Download Suggestion from clinicians

Enalapril vs. Ramipril vs. Other ACEi
Replacement to the List
Peer Feedback:
“ramipril (better mortality in CHF, See Pilote et all CMAJ 2008), dosing in study table of enalipril is
incorrect - it is BID not OD. Same cost”
“lisinopril/ramipril - enalapril is BID drug for heart failure and frequently for HTN"
“Comment: Add ace-inhibitors: perindopril, Lisinopril, ramipril, trandilopril”
"Comment: Other notes- hypertension is one of the most common problems for all physicians.
You do not have diltiazem CD or other ACEi on your list (lisinopril, rampril, perindopril).
Perindopril and ramipril are the cheapest, both long acting and both with fantastic supporting RCT
evidence."
Literature Review Question:
Does Ramipril have better efficacy then enalipril?
What is the most effective ACE inhibitor?
Literature Search:
Include article cited by peer reviewer
Cochrane Review
CADTH
Pubmed: “ramipril AND enalapril AND efficacy AND comparison”; “(angiotensin-converting
enzyme inhibitors OR ace inhibitors) AND (efficacy OR safety OR mortality) AND (enalapril OR
ramipril OR perindopril OR lisinopril OR trandolapril) AND (hypertension OR heart failure)”
eCPS - Cardiovascular Disorders: Heart Failure, Cardiovascular Disorders: Hypertension
Different ACEi and Mortality (2015)
A total of 989,489 ACE inhibitors initiators were included in the analysis.
The results of this study showed that among ACE initiators, captopril was associated with an
increased risk, while enalapril and fosinopril were associated with a significant but lesser
increased risk of death as compared with ramipril. The increased risk associated with these three
ACE inhibitors was consistently observed across a range of subgroups of hypertensive patients
with or without a variety of complications. Perindopril, lisinopril, and imidapril had similar mortality
risk as ramipril. ACE inhibitors may differ with respect to reducing mortality for patients with
hypertension.
Among all ACE inhibitors, ramipril and perindopril were the most comprehensively evaluated
agents in patients with a variety of underlying conditions.17–24 Although generally being
beneficial, the results of ACE inhibitor trials regarding trandolapril, quinapril, and lisinopril have
not always been consistent.25–28 No large randomized controlled trial evaluating the long-term
outcome has been reported for imidapril.
The beneficial effects of enalapril and fosinopril were inconsistent across trials.30–32 The present
study again suggests that the mortality risk profile for ramipril is better than enalapril and
fosinopril in patients with hypertension. Besides, the increased cancer mortality risk associated
with fosinopril should be interpreted with caution because the follow-up of the current study might
not be long enough to identify the small differences in cancer death.33
In summary, enalapril and fosinopril were associated with a modestly increased risk compared to
lisinopril, perindopril, ramipril, and imidapril. However, the differences in mortality risk among
individual ACE inhibitors were only marginal and might be of limited clinical significance. On the
other hand, despite that uncontrolled confounding might still exist, there was a consistent
increased mortality risk associated with captopril use. It might be reasonable to avoid long-term
captopril use in hypertensive patients if there was no other evidence-supported indication. The
current study suggests that there are modest differences in overall and cause-specific mortality
risk among individual ACE inhibitors, although the observed association might be due to residual
confounding effect. The clinical significance of these findings should be further evaluated and
clarified.
Chang, Chia-Hsuin, et al. "Different angiotensin-converting enzyme inhibitors and the
associations with overall and cause-specific mortalities in patients with hypertension." American
journal of hypertension 28.6 (2015): 823-830.
CADTH (2015)
Patients with diabetes mellitus type II
While both imidapril and ramipril significantly reduced blood pressure, UAE, and BNP in patients
with DM, HTN, and microalbuminurea, the reduction of UAE was statistically significantly more
profound with imidapril than ramipril starting from the sixth week and onwards.11 The addition of
bendoflumethiazide to captopril in patients with HTN and DM led to better control of BP when
compared with captopril alone. However, this combination also led to deterioration in fasting
blood glucose level.12
Patients with heart failure
One systematic review identified three trials that compared perindopril to enalapril. Authors of the
review reported greater effectiveness of enalapril for improving cardiac sympathetic nerve activity,
NYHA functional class, and BNP.13
Patients with hypertension
Pretax (perindopril and indapamide) was shown, in two double blind RCTs, to be more effective in
reducing diastolic BP than cilazapril monotherapy.14,16 However, the combination also led to a
reduction in the benefits obtained from statin therapy on patients’ metabolic profile.14 ACE
inhibitors that contained a phosphonate group (namely fosinopril) were associated with more
coughing and hypotension than ACE inhibitors that contained di-carboxyl group (namely enalapril,
lisinopril, and ramipril). While the di-carboxyl group containing ACE inhibitors were associated
with more cases of nausea than the phosphate containing ACE inhibitor.15
Patients with myocardial infarction
In patients with left ventricular dysfunction after acute MI, zonfenopril significantly decreased
cardiac hospitalization when compared to ramipril.17 This reduction in hospitalization led to
zonfenopril being more cost-effective when compared to ramipril.18
In 2008, a previous report published by CADTH7 on the topic of comparative effectiveness of
ACE inhibitors concluded that there is “limited evidence that not all ACE inhibitors are equally
efficacious for various outcomes including blood pressure control, and mortality rates post MI”.
New evidence identified since 2008 reinforces the previous conclusion, suggesting that imidapril
might be better than ramipril in reducing urinary albumin excretion in diabetic patients with HTN,
11 and that zofenopril could be clinically better than ramipril for reducing the number of
hospitalizations in post-acute MI patients, and more cost-effective. 17 Zofenopril, however, is not
currently available in Canada. Evidence over other outcomes remains largely scarce with major
limitations in methodology.
CADTH; Angiotensin-Converting Enzyme (ACE) Inhibitors: A Review of the Comparative Clinical and Cost-Effectiveness;
12 June 2015
CADTH (2008)
The purpose of this report was to provide information regarding the comparative effectiveness
and safety profiles of different ACE inhibitors. Placebo-controlled randomized controlled trials
(RCTs) and head-to-head RCTs were included in the assessment of effectiveness, and RCTs or
large, good-quality observational studies were included in the assessment of harms. Included
interventions were treatment with benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril,
moexipril, quinapril, ramipril, perindopril, or trandolapril. Outcomes varied according to the clinical
indication.
A number of studies were identified that compared different ACE inhibitors for the treatment of
patients with hypertension, recent myocardial infarction, and congestive heart failure. However,
studies comparing the effectiveness of different ACE inhibitors for kidney protection were lacking.
Although there is limited evidence that not all ACE inhibitors are equally efficacious for various
outcomes including blood pressure control, and mortality rates post MI,16,17,36 the majority of
the available trials suggest that there is no clear advantage of using one ACE inhibitor over
another. Until more conclusive evidence is available, formulary decisions should also take clinical
experience and acquisition costs into consideration.
CADTH; Angiotensin-Converting Enzyme (ACE) inhibitors: A Comparative Effectiveness Review;
08 April 2008
Pilote et al. CMAJ 2008
Patient population: Elderly patients with congestive heart failure who filled a prescription for an
ACE inhibitor within 30 days after discharge from hospital. First admission was for congestive
heart failure.
Our study shows that, at currently prescribed doses, enalapril and captopril were associated with
about 10%–15% higher mortality than ramipril among elderly patients with congestive heart
failure. Patients who filled prescriptions for fosinopril, lisinopril, quinapril, perindopril and cilazapril
did not have a significantly different mortality than those who filled prescriptions for Ramipril.
In summary, our results suggest that physicians choosing an ACE inhibitor for patients with
congestive heart failure should consider the possible 10%–15% increase in mortality that we
observed with enalapril and captopril use compared with ramipril use. Further evidence is required
to fully assess the comparability between ramipril and all newer ACE inhibitors.
Pilote, L., Abrahamowicz, M., Eisenberg, M., Humphries, K., Behlouli, H., & Tu, J. V. (2008). Effect of different
angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure. Canadian
Medical Association Journal, 178(10), 1303-1311.
Cochrane Review 2007
This review provides a reasonable amount of data to assess the trough BP lowering effect of 14 different
ACE inhibitors. When the different ACE inhibitors are compared, there is a remarkable similarity in their BP
lowering effects at trough. When the best estimate of the BP lowering efficacy of these 14 drugs is
compared, they range from -6/-4 mm Hg to -9/-5 mm Hg. The data are most consistent with the near
maximum BP lowering effect of the each of the drugs being the same. However, for most of the drugs there
are insufficient data over a broad dose range. It is therefore impossible with this analysis to be certain that
there are no blood pressure lowering differences between one or more of the drugs. It would require headto-head trials of different ACE inhibitors at equivalent BP lowering doses to assess whether or not there are
differences between different drugs. This review will provide useful information for estimating equivalent
doses and thereby designing trials to compare different ACE inhibitors. However, at the present time given
that all the drugs are working by the same mechanism and the similarities in the blood pressure lowering
effect it is most likely that the near maximal BP lowering of the different ACE inhibitors is the same.
Conclusions
1. The review provides data on the dose-related blood pressure lowering efficacy of 14 different ACE
inhibitors at trough. The best estimate of the blood pressure lowering efficacy of these 14 drugs ranges
from -6/-4 to -9/-5 mm Hg. The data do not suggest that any one ACE inhibitor is better or worse at
lowering blood pressure when used at doses of one-half the manufacturer’s maximal recommended
dose and above.
2. A dose-response relationship for the blood pressure lowering effect of the ACE inhibitors was evident. A
dose of 1/16 of the maximum recommended dose had no measurable blood pressure lowering effect. A
dose of 1/8 or 1/4 of the maximum recommended daily achieved a blood pressure lowering effect that
was 60 to 70% of the blood pressure lowering effect of the maximum recommended dose. A dose of 1/2
3.
4.
5.
6.
7.
8.
of the maximum recommended dose achieved a blood pressure lowering effect that was 90% of the
maximum recommended dose.
ACE inhibitor doses above the maximum recommended dose did not significantly lower blood pressure
more than the maximum recommended dose.
Combining the effects of half maximum recommended doses and higher gives an estimate of the
average trough blood pressure lowering efficacy for ACE inhibitors as a class of drugs of -8 mm Hg for
SBP and -5 mm Hg for DBP.
ACE inhibitors reduced blood pressure measured 1 to 12 hours after the dose by about 11/6 mm Hg.
ACE inhibitors reduced trough pulse pressure by about 3 mm Hg.
ACE inhibitors did not significantly affect resting blood pressure variability or heart rate.
All doses of ACE inhibitors, whether analyzed individually or combined, did not change WDAE as
compared to placebo; however, this outcome was not reported for about half the trials so there is judged
to be a high risk of selective reporting bias.
Heran, Balraj S., et al. "Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors
for primary hypertension." The Cochrane Library (2008).
eCPS (2015)
Heart Failure
ACE inhibitors are recommended in all patients because they improve symptoms and reduce the
risk of hospitalization, MI and death in patients with systolic HF. 9,10,11 Start with a low dose and
titrate at 7- to 14-day intervals to the target dose, or maximum tolerated dose if the target dose
cannot be reached. Treatment with target doses is more effective than low doses. 12 Measure
serum creatinine, potassium and blood pressure before initiating an ACE inhibitor or increasing
the dose and 7–14 days after any increase in dosage.5 An increase in serum creatinine of up to
30% is expected and acceptable after initiation of an ACE inhibitor.1 If the increase in serum
creatinine is greater than 30%, other causes of worsening renal function should first be excluded.
In particular, assess volume status, as an increase in serum creatinine often appears in patients
who are hypovolemic because of excessive diuresis. If no other cause for the worsening renal
function can be identified, reduce the dose or discontinue the ACE inhibitor. Although data are
limited, the authors recommend periodically reassessing the potential of restarting ACE inhibitors
or increasing the dose if the patient's condition improves. Patients at greatest risk of
hyperkalemia are those with moderate to severe renal dysfunction, high baseline potassium,
diabetes mellitus and those receiving potassium-sparing diuretics.13
Drug
Dosage
Adverse Effects
Drug Interactions
Comments
Costa
ACE
Inhibitorsb
captopril
generics
Initial:6.25–12.5 mg TID po
Target: 50 mg TID
enalapril
Vasotec,
generics
Initial: 1.25–2.5 mg BID po
Target: 10 mg BID
ACE
Inhibitorsb
lisinopril
Prinivil, Zestril,
generics
Initial: 2.5–5 mg once daily po
Target: 20–35 mg once daily
ACE
Inhibitorsb
ramipril
Initial: 1.25–2.5 mg BID po
Altace, generics Target: 5 mg BID
Diuretics: hypotension 
(monitor BP).
Potassium-sparing
diuretics, potassium
supplements, ARBs:
hyperkalemia (monitor
K+).
NSAIDs: reduced
hypotensive effect
(monitor BP), fluid
retention, renal failure.
Monitor serum
creatinine and
potassium 7–14
days after initiation
of therapy or dose
changes.
Some experienced
clinicians use doses
higher than usual
target doses.
Avoid in pregnancy.
$$$
ACE
Inhibitorsb
Hypotension,
hyperkalemia, dry
cough, renal
insufficiency,
angioedema (rare),
skin rashes, taste
disturbance,
proteinuria,
neutropenia (rare),
headache, dizziness.
ACE
Inhibitorsb
trandolapril
Mavik
Class
Legend: $ < $25
Lithium: lithium toxicity
(monitor lithium levels).
Initial: 1 mg once daily po
Target: 4 mg once daily
$$ 25–50
$$$ 50–75
$$$$ 75–100
$$$$$100–125
Cardiovascular Disorders: Heart Failure; Simon de Denus, B. Pharm, MSc, PhD and Michel
White, MD, FRCPC, FACC, FESC; Date of revision: May 2015
Hypertension
$
$
$
$$
Angiotensin-converting enzyme (ACE) inhibitors are first-line agents for non-black patients with
uncomplicated hypertension and for patients with diabetes, ischemic heart disease, recent MI,
heart failure or chronic kidney disease.
Drug
Dosage
Adverse Effects
Drug Interactions
Comments
Costa
ACE
Inhibitors
benazepril
Lotensin, generics
Initial: 10 mg/day
Usual: 20 mg/day
Maximum: 40 mg/day
Once daily or divided BID po
captopril
generics
Initial: 25 mg/day
Usual: 75 mg/day
Maximum:150 mg/day
Divided BID or TID po
ACE
Inhibitors
cilazapril
Inhibace, generics
Initial: 2.5 mg/day
Usual: 2.5–5 mg/day
Maximum: 10 mg/day
Once daily or divided BID po
Marked increase in
serum K+ in
patients receiving
K+supplements
and/or K+-sparing
diuretics.
Reduced
hypotensive effect
with NSAIDs and
increased risk of
renal dysfunction.
Contraindicated in
pregnancy—caution when
prescribing to women of
child-bearing
potential.5,6 Use lower
(50%) initial doses if on
diuretics (increased risk of
hypotension with
hypovolemia).
Hyperkalemia usually
occurs only in those on
K+supplements or drugs that
cause K+ retention, those
with renal impairment or
diabetics with high serum
K+ levels. Assess SCr and
K+after a few days, then
regularly.
$$
ACE
Inhibitors
Dry cough,
hyperkalemia.
Unusual:
angioedema.
Can precipitate
renal failure in
renovascular
disease, volume
depletion or those
receiving
NSAIDs.
Class
Elevated Li+ levels
(potential toxicity).
$$
$
ACE
Inhibitors
enalapril
Vasotec, generics
Initial: 5 mg/day
Usual: 10–40 mg/day
Maximum: 40 mg/day
Once daily or divided BID po
ACE
Inhibitors
fosinopril
generics
Initial: 10 mg/day
Usual: 20 mg/day
Maximum: 40 mg/day
Once daily or divided BID po
ACE
Inhibitors
lisinopril
Initial: 10 mg/day
Prinivil, Zestril, generics Usual: 20 mg/day
Maximum: 40 mg/day
Once daily po
$
ACE
Inhibitors
perindopril
Coversyl, generics
Initial: 4 mg/day
Maximum: 8 mg/day
Once daily or divided BID po
$$
ACE
Inhibitors
quinapril
Accupril, generics
Initial: 10 mg/day
Maximum: 40 mg/day
Once daily or divided BID po
$$
ACE
Inhibitors
ramipril
Altace, generics
Initial: 2.5 mg/day
Usual: 10 mg/day
Maximum: 20 mg/day
Once daily or divided BID po
$
ACE
Inhibitors
trandolapril
Mavik
Initial: 1 mg/day
Maximum: 4 mg/day
Once daily po
$$
Legend:
60–80
$<20
$-$$ <20–40
$
$
$$ 20–40
$$$ 40–60
$$$$
Cardiovascular Disorders: Hypertension; Norm R.C. R. C. Campbell, MD, FRCPC, Paul Gibson, MD,
FRCPC, and Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC; Date of Revision: March 2015
Medication
Enalapril
Uses
hypertension,
left ventricular
dysfunction,
heart failure
Contraindications (CI), drug
interactions (DI) or cautions
CI: renal dysfunction, angioedema,
pregnancy (T1, T2, T3)
DI: diuretic (potassium sparing),
lithium
Adverse Effects
(common and
severe)
hypotension,
dizziness, headache,
chest pain, cough,
rash, hyperkalemia,
nausea , vomiting
Initial dose;
typical dose
5mg; 10-40mg one
time a day or
divided dose BID
Per RxTx app
(CPS)
Monitoring
renal
dysfunction:
SCr, blood
urea nitrogen
(BUN),
electrolytes