Switch to niacin 3 (2.0) 0 (.0) Patient 3. A high-risk, middle-aged woman with metabolic syndrome, mixed dyslipidemia, and a family history of diabetes and coronary heard disease. Lipid profile: TC, 254 mg/dl; TGs, 190 mg/dl; HDL-C, 40 mg/dl; LDL-C, 165 mg/dl. Primary target of therapy for risk-reduction LDL-C and non HDL-C 63 (42.3) 70 (49.0) LDL-C 74 (49.7) 61 (42.7).23 TGs 2 (1.3) 3 (2.1) Total cholesterol 10 (6.7) 9 (6.3) Initial dyslipidemia treatment selection Statin 136 (91.3) 133 (93.0).58 Niacin 9 (6.0) 2 (1.4) Fenofibrate 2 (1.3) 3 (2.1) Omega-3 fatty acid 2 (1.3) 5 (3.5) Patient adhered to treatment regimen. New lipid profile: LDL-C at goal; TGs, 200; HDL-C, 44 mg/dl. Despite LDL-C at goal, residual risk is: 20% 56 (37.6) 50 (35.7) 33% 75 (50.3) 69 (49.3) 50% 14 (9.4) 17 (12.1) 66% 4 (2.7) 4 (2.9).99 Optimal HDL-C target.03 >40 mg/dl 17 (11.4) 18 (12.7) >45 mg/dl 28 (18.8) 31 (21.8) >50 mg/dl 77 (51.7) 50 (35.2) <.005 >55 mg/dl 12 (8.1) 13 (9.2) >60 mg/dl 15 (10.1) 30 (21.1) If statin was initial treatment, would now: Continue current medication 8 (5.4) 10 (7.0) Add niacin 54 (36.5) 46 (32.2) Add fenofibrate 57 (38.5) 50 (35.0).53 Add omega-3 fatty acid 29 (19.6) 37 (25.9) Patient 4: A very high-risk, elderly, obese, and poorly controlled hypertensive smoker with previous cardiovascular disease and mixed dyslipidemia. Lipid profile: TGs, 290 mg/dl; HDL-C, 34 mg/dl; LDL-C, 184 mg/dl. Statin only 31 (21.1) 32 (22.4) Fenofibrate only 2 (1.4) 2 (1.4) Table 4 continues to page 73

9 CE MEasure Volume 3, Issue Table 4. Clinical Decision-Making Patterns of Primary Care Providers in Dyslipidemia Management* (CONT.) Parameter PCPs (n = 149) NP/PAs (n = 143) P Combination therapy of statin and ezetimibe 62 (42.2) 59 (41.3) Combination therapy of statin and niacin 52 (35.4) 50 (35.0).53 *PCPs indicates primary care physicians; NP/PAs, nurse practitioners/physician assistants; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. P values test preferred versus non-preferred responses; level of significance set at <.05. Evidence-based preferred answer. a low HDL-C (Patient #2); instead, 34% would only increase the statin dose. When presented with a middleaged patient with hypertension, type 2 diabetes, mixed dyslipidemia, and the metabolic syndrome who has attained LDL-C goal (Patient #1), 16% would not add fenofibrate to the current statin treatment regimen. Finally, 64% of PCPs and 55% of NP/PAs would not use both a statin and fenofibrate in a patient with type 2 diabetes, the metabolic syndrome, and mixed dyslipidemia (Patient #1). Thirty-two percent of PCPs and 25% of NP/PAs would treat with a statin only. In addition, in a very high-risk patient (Patient #2) with persistent atherogenic dyslipidemia (high LDL-C, low HDL-C, and elevated TGs despite low-dose statin therapy), 47% of PCPs and 44% of NP/PAs would not increase statin dose and add niacin; rather, 23% in both groups would increase statin dose only. Further, 65% in both groups would not initiate treatment with both a statin and niacin in a very high-risk patient with mixed dyslipidemia (Patient #4). Discussion This study identified a number of potential gaps among HCPs in the management of mixed dyslipidemia. More than a third of PCPs and NP/PAs, as well as a smaller but significant portion of cardiologists and endocrinologists, lacked familiarity with NCEP ATP III management recommendations for low HDL-C and elevated TGs. Clinicians did not generally favor dual lipid lowering therapies aimed at bringing LDL-C and non HDL-C to goal, even in very high-risk patients. These findings are congruent with those from the 2003 NCEP Evaluations Project Utilizing Novel E-Technology (NEPTUNE II) survey of patients treated by clinicians who were high prescribers of lipid lowering therapy [19]. Even among these aggressive treaters, only 52% of individuals with CHD or equivalent and with TGs >200 mg/dl achieved LDL-C goal, and a mere 27% achieved both LDL-C and non HDL-C goals. The HDL-C and TG abnormalities that characterize atherogenic dyslipidemia commonly occur in patients with the metabolic syndrome and type 2 diabetes and are thus prevalent among individuals with the highest CV risk [20]. Non HDL-C, which reflects the level of apob lipoproteins, is strongly associated with these 2 lipid parameters. ATP III has defined non HDL-C as a secondary target in dyslipidemia management in patients with TG levels 200 mg/dl [9]. Although statins can favorably alter HDL-C and triglycerides to a modest degree, niacin and fibrates have a greater impact on these lipid parameters. Accordingly, ATP III recommends consideration of a fibrate or nicotinic acid in addition to LDL-lowering therapy in order to bring non HDL-C to goal in high-risk patients with elevated TGs and low HDL-C [9]. Therapy that combines statins with niacin or a fibrate can have synergistic lipid effects in patients with mixed dyslipidemia [21-29] and has been shown to exert much broader effects across the entire plasma lipoprotein profile than a statin alone, thus favorably affecting lipoprotein classes that independently influence the risk for CV events [29]. Clinicians who do not opt to include non HDL-C as a secondary target for therapy and who use only LDL-C lowering therapies may be missing important intervention opportunities in especially vulnerable and high-risk populations. Conclusions There are several limitations to this study. First, this study used a survey as a surrogate measure of actual practice patterns in the outpatient setting. The use of case vignettes, however, has been shown to provide good insight into clinicians actual practice patterns [16-18]. Second, only 4 clinical scenarios were used in each survey, which does not cover the full spectrum of high-risk cardiovascular patients. Furthermore, since the 2004 NCEP Update guidelines recommend that consideration be given to reducing LDL-C to below 70 mg/dl in certain high-risk or very high-risk patients, it would be feasible for some clinicians to select intensification of statin therapy in a sample patient with mixed dyslipidemia and LDL-C <100 mg/dl (but >70 mg/dl) prior to addition of a second agent (Patient #1 in our survey). Additionally, although the terms high-risk and very high-risk are clearly defined in ATP III guidelines, the absence of Framingham risk scores in the patient cases may have negatively impacted the responses of clinicians more familiar with risk stratification based on absolute risk scores than broader categories such as high-risk and very high-risk. Although this study explored familiarity with relevant guideline recommendations, it did not assess perceptions

10 74 Granstaff et al about safety and tolerability and did not examine patient and system barriers that may influence the use of combination therapy. These issues may be useful to assess in future studies. Further, although high-quality studies documenting the benefits of fibrates and nicotinic acid on non HDL-C cholesterol and TGs are well documented [12-14,28,30], there are at present no results from randomized clinical trials demonstrating reduction of major CV events in patients receiving combination therapy (statin + fibrate or statin + niacin) compared with patients receiving statin monotherapy. Several largescale, randomized trials, however, are currently underway to address this very question. These include the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High TG and Impact on Global Health Outcomes (AIM-HIGH) study, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, and the Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study. Current guidelines on dual therapy for mixed dyslipidemia will be further bolstered if these studies reveal a significant reduction in CV endpoints (such as mortality) with use of fibrates and/or nicotinic acid [31-33]. At the time of NCEP Update publication, controlled clinical trial data were insufficient to justify setting a particular goal value for raising HDL-C. Although several clinical trials to date support fibrate and nicotinic acid therapy, the evidence base for these agents is not as strong as it is for statin therapy. As more studies validate the positive treatment effects of fibrates and nicotinic acid on total lipid profiles, more physicians may begin to implement these drugs in dyslipidemia management, especially in combination with statins. In summary, despite guidelines and evidence to assist physicians in managing high-risk and very high-risk patients with mixed dyslipidemia, some of the findings in this study suggest that adherence to evidencebased guidelines is at times suboptimal. Although the majority of cardiologists and endocrinologists reported familiarity with relevant guideline recommendations, this is not consistently reflected in clinical decision making. PCPs and NP/PAs reported less familiarity with guidelines, suggesting that a knowledge gap may in part contribute to the more conservative treatment of dyslipidemia by these clinicians. Educational interventions are needed to enhance awareness of residual CV risk, more clearly elaborate characteristics of highrisk and very high-risk patients, augment understanding of non HDL-C as a secondary therapeutic target, and discuss the safety and efficacy of combination lipid lowering therapies. Acknowledgements This study was supported by Abbott Laboratories. We appreciate the assistance provided by Jill Foster, MD, in developing this manuscript. References 1. Gotto AM Jr. Triglyceride as a risk factor for coronary artery disease. Am J Cardiol. 1998;82:22Q-25Q. 2. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992;85: Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62: Superko HR, Gadesam RR. Is it LDL particle size or number that correlates with risk for cardiovascular disease? Curr Atheroscler Rep. 2008;10: Rosenson RS, Otvos JD, Freedman DS. Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial. Am J Cardiol. 2002;90: Tenenbaum A, Fisman EZ, Motro M, Adler Y. Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins. Cardiovasc Diabetol. 2006;5: Carroll MD, Lacher DA, Sorlie PD, et al. Trends in serum lipids and lipoproteins of adults, JAMA. 2005;294: National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106: Grundy SM, Cleeman JI, Merz CN, et al, for the Coordinating Committee of the National Cholesterol Education Program, and Endorsed by the National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, and American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110: Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005;46: Baigent C, Keech A, Kearney PM, et al, for the Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366: Hausenloy DJ, Yellon DM. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels. Heart. 2008;94: Tenkanen L, Mänttäri M, Kovanen PT, Virkkunen H, Manninen V. Gemfibrozil in the treatment of dyslipidemia: an 18-year mortality follow-up of the Helsinki Heart Study. Arch Intern Med. 2006;166:

11 CE MEasure Volume 3, Issue Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care. 2003;26: Davidson MH, Maki KC, Pearson TA, et al. Results of the National Cholesterol Education (NCEP) Program Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations. Am J Cardiol. 2005;96: Peabody JW, Luck J, Glassman P, Dresselhaus TR, Lee M. Comparison of vignettes, standardized patients, and chart abstraction: a prospective validation study of 3 methods for measuring quality. JAMA. 2000;283: Peabody JW, Luck J, Glassman P, et al. Measuring the quality of physician practice by using clinical vignettes: a prospective validation study. Ann Intern Med. 2004;141: DeSanto-Madeya S. Using case studies based on a nursing conceptual model to teach medical-surgical nursing. Nurs Sci Q. 2007;20: Maki KC, Galant R, Davidson MH. Non-high-density lipoprotein cholesterol: the forgotten therapeutic target. Am J Cardiol. 2005;96:59K-64K; discussion 34K-35K. 20. St-Pierre AC, Cantin B, Dagenais GR, et al. Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Québec Cardiovascular Study. Arterioscler Thromb Vasc Biol. 2005;25: Kashyap ML, McGovern ME, Berra K, et al. Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol. 2002;89: Haffner SM, American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care. 2004;27(Suppl 1):S68-S American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2007;30(Suppl 1):S4-S Wolfe ML, Vartanian SF, Ross JL, et al. Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia. Am J Cardiol. 2001;87: , A Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110: Vega GL, Ma PT, Carter NB, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol. 2003;91: Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin. 2006;22: Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345: McKenney JM, Jones PH, Bays HE, et al. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis. 2007;192: Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefits with niacin. J Am Coll Cardiol. 1986;8: ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007;99:21i 33i. 32. National Hearth, Lung, and Blood Institute (NHLBI). AIM-HIGH: Niacin plus statin to prevent vascular events. ClinicalTrials.gov. Available at: show/nct ?term=aim-high&rank=1. Accessed November 18, University of Oxford. Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE. ClinicalTrials. gov. Available at: NCT ?term=HPS2-THRIVE&rank=1. Accessed November 18, 2009.