patients) resulted in a mean reduction in blood pres-
results of the HOPE study and MICRO-HOPE Substudy. Lancet 2000;355:253–
sure of only 2.4/1.0 mm Hg.
Our findings mirror other recent practice audits in
the United States (36% of diabetic patients who un-
derwent coronary revascularization were discharged
on an ACE inhibitor from a university center in 1998
and 1999) and Europe (43% ACE inhibitor use after
coronary revascularization).10,11 This incomplete
translation of the evidence from the HOPE/MICRO-
HOPE Trial to the care of our CABG patients with
diabetes mellitus occurred despite the fact our center
was 1 of the study sites in the HOPE/MICRO-HOPE
Trial. This is not surprising, as gaps between physi-
cian knowledge and their prescribing practices are
commonly recognized in cardiovascular disease.12,13
However, the post-CABG period is an ideal opportu-
nity to address cardiovascular risk factors and to op-
timize secondary prevention in high-risk patients,
such as diabetics with coronary artery disease, partic-
ularly as therapies initiated in hospital are most likely
to be continued by patients and their primary care
physicians subsequently.14
In summary, although our tertiary-care center
participated in the HOPE/MICRO-HOPE Trial,
audit of our diabetic patients who underwent
CABG in the year after publication of HOPE/
MICRO-HOPE revealed that only 57% were tak-
ing ACE inhibitors before surgery and only 43%
were discharged on an ACE inhibitor. Thus,
knowledge of the potential benefits from a medica-
tion and familiarity with its use are not enough to
ensure the uptake of efficacious therapies.
1. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an
angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. N Engl J Med 2000;342:145–153.
2. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril
Effectiveness of Statin Titration on Low-Density
Lipoprotein Cholesterol Goal Attainment in Patients at
High Risk of Atherogenic Events
Kathleen A. Foley, PhD, Ross J. Simpson, Jr., MD, PhD, John R. Crouse III, MD,
Thomas W. Weiss, DrPH, Leona E. Markson, ScD, and Charles M. Alexander, MD
T he failure of many patients to achieve low-density
lipoprotein (LDL) cholesterol goal suggests that
there is a gap between the efficacy of statins seen in
From the Outcomes Research and Management, U.S. Medical and
Scientific Affairs, Merck & Co., Inc., West Point, Pennsylvania; Divi-
sion of Cardiology, University of North Carolina, Chapel Hill, North
Carolina; and Preventive Cardiology Program, Lipid Clinic, Wake
Forest University School of Medicine, Winston-Salem, North Carolina.
This study was conducted and funded by Merck & Co., Inc., West
Point, Pennsylvania. Dr. Simpson’s address is: Division of Cardiology,
CB #7075, Bioinformatics Bldg, Chapel Hill, North Carolina 27599.
E-mail: rsimpson@med.unc.edu. Manuscript received November 12,
2002; revised manuscript received and accepted March 12, 2003.
©2003 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 92 July 1, 2003
on cardiovascular and microvascular outcomes in people with diabetes mellitus:
259.
3. Majumdar SR, Chang WC, Armstrong PW. Do the investigative sites that take
part in a positive clinical trial translate that evidence into practice? Am J Med
2002;113:140 –145.
4. Lonn EM, Yusuf S, Dzavik V, Doris I, Yi Q, Smith S, Moore-Cox A, Bosch
J, Riley WA, Teo KK, for the SECURE Investigators. Effects of ramipril and
vitamin E on atherosclerosis. The Study to Evaluate Carotid Ultrasound changes
in patients treated with Ramipril and vitamin E (SECURE). Circulation 2001;
103:919 –925.
5. Kjoller-Hansen L, Steffensen R, Grande P. The Angiotensin-converting En-
zyme Inhibition Post Revascularization Study (APRES). J Am Coll Cardiol
2000;35:881–888.
6. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pederson
C, Ball S, Pogue J, Moye L, Braunwald E, for the ACE-Inhibitor Myocardial
Infarction Collaborative Group. Long-term ACE-inhibitor therapy in patients
with heart failure or left-ventricular dysfunction: a systematic overview of data
from individual patients. Lancet 2000;355:1575–1581.
7. Teo KK, Burton JB, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V,
Taylor D, Yokoyama S, Montague TJ, for the SCAT Investigators. Long-term
effects of cholesterol lowering and angiotensin-converting enzyme inhibition on
coronary atherosclerosis. The Simvastatin/Enalapril Coronary Atherosclerosis
Trial (SCAT). Circulation 2000;102:1748 –1754.
8. Oosterga M, Voors AA, Pinto YM, Buikema H, Grandjean JG, Kingma JH,
Crijns HJGM, van Gilst WH. Effects of quinapril on clinical outcome after
coronary artery bypass grafting (The QUO VADIS Study). Am J Cardiol 2001;
87:542–546.
9. Warnica JW, Van Gilst W, Baillot R, Johnstone D, Block P, Myers MG,
Chocron S, Dalle Ave S, Martineau P, Rouleau JL, on behalf of the IMAGINE
Investigators. Ischemic management with accupril post bypass graft via inhibition
of angiotensin converting enzyme (IMAGINE): a multicentre randomized trial—
design and rationale. Can J Cardiol 2002;18:1191–1200.
10. Allen JK, Blumenthal RS, Margolis S, Young DR. Status of secondary
prevention in patients undergoing coronary revascularization. Am J Cardiol
2001;87:1203–1206.
11. The European Action on Secondary Prevention by Intervention to Reduce
Events I, and II Investigators. Clinical reality of coronary prevention guidelines:
a comparison of EUROASPIRE I and II in nine countries. Lancet 2001;357:995–
1001.
12. Ayanian JZ, Hauptman PJ, Guadagnoli E, Antman EM, Pashos CL, McNeil
BJ. Knowledge and practices of generalist and specialist physicians regarding
drug therapy for acute myocardial infarction. N Engl J Med 1994;331:1136 –
1142.
13. Ayanian JZ, Guadagnoli E, McNeil BJ, Cleary PD. Treatment and outcomes
of acute myocardial infarction among patients of cardiologists and generalist
physicians. Arch Intern Med 1997;157:2570 –2576.
14. Muhlestein JB, Horne BD, Blair TL, Li Q, Madsen TE, Pearson RR,
Anderson JL. Usefulness of in-hospital prescription of statin agents after angio-
graphic diagnosis of coronary artery disease in improving continued compliance
and reduced mortality. Am J Cardiol 2001;87:257–261.
controlled clinical trials1,2 and their effectiveness in
clinical practice. One reason why patients may fail to
achieve LDL cholesterol goal with statin treatment is
because the statins are not appropriately titrated.1,3
The objective of this prospective, observational study
was to determine how often high-risk patients with
hyperlipidemia were evaluated and whether doses of
statins were titrated during a 6-month period.
•••
We studied a subgroup of patients who had suffi-
cient follow-up time for titration and potential goal
attainment from a data set of a prospective 26-week
0002-9149/03/$–see front matter 79
doi:10.1016/S0002-9149(03)00474-0
 TABLE 1 Patient Demographics and Baseline Characteristics TABLE 2 Adjusted (multivariate) Odds Ratios for Association
(n ⫽ 2,829) of Patient and Provider Characteristics With Titration of the
Statin Dose in 1,464 Patients Not at their LDL Cholesterol
Patient Characteristic % or Mean Goal of 100 mg/dl With Initial Statin Dose
Men 72.3% Adjusted
Mean age ⫾ SD 63.6 ⫾ 11.9 Odds 95% Confidence
Age ⱖ65 yrs 50.4% Ratios Intervals
Caucasian 86.7%
African-American 5.8% Baseline lipid profile
Hispanic 5.2% HDL Cholesterol 0.981 0.962–1.000
Coronary heart disease only 62.3% Follow-up lipid profile*
Diabetes only 17.9% LDL Cholesterol between 1.360 1.039–1.780
Coronary heart disease and diabetes 19.8% 130–159 mg/dl
Mean LDL cholesterol (⫾ SD) 149.6 ⫾ 31.2 LDL Cholesterol ⱖ160 mg/dl 1.597 1.067–2.391
HDL cholesterol (⫾SD) 36.9 ⫾ 5.6 Triglycerides 1.002 1.000–1.004
Mean non–HDL cholesterol (⫾) 186.7 ⫾ 34.8 Physician characteristics*
Median triglycerides* 171 (126–230) Midwest Region 1.472 1.019–2.125
Initial statin Family or General Practice 0.305 0.188–0.495
Simvastatin 55.4% Baseline statin and dose*
Atorvastatin 29.0% Simvastatin 1.574 1.139–2.176
Pravastatin 10.2% Atorvastatin 1.642 1.145–2.355
Other statin 5.4% Above recommended starting 0.491 0.359–0.672
dose
*Triglycerides are reported as medians and interquartile ranges.
*Follow-up lipid profiles are taken as the lipid profile just before titration for
patients and as the final lipid profile for those whose statin dose was not
titrated. The reference group for the interim LDL cholesterol variables includes
patients with LDL cholesterol ⬍130 mg/dl. The reference group for practice
region variables includes physicians in the south. The reference group for the
specialty variables includes cardiologists. The reference group for the statin
variables includes patients on pravastatin, cerivastatin, fluvastatin, or lova-
statin.

cause the 6-month time frame would not allow time to

FIGURE 1. Flowchart of goal attainment with initial statin dose
and subsequent titration and goal attainment for 2,829 patients.
Only 14% of patients (203 of 1,464) who did not attain the LDL
goal with the initial dose reached their goal within 6 months.
observational study of the process of care of high-risk
patients. A large number of physicians (n ⫽ 378) from
geographically diverse areas and specialties were in-
cluded; 71% were cardiologists. Study compensation to
physicians was based on the amount of work performed.
Each physician enrolled approximately 11 patients. Phy-
sicians were instructed to enroll patients regardless of the
type of statin used and were free to use any statin for
treatment. Patients eligible for the study were required to
have coronary heart disease or diabetes, an elevated LDL
cholesterol concentration relative to guidelines or be
above the physician selected goal, and to have a high-
density lipoprotein (HDL) cholesterol level ⬍45 mg/dl.
Central institutional review board approval was ob-
tained, and patients completed a record release during
enrollment. An attempt was made to recruit a diverse
patient population.
The study protocol instructed sites to treat eligible
patients as suggested by guidelines,4 – 6 to follow the
prescribing information for whichever statin was used, to
counsel patients on the appropriate low-fat, low-choles-
terol diet, and to titrate the prescribed statin as necessary
to achieve goals for LDL cholesterol ⬍100 mg/dl. Be-
observe changes in the lipid profile if the statin was
switched or combination therapy was initiated, these
were not permitted. Drug supplies were not provided.
Dosage titration and LDL cholesterol goal attainment
were followed for ⱖ5 months to provide sufficient time
to observe 1 and possibly 2 (6-week interval) dose titra-
tions. For those patients who did not obtain their LDL
cholesterol goal with the initial statin dose, logistic re-
gression models were employed to assess factors asso-
ciated with dose titration. The model included patient
and physician characteristics, practice region, presence
of formulary restrictions, physician specialty, baseline
and interim lipid values, age, gender, ethnicity, disease
state (coronary heart disease, diabetes, or both), the statin
prescribed, and whether the starting dose was above or
below the recommended starting dose of the particular
statin, as defined by the prescribing information. Dichot-
omous indicators for LDL cholesterol ⱖ130 and ⬎160
mg/dl and LDL cholesterol ⱕ160 mg/dl were employed,
with LDL cholesterol ⬍130 mg/dl as the reference
group. HDL cholesterol and triglycerides were measured
as continuous variables. For patients whose statin dose
was titrated, interim lipid profiles just before statin titra-
tion were identified. For patients whose prescription was
not titrated, the final lipid profile was used as the interim
value. All statistical analysis was conducted using SAS
8.0 (SAS Institute, Cary, North Carolina).
Patient enrollment began on March 25, 1999, and
ended September 30, 1999. A total of 5,121 patients
were enrolled in the main study. Patients were ex-
cluded from analysis due to loss to follow-up (n ⫽
936), ineligibility or incomplete baseline data (n ⫽

80 THE AMERICAN JOURNAL OF CARDIOLOGY姞 VOL. 92 JULY 1, 2003

54), protocol exclusions, including statin switching (n
⫽ 146), follow-up of ⬍150 days (n ⫽ 824), or no
follow-up LDL cholesterol value (n ⫽ 332). The final
analytic data set consisted of 2,829 eligible patients.
Patients excluded from the analysis cohort because of
loss to follow-up and for other reasons had similar
baseline LDL cholesterol and total cholesterol com-
pared with those who were included and the propor-
tion receiving each statin was similar in the analysis
cohort and the excluded cohort.
Patient demographics and baseline characteristics
are listed in Table 1. Fifty percent of patients completed
their final visit within 6 months and 90% within 8
months. Goal attainment according to initial statin and
dose titration is shown in Figure 1. Most patients were
initiated at the recommended start dose (74% of atorva-
statin patients, 70% of simvastatin patients, and 63% of
patients on other statins). The median time to titration
was 106 days. Forty-eight percent of patients achieved
an LDL cholesterol ⬍100 mg/dl with their initial dose.
Of those who did not achieve goal with their initial dose,
45% had their dosage titrated. Most of these patients had
the statin titrated once, and only 31% of these patients
reached their LDL cholesterol goal of ⬍100 mg/dl.
Thus, among statin-treated patients who did not achieve
the LDL cholesterol goal with their initial dose, only
14% (203 of the 1,464 patients) attained the goal within
6 months of starting treatment.
Factors associated with titration for patients eligi-
ble for titration are shown in Table 2. With the excep-
tion of high HDL cholesterol, the baseline lipid profile
had little association with statin dose titration. In con-
trast, patients with higher interim LDL cholesterol
values were more likely to have dose titration. Physi-
cians in family and general practice were less likely to
titrate than cardiologists. Patients started on a statin
dose above the recommended starting dose were also
less likely to have dose titration.
•••
Clinical trials of statins show that between 76%
and 95% of patients reach guideline recommended
LDL cholesterol goals.1,2,7–9 These results are in con-
trast to clinical experience, which shows goal attain-
ment rates as low as ⱕ25%.10 –12 Only 48% of patients
in our study achieved LDL cholesterol goals with their
initial starting dose. Of those who did not reach their
goals with their initial dose, less than half had the dose
titrated despite the allowance of 6 months, which was
believed to be a sufficient amount of time to titrate the
statin dose. Thus, lack of titration may contribute to the
previously reported low rate of success in achieving
LDL cholesterol treatment goals.10 –12 Examination of
the factors associated with titration suggests that physi-
cians are more likely to titrate dosages for patients with
the highest LDL cholesterol and triglyceride values and
that patients started on a dose above the recommended
starting dose are less likely to have the statin dose ti-
trated. Physicians appear to use the highest doses spar-
ingly even among these high-risk patients.
Factors not captured in this study may play a role
in whether patients obtain goal. Lack of patient ad-
herence to statin treatment, and to diet and exercise
recommendations may be important in failures to
achieve goals.13 The lack of titration and goal attainment,
even where titration occurred, suggests a need for re-
search on the roles played by patient adherence to rec-
ommended treatments as well as health system and atti-
tudinal barriers in treating patients to goal. Another pos-
sibility is that 6 months is not a long enough observation
period to record titration in subsequent titration out-
comes. It is likely that physicians who participated in this
study are more aggressive in treating patients than the
average physician. Therefore, we may have overesti-
mated the percent of patients who achieved LDL cho-
lesterol goals. True titration and goal attainment rates of
high-risk patients are likely to be lower than we have
reported here. Our study, however, captures treatment
patterns of a more generalized group of hyperlipidemic
patients than typically found in clinical trials14 and pro-
vides insight into the causes of the gap between clinical
efficacy of statins and effectiveness in clinical practice.
Our data suggest that dosage titration occurs
only in a few patients treated in a practice setting
and that many patients do not reach goals within a
reasonable period of time. Dosage titration does
not appear to be aggressive enough for most pa-
tients to achieve their LDL cholesterol goals.
1. Andrews TC, Ballantyne CM, Hsia JA, Kramer JH. Achieving and maintaining
national cholesterol education program low-density lipoprotein cholesterol goals
with five statins. Am J Med 2001;111:185–191.
2. Davidson M, Ma P, Stein E, Gotto A, Raza A, Chitra R, Hutchison H.
Comparison of effects on low-density lipoprotein cholesterol and high-density
lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type
IIa or IIb hypercholesterolemia. Am J Cardiol 2002;89:268 –275.
3. Vicari R, Wan G, Aura M, Alexander C, Markson L, Teutsch S, for the
Simvastatin Combined Hyperlipidemia Registry Group. Use of simvastatin treat-
ment in patients with combined hyperlipidemia in clinical practice. Arch Fam
Med 2000;9:898 –905.
4. NCEP Expert Panel. Executive summary of 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).
JAMA 2001;285:2486 –2497.
5. American Diabetes Association. Diabetes Care 1999;22(Suppl 1):S56 –S59.
6. AHA/ACC guidelines for preventing heart attack and death in patients with
atherosclerotic cardiovascular disease: 2001 update. Circulation 2001;104:1577–
1579.
7. Muls E, De Backer G, Brohet C, Heller F, LIPI-GOAL Investigators. The
efficacy of atorvastatin in treating patients with hypercholesterolaemia to target
LDL-cholesterol goals: the LIPI-GOAL trial. Acta Cardiologica 2001;56:109 –
114.
8. Garmendia F, Brown AS, Reiber I, Adams PC. Attaining United States and
European guideline LDL-cholesterol levels with simvastatin in patients with
coronary heart disease (the GOALLS study). Cur Med Res Opin 2000;16:208 –
219.
9. Hunninghake D, Bakker-Arkema RG, Wigand JP, Drehobl M, Schrott H, Early
JL, Abdallah P, McBride S, Black DM. Treating to meet NCEP-recommended
LDL cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or sim-
vastatin in patients with risk factors for coronary heart disease. J Fam Pract
1998;47:349 –356.
10. Sueta CA, Chowdhury M, Boccuzzi S, Smith SC, Alexander CM, Londhe A,
Lulla A, Simpson RJ. Analysis of the degree of undertreatment of hyperlipidemia
and congestive heart failure secondary to coronary artery disease. Am J Cardiol
1999;83:1303–1307.
11. Pearson T, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment
Project. Arch Intern Med 2000;160:459 –467.
12. Fonarow G, Gawlinksi A, Moughrabi S, Tillisch J. Improved treatment of
coronary heart disease by implementation of a Cardiac Hospitalization Athero-
sclerosis Management Program (CHAMP). Am J Cardiol 2001;87:819 –822.
13. Pearson T, Feinberg W. Behavioral issues in the efficacy versus effectiveness
of pharmacological agents in the prevention of cardiovascular disease. Ann Behav
Med 1997;19:230 –238.
14. Black N. Why we need observational studies to evaluate the effectiveness of
health care. BMJ 1996;312:1215–1218.
BRIEF REPORTS 81