Improving Reperfusion in Patients with Myocardial Infarction doc

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 percutane

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Improving Reperfusion in Patients with Myocardial

Infarction

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e d i t o r i a l s

n engl j med 358;6 www.nejm.org february 7, 2008 634

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 studies1,2 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 achievprovid-ed 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 inflarevasculariza-tion 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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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

Fig # Title ME DE

COLOR FIGURE

Version 7

Vetrovec

1 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

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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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 AmeriAmeri-can 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 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 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.

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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 intervenaspira-tion 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.

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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 of Biomarker Specificity

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

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.

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n engl j med 352;16 www.nejm.org april 21, 2005

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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

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

gram-negative bacterium, might be an infectious vector

of atherogenesis and, hence, a target for therapy

common-ly causes respiratory infection, is frequentcommon-ly found

in atherosclerotic plaque, and is susceptible to mac-rolide and quinolone antibiotics.3

Indeed, studies

in animal models have demonstrated that C

anti-biotics can suppress it.3 Initial clinical studies from the United King-dom4

and Argentina5

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 me6

and, later, by others in studies of intermediate size7-10 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

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) trial2 add major new information The ACES trial1 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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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 perper-cent) 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 limitconsider-ations 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.*

No.

Duration of Therapy and

ACADEMIC 6

ISAR-3 7

2001 1020 Post–percutaneous coronary

intervention

Roxithromycin 1 mo; 6–12 mo Negative CLARIFY 8

ANTIBIO 9

AZACS 10

WIZARD 11

ACES 1

PROVE IT–TIMI 2

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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 periodontiarthri-tis, 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

healthy volunteers or in vivo in circulating mono-cytes from patients who had been treated for coro-nary heart disease was refractory to azithromycin13

: 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

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 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 burden3

) 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.

the secondary prevention of coronary events N Engl J Med 2005; 352:1637-45.

N Engl J Med 2005;352:1646-54.

ed Acute coronary syndromes: a companion to Braunwald’s Heart Disease Philadelphia: Saunders, 2003:88-107.

Camm AJ Elevated Chlamydia pneumoniae antibodies, cardiovas-cular events, and azithromycin in male survivors of myocardial infarction Circulation 1997;96:404-7.

Ran-domised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study Lancet 1997;350:404-7.

sec-ondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study Cir-culation 2000;102:1755-60.

Chlamy-dia pneumoniae infection with roxithromycin and effect on neoin-tima proliferation after coronary stent placement (ISAR-3): a ran-domised, double-blind, placebo-controlled trial Lancet 2001;357: 2085-9.

antimicrobial treatment with clarithromycin in acute non-Q-wave coronary syndrome Circulation 2002;105:1555-60.

acute myocardial infarction: a prospective randomized study Circu-lation 2003;107:1253-9.

with azithromycin on recurrent ischaemic events in patients with

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acute coronary syndrome in the Azithromycin in Acute Coronary

Syndrome (AZACS) trial: a randomised controlled trial Lancet 2003;

361:809-13.

the secondary prevention of coronary heart disease events: the

WIZARD study: a randomized controlled trial JAMA 2003;290:

1459-66.

Val-lance P Risk of myocardial infarction and stroke after acute

infec-tion or vaccinainfec-tion N Engl J Med 2004;351:2611-8.

in-fection in circulating human monocytes is refractory to antibiotic treatment Circulation 2001;103:351-6.

activities of rifamycin derivatives ABI-1648 (rifalazil, KRM-1648), ABI-1657, and ABI-1131 against Chlamydia trachomatis and recent clinical isolates of Chlamydia pneumoniae Antimicrob Agents Chemother 2003;47:1135-6.

cardiovascular disease: a new opportunity for prevention and the need for further studies Circulation 2003;108:2730-6.

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