Clin. Cardiol. Vol. 23 (Suppl.
IV), IV-15-IV-19 (2000)
Class Effects and Evidence-Based Medicine
CURTD.FURBERG, M.D., PH.D.
Wake Forest University School of Medicine, Winston-Salem, North Carolina. USA
Summary: Drugs grouped into a therapeutic class on the
basis of a common mechanism of action often have consider-
ably different pharmacodynamicand pharmacokineticprop-
erties. Among angiotensin-convertingenzyme (ACE) inhib-
itors, differences with potential clinical relevance include
potency, whether the drug is an active compound or requires
metabolic activation, lipophilicity, route(s) of elimination,
and half-life. Large clinical trials have documented the clini-
cal benefits of several ACE inhibitors in various patient popu-
lations, and many clinical effects of ACE inhibitors are likely
to be the same. However, there are possible quantitative dif-
ferences among ACE inhibitors that may alter the overall
therapeutic benefits for specific patient populations and indi-
cations. Equipotency in terms of clinical efficacy is difficult
to determine. Since the concept of ‘‘class effect” is a term of
convenience that has no universally accepted definition and
subsequently should not form the basis for the practice of ev-
idence-based medicine, untested drugs of a “class” should be
considered to be unproven drugs.
Key words: angiotensin-converting enzyme inhibitor, phar-
macokinetic, pharmacodynamic, cardiovascular morbidity
and mortality, Heart Outcomes Prevention Evaluation study,
lipophilicity
Introduction
“Classeffect”is a concept that has gained widespreaduse in
the recent decades. Third-party payers and institutions with
formulary systems rely on it to control drug expenditure by
limiting the number of drugs from a specific therapeutic class
that can be prescribed for patients and/or reimbursed by the
Supported by a grant from Monarch Pharmaceuticals.
Address for reprints:
Curt D. Furberg, M.D., Ph.D.
Director of the Office of Academic Program Development
Wake Forest University School of Medicine
Medical Center Boulevard
Winston Salem, NC 27 157-1063, USA
payer. While the driving force is often cost, the underlying
premise is that compelling findings from large clinical trials of
one member of a therapeutic class are applicable to all other
members of the same class.
There is, however, no standard definition of “class effect.”
Instead, a related term, “class labeling,” is used by the Food
and Drug Administration(FDA).Class labeling “assumes that
all products within aclass are closely related in chemical struc-
ture, pharmacology, therapeutic activity, and adverse reac-
tions.” Two important caveats inherent in this definition are
that the drugs are assumed, but not necessarily shown, to be
closely related, and that the characteristics of the drugs that
confer their close relation(s) are not defined. Two sets of crite-
ria are used to determine class effect: the regulatory criteria
used by the FDA to determine class labeling, and the pragmat-
ic clinical criteria, the latter being concerned with therapeutic
benefit, long-term safety, cost, and comparative efficacy
among members of a class.
The recently published Heart Outcomes Prevention Eval-
uation (HOPE) study on ramipril’ (10 mg once daily) raised
anew the question of class effects for angiotensin-converting
enzyme (ACE) inhibitors.While there are pharmacologic sim-
ilarities among ACE inhibitors, there are also salient differ-
ences. By definition, all ACE inhibitors inhibit the conversion
of the relatively inactive angiotensin I to the active metabolite
angiotensin IL2 But within the group, specific drugs are ap-
proved for the treatment of hypertension, heart failure, myo-
cardial infarction, asymptomatic left ventriculardysfunction,
and diabetic nephropathy.
Chemical Structure
All ACE inhibitors share an important feature-the bind-
ing of the functional group to the zinc component of the ACE
active site3-and it is this commonality that divides the class
into its three subgroups: the sulfhydryl-containing ACE in-
hibitors for which captopril is the prototype; the carboxyl- or
dicarboxyl-containing ACE inhibitors, which is the largest
group of ACE inhibitors and for which enalapril and ramipril
are representative members; and the phosphorous-containing
or phosphinyl ACE inhibitors, which are structurally related to
fosinopril (Fig.
In general, the overall benefit of a drug is determined by the
sum of its desired and untoward (adverse)effects. Experience
with other classes of agents such as nonsteroidal anti-inflam-
 19328737, 2000, S4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960230705 by Nat Prov Indonesia, Wiley Online Library on [06/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
IV-16 Clin. Cardiol. Vol. 23 (Suppl IV) July 2000

Captopril

COOH
H a
Enalapril COOC,H, COOH
(a) Sulfhydtyl-containing A C E inhibitor

CH,CH,-C-N-C-C-N

Fosinopril COONa 0 :
H O
II

(c) Phosphorus-containingACE inhibitors (b) Dicarboxyl-containingACE inhibitors

FIG.1 Chemical structures of angiotensin-convertingenzyme (ACE) inhibitors according to functional group.

matory drugs has shown that while efficacy among members
of a class tend to be similar,there can be marked differencesin
safety. Notably, small differences in chemical structure may
sometimesproduce profound pharmacologic differences.
Pharmacology and Pharmacokinetics
Pharmacologic differences among ACE inhibitorsinclude
variations in The potency of an ACE inhibitor
relates to the affinity of the functional group for the zinc com-
ponent as well as a number of additional binding sites on
ACE.Another pharmacologic difference among ACE inhib-
itors is whether ACE inhibition is a result of the drug itself or
dependent on conversion from a prodrug to an active metabo-
lite.24 Only captopril and lisinopril are active drugs that do
not require hepatic activation; all other ACE inhibitors are
prodrugs. Conversion from the prodrug to the active metabo-
lite may be delayed or incomplete in patients with severe hep-
atic dysfunction.
There are also differences in the pharmacokinetics of ACE
inhibitors (Table 1): which affect their dosing schedule.Drug
lipophilicity is a physicc-chemical characteristic that not only
influencespharmacokinetics, but indicates the extent of drug
tissue penetration. For ACE inhibitors, greater drug lipophilic-
ity correlates with greater inhibition of tissue ACE in animal
and ex vivo studies? However, differencesin lipophilicityhave
not yet been shown to be associated with differencesin clinical
effect^.^^^ Differences in lipophilicity and the inhibition of tis-
sue ACE may be clinically relevant.
The route of elimination for ACE inhibitors is also of po-
tential clinical relevance. Since most ACE inhibitors are ex-

TABLE
I Selectedpharmacokheticparameters of angiotensin-convertingenzyme (ACE) inhibitors
ACE inhibitor Lipophilicity tmax (h) Half-life (h) Eliminationroute
Benazepril + 1.5 21.0 Renal + hepatic
Captopril + 1.o 2.0 Renal
Enalapril ++ 4.0 11.0 Renal
Fosinopril +++ 3.0 12.0 Renal +hepatic (50/50)
Lisinopril 0 7.0 13.0 Renal
Perindopril + 4.0 9.0 Renal
Quinapril ++ 2.0 3.0 Renal
Ramipril + 3.0 12.0 Renal +hepatic (70/30)
Spirapd + 2.5 30.0 Renal + hepatic (50/50)
Trandolapril ++ 4.0 16-24 Renal +hepatic (30/70)
Abbreviations: ACE = angiotensin-convertingenzyme, tmm = time to reach maximum plasma concentration,+ = slight, ++ = moderate,
+++ =high.
Adaptedfrom Ref. No. 4 with permission.
 19328737, 2000, S4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960230705 by Nat Prov Indonesia, Wiley Online Library on [06/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C.D. Furberg: Evidence-based medicine IV-17

creted predominantly by the kidneys, plasma clearance and
elimination is diminished in patients with impaired renal func-
tion, thereby requiring a reduction in dose. There are, how-
ever, exceptions: fosinopril and spirapril have balanced renal/
hepatic elimination, trandolapril has a renal-hepatic elimina-
tion ratio of30 to 70, and ramipril has a renal-hepatic elimina-
tion ratio of 70 to 30.24 The duration of action ofa drug deter-
mines dosing frequency; drugs with a longer duration of
action require fewer daily doses. All ACE inhibitors except
captopril can be dosed once daily? which generally improves
patient compliance.
Clinical lkial Data
Several ACE inhibitors have been shown to reduce the risk
of cardiovascular morbidity and mortality in patients with
cardiovascular disease.2 They are currently indicated for the
treatment of patients with hypertension, particularly those
with diabetes, and postinfarction patients with left ventricular
dysfunction or congestive heart failure. However, none of the
commercially available ACE inhibitors have been studied in
all of these patient populations in large clinical trials (Table
II).'."22 The magnitude ofthe benefit demonstrated with each
ACE inhibitor varies among trials. In patients with congestive
heart failure or left ventricular dysfunction, the reduction in
all-cause mortality with ACE inhibitor treatment ranged from
8% with enalapri19to 27% with ramipril,20while the risk re-
duction for myocardial infarction ranged from 11% with
ramipri12"to 25% for captopriL6Studies in patients with coro-
nary heart disease have shown similar variability: from no ef-
fect on disease progression and cardiovascular events with
quinapril" to a significant 25% reduction (p = 0.0004) with
ramipril in a composite endpoint of myocardial infarction,
stroke, and death from cardiovascular causes.I
Such findings ostensibly suggest that ACE inhibitors can-
not be assumed to be equivalent with respect to clinical ef-
fects. However, it is difficult to compare studies since there
are differences not only in the drugs themselves and their
dosages, but also in study populations, study design, outcome
measures, concomitant therapy, and other variables. Direct
comparative trials with various ACE inhibitors are necessary
to determine whether they indeed have equivalent clinical ef-
fects. Until such studies are done, physicians should not as-
sume that all members of the ACE inhibitor class are equiva-
lent in terms of benefits. Another issue relates to dosing.
Should we really assume that short-term changes in blood
pressure are reliable determinants of the optimal drug dose for
treatment of congestive heart failure?
Although the ability of ACE inhibitors to reduce the risk of
chronic heart failure is largely a class effect, the optimal dose
for each ACE inhibitor that will effectively reduce mortality
and morbidity remains unknown.23The importance of a cor-
rect dose was demonstrated in a study that evaluated the risk
of hospital readmission within 90 days for patients with heart
failure.24The strongest predictor of readmission was not be-
ing prescribed an ACE inhibitor, and the second strongest
predictor was an inadequate dose of an ACE inhibitor (Fig. 2).
Increasing doses of an ACE inhibitor were associated with
impressively lower readmission rates for patients with heart
failure. Dose-response trials are needed to determine optimal
dosing.

TABLE
II Large clinical trials documenting effects ofangiotensin-convertingenzyme (ACE)inhibitors.
Clinical trial
ACE inhibitor CHFLVD MVCHD HPT Type 2 Diabetes
Benazepril 0 0 0 0
Captopril SAVE SAVEYTSIS-4 CAPPP 0
Enalapril SOLVD SOLVD 0 ABCD
CONSENSUS
Fosinopril 0 0 0 FACET
Lisinopril ATLAS GISSI-3 0 0
Perindopril 0 0 0 0
Quinapril 0 0 0 0
Ramipril AIRE AIFWHOPE HOPE HOPE
Spirapril 0 0 0 0
Trandolapril TRACE TRACE 0 0
Abbreviations: ACE = angiotensin-convertingenzyme, CHF = congestive heart failure, LVD = left ventricular dysfunction, MI = myocardial in-
farction,CHD = coronary heart disease, HPT = hypertension, ABCD = Appropriate Blood pressure Control in Diabetes, AIRE = Acute Infarction
Ramipril Efficacy, ATLAS = Assessment of Treatment with Lisinopril And Survival, CAPPP = CAPtopril Prevention Project, CONSENSUS =
Cooperative North Scandinavian ENalapril Survival Study, FACET = Fosinopril versus Amlodipine Cardiovascular Events Trial, GISSI-3 =
Gruppo Italian0 per lo Studio della Sopravvivenza nell'hfarto miocardico, HOPE = Heart Outcomes Prevention Evaluation, ISIS-4 = Fourth
International Study of Infarct Survival, SAVE = Survival And Ventricular Enlargement, SOLVD = Studies of Left Ventricular Dysfunction,
TRACE = TRAndolaprilCardiac Evaluation.

IV- 18
I\
1,oo .... .... .................................................................
0.00 '
0 10
I
20 30
I
Enalapril equivalent units (mg)
FIG.2 Relative risk (RR) of hospital readmission for heart failure
with respective 95% confidence intervals as a function of ACE in-
hibitor dose received expressed as mg of enalapril. Reprinted from
the American Journal of Cardiology 1998; 82: 4 6 5 4 6 9 with per-
mission from Excerpta Medica Inc.
In the United States, a drug has to be more effective than
placebo to be approved. Newer compounds from the same
therapeutic class typically need less stringent documentation
for regulatory approval. Currently, 10 ACE inhibitors are ap-
proved for use in the United States. The approval of the most
recently marketed ACE inhibitor, perindopril,was based on its
ability, in two separate trials, to lower blood pressure in more
than 350 patients with mild-to-moderate hyperten~ion.2~9 26 By
mere inference to the major clinical trials of ACE inhibitors
(Table II), perindopril and other less tested ACE inhibitors
may, if the price is right, be selectedby third-party payers and
formulary committees as the ACE inhibitor of choice. How-
ever, comparativeclinical trials that establish equipotentdoses
of ACE inhibitors for each indicationought to be required pri-
or to marketing.
Conclusions
The health effects of a drug are determined by its favorable
and unfavorable actions.The concept of class effect is a conve-
nient term, but has no universally accepted definition.While
it is useful to group drugs on the basis of chemical structure
and common mechanisms of action, drugs within a therapeu-
tic class may also have substantially different pharmacologic
properties. These pharmacologic differences among ACE in-
hibitors of potential clinical relevance include potency of tis-
sue ACE inhibition, lipophilicity, and adverse events associ-
ated with specific chemical structures. Pharmacokinetic
differencesinclude whether a drug is an active compound or a
prodrug requiring conversion to an active metabolite, route(s)
of elimination, and half-life. While large clinical trials that
document the clinicaleffects of all ACE inhibitorsfor every in-
dication have not yet been done, the qualitativeclinical effects
of ACE inhibitors are likely to be similar: reductions in the
overall risk of cardiovascular disease as well as in cardiovas-
19328737, 2000, S4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clc.4960230705 by Nat Prov Indonesia, Wiley Online Library on [06/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Clin. Cardiol. Vol. 23 (Suppl IV) July 2000
cular morbidity and mortality in patients with established dis-
ease. However, there are likely to be quantitative differences
because equipotent or optimal doses of ACE inhibitorsthat are
of therapeutic benefit in the various indications are unknown.
Untested drugs with respect to morbidity and mortality out-
comes should be considered unproven drugs. The practice of
medicine, including third-party payer and formulary commit-
tee decisions, should be evidence based; the decision to pre-
scribe specificdrugs at given doses should be based on clinical
trial experience. Thus, the results of the HOPE study with its
unique population and findmgs of other important clinical tri-
00
als, although impressive, should not be extended to the ACE
inhibitors that have not been shown to reduce cardiovascular
morbidity and mortality.
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