Clinical Pharmacy Specialist Implementation

of Lisinopril Therapy in Patients

with Coronary Artery Disease and Diabetes Mellitus
Karen J. McConnell, Pharm.D., Tammy L. Humphries, Pharm.D., Marsha A. Raebel, Pharm.D., and
John A. Merenich, M.D., for the Clinical Pharmacy Cardiac Risk Service Study Group
Study Objective. As the results of the Heart Outcomes Prevention Evaluation
trial suggested that patients with both coronary artery disease (CAD) and
diabetes mellitus would benefit from angiotensin-converting enzyme (ACE)
inhibitor therapy, our objective was to increase the percentage of patients
with both of these conditions receiving the goal dosage (20 mg/day) or
highest tolerated dosage of the ACE inhibitor lisinopril through
intervention of a clinical pharmacy service.
Study Design. Prospective study with historic comparison (control group).
Setting. Clinical Pharmacy Cardiac Risk Service.
Patients. Hospitalized patients with CAD and type 2 diabetes mellitus.
Measurements and Main Results. At hospital discharge, lisinopril 5 mg/day
was started in eligible patients; the drug was titrated to a goal dosage of 20
mg/day or the highest tolerated dosage. Potassium level, serum creatinine
level, and blood pressure were monitored at baseline, at each dosage
titration, and 2 weeks after the goal or highest tolerated dosage was
reached. The group receiving usual care (control group) consisted of 95
patients; the treatment group had 101 patients. At baseline, 19 patients
(20%) in the control group were receiving the goal dosage of lisinopril, 34
(36%) were taking a suboptimal dosage, 16 (17%) were excluded from
treatment, and 26 (27%) were eligible but were not receiving lisinopril
therapy. After 9 months, ACE inhibitor dosages had changed minimally in
the control group. In the treatment group, at baseline, 37 patients (36%)
were at their goal dosage and therefore titration was not necessary; 15
(15%) were receiving a suboptimal dosage, 35 (35%) were excluded from
treatment, and 14 (14%) were eligible but not receiving therapy. After the
titration period, 55 (54%) treatment group patients were at the goal dosage,
11 (11%) were taking a suboptimal dosage, and 35 (35%) were not
candidates for ACE inhibitor therapy. The most common reasons for
exclusion were renal insufficiency, cough, and baseline hypotension.
Changes in potassium level, serum creatinine level, and blood pressure
were not significant during the study.
Conclusion. The clinical pharmacy service more than doubled the number of
patients with CAD and diabetes who achieved the goal dosage of an ACE
inhibitor, a drug class that has been shown to decrease morbidity and
mortality in this patient population.
Key Words: lisinopril, coronary artery disease, diabetes mellitus, pharmacist.
(Pharmacotherapy 2003;23(12):1564–1572)
 PHARMACIST-IMPLEMENTED LISINOPRIL THERAPY McConnell et al
Two thirds of patients with diabetes mellitus
die of cardiovascular disease.1 Epidemiologic
studies show that the risk of cardiovascular
mortality is 2 times higher in men with diabetes
and 2–3 times higher in women with diabetes
than in people without the disease.1 The age-
adjusted prevalence of coronary artery disease
(CAD) in Caucasian adults who have diabetes is
approximately 45% versus 25% in those without
diabetes.2
Angiotensin-converting enzyme (ACE)
inhibitors have been shown to be beneficial in
patients with cardiovascular diseases and
diabetes. Since the late 1980s, large trials have
shown the benefits of these drugs in patients
with heart failure. Trials such as the Cooperative
North Scandinavian Enalapril Survival Study
(CONSENSUS),3 the Studies of Left Ventricular
Dysfunction (SOLVD), 4 and the second
Vasodilator–Heart Failure Trial (V-HeFT II)5 have
confirmed the protective effects of ACE inhibitor
therapy on survival in patients with mild-to-
severe heart failure. Studies such as the fourth
International Study of Infarct Survival Trial (ISIS-
4)6 and the Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto miocardico (GISSI-3)7
have shown that ACE inhibitor administration
soon after myocardial infarction reduces
mortality. Three other trials have demonstrated
that ACE inhibitor therapy started days after
myocardial infarction and continued long-term in
patients with clinical signs of left ventricular
dysfunction significantly reduces mortality.8–10
Studies have also demonstrated that ACE
inhibitor therapy decreases proteinuria and
preserves the glomerular filtration rate in patients
with diabetes.11, 12
The Heart Outcomes Prevention Evaluation
(HOPE) study evaluated 9297 high-risk patients
who were not known to have a low ejection
From the Schools of Pharmacy (Drs. McConnell,
Humphries, and Raebel) and Medicine (Dr. Merenich),
University of Colorado Health Sciences Center; and the
Clinical Pharmacy Cardiac Risk Service Study Group (Drs.
McConnell, Humphries, and Merenich), the Clinical
Research Unit (Dr. Raebel), and the Colorado Permanente
Medical Group Department of Endocrinology (Dr.
Merenich), Kaiser Foundation Health Plan of Colorado,
Denver, Colorado.
Presented in part at the American College of Clinical
Pharmacy 2002 Spring Practice and Research Forum,
Savannah, Georgia, April 7–10, 2002.
Address reprint requests to Karen J. McConnell,
Pharm.D., BCPS, Kaiser Permanente Colorado Region,
Clinical Pharmacy Cardiac Risk Service, 16601 East
Centretech Parkway, Aurora, CO 80011; e-mail:
Karen.McConnell@kp.org.
1565
fraction or heart failure.13 Patients were eligible
for the study if they had a history of CAD, stroke,
peripheral vascular disease, or diabetes plus one
other cardiovascular risk factor (hypertension,
elevated total cholesterol level, low high-density
lipoprotein cholesterol level, cigarette smoking,
or documented microalbuminuria). The ACE
inhibitor ramipril significantly reduced the rate
of death, myocardial infarction, and stroke in a
broad range of these high-risk patients. Thirty-
nine percent of the high-risk population had
diabetes mellitus, and a substudy—the
Microalbuminuria, Cardiovascular, and Renal
Outcomes–Heart Outcomes Prevention
Evaluation (MICRO-HOPE) 2 —evaluated the
specific benefit of ramipril in this population.
The drug significantly lowered the risk of major
cardiovascular outcomes by 25–30% in patients
with diabetes and lowered the risk of overt
nephropathy.
These trials clearly show that ACE inhibitor
therapy provides significant benefit for several
patient populations, such as patients with
diabetes or heart failure, those who experienced
myocardial infarction, and those at high risk for
or diagnosed with CAD. Therefore, the objective
of this study was to increase the percentage of
patients with both CAD and diabetes receiving
the goal dosage or highest tolerated dosage of
ACE inhibitor therapy through the intervention
of a clinical pharmacy service. Study results were
compared with outcomes achieved with
conventional treatment.
Methods
Study Design
This was a prospective study with historic
comparison (control group). The study protocol
was approved by the institutional review board of
the Kaiser Foundation Research Institute.
The Clinical Pharmacy Cardiac Risk Service
(CPCRS) designed and implemented this study.
The CPCRS is a clinical service provided by
clinical pharmacy specialists with extensive
training in cardiovascular drug management.
The CPCRS pharmacists serve as regionwide
consultants and provide patient counseling on a
variety of CAD-related drug management issues.
All patients enrolled in the CPCRS are diagnosed
with CAD. For these patients, the service is
responsible for routine lipid profile management,
routine hypertension management, provision of
smoking cessation programs, and orchestration
of drug regimens, including combination
1566 PHARMACOTHERAPY Volume 23, Number 12, 2003

regimens for patients with refractory combined
dyslipidemia, alternatives to aspirin therapy, and
appropriate administration of b-blockers and
ACE inhibitors after myocardial infarction. In
addition, the service monitors for potential
interactions of all these drugs and other drugs
prescribed for patients with CAD and continually
monitors their status of CAD risk factors. For
example, patients are referred to appropriate
health care professionals for counseling and
treatment regarding diet, exercise, weight loss,
and diabetes.14
Patients in both the treatment and the control
groups were screened with the same inclusion
and exclusion criteria. Patients were included in
the study if they were age 18 years or older, had
both type 2 diabetes mellitus and CAD, and were
hospitalized within the designated time frame.
Patients were excluded from the study if they
were already receiving (or were above) the
lisinopril goal dosage of 20 mg/day; were
pregnant or lactating; had renal artery stenosis,
an estimated creatinine clearance below 30
ml/minute, aortic stenosis, hyperkalemia
(potassium level > 5.5 mEq/L), chronic liver
disease or an alanine aminotransferase level 2.5
times the upper limit of normal or higher, or
known hypersensitivity to ACE inhibitor therapy;
were noncompliant with or unwilling to follow
the study protocol (determined through
telephone follow-up); or died during their
hospital stay.
Patient demographics, such as age, sex,
previous ACE inhibitor therapy, and history of
coronary events, smoking, hypertension, hyper-
lipidemia, and heart failure were documented for
all patients in both groups.
The control group was a historic sample drawn
from a database (Microsoft Access 97, Microsoft
Corp., Redmond, WA) used by CPCRS staff to
manage patients. The database contains
demographics, laboratory data, and drug data.14
Control patients had a diagnosis of diabetes
mellitus, a discharge diagnosis related to CAD,
and a discharge date from a Kaiser Permanente
contract hospital from July 1, 2000–October 31,

Excluded:
Not eligible for ACE Hospital assessment
inhibitor therapy (n=33)
or taking ACE inhibitor
at goal dosage or Eligible for ACE inhibitor therapy
higher (n=37) (n=29)

Not taking ACE inhibitor Taking lisinopril 5 mg/day Taking lisinopril 10 mg/day
(n=22) (n=4) (n=3)

Start lisinopril 5 mg/day Enroll Enroll

After 2 weeks, laborator y and BP monitor ing perfor med

Titrate to 10 mg/day Titrate to 10 mg/day Titrate to 20 mg/day

After 2 weeks, laboratory and BP monitoring performed After 2 weeks, final laboratory
and BP monitoring performed
Titrate to 20 mg/day Titrate to 20 mg/day

After 2 weeks, final laboratory and BP monitoring performed

Figure 1. Lisinopril dosage titration schedule for treatment group patients eligible to receive angiotensin-converting enzyme
(ACE) inhibitor therapy. BP = blood pressure.
 PHARMACIST-IMPLEMENTED LISINOPRIL THERAPY McConnell et al
2000. The exclusion criteria were applied to
determine whether the patient would have been
eligible for ACE inhibitor therapy titration.
Efforts were made to educate the staff of the
Colorado Permanente Medical Group and thus
help increase the use of lisinopril. One-on-one
communication in the hospital between the
clinical pharmacy specialist and the cardiologists
and hospital-based practitioners took place. In
addition, voice-mail communications regarding
the initiative and the HOPE trial findings13 were
sent to all physicians.
To further increase the percentage of patients
receiving ACE inhibitor therapy, treatment group
patients were identified by a CPCRS pharmacist
who assessed hospitalized patients daily. Those
with diabetes mellitus, aged 18 years or older,
and whose hospitalization was related to CAD
(myocardial infarction, coronary artery bypass
graft, stent placement, or angina with objective
evidence of CAD) from December 18, 2000–March
30, 2001, were screened. Baseline laboratory data
(potassium level, serum creatinine level) and
blood pressure measurements were documented.
Patients were screened based on the established
exclusion criteria. Eligible patients were
discharged with a low-dose prescription for
lisinopril 5 mg/day. (Patients in the HOPE trial
were administered ramipril, but lisinopril is the
formulary ACE inhibitor at Kaiser Permanente of
Colorado.) Patients who were already taking
lisinopril but were below the goal dosage were
enrolled for dosage titration. Each patient
received counseling from the pharmacist
regarding the therapy.
Once the inpatient pharmacist began ACE
inhibitor therapy management, an outpatient
CPCRS pharmacist managed the titration (Figure
1). Each patient was assigned to an outpatient
clinical pharmacy specialist in the CPCRS who
contacted the patient within 2 weeks of hospital
discharge and answered questions regarding
therapy. The patient’s ability to tolerate the ACE
inhibitor was determined through both
subjective and objective evidence. To monitor
subjective adverse drug reactions, CPCRS
pharmacists questioned their respective patients
through telephone follow-up every 2 weeks.
Objective adverse drug reactions (hypotension,
increased potassium and serum creatinine levels)
were monitored before and 2 weeks after each
dosage titration.
Patients were scheduled for a follow-up visit
with the primary care physician or a CPCRS
pharmacist within 2–4 weeks of discharge. Blood
1567
pressure and laboratory values for serum
creatinine and potassium levels were obtained at
baseline and 2 weeks after each lisinopril dosage
titration. The dosage was titrated to 10 mg/day
within 2 weeks of discharge if deemed clinically
appropriate. If the patient tolerated 10 mg/day
for 2 weeks, the dosage was increased to 20
mg/day, the optimal dosage. If the patient was
taking lisinopril before discharge, the dosage was
titrated to the next appropriate one (from 5 to 10
mg, from 10 to 20 mg).
Six weeks after discharge, a final evaluation of
blood pressure and laboratory data was performed
to verify that the patient was tolerating lisinopril.
Each dosage titration and adverse drug reaction
was documented in the patient’s electronic
medical record and sent to the primary care
physician for review. After the final 6-week
evaluation, the patient resumed the usual care
provided by the primary care physician and was
no longer actively followed by a CPCRS
pharmacist for ACE inhibitor dosage titration.
The CPCRS continued to address the patient’s
cardiac risk factors.
The ACE inhibitor dosages prescribed for the
control group were compared with those
prescribed for the treatment group, both at
baseline and after completion of the titration
period. Data (blood pressure, potassium and
serum creatinine levels) were compiled for
patients whose lisinopril dosages were increased
from baseline to 5 mg/day, 5 to 10 mg/day, and 10
to 20 mg/day. Although the treatment group had
4 months during which the daily ACE inhibitor
dosage could be titrated to goal or highest
tolerated dosage, the control group had 9 months
from baseline (July 2000–March 2001), since
final data for both groups were collected in
March 2001.
Statistical Methods
A x 2 test was used to analyze categoric
demographic data; a two-sample t test was used
for continuous demographic data. A x2 test also
was used to compare the proportion of patients
excluded for each reason in the treatment and
control groups.
An a value of 0.05 or less was assumed. To
achieve 80% power using a one-sided test, the
effect size needed was 0.567. Because the
proportion of patients receiving ACE inhibitors
was expected to change in both the treatment
and the control groups, the anticipated effect
sizes in both groups were estimated. Using an
1568 PHARMACOTHERAPY Volume 23, Number 12, 2003
Table 1. Characteristics of Control and Treatment Group Patients Screened Compared with Those Enrolled
No. (%) of Patients Screened No. (%) of Patients Enrolled
Control Group Treatment Group Control Group Treatment Group
Characteristic (n=95) (n=101) p Value (n=60) (n=29) p Value
Age, mean (yrs) 65.9 66.7 0.996 63.9 66.3 0.758
Women 28 (29.5) 28 (27.7) 0.786 18 (30.0) 9 (31.0) 0.921
Medical history
CAD 38 (40) 52 (51.5) 0.107 24 (40.0) 17 (58.6) 0.099
Hypertension 65 (68.4) 70 (69.3) 0.894 40 (66.7) 21 (72.4) 0.584
Hyperlipidemia 83 (87.4) 73 (72.3) 0.001 52 (86.7) 23 (79.3) 0.371
Heart failure 11 (11.6) 14 (13.9) 0.632 7 (11.7) 4 (13.8) 0.744
Current smoker 17 (17.9) 11 (10.9) 0.161 1 (18.3) 4 (13.8) 0.765
CAD = coronary artery disease.

effect size of 0.52 for treatment group patients ACE inhibitor dosage (< 20 mg/day). Nineteen
and 0.20 for control patients, 86 patients were (20%) of the control patients were at or above the
needed in the study group and 178 in the control goal lisinopril dosage (Figure 2); because these
group to achieve 80% power at an a value of 0.05 patients were receiving the optimal dosage (≥ 20
or less using a one-sided test. mg), they were excluded. Other reasons for
patient exclusion included cough, hypotension,
Results renal insufficiency, aortic stenosis, and death
(Table 2).
A total of 196 patients were screened for this The ACE inhibitor dosages of the control
study: 95 patients in the control group and 101 group were evaluated at the end of the study. As
in the treatment group. Characteristics of shown in Figure 2, there was little change after 9
patients enrolled in both groups were similar months. The dosage was either decreased or
(Table 1). Sixty (63%) control group patients discontinued in three of the patients receiving
were eligible for ACE inhibitor titration; 35 lisinopril 20 mg. The dosage was reduced to 5
(37%) were excluded. Twenty-six (27%) of the mg/day in one patient with hyperkalemia, and
95 control patients were not receiving lisinopril therapy was discontinued in two patients with
therapy; 34 (36%) were receiving a suboptimal cough. The dosage was titrated to 20 mg/day or
more over the study period in seven patients who
were not previously at the goal dosage. Two
patients who were previously receiving ACE
60 inhibitor therapy had stopped taking the drug
55
either on their own or for an unknown reason.
50 In the treatment group, 29 (29%) patients were
included and 72 (71%) were excluded from ACE
40 inhibitor dosage titration. As illustrated in
3
35 35 Figure 2, only about half as many patients were
30 2 eligible for dosage titration in the treatment
26
23
group as in the control group. Thirty-seven
1
(36%) of the 101 patients screened were at or
20 1 1
14
16 16 16 above the goal lisinopril dosage and therefore
12
were excluded. Thirty-five (35%) patients were
10
5 6 excluded for other reasons; renal insufficiency
3
0 and ACE inhibitor–induced cough were the most
0
common (Table 2). Fourteen patients were not
5 10 20
receiving lisinopril, and 15 were receiving a
suboptimal dosage (< 20 mg/day).
Of the 29 included patients, the lisinopril
Figure 2. The angiotensin-converting enzyme (ACE) dosage was titrated for 18 patients by the CPCRS
inhibitor dosage distributions for control patients and pharmacist to the goal dosage. In the remaining
treatment group patients over 9 months. 11 patients, the dosage was titrated to the highest
 PHARMACIST-IMPLEMENTED LISINOPRIL THERAPY McConnell et al 1569
Table 2. Reasons for Patient Exclusion
No. (%) of Patients
Control Group Treatment Group
Reason (n=35) (n=72) p Value
Lisinopril dosage ≥ 20 mg/day 19 (54.3) 37 (51.4) 0.892
Cough 7 (20) 9 (12.5) 0.191
Hypotension 3 (8.6) 4 (5.6) 0.684
Renal insufficiency 3 (8.6) 10 (13.9) 0.537
Death 2 (5.7) 0 0.109
Aortic stenosis 1 (2.8) 3 (4.2) 1.000
Noncompliance 0 4 (5.6) 0.299
Allergy 0 2 (2.8) 0.551
Hyperkalemia 0 2 (2.8) 0.551
Elevated liver enzyme levels 0 1 (1.4) 1.000

tolerated dosage (to 10 mg/day in six patients, to
≤ 5 mg/day in five patients). The number of
patients included was too small to evaluate a
statistical difference between groups with
confidence.
The most common reason for drug intolerance
was hypotension (systolic blood pressure < 100
mm Hg with increased dosage). One patient
developed hyperkalemia when her dosage was
increased from 5 to 10 mg/day. After decreasing
back to 5 mg/day, her potassium level returned to
normal. No cases of renal insufficiency developed
during lisinopril titration.
With each dosage titration (every 2 wks),
potassium level, serum creatinine level, and
blood pressure measurements were obtained.
Potassium levels increased the most on initial
titration (from baseline to 5 mg) by a mean ± SD
of 0.181 ± 0.554 mEq/L. Changes in potassium
level with other dosage titrations were negligible.
Serum creatinine levels decreased only slightly.
The largest decrease in blood pressure also
occurred with initial dosage titration: mean
systolic blood pressure decreased by 8.6 mm Hg,
mean diastolic blood pressure by 3.1 mm Hg.
The large decreases in blood pressure mainly
occurred in patients with hypertension and not
in normotensive patients. When patients with
hypertension were excluded from analysis, very
little change in blood pressure was seen.
Decreases with dosage titrations from 5 to 10 mg
were negligible, and mean ± SD systolic blood
pressure increased slightly (by 2.64 ± 19.23 mm
Hg) with the final titration.
Discussion
Angiotensin-converting enzyme inhibitors are
beneficial for many different disease states. They
can be administered to lower blood pressure,
slow the progression of heart failure, decrease
morbidity and mortality after myocardial
infarction, and provide renal protection in
patients with diabetes. The HOPE trial also
showed that ACE inhibitors decrease mortality in
high-risk patients with one additional cardio-
vascular risk factor.13
The objective of our study was to increase the
number of patients with diabetes and CAD who
were taking the optimal or highest tolerated ACE
inhibitor dosage. A review of our database
showed that only 20% of patients were receiving
the optimal dosage of the ACE inhibitor lisinopril
(20 mg/day). A protocol developed by the
CPCRS was used to screen patients with diabetes
who were admitted to the hospital for a CAD
event. Therapy was begun during the hospital
stay because of the increased compliance shown
when drugs are started at this time (the “golden
moment”).15 In eligible patients, lisinopril was
titrated to the optimal or highest tolerated
dosage.
Extensive time and effort were spent in
communication with the Colorado Permanente
Medical Group regarding this ACE inhibitor
initiative and the dissemination and discussion of
the HOPE trial 13 findings after the historic
control data were gathered. Subsequently, the
proportion of patients receiving the optimal ACE
inhibitor dosage increased from 20% in the
control group at baseline to just over 36% in the
treatment group at baseline. However, we sought
to improve these percentages further.
Twenty-nine treatment group patients were
eligible for titration after the educational efforts
compared with 60 who were eligible in the
control group. The educational efforts probably
were one reason for this difference since the
physicians seemed more likely to titrate the
lisinopril to the goal dosage on their own.
1570 PHARMACOTHERAPY Volume 23, Number 12, 2003
However, more patients were excluded in the
treatment group than in the control group.
Reasons for this are unknown since patients in
both groups were screened based on the same
inclusion and exclusion criteria, from the same
hospital, during similar time frames.
Characteristics of the patient groups screened
were similar, except for the frequency of a history
of hyperlipidemia (Table 1). After the CPCRS
titration period, the proportion of treatment
group patients receiving the optimal ACE
inhibitor dosage increased from 36% to 55%,
compared with the control patients, which
increased from 20% to 24%. Therapy was begun
in all treatment group patients who were eligible
to receive an ACE inhibitor, and the dosage was
titrated to the highest one tolerated. The
proportion of patients receiving any ACE
inhibitor dosage actually decreased in the control
group (from 56% to 51%); in the treatment group
the proportion increased from 51% to 65%.
The clinical pharmacy specialists filled a
treatment gap by identifying patients who would
benefit from ACE inhibitor therapy and providing
consistent follow-up. If lisinopril-eligible patients
were not receiving the drug, or if they were
receiving suboptimal dosages, the specialists
titrated the dosage to the goal or highest
tolerated dosage. By screening all patients
discharged from the hospital, the specialists
ensured that no patients were lost to follow-up.
As the treatment group patients were evaluated,
if few or no obstacles to starting lisinopril
therapy were observed, therapy was begun
through usual care; therapy was not initiated in
patients with borderline low blood pressure or
elevated serum creatinine levels. However, in the
titrations managed by the CPCRS pharmacists,
there was no such selection bias. Lisinopril was
started and closely monitored in all patients who
were eligible according to the inclusion and
exclusion criteria, and many of these patients
achieved their goal dosages.
Changes in potassium level, serum creatinine
level, and blood pressure were tracked with each
dosage titration, thus valuable data were
provided to support modifications in the protocol
for ACE inhibitor dosage titration. By knowing
how much each parameter changed with each
dosage titration, the clinical pharmacy specialists
could alter the laboratory monitoring schedule
and check potassium level, serum creatinine
level, and blood pressure only when necessary.
The CPCRS applied, in a practical manner, a
large clinical trial to a patient population that
would benefit from the results. The clinical
pharmacy specialists also identified areas that are
more difficult to manage in real life than in a
clinical trial, and they worked to remedy these
problems. Finally, by increasing the number of
patients with CAD and diabetes who were
receiving ACE inhibitors, morbidity and
mortality from cardiovascular disease should
decrease, as statistically illustrated by the HOPE
trial.2
This study has limitations. The ACE inhibitor
used in the HOPE trial was ramipril.13 In our
study, lisinopril was administered because it is
the formulary ACE inhibitor for Kaiser
Permanente of Colorado. However, we did not
feel this was a significant issue because we
assumed that the benefits of ramipril resulted
from an effect of drug class rather than individual
drug. This conclusion was derived based on data
regarding both hypertension and heart failure.
According to some authors, the major differences
in ACE inhibitors lie in their pharmacokinetic
properties, not their pharmacologic properties.16
The mortality reduction associated with ACE
inhibitor therapy is likely an effect of drug class.
For patients with heart failure, ramipril and
lisinopril (both approved by the Food and Drug
Administration for treatment of heart failure)
seem to be dose equivalent, with 10 mg/day
being the target dosage for survival benefit with
both drugs.16 The maximum effective dosage for
lisinopril is 20 mg/day for patients with heart
failure. However, in patients with hypertension,
the dose equivalents seem to be different. In a
trial comparing lisinopril with ramipril for
lowering blood pressure, lisinopril 10 mg/day
was roughly equivalent to ramipril 2.5 mg/day.17
Therefore, for lowering blood pressure, lisinopril
40 mg/day is assumed to be equivalent to
ramipril 10 mg/day. However, little additional
lowering of blood pressure is usually seen when
the lisinopril dosage is titrated from 20 to 40
mg/day.
Moreover, only a small portion of the benefits
seen in the HOPE trial were attributed to a
reduction in blood pressure. 13 The ACE
inhibitors probably exert additional direct
mechanisms on the heart or the vasculature, such
as antagonizing the direct effects of angiotensin II
on vasoconstriction, proliferation of vascular
smooth muscle cells, and rupture of plaques.
The ACE inhibitors also have improved vascular
endothelial function, reduced left ventricular
hypertrophy, and enhanced fibrinolysis. 13
Because ACE inhibitor therapy was started in our
 PHARMACIST-IMPLEMENTED LISINOPRIL THERAPY McConnell et al
patient population for its cardioprotective
benefits, the lisinopril dosage of 20 mg/day was
chosen based on dosage ranges and maximum
effective doses. We recognize that no data exist
comparing lisinopril with ramipril in the
population enrolled in our study. Goals for
future studies include evaluating the long-term
morbidity and mortality data of lisinopril.
A second limitation of our study was its short
duration, which precluded gathering long-term
morbidity and mortality data. Another limitation
was applying a large clinical trial to one with a
diverse patient population. Using strict
exclusion criteria to screen patients becomes
difficult in real-world situations; in addition, we
used a historic, rather than prospective, control
group. Because current evidence demonstrates
beneficial effects with ACE inhibitor therapy,
deliberately withholding therapy could not be
justified. This also would have contradicted our
objective, which was to increase the number of
patients receiving ACE inhibitor therapy. Finally,
because of the small number of patients in both
the treatment and the control groups, our study
was underpowered to evaluate statistical
significance of the primary objective. Thus, the
chance is increased for making a type II error,
that is, not finding a difference in the measured
variables when differences actually exist.
Conclusion
Based on the success of our study, the CPCRS
is continuing the screening and administration of
ACE inhibitor therapy in the patient population
described. The titration protocol will be
modified according to the changes seen in
potassium level, serum creatinine level, and
blood pressure. The frequency of monitoring
laboratory data and blood pressure will be
decreased and performed only when necessary.
Patients who are normotensive or hypertensive
will begin receiving therapy with lisinopril 10
mg/day. Potassium and serum creatinine levels
will be checked 2 weeks after therapy is begun
and blood pressure checked within 1 month. If
10 mg/day is tolerated, the dosage will be
increased to 20 mg/day with the same monitoring
parameters. However, if blood pressure is below
120/80 mm Hg at baseline, lisinopril 5 mg/day
will be started, with monitoring every 2 weeks
throughout the titration period.
Therapy with an ACE inhibitor decreases
morbidity and mortality in patients with diabetes
and coronary artery disease. The CPCRS
1571
increased the number of patients receiving the
optimal dosage of lisinopril (20 mg/day) through
both direct dosage titration and indirect
educational efforts. The service continues to
focus on population management in addition to
individualized care. The care given by the
clinical pharmacy specialists, such as ACE
inhibitor dosage titration, allows physicians to
focus on more acute health-related problems
when seeing patients. Studies such as ours
continue to confirm the value and versatility of
pharmacist involvement in the management and
monitoring of drug therapy.
References
1. American Heart Association. 2000 heart and stroke statistical
update. Dallas TX: American Heart Association, 1999.
2. Heart Outcomes Prevention Evaluation (HOPE) Study
Investigators. Effects of ramipril on cardiovascular and
microvascular outcomes in people with diabetes mellitus:
results of the HOPE study and MICRO-HOPE substudy. Lancet
2000;355(9200):253–9.
3. CONSENSUS Trial Study Group. Effects of enalapril on
mortality in severe congestive heart failure: results of the
cooperative north Scandinavian enalapril survival study
(CONSENSUS). N Engl J Med 1987;318:1429–35.
4. SOLVD Investigators. Effect of enalapril on survival in patients
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