Low-density lipoprotein cholesterol goal attainment in high-risk family medicine patients

Journal of Clinical Lipidology (2009) 3, 195–200

Low-density lipoprotein cholesterol goal attainment in high-risk family medicine patients Joseph P. Vande Griend, PharmD, BCPS*, Joseph J. Saseen, PharmD, BCPS, CLS University of Colorado Denver, School of Pharmacy, 12631 East 17th Ave, Room 1411, Aurora, CO 80045 USA KEYWORDS: Ambulatory care; Atherosclerotic vascular disease; Coronary artery disease; HydroxymethylglutarylCoA reductase inhibitors; Low-density lipoprotein

BACKGROUND: The Adult Treatment Panel III guideline recommends a low-density lipoprotein-cholesterol (LDL-C) goal of ,100 mg/dl for patients with coronary heart disease or risk equivalence (ie, other forms of atherosclerotic vascular disease [peripheral vascular disease, abdominal aortic aneurysm, cerebrovascular disease], diabetes). An optional LDL-C goal of ,70 mg/dl is recommended for patients considered ‘‘very high risk.’’ This category is not well defined, and clinical interpretation of this category varies. METHODS: To define this category and to determine eligibility for an LDL-C goal of ,70 mg/dl, 5 definitions of ‘‘very high risk’’ were developed. Patients with coronary heart disease or risk equivalence within the University of Colorado Family Medicine system over the course of 2 years were identified using International Classification of Diseases, 9th Revision codes (n 5 445). Their medical records were evaluated retrospectively. Patients characterized as ‘‘very high risk’’ according to the 5 definitions were assessed for LDL-C ,70 mg/dl goal attainment. RESULTS: Twenty-seven patients did not have LDL-C measurements and were excluded. Using the 5 definitions, we discovered that prevalence as ‘‘very high risk’’ was 10.8% (atherosclerotic vascular disease [AVD] plus smoking), 19.1% (AVD plus diabetes), 21.5% (AVD plus metabolic syndrome plus uncontrolled hypertension or smoking), 47.1% (AVD plus metabolic syndrome), and 67.2% (All AVD), P , .0001. LDLC ,70 mg/dl was attained in 26.7%, 46.3%, 31.1%, 39.1%, and 35.2%, respectively (P 5 .13). CONCLUSION: Classifying patients as ‘‘very high risk’’ is highly variable depending on individual definitions, but this does not appear to alter the rates of attaining an LDL-C goal of ,70 mg/dl. When the Adult Treatment Panel IV guidelines are developed and issued, simplicity and clarity will be important in assisting clinicians in defining patient risk and developing LDL-C goals. Ó 2009 National Lipid Association. All rights reserved.

The 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 [ATP III]) focuses on lowering lowdensity lipoprotein-cholesterol (LDL-C) as the primary target for the prevention of major cardiovascular events. ATP III recommends an LDL-C goal of ,100 mg/dl for * Corresponding author. E-mail address: [email protected] Submitted December 18, 2008. Accepted for publication April 30, 2009.

patients deemed at ‘‘high risk’’ for a coronary event. Highrisk patients have either coronary heart disease (CHD) or CHD risk equivalence. This classification includes those with existing atherosclerotic vascular disease (AVD), including previous myocardial infarction, angina without myocardial infarction, peripheral vascular disease, abdominal aortic aneurysm, carotid artery disease, and those with diabetes mellitus or a Framingham 10-year risk of .20%.1 After the publication of ATP III, 5 randomized controlled clinical trials were published that provided new evidence and further insight into the management of patients with dyslipidemia, especially those considered high risk.2-6 These new

1933-2874/$ -see front matter Ó 2009 National Lipid Association. All rights reserved. doi:10.1016/j.jacl.2009.04.055

196 data resulted in publication of the NCEP report ‘‘Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.’’7 This update added an optional, more aggressive, LDL-C goal of ,70 mg/dl for patients at ‘‘very high risk’’ for a coronary event. Data published subsequent to the NCEP update appear to support the optional, lower, LDL-C goal.8-10 In the NCEP update report, patients at ‘‘very high risk’’ are classified as having ‘‘established CVD plus 1) multiple major risk factors (especially diabetes), 2) severe and poorly controlled risk factors (especially continued cigarette smoking), 3) multiple risk factors of the metabolic syndrome (especially high triglycerides $200 mg/dl plus non-high-density lipoprotine cholesterol [HDL-C] $130 mg/dl with low HDL-C [ , 40 mg/dl]), and 4) acute coronary syndrome.’’7 This definition of ‘‘very high risk’’ may be considered vague by some clinicians and can leave substantial room for interpretation. In addition, the NCEP update report recommends that if a lipid-lowering regimen is initiated, it is prudent to initiate a drug and dose that will provide at least a 30-40% LDL-C reduction, regardless of the baseline LDL-C.7 The primary objectives of this study were to categorize patients with CHD or CHD risk equivalence as eligible for an LDL-C goal of ,70 mg/dl according to 5 different definitions of ‘‘very high risk’’ and to assess LDL-C , 70 mg/dl goal attainment rates based on these definitions. Secondary objectives included describing the percentage of patients prescribed a lipid-lowering regimen capable of providing at least 30-40% LDL-C reduction, describing the percentage of patients achieving an LDL-C of ,100 mg/dl and ,70 mg/dl overall, and estimating which lipid-lowering medication changes would be required to achieve LDL-C goals of ,70 mg/dl and ,100 mg/dl in subjects not already achieving these values.

Methods Five specific definitions of ‘‘very high risk’’ were created based on the definition provided in the NCEP report update.7 The specific definitions were developed to simulate examples of what clinicians might use to characterize a patient as ‘‘very high risk.’’ The definitions range from restrictive to more open interpretations. The 5 definitions were as follows: 1) presence of AVD, 2) AVD plus continued cigarette smoking, 3) AVD plus presence of the metabolic syndrome, 4) AVD plus the metabolic syndrome plus one additional major risk factor, and 5) AVD plus diabetes mellitus. The metabolic syndrome was considered present if patients had at least 3 of the 5 cardiometabolic criteria (increased blood pressure [ $ 130 mm Hg systolic or $85 mm Hg diastolic] or drug treatment for hypertension; elevated fasting glucose [ $ 100 mg/dl] or drug treatment for increased fasting glucose; reduced HDL-C [ , 40 mg/dl for men, ,50 mg/dl for women] or drug treatment for reduced HDL; increased triglycerides [ $ 150 mg/dl] or drug treatment for elevated triglycerides; and abdominal obesity).11 Body mass index ($30 kg/m2) was used in place of increased waist circumference in

Journal of Clinical Lipidology, Vol 3, No 3, June 2009 defining abdominal obesity because waist circumference measures were not available in the medical record.12 Patients with AVD or diabetes mellitus were identified by the use of International Classification of Diseases, 9th Revision codes generated from University of Colorado Family Medicine Clinics (250.xx, 357.2, 410.xx, 411.0, 411.1, 411.81, 411.89, 412, 413.0, 413.1, 413.9, 414.xx, 429.xx, 434.00, 434.01, 435.8, 435.9, 436, 437.0, 437.1, 440.0, 440.8, 440.9, 441.4, 443.89, or 443.9). The patients identified were seen for a clinic visit between January 1, 2005, and December 31, 2006. Exclusion criteria included patients without an LDLC value. Patients with a Framingham risk score of .20%, but without clinically evident CHD or CHD risk equivalence, were not included as ‘‘high risk’’ because the electronic medical record was unable to identify them. For the secondary objective of estimating the modification of the LDL-C2lowering regimen needed to achieve LDL-C goal recommendations, an LDL-C2lowering algorithm was developed (Fig 1). On the basis of the algorithm, a doubling of statin dose was assumed to provide another 10 mg/dl reduction in LDL-C. For example, a patient currently receiving atorvastatin 10 mg daily with an LDL-C of 120 mg/dl would have a 10 mg/dl LDL-C lowering when given a dose increase to atorvastatin 20 mg daily. In addition, the use of a statin with greater potency could also result in a 10 mg/dl reduction in LDL-C. Each step increase in the algorithm represents a 10 mg/dl decrease in LDL-C. This stepwise approach was adapted from a previously published therapeutic conversion algorithm and from available clinical evidence.13,14 The addition of ezetimibe to the current regimen was also an option, and its effect on lowering LDL-C was determined from available clinical evidence. When added as monotherapy to patients currently receiving no cholesterol-lowering medication, ezetimibe has been shown to lower LDL-C by approximately 25-30 mg/ dl.15,16 When added to or co-administered with ongoing atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, or rosuvastatin therapy, ezetimibe provides an additional 2233 mg/dl decrease in LDL-C.17-27 Therefore, we assumed that the addition of ezetimibe, either as monotherapy or as add-on therapy to the current cholesterol-lowering regimen, would provide an additional 25 mg/dl reduction in LDL-C, or a 2.5-step increase. The algorithm allowed us to predict the LDL-C2lowering regimen modification needed to attain the desired LDL-C goal. The Allscripts electronic medical record (Allscripts, Chicago, IL) was used to retrospectively collect data. Data collected included age, sex, smoking status, diagnosis, HgbA1c, lipid panel results, fasting blood glucose, most recent blood pressure measurement, body mass index, and currently prescribed LDL-C lowering, HDL-C raising, triglyceride lowering, diabetes, or hypertension pharmacotherapy.

Statistical analysis Descriptive statistics were used for all data and are presented in terms of mean (6 standard deviation) and

Vande Griend and Saseen

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LDL-C attainment in high-risk patients

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Addition of ezetimibe lowers LDL-C ~ 2.5 steps

Figure 1 LDL-C 2 Lowering algorithm. *Rosuvastatin should only be increased to 40 mg if patient was initially taking rosuvastatin. R-5/ 10/20/40 5 rosuvastatin 5/10/20/40 mg; A-10/20/40/80 5 atorvastatin 10/20/40/80 mg; S-10/20/40/80 5 simvastatin 10/20/40/80 mg; L-20/40/80 5 lovastatin 20/40/80 mg; P-20/40/80 5 pravastatin 20/40/80 mg; F-40/80 5 fluvastatin 40/80 mg.

percentage. Chi-square analysis was used to assess differences in the percentage of patients categorized as ‘‘very high risk’’ among the 5 definitions and to assess differences in the percentage of subjects attaining LDL-C goal among the five definitions.

Results Four hundred and forty-five subjects with AVD or diabetes mellitus were identified. Twenty-seven did not have LDL-C measurements and were excluded from analysis. The most common reason for not having an LDL-C concentration was a triglyceride concentration .400 mg/dl (63%). Baseline characteristics for all 418 analyzed patients and a flow diagram explaining how patients were categorized as ‘‘very high risk’’ for all 445 identified subjects are shown in Table 1 and Figure 2, respectively. Simvastatin and atorvastatin were the most common statins prescribed (34.7% and 31.1%, respectively). In addition, 19.4% of subjects were prescribed ezetimibe (alone or in combination with simvastatin), and 12.2% were prescribed fibric acid derivatives or bile-acid sequestrants. Using the 5 definitions, the prevalence of ‘‘very high risk’’ status was 10.8% (AVD plus smoking), 19.1% (AVD plus diabetes), 21.5% (AVD plus metabolic syndrome plus uncontrolled hypertension or smoking), 47.1% (AVD plus metabolic syndrome), and 67.2% (All AVD). Categorization of very high risk differed significantly between definitions (P , .0001). The LDL-C goal of ,70 mg/dl was attained in 26.7%, 46.3%, 31.1%, 39.1%, and 35.2%, for these definitions respectively (Fig 3). The likelihood of LDL-C goal attainment was no different between definitions (P 5 .13). Overall, 67.2% of patients achieved an LDL-C ,100 mg/ dl, 32.5% achieved an LDL-C ,70 mg/dl, and 72% were prescribed a regimen capable of providing at least 30-40% LDL-C reduction. More than 32% of all patients with diabetes achieved an LDL-C ,100 mg/dl, and 18.9% achieved an

LDL-C ,70 mg/dl. In addition, 38% of patient with diabetes but without AVD achieved an LDL-C ,100 mg/dl, and 18.2% achieved an LDL-C ,70 mg/dl. For all subjects not attaining an LDL-C ,100 mg/dl and for those not attaining an LDL-C ,70 mg/dl, the modification of the current lipid-lowering regimen needed to attain each goal was evaluated (Table 2). Only 32.5% of subjects evaluated attained an LDL-C ,70 mg/dl but 85.4% were considered able to attain this LDL-C goal with available pharmacotherapy.

Discussion This analysis identified .400 patients with CHD or CHD risk equivalence at University of Colorado Family Medicine Clinics during a 2-year period. These patients were evaluated by their provider after the publication of the NCEP report update, which recommended an LDL-C goal Table 1

Patient demographics (n 5 418) Mean (6 SD)

Age (year) 62 (6 11) BMI 30.7 (6 7) Fasting lipids (mg/dl) Total cholesterol 165.6 (6 42) LDL-C 89.1 (6 37) HDL-C 44.8 (6 14) Triglyceride 157.9 (6 77)

n (%) Smoker Gender Male Female Disease MetaSyn AVD Diabetes CHD CVD PAD AAA

64 (15) 252 (60) 166 (40) 321 281 217 230 50 32 7

(77) (67) (52) (55) (12) (8) (2)

AAA, abdominal aortic aneurysm; BMI, body mass index; CHD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease; SD, standard deviation.

198

Journal of Clinical Lipidology, Vol 3, No 3, June 2009 Patients identified with CHD or CHD equivalence (n = 445)

Excluded if no LDL-C available (n = 27)

No AVD* (n = 137)

AVD (n = 281)

Smoking (n = 45)

Diabetes (n = 80)

Metabolic Syndrome + 1 other risk factor (n = 90)

Metabolic Syndrome (n = 197)

Figure 2 Flow diagram: categorization as ‘‘very high risk.’’ *Patients had diabetes, a CHD risk equivalent, but no atherosclerotic vascular disease. CHD, coronary heart disease.

of ,70 mg/dl for patients considered ‘‘very high risk’’ for coronary events.7 Our attempt to evaluate various clinical interpretations of the very high risk subgroup of patients in a primary care setting is novel. The percentage of high-risk patients with CHD or CHD risk equivalence designated as ‘‘very high risk’’ was highly variable between definitions. For instance, the definition that used only the presence of AVD gave 67.2% prevalence, whereas the definition that used AVD plus smoking identified only 10.8%. However, this variability in prevalence is irrelevant when considering that the percentage of patients with an LDL-C ,70 mg/dl was no different among definitions. On the basis of this finding, it is likely that physicians within this clinical setting are not considering the presence

AVD AVD + Smoking AVD + MetSyn (+1 major risk factor) AVD + MetSyn AVD + Diabetes

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p < 0.0001 p <0.13

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20

0 Categorized as "Very High Risk"

Attainment of LDL-C <70 mg/dL

Figure 3 LDL-C categorization and attainment. MetSyn, metabolic syndrome.

or absence of additional risk factors that might influence the decision to target more aggressive LDL-C lowering goals. More than 30% of patients did not achieve the minimum treatment goal of LDL-C ,100 mg/dl, and nearly 70% did not achieve an LDL-C of ,70 mg/dl. This percentage of LDL-C ,100 mg/dl and LDL-C ,70 mg/dl attainment for high-risk patients is similar to other published data in an elderly and a diabetic population studied after the publication of the NCEP report update in 2004.28,29 Data evaluating LDL-C goal attainment rates in primary care patients after the publication of the NCEP report update are not currently available. By using the algorithm and patient-specific data, we found that approximately 80% of patients who had not attained an LDL-C goal of ,70 mg/dl could reasonably reach the desired target with currently available pharmacotherapy. Options for achieving goal values in these patients included the initiation of ezetimibe or statin therapy in approximately 33%, maximizing current statin therapy or switching to a greater potency statin and maximizing the dose in 32%, or maximizing current statin therapy or switching to a greater potency statin and adding ezetimibe in 13%. Our projected data identified that 21.6% of those not currently at LDLC ,70 mg/dl would not be able to attain the aggressive goal despite the use of high-potency statin therapy and the addition of ezetimibe. These patients will likely require multiple-drug regimens, use of other lipid-lowering agents (eg, bile acid sequestrants, niacin), or referral to a lipid specialist. For those exceptional circumstances in which patients with existing AVD are unable to attain an LDL-C ,70 mg/dl with current medication therapy, a reduction in LDL-C of .50% should be targeted.30 This is recommended by the American Heart Association as a reasonable and evidence-based means to provide cardiovascular risk reduction therapy.

Vande Griend and Saseen Table 2

LDL-C attainment in high-risk patients

199

Modification needed to achieve LDL-C goal (n 5 418); data are n (%) LDL-C goal

mg/dL above goal

, 70 mg/dl

, 100 mg/dl

Achieved ,31 mg/dl 31–60 mg/dl 61–90 mg/dl Beyond

136 148 79 39 16

281 82 33 18 4

Action required, but without CHD or CHD risk equivalence Achieved Initiate lipid-lowering agent* , 50% lipid lowering needed . 50% lipid lowering needed Maximize current statin or switch to hp statin Maximize current statin or switch to hp statin and add ezetimibe Beyond pharmaceutical intervention

(32.5) (35.4) (18.9) (9.3) (3.8)

136 (32.5) 78 16 90 37 61

(18.7) (3.8) (21.5) (8.9) (14.6)

(67.2) (19.6) (7.9) (4.3) (0.9)

281 (67.2) 60 3 39 10 25

(14.4) (0.7) (9.3) (2.4) (6)

hp, high-potency statin (eg, atorvastatin, rosuvastatin). *Ezetimibe 10 mg/day, varying potency statin, or both

Limitations There are limitations in our study that are important to note. Patients with a 10-year Framingham risk score of .20% were not included as part of the high-risk group evaluated despite the fact that these patients are considered to be a CHD risk equivalent. Patients with this level of calculated risk may meet criteria for being considered ‘‘very high risk,’’ but the electronic medical record used was not able to identify them. Patients with acute coronary syndrome were also not included in the evaluation, despite the fact that these patients are considered ‘‘very high risk.’’ Again, the electronic medical record used was not able to identify them. The algorithm used to determine medication regimen modifications required several assumptions. Patients were assumed to be adherent to their currently prescribed regimen; it was assumed that patients could afford, tolerate, and would adhere to increased therapy; and it was assumed that no significant drug interactions existed that would limit statin or ezetimibe dosing. Bile acid sequestrants or niacin were also not included in the algorithm. Given recent data and subsequent concerns surrounding ezetimibe therapy, the use of bile acid sequestrants and niacin may currently play a larger role in LDL-C reduction therapy. Finally, this analysis was retrospective in nature. The data collected was limited to the data that were documented in the electronic medical record.

Conclusion Classifying patients as ‘‘very high risk’’ is highly variable depending on individual definitions, but this classification does not appear to predict differences in rates of LDL-C goal attainment of ,70 mg/dl. The majority of patients not currently attaining the aggressive LDL-C goal of ,70 mg/dl can reach this goal with the use of currently available pharmacotherapy. When the Adult Treatment Panel IV guidelines

are developed and issued, simplicity and clarity should be strongly advocated to assist clinicians in appropriately defining patient risk and developing LDL-C goals.

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