Improving Reperfusion in Patients with Myocardial Infarction doc

Improving Reperfusion in
Patients with Myocardial
Infarction

e d i t o r i a l s
n engl j med 358;6 www.nejm.org february 7, 2008
634
T h e n e w e ngl a n d j o u r na l o f me dicine
Improving Reperfusion in Patients with Myocardial Infarction
George W. Vetrovec, M.D.
A little over 50 years ago, my father had a heart
attack. He was driven to the hospital by friends
after having “indigestion” for 2 days. He spent
2 weeks as an inpatient on an unmonitored reha-
bilitation ward and was treated principally with
warfarin and digitalis. He was lucky and sur-
vived, but in that era, more than 20% of patients
with an acute myocardial infarction died. Fast-
forward to today, when public education about
early recognition of symptoms, emergency trans-
port, monitored coronary care units, and early
reperfusion by means of primary percutaneous
coronary intervention (PCI) have markedly re-
duced mortality from acute myocardial infarction
to less than 5%.
Major contributors to this remarkable im-
provement in outcome are based on pathologi-
cal studies
1,2

showing thrombotic occlusion of an
artery associated with acute myocardial infarc-
tion (Fig. 1A), in parallel with diagnostic and
therapeutic advances from cardiac catheteriza-
tion laboratories. By performing coronary angi-
ography during evolving myocardial infarction,
DeWood et al.
3
observed total coronary-artery
occlusion in patients with acute myocardial in-
farction, with frequent, early, spontaneous re-
perfusion. Coincidentally, angiographic features
of the thrombus were characterized, helping to
identify the role of clots in acute coronary syn-
dromes.
4,5
Most of the remarkable improvements have
occurred over the 30 years since the introduction
of coronary angioplasty.
6
Rentrop et al.
7
demon-
strated that reperfusion with the use of mechani-
cal or thrombolytic revascularization could avert
evolving infarction. Most recently, the recognized
importance of early and complete reperfusion
by means of PCI has led to a strategy of using
PCI as the preferred therapy for acute myocar-
dial infarction, with a goal of reestablishing

flow within 90 minutes after presentation (i.e.,
a door-to-balloon time of <90 minutes), provid-
ed that this can be achieved without major de-
lays in transport.
8
Thus, the improvement in
outcomes for patients with acute myocardial in-
farction is principally due to earlier, more effec-
tive mechanical resolution of thrombotic occlu-
sion of a coronary artery to maximally and
quickly restore effective myocardial perfusion.
Technically, the current method of primary
PCI is to cross the occlusion with a balloon
catheter, which, after a brief period of inflation,
reestablishes flow. Subsequently, one or more
stents are placed to provide stable revasculariza-
tion (
Fig. 1B
). The initial inflation expedites reper-
fusion and provides visualization of the occlud-
ed segment for accurate stent sizing. However,
as a consequence of manipulations of the bal-
loon and stent, distal clot embolization occurs,
at times visibly reducing distal reperfusion
through the occlusion of macrovessels and micro-
vessels. Reduced distal flow is indicated by slow
coronary flow (Thrombolysis in Myocardial In-
farction flow grade 2), incomplete resolution of
the injury seen on the electrocardiogram, ab-
normal myocardial blush, or any combination

of these. Abnormal blush (represented by a low
blush grade) reflects slow or absent washout of
injected contrast medium within the reperfused
arterial system. Each of these indicators has
been associated with a less favorable long-term
prognosis.
9
In this issue of the Journal, Svilaas et al.
10
de-
scribe passing a guidewire through the occluded
infarct-related artery, but instead of then open-
ing the artery with a balloon, a small catheter is
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n engl j med 358;6 www.nejm.org february 7, 2008
635
advanced into the occluded segment. Direct as-
piration of the occluding thrombus is then per-
formed (
Fig. 1C
; also see the animated illustra-
tion available with the full text of this article at
www.nejm.org). After aspiration, stenting was
performed, without balloon dilation beforehand
in the majority of patients, unless the stent
could not be delivered. Conceptually, this tech-
nique limits the embolization of distal clots,
thus improving distal myocardial perfusion.

To test this hypothesis, Svilaas et al. ran-
domly assigned 1071 patients to undergo initial
aspiration with stenting or conventional primary
PCI with the use of a balloon and stent. They
01/23/08
AUTHOR PLEASE NOTE:
Figure has been redrawn and type has been reset
Please check carefully
Author
Fig #
Title
ME
DE
Artist
Issue date
COLOR FIGURE
Version 7
Vetrovec
1
LAM
02/07/08
Refining reperfusion
GDC
JL
Thrombus occluding vessel
Area of potential infarct
Blockage within branch of
left anterior descending
coronary artery
B Standard approach to revascularization

A
C Revascularization using a thrombectomy aspiration catheter
Guidewire
Aspiration catheter
Nonoccluding plaque
Thrombus
occluding vessel
Thrombus
occluding
blood flow
No blood flow
Blood flow
Guidewire
Aspiration catheter
suctions thrombotic
material
Balloon angioplasty
catheter
Stent deployed
Stent deployed after
removal of thrombus
Balloon inflated to
restore blood flow
Lumen
of vessel
Thrombus
occluding
blood flow
Figure 1. Thrombotic Occlusion of an Artery Associated with Acute Myocardial Infarction and Subsequent Percutaneous Coronary Inter-
vention (PCI).

In an occluded infarct-related artery (Panel A), reperfusion can be achieved by the standard means of primary PCI (Panel B) or by the
new method of thrombus aspiration (Panel C), followed by stenting. Also see the animated illustration, available with the full text of this
article at www.nejm.org.
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T h e n e w e ngl a n d j o u r na l o f me dicine
n engl j med 358;6 www.nejm.org february 7, 2008
636
used the ST-segment characteristics on electro-
cardiography as well as the myocardial blush
grade to assess the efficacy of clot extraction
before stenting on distal perfusion. There was a
clear correlation between the resolution of elec-
trocardiographic changes and improvement in
myocardial blush scores: complete resolution of
ST-segment elevation, the absence of persistent
ST-segment deviation, and myocardial blush grade
of 0 or 1 were all significantly more frequent in
the patients who underwent aspiration than in
those who underwent conventional PCI. In addi-
tion, histological assessment of the aspirate from
nearly three quarters of the patients who under-
went aspiration revealed platelet thrombi, consis-
tent with current understanding of the role of
such thrombi in the pathophysiological charac-
teristics of acute myocardial infarction.
Clinical outcome at 30 days was significantly
related to the extent of myocardial reperfusion.
Mortality was higher among patients with per-
sistent abnormalities in myocardial blush than

among patients with improved myocardial distal-
bed perfusion. The frequencies of other adverse
events were similar to that of death.
Reasons for the reported benefit of reduced
embolization in patients who underwent aspira-
tion seem related to enhanced distal-bed perfu-
sion. Neumann et al.
11
showed that increases in
ejection fraction correlated with improved peak
Doppler flow velocity in patients receiving a
platelet glycoprotein IIb/IIIa inhibitor that mini-
mizes distal thrombotic occlusion of small ves-
sels. The significance may be that maintaining
arterial flow limits apoptosis and potentially
adverse remodeling,
12
thus providing a mecha-
nism for the favorable outcomes associated with
improved microvascular reperfusion.
Although the study by Svilaas et al. reports
encouraging results for coronary-thrombus ex-
traction, previous extraction trials of different
designs have had various results. Caveats re-
garding the trial by Svilaas et al. include the fact
that it was a single-center study performed by
highly experienced interventionalists who had
a low failure rate with regard to delivering the
catheter. It is unknown whether more general use
will demonstrate similar safety and favorable out-

comes. Furthermore, there is concern that such
catheters can dissect or damage the arterial seg-
ment, necessitating longer stents, which could
increase the risk of late restenosis. In addition,
some operators believe that direct stenting with-
out multiple balloon inflations reduces the risk
of distal emboli. In the trial by Svilaas et al., the
majority of patients in the thrombus-aspiration
group had stents placed directly, whereas the
majority in the conventional-PCI group had bal-
loon angioplasty followed by stenting, which
might have increased the relative incidence of
embolization in the conventional-PCI group.
In addition, current guidelines of the Ameri-
can College of Cardiology, the American Heart
Association, and the Society for Cardiovascular
Angiography and Interventions emphasize the
door-to-balloon time as the primary temporal
marker of quality. If strategies involving throm-
bus extraction evolve to become a primary re-
perfusion strategy, quality indicators must en-
compass reperfusion by multiple methods,
specifically balloon inflation or catheter place-
ment through the occlusion as interchangeable
markers of reperfusion.
Potential adverse issues aside, on the basis of
the data of Svilaas et al., thrombus extraction is
conceptually sound and appears to reduce the
risk among patients undergoing primary PCI.
With the current low risk of death associated

with early reperfusion in patients with acute myo-
cardial infarction, refinements can be expected
to make only small, albeit clinically significant,
improvements in outcome. Thrombus aspiration
appears to be such a favorable improvement.
No potential conflict of interest relevant to this article was re-
ported.
From the Virginia Commonwealth University Pauley Heart Cen-
ter, Medical College of Virginia Hospitals, Virginia Common-
wealth University, Richmond.
Falk E. Plaque rupture with severe pre-existing stenosis pre-
cipitating coronary thrombosis: characteristics of coronary ath-
erosclerotic plaques underlying fatal occlusive thrombi. Br Heart
J 1983;50:127-34.
Davies MJ, Thomas A. Thrombosis and acute coronary-
related lesions in sudden cardiac ischemic death. N Engl J Med
1984;310:1137-40.
DeWood MA, Spores J, Notske R, et al. Prevalence of total
coronary occlusion during the early hours of transmural myo-
cardial infarction. N Engl J Med 1980;303:897-902.
Vetrovec GW, Cowley MJ, Overton H, Richardson DW. Intra-
coronary thrombus in syndromes of unstable myocardial ische-
mia. Am Heart J 1981;102:1202-8.
Vetrovec GW, Leinbach RC, Gold HK, Cowley MJ. Intracoro-
nary thrombolysis in syndromes of unstable ischemia: angio-
graphic and clinical results. Am Heart J 1982;104:946-52.
Gruntzig A. Transluminal dilatation of coronary-artery ste-
nosis. Lancet 1978;1:263.
Rentrop KP, Blanke H, Karsch KR, Kreuzer H. Initial experi-
ence with transluminal recanalization of the recently occluded

infarct-related coronary artery in acute myocardial infarction
— comparison with conventionally treated patients. Clin Car-
diol 1979;2:92-105.
1.
2.
3.
4.
5.
6.
7.
Copyright © 2008 Massachusetts Medical Society. All rights reserved.
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n engl j med 358;6 www.nejm.org february 7, 2008
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Nallamothu BK, Bradley EH, Krumholtz HM. Time to treat-
ment in primary percutaneous coronary intervention. N Engl J
Med 2007;357:1631-8.
Poli A, Fetiveau R, Vandoni P, et al. Integrated analysis of
myocardial blush and ST-segment elevation recovery after suc-
cessful primary angioplasty: real-time grading of microvascular
reperfusion and prediction of early and late recovery of left ven-
tricular function. Circulation 2002;106:313-8.
Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspira-
tion during primary percutaneous coronary intervention. N Engl
J Med 2008;358:557-67.
8.
9.
10.
Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycopro-

tein Ib/IIIa receptor blockade on recovery of coronary flow and
left ventricular function after placement of coronary-artery
stents in acute myocardial infarction. Circulation 1998;98:
2695-701.
Abbate A, Bussani R, Biondi-Zoccai GG, et al. Infarct-related
artery occlusion, tissue markers of ischaemia, and increased ap-
optosis in the peri-infarct viable myocardium. Eur Heart J 2005;
26:2039-45.
Copyright © 2008 Massachusetts Medical Society.
11.
12.
Pharmacogenomic Biomarkers for Prediction
of Severe Adverse Drug Reactions
Magnus Ingelman-Sundberg, Ph.D., B.Sc.Med.
The accumulating knowledge of human genomic
variation is being used for the development of
personalized medicine, with the aims of de-
creasing the number of adverse drug reactions
and increasing the efficacy of drug treatment.
Considerable pharmacogenomic research has fo-
cused on understanding the molecular mecha-
nisms behind adverse drug reactions and find-
ing biomarkers that identify people at risk.
Serious adverse drug reactions have been
shown to cause or contribute to 6 to 7% of all
hospitalizations, a 2-day increase in the average
length of hospitalization, and 100,000 deaths
annually in the United States — and may, ac-
cording to some estimates, cost about as much
as the drug treatment itself.

1
During the period
1998–2005, the numbers of reported adverse drug
reactions and deaths related to such reactions
have increased, both by a factor of about 2.6.
2

Adverse drug reactions are also a major problem
during the development of a drug. In total, ap-
proximately 4% of all new medical agents are
withdrawn from the market owing to adverse
drug reactions.
1
During the period 1995–2005,
at least 34 drugs were withdrawn, mainly as a
result of hepatotoxic or cardiotoxic effects — no-
tably, cerivastatin, nefazodone, rofecoxib (Vioxx),
terfenadine, and troglitazone.
3
The search for pharmacogenomic biomarkers
that could be used to identify patients at increased
risk for drug-related toxic effects has often focused
on variation within genes encoding drug-metab-
olizing enzymes. Altered enzymatic activity can
lead to elevated levels of the substrate drug, or
alternatively, increased amounts of a reactive me-
tabolite, either of which could have toxic effects.
For immune-mediated toxic effects, much fo-
cus has been placed on the major-histocompati-
bility-complex class I genes. A review of pharma-

cogenomic biomarkers reveals only a limited
number of potentially useful examples (
Table 1
),
with the highest specificity seen among the HLA
allelic variants. Thus, many more biomarkers
remain to be identified. Unfortunately, much
of the existing research in this area has been
hampered by limitations in study design, such as
poorly defined case and control groups, the use
of retrospective and nonblind study protocols,
and nonoptimal selection of gene variants. In
addition, polygenic influences on many adverse
drug reactions, instances of treatment with mul-
tiple drugs, and variation in the severity of clini-
Table 1. Pharmacogenomic Biomarkers as Predictors of Adverse Drug
Reactions.
Gene or Allele Relevant Drug
Specificity
of Biomarker
Percent of Patients
with an Adverse
Reaction to Drug*
TPMT (mutant)
6-Mercaptopurines Very good 1–10
UGT1A1*28 Irinotecan Good 30–40
CYP2C9 and
VKORC1
Warfarin† Good 5–40
CYP2D6 (mutant)

Tricyclic anti-
depressants
Relatively good 5–7
HLA-B*5701 Abacavir Very good 5–8
HLA-B*1502 Carbamazepine Very good 10
HLA-DRB1*07
and DQA1*02
Ximelagatran Good 5–7
* Percentages are of affected whites except that for HLA-B*1502, which is the
percentage of affected Asians.
† Carriage of the CYP2C9 and VKORC1 alleles affects warfarin dosing.
Copyright © 2008 Massachusetts Medical Society. All rights reserved.
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The

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1706

editorial

Infection, Antibiotics, and Atherothrombosis —
End of the Road or New Beginnings?

Jeffrey L. Anderson, M.D.

Two large, high-quality, and convincingly negative
clinical trials for the secondary prevention of coro-
nary heart disease,

1,2

published in this issue of the

Journal,

raise questions as to whether we are at the
end of the road or should move on to new begin-
nings as we explore the hypothesis that infection
plays a role in atherosclerosis. Evidence that vascu-
lar inflammation is an important mechanism in-
volved in all stages of atherogenesis continues to
accumulate. Such evidence has legitimately raised
the question of whether infection is one of the in-
flammatory stimuli that operate in the pathophysi-
ology of atherothrombosis, either locally, within
vascular tissue, or systemically, through inflamma-

tory mediators.

3

Furthermore, data from animal
models and seroepidemiologic and pathological
observations have raised the possibility that

Chla-
mydia pneumoniae,

a species of intracellular gram-
negative bacterium, might be an infectious vector
of atherogenesis and, hence, a target for therapy.

C. pneumoniae

is an obligate microbe that common-
ly causes respiratory infection, is frequently found
in atherosclerotic plaque, and is susceptible to mac-
rolide and quinolone antibiotics.

3

Indeed, studies
in animal models have demonstrated that

C. pneu-
moniae

can accelerate atherogenesis and that anti-
biotics can suppress it.

3

Initial clinical studies from the United King-
dom

4

and Argentina

5

reported that antibiotic ther-
apy might lead to large reductions in secondary
cardiovascular risk in patients with stable coronary
heart disease or acute coronary syndromes. Subse-
quent work by my colleagues and me

6

and, later, by
others in studies of intermediate size

7-10

failed to
confirm a large benefit (Table 1). However, these
studies left open the possibility of limited-to-mod-

erate clinical benefits (i.e., risk reductions of 20 to
30 percent), which would require testing in trials
involving several thousand patients.
Subsequently, the Weekly Intervention with
Zithromax for Atherosclerosis and its Related
Disorders (WIZARD) study, a megatrial involving
7724 patients with stable disease who had a histo-
ry of myocardial infarction and serologic evidence
of

C. pneumoniae,

failed to find a long-term benefit,
even though a favorable trend was noted during and
shortly after a three-month course of treatment with
azithromycin.

11

Similarly, with regard to acute cor-
onary syndromes, the Azithromycin in Acute Cor-
onary Syndromes study (AZACS), a moderately large
trial involving 1439 patients, did not show a bene-
fit, but its conclusions were limited by its short du-
ration of therapy (azithromycin for five days).

10

To these earlier trials, the Azithromycin and
Coronary Events Study (ACES)

1

and the Pravastatin
or Atorvastatin Evaluation and Infection Therapy–
Thrombolysis in Myocardial Infarction (PROVE IT–
TIMI) trial

2

add major new information. The ACES
trial

1

which was sponsored by the National Insti-
tutes of Health, was a randomized, double-blind,
placebo-controlled trial involving 4012 adults with
stable coronary heart disease who were enrolled
without regard to their serologic

C. pneumoniae

sta-
tus. Participants received weekly azithromycin or
placebo for one year. The mean period of follow-
up was four years. The primary end point, a compos-
ite of death due to coronary heart disease, nonfatal
myocardial infarction, hospitalization for unstable
angina, or coronary revascularization, occurred in

22.4 percent of the patients who received placebo
and 22.3 percent of those who received azithromy-
cin — a relative-risk reduction of less than 1 per-
cent, with narrow confidence intervals (¡13 percent
to 13 percent). Furthermore, unlike the WIZARD
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1707

trial, ACES showed no trend toward an early bene-
fit during the period of active therapy. Individual
components of the primary end point and the sec-
ondary end points were unaffected. The frequency
of gastrointestinal side effects increased to some
extent. The investigators concluded that azithromy-
cin, even when given regularly for one year, is inef-
fective for the prevention of secondary cardiovas-
cular events.
The PROVE IT–TIMI study,

2

a double-blind,
randomized, two-by-two factorial trial involving
4162 patients at multiple centers, addressed two
complementary issues: the secondary prevention
of cardiovascular events after acute coronary syn-
dromes and, in addition, antibiotic therapy with
gatifloxacin, a potentially more efficacious antibi-
otic than azithromycin. Results of the first random-
ization, which involved intensive as compared with
moderate reductions in lipid levels, have been re-
ported previously. The second randomization com-
pared the results of treatment with gatifloxacin and
placebo, given, after initial dosing, for 10 days each
month during a follow-up period of 18 to 32 months
(mean, 24 months).
The primary end point — a composite of death
from any cause, myocardial infarction, unstable
angina requiring hospitalization, revascularization
performed at least 30 days after randomization, or
stroke — occurred in 25.1 percent of the patients
who received placebo and 23.7 percent of those
who received gatifloxacin; this represented a 5 per-
cent reduction in the hazard ratio, an insignificant
difference with narrow confidence intervals (¡8 per-
cent to 16 percent). No benefits were noted in any
major subgroup, including those stratified accord-
ing to the level of C-reactive protein or

C. pneumoniae

seropositivity. Antibiotic therapy reduced the inci-
dence of upper respiratory infection, but it caused
more gastrointestinal side effects, and it did not
reduce C-reactive protein levels. The investigators
concluded that gatifloxacin, even when given over
the long term, is ineffective for the secondary pre-
vention of cardiovascular events after acute coro-
nary syndromes.
The expectation that these antibiotic trials might
provide insight into the validity (or fallacy) of the
infection hypothesis must be tempered by consider-
ation of important limitations and uncertainties.
Such drawbacks suggest that the hypothesis does
not easily lend itself to proof or disproof accord-
ing to Koch’s classic postulates. Even if studies
yield positive results, the hypothesis is not entirely
proved, because nonspecific antiinflammatory ef-
fects or antiinfective actions against other organ-
isms might be operative. Antibiotic intervention
targeted to

C. pneumoniae

through the prevention of

* The studies used a variety of inclusion criteria and exclusion criteria and tested various doses and durations of therapy.
† ACADEMIC denotes Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infarction with Chlamydia,
ISAR-3 Intracoronary Stenting and Antibiotic Regimen 3, CLARIFY Clarithromycin in Acute Coronary Syndrome Patients

in Finland, ANTIBIO Antibiotic Therapy after Acute Myocardial Infarction, AZACS Azithromycin in Acute Coronary Syn-
drome, WIZARD Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, ACES Azithromycin
and Coronary Events Study, and PROVE IT–TIMI Pravastatin or Atorvastatin Evaluation and Infection Therapy–Throm-

bolysis in Myocardial Infarction.

Table 1. Large and Intermediate-Size Trials of Antibiotics for the Secondary Prevention of Coronary Heart Disease.*
Trial† Year
No.
of Patients Indication or Setting Antibiotic
Duration of
Therapy and
Follow-up Result

ACADEMIC

6

2000
302 Coronary heart disease Azithromycin 3 mo; 2 yr Negative
ISAR-3

7

2001
1020 Post–percutaneous coronary
intervention
Roxithromycin 1 mo; 6–12 mo Negative
CLARIFY

8

2002
148 Acute coronary syndromes Clarithromycin 3 mo; 18 mo Trend
ANTIBIO

9

2003
872 Myocardial infarction Roxithromycin 6 wk; 12 mo Negative
AZACS

10

2003
1450 Acute coronary syndromes Azithromycin 5 days; 6 mo Negative
WIZARD

11

2003
7724 Coronary heart disease Azithromycin 3 mo; 3 yr Negative
ACES

1

2005
4012 Coronary heart disease Azithromycin 12 mo; 4 yr Negative
PROVE IT–TIMI

2

2005
4162 Acute coronary syndromes Gatifloxacin 18 mo; 24 mo Negative
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typical periodontal, respiratory tract, and urinary
tract infections could prevent the progression of
cardiovascular disease if the treatment suppressed
infection-related, circulating inflammatory media-
tors of atherothrombosis. Indeed, that there is an
infection-related increase in the risk of myocardial

infarction and stroke was strongly supported by a
recent study in the

Journal

.

12

Moreover, tetracyclines
(e.g., minocycline and doxycycline), which have
been touted for the treatment of a variety of inflam-
matory conditions, including rheumatoid arthri-
tis, chronic periodontitis, and acute coronary syn-
dromes, may have anti–matrix metalloproteinase
activity in doses even lower than those for antimi-
crobial uses; this activity could represent a mecha-
nism of potential benefit unrelated to antibiotic
effects.
Negative outcomes, which have been noted in
most of the recent studies (Table 1), might be ex-
plained not only by the use of an incorrect hypoth-
esis (i.e., that infection is not atherogenic) but
also by an inadequate sample size or by the use of
an ineffective antibiotic regimen. The ACES and
PROVE IT–TIMI trials address most of the concerns
about study design, including sample size (and its
effect on the power of the study) and the duration
of therapy, but they leave open the possibility of
ineffectiveness. Indeed, Gieffers et al. found that

C. pneumoniae

infection in vitro in monocytes from
healthy volunteers or in vivo in circulating mono-
cytes from patients who had been treated for coro-
nary heart disease was refractory to azithromycin

13

:
antibiotic treatment did not inhibit chlamydial
growth within monocytes, and after withdrawal of
antibiotic therapy,

C. pneumoniae

could be cultured
from monocyte cell lines. In contrast, antibiotics
eliminated

C. pneumoniae

from epithelial cells.

13

Whether gatifloxacin would perform better is un-
certain. Hence, whereas ACES and PROVE IT–TIMI,
together with other studies (Table 1), appear con-

clusively to eliminate azithromycin, gatifloxacin,
and related agents as useful preventive therapies for
secondary cardiovascular events, they leave open the
possibility that novel antibiotics with more potent
bactericidal activity against intracellular microbes
could lead to a different outcome.

14

However, event
rates in ACES and PROVE IT–TIMI were unaffected
even during the long periods of ongoing (and pre-
sumably suppressive) therapy. Hence, another rea-
son for a negative trial result should be considered:
that an advanced, unmodifiable stage of disease was
chosen for study.
A large body of negative clinical-trial results sug-
gests that antibiotics effective for clinical

C. pneu-
moniae

infection are not useful for secondary pre-
vention (Table 1). The testing of these agents for
the treatment of advanced coronary heart disease
appears to be at the end of the road. On the other
hand, evidence that infection can be a stimulus for
atherothrombosis continues to mount.

3,12,15

These
positive observations suggest that we should re-
think, revise, and reformulate hypotheses and re-
search strategies — that is, that we should begin
anew, rather than discard the possibility of infec-
tion as an etiologic factor. We should focus on ex-
panding our limited knowledge base with regard to
proatherogenic mechanisms (including viral vec-
tors); we should include sophisticated preclinical
models in our research plans; and, when appro-
priate, we should return to the clinical arena with
trials that better select target patients (e.g., those at
an earlier stage of atherosclerosis or those with bet-
ter markers of latent or active infection or with a high
total or viral burden

3

) and interventions, including
novel antiinfective agents and vaccines.

3,14,15

Mean-
while, standard antibiotics do not work for the sec-
ondary prevention of cardiovascular heart disease.

From the University of Utah School of Medicine, LDS Hospital,
Salt Lake City.

1.

Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for
the secondary prevention of coronary events. N Engl J Med 2005;
352:1637-45.

2.

Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treat-
ment of

Chlamydia pneumoniae

after acute coronary syndrome.
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