POINT/COUNTERPOINT

Angiotensin Receptor Blockers Do Not Reduce

Risk of Myocardial Infarction, Cardiovascular
Death, or Total Mortality
Further Evidence for the ARB-MI Paradox

Opposing Viewpoint, see p 2085 Martin H. Strauss, MD,

BSc
ANGIOTENSIN RECEPTOR BLOCKERS: MYOCARDIAL INFARCTION IS Alistair S. Hall, MB ChB,
PhD
NOT REDUCED
Downloaded from http://circ.ahajournals.org/ by guest on June 1, 2017

Individual trials of angiotensin II receptor blockers (ARBs) and systematic meta-anal-

yses have repeatedly demonstrated the ARB class to significantly reduce systemic
blood pressure, stroke, and the subsequent development of heart failure and diabe-
tes mellitus.1 However, no individual trial or meta-analysis has observed an impact
of ARB treatment on the incidence of myocardial infarction (MI), cardiovascular mor-
tality, or all-cause mortality (Table). All-cause mortality is the most comprehensive
summary indicator of cardiovascular benefit of treatment2 and, consequently, it is
surprising that ARBs have no impact given the other clinical benefits we have just
acknowledged.
A systematic review/meta-analysis conducted by Bangalore et al3 demonstrated
that in 20 trials of ARB versus placebo (n=66282) and 21 trials of ARB versus active
comparator (n=39738), ARB in no individual trial improved all-cause mortality. Fur-
thermore, when the trials were analyzed in combination, the impact of ARB on mor-
tality was precisely zero compared with placebo (odds ratio, 1.01; 95% confidence
limit, 0.961.06) and virtually zero compared with an active comparator (odds ratio,
0.99; 95% confidence limit, 0.951.03). Placebo-controlled trials are the most rigor-
ous method of assessing treatment efficacy (as well as harm), and, consequently,
it is concerning that other meta-analyses of ARBs versus placebo-controlled trials
have also reported a lack of mortality reduction in patients with high risk (Savarese),4
those with diabetes mellitus (Cheng),5 and patients with hypertension (Thomopoulos
et al),6 as well as no reduction in MI or cardiovascular mortality (Table). The opinions expressed in this
Thomopoulos et al6 also reported the impact of different drug classes compared article are not necessarily those
with placebo in the treatment of systemic hypertension. Indapamide, calcium chan- of the editors or of the American
nel blockers, and angiotensin-converting enzyme inhibitors (ACEIs) all statistically Heart Association.
significantly reduced mortality, whereas 4 other drug classes reduced mortality but Correspondence to: Martin H.
not to a degree that was of statistical significance. ARB was the only drug class Strauss, MD, North York General
that failed to reduce death compared with placebo, despite representing the largest Hospital, 107-4800 Leslie St,
Toronto, Ontario, Canada M2J
group of patients studied (n=65256) and despite an average blood pressure reduc-
2K9. E-mail dr.marty@bellnet.ca
tion of 3.7/2.0 mmHg. Because stroke was reduced by ARBs, cardiovascular and
all-cause mortality must have been driven by an excess risk of fatal MI and sudden Key Words: angiotensin II
receptor blocker angiotensin
death. ACEIs but not ARBs reduced coronary heart disease (including nonfatal MI) converting enzyme inhibitor
and cardiovascular death (including fatal MI6), despite both being inhibitors of the cardiovascular mortality
renin-angiotensin-aldosterone system. hypertension meta-analysis
ACEIs suppress angiotensin II, thereby preventing pathological effects, but they myocardial infarction
also prevent the breakdown of bradykinin, thereby inducing additional cardioprotec- 2017 American Heart
tive effects. This profile is distinct from the one achieved by use of an ARB that Association, Inc.

2088 May 30, 2017 Circulation. 2017;135:20882090. DOI: 10.1161/CIRCULATIONAHA.117.026112

 Angiotensin Receptor Blockers: Mortality Is Not Reduced

FRAME OF REFERENCE
Table. Risk of Myocardial Infarction, Cardiovascular Mortality, and All-Cause Mortality in Parallel Meta-
Analyses of Placebo-Controlled Trials of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor
Blockers
ACEI vs Placebo ARB vs Placebo
Myocardial Cardiovascular All-Cause Myocardial Cardiovascular All-Cause
Infarction Death Death N Infarction Death Death N
High risk, Bangalore 0.83 0.83 0.89 0.93 1.02 1.01
62398 66282
et al3 (0.780.9) (0.70.99) (0.801.0) (0.851.03) (0.921.14) (0.961.06)
High risk, Savarese4 0.81 0.9 0.91 0.9 1.03 1.01
53791 54421
(0.750.88) (0.781.03) (0.850.98) (0.81.02) (0.851.26) (0.941.08)
Diabetes mellitus, 0.83 0.89 1.21 1.03
NA 21997 NA 13304
Cheng5 (0.700.99) (0.790.99) (0.811.8) (0.891.18)
Hypertension, 0.87 0.91 1.03 1.01
NA 49440 NA 65256
Thomopoulos et al6 (0.780.98) (0.850.98) (0.941.13) (0.971.06)
Values indicate hazard ratio (95% confidence interval). ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

induces selective antagonism of the AT1 angiotensin II (n=146838) by the BPLTTC (Blood Pressure Lowering
Downloaded from http://circ.ahajournals.org/ by guest on June 1, 2017

receptor, inhibiting a negative feedback loop and con-
sequently increasing angiotensin II levels by 200% to
300%. This may lead to MI as a result of stimulation of
the AT2 receptors, which are markedly upregulated and
active in atheromatous plaques.1 ACEIs in meta-analyses
of placebo-controlled trials conducted in parallel to the
ARB meta-analyses discussed above (Thomopoulos et
al,6 Savarese,4 Cheng,5 Bangalore et al3) demonstrated
a robust 9% to 11% risk reduction in all-cause mortality,
10% to 17% risk reduction in cardiovascular mortality,
and 17% to 19% risk reduction in MI (all P<0.05; Table).
The divergent effects of ACEI and ARB on both all-cause
and cardiovascular mortality are despite their compara-
tor arms having similar risks of both (7.8% versus 9%,
4.7% versus 5.2%, respectively).3
These observations are consistent with an earlier
meta-analysis1 that reported that ARBs versus all com-
parators (11 trials, n=55050) did not reduce mortality
(odds ratio, 1.01; 95% confidence interval, 0.961.06,
P=0.8) and the risk of MI actually increased 8% (odds ra-
tio, 1.08; 95% confidence interval, 1.011.16; P=0.03),
with that increase qualitatively apparent in 9 of the trials
and statistically significant in 2. This article also included
a parallel meta-analysis of ACEI trials. ACEIs versus all
comparators (39 trials, n=150943) reduced the relative
risk of total mortality 9% (P<0.0001) and MI by 14%
(P<0.0001). The divergent effects in the parallel ACEI
and ARB meta-analyses on MI and death were marked,
despite their comparator arms having similar cardiovas-
cular risks; rates of global death, MI, and stroke (cere-
brovascular accident) were essentially no different (13%
versus 14%, 5.8% versus 6.3%, and 4.2% versus 4.4%,
respectively). In addition, blood pressure lowering com-
parable to the risk reduction in stroke, a blood pressure
dependent phenomenon, was also similar.
Divergent cardiovascular effects of ACEIs and ARBs
were also confirmed in a meta-regression analysis
Treatment Trialists Collaboration), as well as being in-
dependent of blood pressure lowering.1 For any given
blood pressure reduction, ACEIs also reduce the risk of
coronary heart disease by an additional 9% (P=0.002),
independently of the effects of blood pressure lowering.
In contrast, ARBs had no blood pressureindependent
effects on coronary heart disease; rather, there was a
small, nonsignificant increase in the risk of harm of 7%
(7%: 95% confidence interval, 7 to 24; P=NS), a phe-
nomenon we have called the ARB MI paradox. Specifi-
cally, it is paradoxical that no net benefits are observed
with ARBs. Furthermore, and most important, for any
given blood pressure reduction, ACEIs reduced the risk
of MI and death an additional 15% (P=0.002) above that
of an ARB.
Head-to-head trials of ARB versus ACEI are of inter-
est, but there is a paucity of data. In the ONTARGET
trial (Ongoing Telmisartan Alone and in Combination With
Ramipril Global Endpoint Trial),2 the largest ACEI versus
ARB controlled trial reported to date (n=17118), the
ARB telmisartan was not statistically equivalent to the
ACEI ramipril for a combined cardiovascular end point.
The US Food and Drug Administration approved telmisar-
tan as a second-line therapy for those high-risk patients
who are ACEI intolerant (New Drug Application 20850).
This decision was influenced by a lack of superiority of
telmisartan compared with placebo in the parallel TRAN-
SCEND trial (Telmisartan Randomized Assessment Study
in ACE Intolerant Subjects With Cardiovascular Disease),
consistent also with the HOPE-3 trial (Heart Outcomes
Prevention Evaluation-3) conducted in patients at inter-
mediate risk (n=12705; follow-up, 5.6 years)4 in whom
candesartan combined with hydrochlorothiazide failed to
reduce a combination of cardiovascular events despite
a robust reduction in blood pressure of 6.0/3.0 mmHg.
Logic dictates that practice guidelines should recognize
the unique cardiovascular benefits of ACEIs and their prefer-

Circulation. 2017;135:20882090. DOI: 10.1161/CIRCULATIONAHA.117.026112 May 30, 2017 2089

 Strauss and Hall
ential use compared with ARBs. Were such advice to be giv-
en, the predicted impact on lives saved would be profound.
DISCLOSURES
Dr Strauss has received speaker honorarium from and par-
ticipated in advisory boards for Servier. Dr Hall has received
speaker honorarium from Servier.
AFFILIATIONS
From North York General Hospital, Toronto, Ontario, Canada
(M.H.S.); and Leeds MRC Medical Bioinformatics Centre,
Leeds, West Yorkshire, United Kingdom (A.S.H.).
FOOTNOTES
Circulation is available at http://circ.ahajournals.org.
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Circulation. 2017;135:20882090. DOI: 10.1161/CIRCULATIONAHA.117.026112
 Angiotensin Receptor Blockers Do Not Reduce Risk of Myocardial Infarction,
Cardiovascular Death, or Total Mortality: Further Evidence for the ARB-MI Paradox
Martin H. Strauss and Alistair S. Hall

Circulation. 2017;135:2088-2090
doi: 10.1161/CIRCULATIONAHA.117.026112
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