Download Are all angiotensin-converting enzyme inhibitors

Journal of the American College of Cardiology
© 2001 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 37, No. 5, 2001
ISSN 0735-1097/01/$20.00
PII S0735-1097(01)01161-5
VIEWPOINT
Are All Angiotensin-Converting
Enzyme Inhibitors Interchangeable?
Curt D. Furberg, MD, PHD,* Bertram Pitt, MD, FACC†
Winston-Salem, North Carolina and Ann Arbor, Michigan
In the treatment of most medical conditions, there are many choices. A critical question for
practicing clinicians is: “Are all drugs within a class interchangeable?” In the past decade, the
market has seen a proliferation of drugs within popular drug classes. The original drugs within
a class typically have better scientific documentation than the newer ones, which are often
referred to as “me-too” drugs. Due to a lesser financial investment, the latter may be available
at a lower cost. Good reasons exist for grouping drugs, however, there is no accepted
definition of the term “class effect.” Although members of a drug class share main actions,
they may have clinically important differences in terms of efficacy and safety. There are many
such examples in the literature. This article reviews the class effect concept as it applies to the
angiotensin-converting enzyme (ACE) inhibitors. Only half of the 10 ACE inhibitors
available in the U.S. have been shown to improve survival and reduce morbidity in patients
with heart failure or myocardial infarction. It is unknown whether the other five have the
same safety and efficacy profiles or what their optimal doses are. Thus, we do not know
whether all ACE inhibitors are fully interchangeable. The practice of medicine ought to be
based on solid scientific evidence, not on assumptions or extrapolations. For our patients, such
practice is a legitimate expectation. Therefore, it seems prudent to recommend that patients
requiring ACE inhibitor therapy be prescribed one that has been proven effective and safe.
(J Am Coll Cardiol 2001;37:1456 – 60) © 2001 by the American College of Cardiology
In the treatment of most medical conditions, clinicians have
many choices. The alternatives may include drugs from
various “classes” of agents as well as multiple drugs from the
same “class.” In the past decade, the market has seen a
proliferation of drugs within popular drug classes. The
introduction of additional members of a class after the
original drug with proven efficacy and safety is established
has gained widespread acceptance. Sometimes these agents
offer advantages, such as longer duration of action or lower
incidence of side effects. All too often, however, the new
agents offer little, if any, additional advantage to those
already proven effective, and their introduction by a drug
company for a particular indication would appear to be
driven more by the expectation of gaining market share than
by the hope of providing additional patient benefit. Due to
a lesser financial investment in acquiring solid scientific
documentation regarding health benefits, and for approval
for multiple indications, these “me-too” drugs may be
available at a lower cost. Under the assumption of equal
efficacy, this represents a potential attraction for third-party
payers, formulary committees and patients.
A critical question for practicing physicians is: “Are all
drugs within a class interchangeable?” In many instances,
there may not be enough evidence to provide an evidencebased answer. In practice, the answer often relates to how
From the *Department of Public Health Sciences, Wake Forest University,
Winston-Salem, North Carolina; and the †Department of Internal Medicine,
University of Michigan, Ann Arbor, Michigan.
Manuscript received August 24, 2000; revised manuscript received December 6,
2000, accepted December 27, 2000.
convinced clinicians are that all drugs of a class share the
main actions— good and bad—which are often referred to
as the “class effect.” This term conveys the message that the
drugs are interchangeable. The purpose of this article is to
review the class-effect concept as it applies to angiotensinconverting enzyme (ACE) inhibitors.
What’s the definition of class effect? A thorough review
of the literature revealed that there is no accepted definition
of the term “class effect” (1,2). It is a convenience term used
for multiple purposes. There are good reasons for grouping
drugs. However, this term has facilitated incompletely
tested “me-too” drugs to be marketed as interchangeable
alternatives to the proven, often original, members of a drug
group. The lack of a clear scientific definition of the class
effect term has had unfavorable consequences for the practice of medicine.
Do drugs of a “class” share all mechanisms of action?
The grouping of drugs is typically based on one common
mechanism of action. The common action of the ACE
inhibitors is their ability to inhibit the conversion of the
relatively inactive angiotensin I to the active angiotensin II.
The definition is qualitative rather than quantitative. The
potency or degree of inhibition is not part of the definition.
Members of a class are often divided into subclasses based
on the chemical structure. Moreover, since all drugs have
multiple mechanisms of action determined by their unique
chemical structure, each ACE inhibitor probably has some
“not-in-common” actions. When one considers the marked
differences in chemical structure among the available ACE
inhibitors (Fig. 1), it is not surprising that they might have
JACC Vol. 37, No. 5, 2001
April 2001:1456–60
Abbreviations and Acronyms
ACE
⫽ angiotensin-converting enzyme
CONSENSUS ⫽ Cooperative North Scandinavian
Enalapril Survival Study
CHF
⫽ congestive heart failure
SOLVD
⫽ Studies Of Left Ventricular
Dysfunction
different clinical actions. While the effects of the “not-incommon” actions may be unimportant, they could also
enhance or diminish the overall health effects. There are
many examples in the literature of drugs from a class having
different favorable and unfavorable health effects (1,2).
Furberg et al.
Interchangeability of ACE Inhibitors
1457
Thus, members of a drug class share qualitative mechanisms
of action that define the class, but since they are not
identical, the assumption that they are clinically interchangeable for every indication requires empirical validation. It seems prudent to assume that untested members of
a class are not interchangeable for a specific indication until
clinical evidence of interchangeability is available.
Are all ACE inhibitors equally effective? They may or
they may not be. The answer will depend on what we mean
by equal and by effective and in which dose and in which
patient population. Effective should be defined as clinical
effectiveness for a specific indication. Angiotensinconverting enzyme inhibitors have been shown to improve
survival, to decrease the risk of nonfatal complications of
Figure 1. The chemical structures of the 10 ACE inhibitors currently available in the U.S. The term “proven” refers to ACE inhibitors shown to improve
survival or reduce morbidity. ACEI ⫽ angiotensin-converting enzyme inhibitor.
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Furberg et al.
Interchangeability of ACE Inhibitors
JACC Vol. 37, No. 5, 2001
April 2001:1456–60
Figure 2. Mortality findings (relative risk ⫾ 95% confidence intervals) in the large placebo-controlled ACE inhibitor trials of patients with acute myocardial
infarction (AMI), AMI with left ventricular dysfunction, congestive heart failure (CHF) and coronary artery disease/diabetes. ACEI ⫽ angiotensinconverting enzyme inhibitor. AIRE ⫽ Acute Infarction Ramipril Efficacy; CAD ⫽ coronary artery disease; capto ⫽ captopril; CONSENSUS ⫽
Cooperative North Scandinavian Enalapril Survival Study; Diab ⫽ diabetes; enala ⫽ enalapril; GISSI ⫽ Gruppo Italiano per lo Studio della Supravvivenza
nell’ Infarto miocardico; HOPE ⫽ Heart Outcomes Prevention Evaluation; ISIS ⫽ International Study of Infarct Survival; lisino ⫽ lisinopril; LVD ⫽ left
ventricular dysfunction; rami ⫽ ramipril; SAVE ⫽ Survival And Ventricular Enlargement; SOLVD ⫽ Studies Of Left Ventricular Dysfunction;
TRACE ⫽ Trandolapril Cardiac Evaluation; trandola ⫽ trandolapril.
coronary heart disease, congestive heart failure (CHF), left
ventricular dysfunction, hypertension and diabetes and to
reduce the need for cardiovascular procedures and hospitalizations (3–10). The treatment effects on all-cause mortality
observed in the major randomized clinical trials of ACE
inhibitors are shown in Figure 2 by type and dose of study
drug and kind of study population. The relative reductions
in mortality are small for patients with acute myocardial
infarction (approximately 10%) compared with the reductions in patients with left ventricular dysfunction postinfarction or CHF (approximately 25%).
Effectiveness should not be confused with a mechanism
of action, that is, surrogate efficacy, such as blood pressure
reduction. Unfortunately, the demonstration of a blood
pressure lowering potential is sufficient for regulatory approval of ACE inhibitors for hypertension and often forms
the basis for decisions regarding recommended dosages of
other indications. The effective dose of a drug for an
indication such as heart failure may, however, not be the
same as for hypertension (11). The recommended or optimal dose of any ACE inhibitor should also be determined
by clinical efficacy for that clinical indication. Luzier et al.
(12) conducted a very informative dose-response study in
patients after hospital discharge for CHF. The clinical
outcome was readmission for CHF within 90 days. The
optimal dose of enalapril was shown to be ⱖ30 mg/day,
which is even a higher dose than that evaluated in some
large-scale clinical trials of enalapril for that indication. The
mortality benefit of 40 mg of enalapril (Cooperative North
Scandinavian Enalapril Survival Study [CONSENSUS])
was larger than that of 20 mg (Studies Of Left Ventricular
Dysfunction [SOLVD]), 27% versus 16% (Fig. 2). The
issue of dose may be more than theoretical. For example,
quinapril 20 mg daily, a dose shown to be effective in
lowering blood pressure, was evaluated in a placebocontrolled trial of coronary patients with preserved ventricular function after angioplasty (13). There was no
difference between quinapril 20 mg daily and placebo in
three-year incidence of a combined coronary disease
event outcome. An alternative explanation, other than an
inadequate sample size and duration of observation, is
that quinapril at the dose studied, 20 mg daily, lacks the
preventive effect demonstrated for other ACE inhibitors.
Moreover, its tissue-binding capacity has no proven
clinical relevance.
Comparative clinical effectiveness can only be determined
by large randomized outcome trials comparing drugs or
dosages head-to-head. It is important to know how ACE
inhibitors in different dosages compare with each other. For
example, ramipril 2.5 mg every day was shown to be
ineffective in preventing the progression of carotid atherosclerosis, as assessed by B-mode ultrasonography, while
10 mg every day was effective (14). Patients should have
access to the optimal dose of the best ACE inhibitor. In
clinical medicine, assumptions or extrapolations regarding
clinically effective dosages based on surrogate outcomes like
blood pressure are unwarranted. Decisions regarding interchangeability ought to rely on proper dose-dependent evidence. Ideally, they should not be influenced by marketing
forces and restricted formularies.
It is difficult to know if two ACE inhibitors, shown to
confer a similar effect on the risk of CHF, are also equally
effective in preventing other clinical outcomes, for example,
preservation of renal function or prevention of ischemic
Furberg et al.
Interchangeability of ACE Inhibitors
JACC Vol. 37, No. 5, 2001
April 2001:1456–60
events. A prudent action is the assumption that the benefits
of a particular ACE inhibitor apply primarily to the investigated indication, doses and outcomes.
Can one assume that all ACE inhibitors have the same
safety profile? The purpose of toxicity testing during the
drug development phase is to eliminate candidate molecules
with harmful effects. This safeguard is not always effective.
A number of individual drugs of established drug classes
have been found to cause major harm leading to drug
withdrawal after marketing. Large-scale, long-term trials
provide opportunities for evaluating long-term safety and
for determining risk-benefit ratios. The problem with
first-dose hypotension observed when enalaprilat was
given intravenously to hypotensive patients on admission
for acute myocardial infarction (15) may not apply to all
ACE inhibitors. There are also reports of differences
among ACE inhibitors regarding the risk of angioedema
(16) and cough (17). However, there have been no
large-scale comparative trials with adequate statistical
power to assess this issue.
Postmarketing surveillance is a crude method for
assessing drug safety. An ACE inhibitor that has not
been tested in long-term trials lacks the long-term safety
documentation of the agents that have been used in trials.
Long-term safety data are essential for decisions regarding interchangeability.
Which ACE inhibitors have adequate documentation of
health benefits and long-term safety? The following ten
ACE inhibitors are currently available on the U.S. market
(alphabetical order): benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril
and trandolapril. Five of them— captopril, enalapril, lisinopril, ramipril and trandolapril— have been tested in largescale trials and have been shown to reduce mortality and
morbidity in heart failure and postinfarction (3–10). Only
ramipril (10 mg every day) has been shown to reduce
mortality in cardiac patients without left ventricular dysfunction and in high-risk patients with diabetes. Another
ACE inhibitor, quinapril, 20 mg daily, was tested in one
large-scale trial in 1,750 patients after percutaneous coronary intervention and was shown to be no better than
placebo for the three-year incidence of cardiac ischemic
events. The other four remain untested in large-scale trials
and lack the regulatory claim in their labeling of beneficial
mortality/morbidity effects. Other ACE inhibitors not
mentioned here fall into the category of “yet untested.”
Clinicians practicing evidence-based medicine should attempt to achieve the target doses shown effective in the
major event trials for specific indications, which were as
follows: captopril—50 mg twice a day/three times a day,
enalapril—10 to 20 mg twice a day, lisinopril—10 to 35 mg
every day, ramipril—10 mg every day and trandolapril— 4 mg
every day.
Conclusions. It is not well understood how clinicians make
their decisions regarding selection of drugs and doses within
a class. The common use in medical practice of untested
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“me-too” drugs, of drugs unproven for specific clinical
indications, and the widespread underutilization of drugs
with documented health benefits and safety suggests that
there is room for improvement. The assumption that drugs
of the same class, however defined, are clinically interchangeable is a misnomer and should not form the basis for
drug selection. Similarly, the assumption that we can
achieve equal risk benefits for the same drug at two different
doses is untenable.
The promotion of evidence-based practice has undeniable
appeal. For our patients, such practice is a legitimate
expectation. Applied to the ten ACE inhibitors on the
market, one would, today, due to a lack of documentation,
dismiss half of them for treatment of patients with CHF
until further documentation as to the dose and indication in
which they are effective in reducing morbidity/mortality is
available. All the others have been shown to be beneficial in
patients with CHF or in postinfarction patients with left
ventricular dysfunction. In addition, ramipril 10 mg once
daily has been shown to be effective in patients with vascular
disease and diabetes without impaired ventricular function,
giving it the most widely approved indications.
There are many pressures on the clinician to use or
substitute a cheaper or formulary-available ACE inhibitor
or to use a lower dose than was shown to be effective in the
major randomized trials. It would, indeed, be unfortunate if
those pressures assuaged our conscience and allowed us to
feel as if we were doing something good for our patients.
Substituting an unproven alternative for a proven treatment
may deny benefit, subject the patient to unnecessary adverse
effects and, despite a lower unit cost, may not be costeffective.
Reprint requests and correspondence: Dr. Curt D. Furberg,
Department of Public Health Sciences, Wake Forest University
School of Medicine, Winston-Salem, North Carolina 27157.
E-mail: [email protected].
REFERENCES
1. Furberg CD. Natural statins and stroke risk. Circulation 1999;99:
185– 8.
2. Furberg CD, Herrington D, Psaty BM. Class effects. Are drugs within
a class interchangeable? Lancet 1999;354:1202– 4.
3. The 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;316:1429 –35.
4. The SOLVD Investigators. Effect of enalapril on survival in patients
with reduced left ventricular ejection fractions and congestive heart
failure. N Engl J Med 1991;325:293–302.
5. Pfeffer MA, Braunwald E, Moyé LA, et al., on behalf of the SAVE
Investigators. Effect of captopril on mortality and morbidity in patients
with left ventricular dysfunction after myocardial infarction: results of
the Survival And Ventricular Enlargement trial. N Engl J Med
1992;327:669 –77.
6. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
Effect of ramipril on mortality and morbidity of survivors of acute
myocardial infarction with clinical evidence of heart failure. Lancet
1993;342:821– 8.
7. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Mio-
1460
8.
9.
10.
11.
12.
Furberg et al.
Interchangeability of ACE Inhibitors
cardico (GISSI-3). Effects of lisinopril and transdermal glyceryl
trinitrate singly and together on six-week mortality and ventricular
function after acute myocardial infarction. Lancet 1994;343:1115–22.
ISIS-4 (Fourth International Study of Infarct Survival) Collaborative
Group (ISIS-4). A randomized factorial trial assessing early oral
captopril, oral mononitrate and intravenous magnesium sulphate in
58,050 patients with suspected acute myocardial infarction. Lancet
1995;345:669 – 85.
Køber L, Torp-Pedersen C, Carlsen JE, et al., for the Trandolapril
Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:
1670 – 6.
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;342:145–53.
Pitt B. Use of ‘Xapril’ in patients with chronic heart failure: a paradigm
or epitaph for our times? Circulation 1994;90:1550 –1.
Luzier AB, Forrest A, Adelman M, et al. Impact of angiotensinconverting enzyme inhibitor underdosing on rehospitalization rates in
congestive heart failure. Am J Cardiol 1998;82:465–9.
JACC Vol. 37, No. 5, 2001
April 2001:1456–60
13. Texter M, Lees RS, Pitt B, et al. The QUinapril Ischemic Event Trial
(QUIET) design and methods: evaluation of chronic ACE inhibitor
therapy after coronary artery intervention. Cardiovasc Drugs Ther
1993;7:273– 82.
14. Lonn EM, Yusuf S, Dzavik V, et al. 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 –25.
15. Swedberg K, Held P, Kjekshus J, et al. on behalf of the CONSENSUS
II Study Group. Effects of the early administration of enalapril on
mortality in patients with acute myocardial infarction: results of
the Cooperative New Scandinavian Enalapril Survival Study II
(CONSENSUS II). N Engl J Med 1992;327:678 – 84.
16. Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have
an increased rate of angiotensin-converting enzyme inhibitorassociated angioedema. Clin Pharmacol Ther 1996;60:8 –13.
17. David D, Jallad N, Germino W, et al. A comparison of the cough profile
of fosinopril and enalapril in hypertensive patients with a history of ACE
inhibitor-associated cough. Am J Ther 1995;2:806 –13.