Intensity of lipid-lowering therapy and low-density lipoprotein cholesterol goal attainment among the elderly before and after the 2004 National Cholesterol Education Program Adult Treatment Panel III update

Prevention and Rehabilitation

Intensity of lipid-lowering therapy and low-density lipoprotein cholesterol goal attainment among the elderly before and after the 2004 National Cholesterol Education Program Adult Treatment Panel III update Gregory A. Nichols, PhD,a Soma Nag, PhD,b and Wiley Chan, MDc Portland, OR; and West Point, PA

Background In 2004, the Coordinating Committee of the National Cholesterol Education Program issued an update to the Adult Treatment Panel III guidelines on cholesterol management (the Update). Our objectives were to compare the proportion of elderly patients receiving intensive or minimal-guideline lipid-lowering therapy and the proportions meeting low-density lipoprotein cholesterol (LDL-C) goals before and after the update. Methods We used dispense records from Kaiser Permanente Northwest (Portland, OR) to identify elderly patients who received statin therapy in 2003 (n = 14 425) and 2005 (n = 19 422) and laboratory records to assess LDL-C goal attainment. Results Among new statin initiators, 85.4% of very-high-risk patients received minimal-guideline therapy in 2005, compared with 65.3% ( P b .0001) in 2003. Of all new initiators, b1% received very aggressive therapy in either year (0.4% vs 0.3%, P = .315). Overall, 77.7% and 59.0% of ongoing users in 2005 and 2003, respectively, received minimal-guideline therapy ( P b .0001). Low-density lipoprotein cholesterol goal attainment did not differ between 2003 and 2005 continuing statin users. Among very-high-risk patients who initiated statin treatment, a significantly greater proportion of patients in 2005 versus 2003 attained the optional goal of b70 mg/dL (45.5% vs 34.4% P = .014). However, there was no significant difference in the proportion attaining b100 mg/dL (77.8% vs 81.8%, P = .281). Conclusion

After the Update, more elderly patients were receiving intensive or minimal-guideline statin therapy. Low-density lipoprotein cholesterol goal attainment was isolated and appeared to occur by shifting already well-controlled patients to lower LDL-C levels. Although these findings may translate into less overall coronary heart disease risk, more aggressive lipid-lowering therapy would likely further reduce risk. (Am Heart J 2007;154:554260.)

In response to 5 recent clinical trials,1-5 the Coordinating Committee of the National Cholesterol Education Program (NCEP) updated its 2001 NCEP Adult Treatment Panel (ATP) III guidelines on cholesterol management.6 The NCEP ATP III update (the Update) defined a new bvery high riskQ category for which a lower optional low-density lipoprotein cholesterol (LDL-C) goal of b70 mg/dL was recommended. In addition, the Update suggested an optional goal of b100 mg/dL (rather than b130 mg/dL) for patients at moderately high risk.

From the aKaiser Permanente Center for Health Research, Portland, OR, bMerck & Co, Inc, West Point, PA, and cNorthwest Permanente, PC, Portland, OR. Merck & Co, Inc, provided funding for this research. Submitted February 1, 2007; accepted April 14, 2007. Reprint requests: Gregory A. Nichols, PhD, Center for Health Research, 3800 N Interstate Avenue, Portland, OR 97227-1098. E-mail: [email protected] 0002-8703/$ - see front matter n 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.04.037

Despite overwhelming evidence that LDL-C treatment with statins reduces cardiovascular disease risk, previous studies on real-world clinical practice have reported low proportions of patients attaining recommended LDL-C goals. For example, the Lipid Treatment Assessment Project found that 38% of subjects attained the LDL-C goal recommended by NCEP ATP II.7 More recently, a Canadian study on high-risk patients found that only about half (51.2%) of patients achieved the LDL-C target of b100 mg/dL, and among the subset of patients at very high risk, only 20.8% reached the optional goal of b70 mg/dL.8 Those results were similar to findings of the NEPTUNE II study (57% and 17.8%, respectively), a highly selective national survey.9 However, because these studies were conducted before the Update was published, the proportions attaining the optional goals could not account for practice changes that may have occurred as a result of the Update. No study to date has compared LDL-C goal attainment before and after the Update. In addition, data among the elderly are scant. Therefore, our objectives were to

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Table I. Characteristics of subjects newly initiating or continuing statin therapy in 2003 and 2005 Newly initiating statin therapy

No. of subjects Age (y) % Women CHD risk (%) Very high High Moderately high Moderate Low 10-y Framingham CHD risk4 (%) b10% 10%-20% N20% Mean 10-y CHD risk4 (%) CHD risk factors (%): CHDy Diabetes Other CHD equivalent diagnosesz Hypertension Metabolic syndrome Current smokers Clinical data: LDL-C HDL-C Triglycerides Total cholesterol Non–HDL-C Fasting plasma glucose Systolic blood pressure Body mass index

2003

2005

2337 73.5 51.3

1880 73.9 54.8

15.3 65.8 11.1 1.6 6.2

Continuing statin therapy P

2003

2005

P

– .075 .023

12 088 74.4 44.4

17 542 74.6 46.5

– .037 .0005

8.9 63.8 17.2 1.6 8.5

b.0001

23.2 50.6 12.0 7.0 7.4

21.5 55.0 11.3 5.5 6.8

b.0001

9.0 43.4 47.6 21.0

9.2 44.9 45.9 20.4

.647

17.2 43.4 39.4 19.3

b.0001

.093

20.8 45.6 33.6 17.7

25.4 45.3 22.7 79.9 55.4 10.0

17.3 33.2 19.3 76.7 54.7 6.1

b.0001 b.0001 .008 .014 .660 b.0001

35.6 35.0 25.0 77.7 53.1 10.1

32.2 39.8 24.1 78.1 57.8 6.8

b.0001 b.0001 .057 .322 b.0001 b.0001

132 52 182 217 166 119 137 29.6

139 50 165 221 172 113 135 29.6

b.0001 b.0001 b.0001 .004 b.0001 b.0001 .0001 .933

97 51 167 180 129 112 133 29.4

96 47 158 175 127 112 132 29.6

.090 b.0001 b.0001 b.0001 b.0001 .193 b.0001 .003

b.0001

4Among those without established coronary artery disease. yHistory of myocardial infarction, stable or unstable angina, angioplasty, or bypass surgery. zPeripheral artery disease, abdominal aortic aneurysm, transient ischemic attacks, or stroke.

compare the proportions of elderly (aged z65) patients receiving statin therapy who (1) attained the risk-category–appropriate lower optional or minimal LDL-C goals before and after the 2004 update and (2) were treated with aggressive versus standard lipidlowering therapy.

Methods The institutional review board of the Kaiser Permanente Center for Health Research (Portland, OR) reviewed and approved the study. The study was conducted within Kaiser Permanente Northwest (KPNW) (Portland, OR), a 480 000member group-model health maintenance organization that uses clinical practice guidelines to assist clinicians in patient management. The health plan maintains comprehensive medical use data that include an electronic medical record of all patient encounters, laboratory results that are analyzed by a single regional laboratory using standardized methods, and dispenses from pharmacies located in all clinics. After the 2004 publication of the Update, the KPNW dyslipidemia management guideline was revised to recommend intensity of treatment sufficient to achieve at least a 30% to 40% reduction in LDL-C

levels, and to state that a more aggressive goal of b70 mg/dL is now an option for patients with very high risk of CHD.

Study population selection Using an observational cohort design, we selected all KPNW members aged z65 who received a dispense of 3-hydroxy-3methylglutaryl-coenzyme A reductase inhibitors (statins) in 2003 (n = 14 425) and repeated the selection in 2005 (n = 19 422). We required patients to have at least 6 months of health plan membership before the first dispense in the cohort year. Within each cohort, we identified patients who newly initiated statin therapy in the cohort year by ensuring that no statin dispense had occurred during the 6 months before the first dispense in the cohort year (n = 2337 in 2003 and n = 1880 in 2005). Remaining subjects were defined as continuing statin users.

Coronary heart disease risk classification We used electronic medical record data, including laboratory values, chart diagnoses, and anthropometric measures, to assign subjects to 1 of 5 coronary heart disease (CHD) risk categories identified by the Update. Very high risk was defined as the presence of established CHD (myocardial infarction

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556 Nichols, Nag, and Chan

Table II. Proportion of subjects newly initiating or continuing statin therapy who received very aggressive,4 aggressive,y or minimal-guideline (revised 2004) therapy,z by cohort year Newly initiating statin therapy 2003 Moderately high risk (%) Very aggressive therapy 0.4 Aggressive therapy 3.1 Minimal-guideline therapy 60.0 High risk (%) Very aggressive therapy 0.2 Aggressive therapy 1.8 Minimal-guideline therapy 66.6 Very high risk (%) Very aggressive therapy 0.3 Aggressive therapy 3.3 Minimal-guideline therapy 64.0 Total, moderately high or greater risk (%) Very aggressive therapy 0.3 Aggressive therapy 2.2 Minimal-guideline therapy 65.3

Continuing statin therapy

2005

P

2003

2005

P

0.6 3.4 83.0

.694 .824 b.0001

0.9 7.7 54.3

1.6 8.1 72.6

.125 .672 b.0001

0.3 2.9 85.5

.762 .078 b.0001

1.2 8.4 57.8

3.0 11.4 77.7

b.0001 b.0001 b.0001

1.2 10.2 88.6

.194 .001 b.0001

1.8 11.9 64.1

5.3 18.6 80.2

b.0001 b.0001 b.0001

0.5 3.7 85.4

.320 .008 b.0001

1.3 9.2 59.0

3.4 12.7 77.7

b.0001 b.0001 b.0001

4Very aggressive therapy defined as doses sufficient to achieve N50% LDL-C reduction. yAggressive therapy defined as doses sufficient to achieve z40% LDL-C reduction. zMinimal guideline therapy defined as doses sufficient to achieve N30% LDL-C reduction.

Table III. Proportion of subjects newly initiating or continuing statin therapy that attained minimal and optional LDL-C goals, by cohort year Newly initiating statin therapy

Moderately high risk (%) Minimal goal (b130 mg/dL) Optional goal (b100 mg/dL) High risk (%) Minimal goal (b100 mg/dL) Very high risk (%) Minimal goal (b100 mg/dL) Optional goal (b70 mg/dL) Total (%) Minimal goal (all 3 risk groups) Optional goal (moderately high and very-high-risk groups only)

Continuing statin therapy

2003

2005

P

2003

2005

P

80.4 41.5

87.0 48.0

.030 .120

84.9 43.9

82.8 40.8

.138 .095

72.1

71.6

.679

66.3

70.7

b.0001

81.8 34.4

77.8 45.5

.281 .014

78.7 22.6

80.6 25.5

.090 .013

74.7 37.4

75.2 47.1

.748 .001

72.3 29.8

74.7 30.8

b.0001 .370

[International Classification of Diseases, Ninth Revision, Clinical Modification code 410.x], stable or unstable angina [411.1, 411.81, 411.89, 413.xx], angioplasty or bypass surgery [procedure codes 36.00, 36.01, 36.02, 36.05, 36.1x]) plus z1 of the following: (1) diabetes (250.xx), (2) cigarette smoking, and (3) multiple risk factors for the metabolic syndrome (especially triglycerides z200 mg/dL, with non– high-density lipoprotein cholesterol (HDL-C) z130 mg/dL and HDL-C b40 mg/dL). High risk was defined as established CHD or CHD risk equivalents (diabetes [250.xx], peripheral artery disease [440.x, 443.81, 443.89, 444.2-.9, 445.0, 445.1], abdominal aortic aneurysm [441.4], stroke [433.x, 434.x, 435.x, 437.0, 437.1]) or 10-year CHD risk N20% based on the Framingham risk score.10 Moderately high risk was defined as 10-year CHD risk of 10% to 20% or z2 risk factors

(hypertension, current smoking, HDL-C b40 mg/dL, or age [family history is also considered a risk factor but is not available in our data]). Note that all subjects were z65 years and therefore met the age risk-factor criterion. Moderate risk was defined as z2 risk factors with 10-year CHD risk b10% and lower risk as 0 to 1 risk factor. Because we found relatively few patients in the moderate and lower-risk categories that were treated with statins, we focused our analyses on the very-high-risk, high-risk, and moderately high-risk groups.

Analytic measures Our first primary outcome was the proportion of subjects who received intensive or at least minimal-guideline lipidlowering therapy in each cohort year. We defined minimalguideline therapy as any therapy expected to produce LDL-C

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Figure 1

Follow-up LDL-C by risk category for subjects newly initiating statin therapy.

reduction of z30% according to the following daily doses: atorvastatin z10 mg, lovastatin z40 mg, simvastatin z20 mg, pravastatin z40 mg, and rosuvastatin z5 mg. Intensive therapy was defined as therapy designed to achieve at least a 40% reduction in LDL-C. We further identified 2 non– mutually exclusive levels of intensive therapy. Aggressive therapy was defined as any therapy expected to reduce LDL-C by N40% per the following doses: atorvastatin z40 mg, simvastatin z80 mg, or rosuvastatin N20 mg. We defined very aggressive therapy as any therapy providing expected LDL-C reduction of z50%: atorvastatin z80 mg, or z10 mg in combination with ezetimibe; simvastatin z80 mg in combination with niacin or resins, or z20 mg in combination with ezetimibe; or rosuvastatin z40 mg, or z5 mg in combination with ezetimibe. For new statin initiators, we selected the dispensation with the highest daily dose within 1 year of the first statin dispense to allow for dose titration. For ongoing statin users, we identified therapy based on the maximal daily dose of any prescription received during the cohort year. In both cohort years, N98% of new initiators and 95% of continuing users received simvastatin or lovastatin. Our second outcome was LDL-C levels that were attained within 1 year of initiating statin therapy or, for ongoing statin users, that occurred during the cohort year. Kaiser Permanente Northwest operates a single regional laboratory that uses standardized methods and quarterly external comparison with reference samples. Low-density lipoprotein cholesterol is calculated using the Friedewald Equation [total cholesterol  HDL-C  (triglycerides/5)]. If triglycerides are N400 mg/dL, LDL-C is measured directly using a homogeneous assay (Genzyme, Cambridge, MA). All statistical analyses were performed using SAS, version 8.2 (SAS, Cary, NC).

Results Elderly patients in the 2003 and 2005 cohorts were of similar age and sex among both new and ongoing statin users (Table I). More statin initiators in 2003 than in 2005 fell into the very-high-CHD-risk category (15.3% vs 8.9%, P b .0001), but the cohorts did not differ in mean 10-year CHD risk. A greater proportion of new initiators in 2003 than in 2005 had existing CHD (25.4% vs 17.3%, P b .0001), diabetes (45.3% vs 33.2%, P b .0001), and other CHD risk equivalent diagnoses (22.7% vs 19.3%, P = .008). However, baseline lipid profiles before statin initiation favored the 2003 cohort (eg, LDL-C 132 vs 139 mg/dL, P b .0001). Among continuing statin users, the 2003 and 2005 cohorts were more similar despite being statistically significantly different. For example, 23.2% of the 2003 cohort had very high CHD risk compared with 21.5% of the 2005 cohort ( P b .0001), but mean 10-year risk was slightly greater in the 2005 cohort (19.3% vs 17.7%, P b .0001). Aggressive statin therapy was more common in 2005 than in 2003 (Table II). Among very-high-risk individuals, 10.2% of new statin users and 18.6% of ongoing users received aggressive therapy in 2005, compared with 3.3% ( P = .001) and 11.9% ( P b .0001), respectively, in 2003. Minimal-guideline therapy was also more common in 2005 than in 2003. Of new statin initiators in 2005, N85% received minimal-guideline therapy, versus 65% in 2003 ( P b .0001), and nearly 78% (vs 59%) of ongoing users received minimal-guideline

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558 Nichols, Nag, and Chan

Figure 2

Low-density lipoprotein cholesterol by risk category for subjects continuing statin therapy.

therapy ( P b .0001). These numbers were similar across all CHD risk categories. Very aggressive statin therapy was rare in either cohort—b1% among new initiators and b4% among ongoing users. Across all risk categories, minimal LDL-C goal attainment did not differ between the 2003 and 2005 statin initiators (Table III). However, a significantly greater proportion of very-high-risk patients in the 2005 versus the 2003 cohort attained the optional goal of b70 mg/dL (45.5% vs 34.4% P = .014). When combining the 2 groups that had optional goals (moderately high and very high risk), the proportion attaining the optional goal in the 2005 cohort was significantly greater compared with the 2003 cohort (47.1% vs 37.4%, P = .001). Low-density lipoprotein cholesterol goal attainment among continuing statin users was, in general, not different between the 2003 and 2005 cohorts. However, a greater proportion of high-risk patients attained the goal of b100 mg/dL in 2005 (70.7% vs 66.3%, P b .0001). Figure 1 displays the distribution of LDL-C levels after statin initiation for the patients who newly initiated statin therapy in 2003 and 2005. As reported, a significantly greater proportion of very-high-risk patients attained b70 mg/dL in 2005 than in 2003, but a much smaller proportion in 2005 versus 2003 fell into the 100 to 129 mg/dL category (32.3% and 47.4%, respectively). The LDL-C distributions in the high-risk groups were remarkably similar between the 2 cohorts. Among moderately high-risk patients, the largest difference

between the 2003 and 2005 cohorts was found in the 70 to 99 mg/dL range (31.9% and 41.5%, respectively). The distribution of LDL-C changed little among ongoing statin users (Figure 2), except that a greater proportion of high-risk users attained LDL-C b70 mg/dL in 2005 compared with 2003 (18.7% vs 13.7%, P b .0001). There was a corresponding reduction in the proportion in the 100 to 129 mg/dL range (23.6% vs 28.0%, P b .0001).

Discussion This observational cohort study of 14 425 elderly patients in 2003 and 19 422 in 2005 suggests that the 2004 update to the NCEP ATP III guidelines on cholesterol management, and the corresponding revision of internal guidelines in a large health maintenance organization, resulted in more patients receiving minimal-guideline statin therapy. Clinical trials have shown that high-dose statin therapy produces fewer coronary events than lower doses.5,11,12 Although the current study was not designed to assess outcomes, the increase in therapy intensity among continuing statin users at moderately high, high, or very high CHD risk, could be expected to reduce coronary event rates. The increase in the proportion receiving minimalguideline statin therapy did not result in substantial improvements in LDL-C goal attainment. The one subgroup in which a significant improvement in goal

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attainment was observed was the very-high-risk CHD patients who newly initiated statin therapy—a larger proportion attained the new optional LDL-C goal of b70 mg/dL in 2005 (compared with 2003). However, the increased proportion appeared to come from patients who would have achieved the minimal goal of b100 mg/dL. In fact, a nonsignificant smaller proportion of these very-high-risk new initiators attained the minimal goal in 2005 than in 2003. Thus, although the Update may have had a favorable impact on the proportion of very-high-risk patients attaining the new optional goal, there was no apparent effect on the approximately 20% of patients who did not achieve the minimal LDL-C goal. The rationale for the new optional goal of b70 mg/dL was based on data from the HPS and the PROVE IT trial.1,5 However, the HPS compared statin treatment with placebo, and PROVE IT was conducted in patients with acute coronary syndrome. Thus, at the time of the Update, there was no definitive generalizable evidence that treating LDL-C to b70 mg/dL provided additional cardiovascular benefit. Since the Update, the TNT study demonstrated that treatment with 80 mg of atorvastatin, resulting in a mean LDL-C of 77 mg/dL, provided a 22% risk reduction in the primary composite CHD end point compared with 10 mg of atorvastatin, which produced a mean LDL-C of 101 mg/dL.11 Whether that difference is the result of the difference in LDL-C or the difference in statin dose has not been analyzed. It remains unclear from any studies to date whether LDL-C reduction produces cardiovascular risk reduction independently of statin exposure.13 The lack of improvement in goal attainment may have been because elderly patients rarely received intensive statin therapy. Although aggressive therapy was more common after the guideline revision, only a minority of patients received it, even among those at very high CHD risk. Very aggressive therapy was rare. Neither the Update nor the revised KPNW guidelines explicitly recommended intensive therapy, opting instead for a recommendation of therapy expected to decrease LDL-C by 30% to 40%.6 After the Update, an impressive proportion of elderly patients were receiving this minimal-guideline level of therapy. Given the results of recent studies that have demonstrated cardiovascular benefit of intensive versus moderate lipid-lowering,5,11,14 aggressive therapy for more patients, including more rapid titration, would appear warranted. Because the Update seemed to substantially increase the proportion of patients receiving minimal-guideline therapy, an additional update and a corresponding revision of internal guidelines urging statin intensification could help achieve this goal. Although we did not directly compare new initiators with continuing statin users in either cohort year, the proportions achieving minimal goals appeared similar in both cohort years. However, despite the substantially

Nichols, Nag, and Chan 559

greater proportion of ongoing users receiving aggressive or minimal-guideline therapy, new initiators were more likely to reach the lower optional LDL-C goals in both 2003 and 2005. Our data do not provide an explanation for this finding. Possibilities include more clinician emphasis on results when initiating statin therapy or better medication compliance early in the course of statin therapy. In the context of other studies on LDL-C goal attainment, our finding that nearly three fourths of statin users had reached their (minimum) recommended goal is encouraging. Older studies have reported low goal attainment rates, especially among the elderly, of between 18% and 38% overall.7,15 More recent studies have reported that 50% to 67% of patients attained LDL-C goals.8,9,16 Still, the better rates seen in the newer studies came before the recent NCEP ATP III update. Thus, we can hope that the Update will further increase patient and provider awareness of the importance of lipid management. Our study has several limitations. First, we did not attempt to account for patient compliance with prescribed therapy. This is one possible explanation for the lack of change in goal attainment despite the increase in the proportion receiving aggressive lipid therapy. Second, because we focused this study on statin therapy, we did not evaluate patients who were at CHD risk but did not receive statins. We also limited the study to elderly patients (z65 years). Because 2 recent studies demonstrated that advanced age was associated with LDL-C goal attainment,8,9 this could explain the relatively high attainment rates we report. In any event, our results may not generalize to younger populations. Finally, our data are entirely observational. Therefore, we cannot conclude that either the Update or the corresponding revision of the KPNW guidelines was responsible for our findings. However, because we conducted the bpostQanalyses so soon after the Update, we may be underestimating its true effect—allowing more time for the recommendations to become known could improve goal attainment beyond our reported rates. In conclusion, we found an increase in the proportion of elderly patients at moderately high to very high CHD risk that received intensive or at least minimal-guideline statin therapy after the Update. Among very-high-risk patients newly initiating statins, a significantly greater proportion reached the new optional goal of b70 mg/dL in 2005 compared with 2003, but that increase was apparently achieved by lowering LDL-C for patients who were already doing well. Among continuing statin users, a greater proportion of high-risk patients attained the goal of b100 mg/dL in 2005. Although these findings may translate into less overall CHD risk, much remains to be done to maximize risk reduction that can be achieved through more aggressive lipid-lowering therapy.

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