Atherothrombosis — Wave Goodbye to Combined Anticoagulation and Antiplatelet Therapy? ppt

residents who were at least 40 years of age in 2000 approximately 8.5 million persons had peripheral arterial disease.2 Although claudication is frequent in and seriously limits the life

Trang 1

Atherothrombosis — Wave

Goodbye to Combined

Anticoagulation and

Antiplatelet Therapy?

Trang 2

n engl j med 357;3 www.nejm.org july 19, 2007 293

e d i t o r i a l s

Atherothrombosis — Wave Goodbye to Combined

Anticoagulation and Antiplatelet Therapy?

Emile R Mohler III, M.D

Atherothrombosis describes the occurrence of both

atherosclerosis and thrombosis in an artery, a

common feature of peripheral arterial disease.1

It is estimated that 1 in 16 U.S residents who were

at least 40 years of age in 2000 (approximately 8.5

million persons) had peripheral arterial disease.2

Although claudication is frequent in and seriously

limits the lifestyle of patients with peripheral

ar-terial disease, the most common cause of death

in these patients is from coexisting

atherothrom-bosis in the coronary or carotid arteries, resulting

in a risk of myocardial infarction or stroke that is

three times as high as the risk in patients without

peripheral arterial disease.3 It is estimated that

half of patients with peripheral arterial disease

have concomitant coronary artery disease.4 The

Re-duction of Atherothrombosis for Continued Health

(known as REACH) Registry, which follows a

co-hort of approximately 68,000 patients, showed that

the annual rate of myocardial infarction, stroke,

or death from cardiovascular causes for patients

with peripheral arterial disease was 5%.5

Two recently published clinical guidelines for

treating peripheral arterial disease, the American

College of Cardiology and American Heart

As-sociation guidelines6 and the Transatlantic

Con-sensus Document on Peripheral Arterial Disease

(often called TASC II),7 recommend long-term

antiplatelet treatment to prevent cardiovascular

events This recommendation is based on reports

such as the Antithrombotic Trialists’

Collabora-tion meta-analysis8 and prospective studies such

as the Clopidogrel versus Aspirin in Patients at

Risk of Ischemic Events trial,9 which showed that

patients with peripheral arterial disease who took

antiplatelet drugs had a reduction of

approximate-ly 25% in the risk of cardiovascular events

Unfor-tunately, however, many patients in these studies still had a cardiovascular event despite antiplate-let treatment

Since the first trial of oral dicumarol in clinical practice, by Allen et al.,10 the mainstay of treat-ment for thrombosis in the venous system has been anticoagulation Therefore, the addition of oral anticoagulation to antiplatelet treatment might

be presumed to be beneficial for the management

of atherothrombosis in patients with peripheral

arterial disease as well In this issue of the

Jour-nal, Anand et al report the results of the

War-farin Antiplatelet Vascular Evaluation (WAVE) trial (ClinicalTrials.gov number, NCT00125671), which addressed this hypothesis.11 After a mean

follow-up of 35 months, patients randomly assigned to receive an oral anticoagulant plus an antiplatelet drug had an absolute but nonsignificant reduc-tion in the combined end point of myocardial infarction, stroke, or death from cardiovascular causes as compared with patients assigned to an-tiplatelet treatment alone A significant increase

in bleeding complications occurred in the com-bined-therapy group as compared with the single-therapy group

Why did the addition of an oral anticoagulant

to antiplatelet therapy not provide beneficial re-duction of cardiovascular events in patients with peripheral arterial disease? Part of the answer to this question may be found in the differences in thrombus formation between the arterial and nous systems The low-flow and low-pressure ve-nous system is susceptible to reduced blood flow (stasis) and systemic activation of the coagula-tion cascade, as Virchow described more than

150 years ago, which predisposes to a thrombus even in a nonstenotic vessel Most venous

Trang 3

T h e ne w e ngl a nd jou r na l o f m e dicine

bi consist predominantly of red cells enmeshed in fibrin and contain relatively few platelets; hence, they have been described pathologically as “red thrombi.”

In contrast, in the high-flow and high-pressure arterial system, thrombi form under the influence

of local shear forces, platelet activation, and ex-posure to thrombogenic substances on damaged vascular surfaces Arterial thrombi, referred to as

“white thrombi,” typically are composed predomi-nantly of platelets with relatively little fibrin or red-cell accumulation Thus, it is plausible to expect that an anticoagulant would be used to prevent venous thromboemboli, whereas an an-tiplatelet agent would be used to prevent arterial thrombosis

However, the differences between arterial and

venous thrombosis are not absolute, since the two types of thrombi are composed, to different de-grees, of platelets and fibrin, red cells and leu-kocytes As shown in Figure 1, platelet and co-agulation activation are inseparable, reciprocally self-amplifying processes The activation of plate-lets occurs in areas of atherosclerotic plaques where procoagulant substances are generated on cell surfaces Combined with non–platelet-depen-dent local activators of the coagulation cascade, these culminate in the formation of thrombin, which is itself a potent stimulus for further plate-let activation In the WAVE trial, Anand et al investigated whether the addition of an antico-agulant would provide additional benefit by in-terfering with fibrin-driven coagulation

The Department of Veterans Affairs

Coopera-C O L O R F I G U R E 07/02/07 Draft 3

1

SBL

Mohler

Author Fig # Title ME DE Artist

Activated platelet

Activated platelet Red cell

Activation

Clopidogrel Ticlopidine

Fibrinogen Fibrinogen

Endothelial cell

Plaque rupture

Aspirin

GP IIb/IIIa receptor

Degranulation

Platelet agonists ADP ATP Serotonin Calcium Magnesium

Thrombin Serotonin Epinephrine Collagen

To neighboring platelet Thromboxane A2

COX-1 ADP

Figure 1 Atherosclerotic Plaque Disruption and Platelet Activation.

The disruption of an atherosclerotic plaque results in exposure of highly thrombogenic material In patients with atherothrombosis, the activation of platelets and coagulation are inseparable, reciprocally self-amplifying processes The inhibition of platelets alone does not block the coagulation activators GP denotes glycoprotein, ADP adenosine diphosphate, and COX-1 cyclooxygenase-1

Trang 4

tive Study was another large, randomized trial

that tested combined oral anticoagulation and

an-tiplatelet therapy in patients with peripheral

arte-rial disease.12 In this smaller trial (831 patients),

there were 133 deaths in the combined-treatment

group and 95 deaths in the group receiving

aspi-rin alone One other study, the Dutch Bypass Oral

Anticoagulants or Aspirin study, evaluated the

efficacy of oral anticoagulants as compared with

aspirin (there was no combination-treatment

group) after infrainguinal bypass surgery.13 There

was no difference between the two groups in the

secondary end points of death from vascular

causes or death from any cause

Several clinical trials have been conducted to

assess the efficacy of the administration of oral

anticoagulants in addition to aspirin to patients

who have survived a myocardial infarction The

re-sults of this combined approach have been mixed

Two studies evaluating oral anticoagulation with a

relatively low international normalized ratio (INR)

showed no benefit of combination therapy as

com-pared with aspirin alone.14,15 A study of 3630

participants, reported in the Journal in 2002 (the

Warfarin, Aspirin, Reinfarction Study [WARIS II]),

showed that warfarin (INR >2.0), alone or in

com-bination with aspirin, was superior to aspirin

alone in reducing the incidence of composite

events after a myocardial infarction.16 Similar to

the WAVE study, WARIS II showed that

antico-agulation therapy was associated with a high risk

of bleeding, which has limited the use of this

approach in routine practice

The totality of evidence shows clearly that the

addition of an anticoagulant to an antiplatelet

drug results in increased rates of bleeding

com-plications In the WAVE trial, patients with known

risk factors, such as long-term use of

nonsteroi-dal antiinflammatory drugs, previous

gastrointes-tinal bleeding, or recent stroke were excluded from

participation to minimize the risk of bleeding

De-spite this restriction, nearly 30% of patients

dis-continued oral anticoagulation therapy during

fol-low-up, many (126 of 319) because of bleeding

episodes

Furthermore, the risks of serious bleeding and

hemorrhagic stroke in the WAVE trial were

high-er than those seen in the post–myocardial

infarc-tion studies that used combined treatment.16

Anand et al speculate that patients with

periph-eral arterial disease who are treated with an oral

anticoagulant may be more likely to have bleeding

complications, consistent with the findings of the

Dutch study of bypass graft patency.13 The reasons for the increased propensity for bleeding that has been seen in patients with peripheral arterial dis-ease are unknown, but potentially include ad-vanced age, more widespread atherosclerosis, de-creased integrity of the vessel wall, and increasing microvascular fragility Although there may be some patients for whom these risks are lower, re-sulting in a risk–benefit ratio that favors adding

an anticoagulant, the data from the WAVE trial do not provide any evidence in this regard

At this time, the data indicate that antiplatelet treatment alone affords a better outcome than does combined therapy with an anticoagulant in the long-term management of peripheral arterial disease Further information on the pathobiologic basis for bleeding in patients with peripheral ar-terial disease is needed to develop successful clini-cal strategies to prevent bleeding and to devise safer antiplatelet and anticoagulant drugs

Dr Mohler reports receiving lecture fees from Bristol-Myers Squibb, Sanofi, and Astra-Zeneca and grant support from Bristol-Myers Squibb and Sanofi No other potential conflict of interest relevant to this article was reported.

From the Department of Medicine, Cardiovascular Division, Sec-tion of Vascular Medicine, University of Pennsylvania School of Medicine, Philadelphia.

Mohler ER III, Schafer AI Atherothrombosis: disease initia-tion, progression and treatment In: Lichtman MA, Kipps TJ, Kaushansky K, Beutler E, Seligsohn U, Prchal JT, eds Williams hematology 7th ed New York: McGraw-Hill, 2006:2067-88.

Allison MA, Ho E, Denenberg JO, et al Ethnic-specific prev-alence of peripheral arterial disease in the United States Am J Prev Med 2007;32:328-33.

Mohler ER Therapy insight: peripheral arterial disease and diabetes — from pathogenesis to treatment guidelines Nat Clin Pract Cardiovasc Med 2007;4:151-62.

Hirsch AT, Criqui MH, Treat-Jacobson D, et al Peripheral arterial disease detection, awareness, and treatment in primary care JAMA 2001;286:1317-24.

Bhatt DL, Steg PG, Ohman EM, et al International preva-lence, recognition, and treatment of cardiovascular risk factors

in outpatients with atherothrombosis JAMA 2006;295:180-9.

Hirsch AT, Haskal ZJ, Hertzer NR, et al ACC/AHA 2005 practice guidelines for the management of patients with periph-eral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American As-sociation for Vascular Surgery/Society for Vascular Surgery, So-ciety for Cardiovascular Angiography and Interventions, SoSo-ciety for Vascular Medicine and Biology, Society of Interventional Ra-diology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management

of Patients with Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Reha-bilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation Circulation 2006;113:e463-e654.

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG Inter-Society Consensus for the management of periph-eral arterial disease (TASC II) J Vasc Surg 2007;45:Suppl S:S5-S67.

Antithrombotic Trialists’ Collaboration Collaborative

meta-1.

2.

3.

4.

5.

6.

7.

8.

Trang 5

analysis of randomised trials of antiplatelet therapy for prevention

of death, myocardial infarction, and stroke in high risk patients

BMJ 2002;324:71-86 [Erratum, BMJ 2002;324:141.]

CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Lancet 1996;348:1329-39.

Allen EV, Barker NW, Waugh JM A preparation from spoiled sweet clover [3,30′-methylene-bis-(4-hydroxy-coumarin)] which prolongs coagulation and prothrombin time of the blood: a clini-cal study JAMA 1942;120:1009-15.

The Warfarin Antiplatelet Vascular Evaluation Trial Investi-gators Oral anticoagulant and antiplatelet therapy and periph-eral arterial disease N Engl J Med 2007;357:217-27.

Johnson WC, Williford WO Benefits, morbidity, and mortality associated with long-term administration of oral anticoagulant therapy to patients with peripheral arterial bypass procedures:

a prospective randomized study J Vasc Surg 2002;35:413-21.

9.

10.

11.

12.

Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (the Dutch Bypass Oral Anticoagu-lants or Aspirin Study): a randomised trial Lancet

2000;355:346-51 [Erratum, Lancet 2000;355:1104.]

Coumadin Aspirin Reinfarction Study (CARS) Investigators Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction Lancet 1997;350:389-96 Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi

P Department of Veterans Affairs Cooperative Studies Pro-gram Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study Circulation 2002;105: 557-63.

Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H Warfarin, aspirin, or both after myocardial infarction N Engl J Med 2002;347:969-74.

13.

14.

15.

16.

Anti-TNF Antibodies for Crohn’s Disease —

In Pursuit of the Perfect Clinical Trial

James D Lewis, M.D., M.S.C.E

For decades, many patients with Crohn’s disease required prolonged courses of corticosteroids, re-peated surgeries, or both, despite treatment with 5-aminosalicylic acid (mesalamine) or immuno-modulators such as azathioprine The introduction

of infliximab, the first antibody against tumor necrosis factor α (TNF-α), dramatically changed the treatment of patients with Crohn’s disease.1 Administered as an intermittent parenteral

thera-py, infliximab proved efficacious in patients whose condition was resistant to treatment, and the drug

is widely used for such patients However, the in-fliximab experience served to reinforce the adage that there often is much to be learned about new medications We soon discovered that patients fared better with maintenance therapy.2 Likewise, infliximab reminded us that effective therapies rarely come without risks.3

Recently, adalimumab, another anti–TNF-α an-tibody, was approved by the Food and Drug Ad-ministration for the treatment of Crohn’s disease

Certolizumab pegol, a pegylated humanized Fab′

fragment of an anti–TNF-α monoclonal antibody, has also been under development The results of two large-scale clinical trials of certolizumab, Peg-ylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy 1 and 2 (PRECISE 1 and PRECISE 2),4,5 are reported in this issue of

the Journal.

The two double-blind, placebo-controlled trials have many features in common and one

unique-ly distinguishing feature Both trials shared the following elements: they enrolled patients with moderate-to-severe Crohn’s disease, were

conduct-ed in more than 140 clinical centers in multiple countries, used the Crohn’s Disease Activity Index

to assess disease activity and response to therapy, followed patients for 26 weeks, used the same dose of certolizumab, and used stratified random-ization according to whether the C-reactive pro-tein (CRP) level was at least 10 mg per liter In addition, the clinical characteristics of the pa-tients who were enrolled in the two trials were nearly identical The major difference was that in the PRECISE 1 study (ClinicalTrials.gov number, NCT00152490), patients were randomly assigned

to receive either certolizumab or placebo at the start of the trial, whereas in the PRECISE 2 study (NCT00152425), all patients received three doses

of certolizumab and then those who had a re-sponse were assigned either to continue certoli-zumab therapy or to receive placebo

The data from the PRECISE 2 trial are com-pelling, showing that certolizumab maintenance therapy prevents relapse in patients who have a response to an initial induction regimen with the drug, regardless of the baseline CRP level The data from the PRECISE 1 trial support the con-clusion that certolizumab is efficacious in improv-ing clinical symptoms of Crohn’s disease in both the short term (6 weeks) and the intermediate term (26 weeks) However, the trial did not show

Trang 6

n engl j med 357;15 www.nejm.org october 11, 2007 1543

e d i t o r i a l s

Primary Prevention of Coronary Artery Disease

Michael J Domanski, M.D

The development and progression of

atheroscle-rosis is an intricate inflammatory process

depen-dent on intimal entry of low-density lipoprotein

(LDL) cholesterol Although myriad genetic and

environmental factors modulate this process, the

centrality of LDL cholesterol to the physiology of

plaque genesis, progression, and instability leads

to the notion that reducing serum LDL cholesterol

might be an effective way to mitigate or even

prevent the disease

A number of clinical trials have unequivocally

demonstrated the clinical utility of lowering LDL

cholesterol levels The three major

cholesterol-lowering trials carried out in people without a

his-tory of coronary events (primary prevention trials)

include the West of Scotland Coronary Prevention

Study (WOSCOPS),1 the Air Force/Texas

Coro-nary Atherosclerosis Prevention Study,2 and the

Anglo-Scandinavian Cardiac Outcomes Trial —

Lipid Lowering Arm.3 Of these trials, WOSCOPS

entered people with the highest levels of LDL

cho-lesterol A total of 6595 men, aged 45 to 64 years,

without a prior myocardial infarction, who had

a mean plasma LDL cholesterol level of 192 mg

per deciliter (5.0 mmol per liter), were randomly

assigned to receive 40 mg of pravastatin daily or

placebo Pravastatin lowered serum LDL

choles-terol by 26% as compared with no lowering with

placebo After an average follow-up of 4.9 years,

there was a statistically significant difference in

the rate of the primary end point, nonfatal

myo-cardial infarction or death from coronary heart

disease, between the pravastatin group and the

placebo group (5.5% vs 7.9%, P<0.001)

In this issue of the Journal, Ford and colleagues4

present the results of a 10-year follow-up of

WOSCOPS that included more than 90% of the

original trial survivors The authors found that

over the post-trial follow-up period, when treat-ment was under the control of the patient and his physician, there was a statistically significant re-duction in death from coronary heart disease or nonfatal myocardial infarction, from 10.3% in the group originally assigned to placebo to 8.6% in the group originally assigned to pravastatin Rates

of death from cardiovascular causes and mortal-ity from any cause were not significantly lower in the patients assigned to pravastatin during post-trial follow-up; however, significant reductions were maintained for the entire study interval (in-cluding both the trial and the post-trial periods)

There was no excess of cancer deaths associated with pravastatin

There are some weaknesses in the study Per-haps most important, there was a statistically sig-nificant (though small) difference between the original pravastatin and placebo groups in the per-centage of patients taking statins during

follow-up Patients did not receive specific advice with regard to statin therapy after the trial but were treated at the discretion of their own physicians

This shortcoming does not detract from the im-portant message of this study, which is that the beneficial effect of statin therapy is durable over the long term

There should no longer be any doubt that the reduction of LDL cholesterol levels has a role in the prevention and treatment of coronary heart disease The central remaining question is what is the greatest therapeutic benefit that can be gained, particularly for primary prevention of the emer-gence of clinical coronary disease? This question has two parts: How early should treatment be started? And how low should the target LDL cho-lesterol level be set?

The data from Ford and colleagues provide

Trang 7

some tantalizing insights into the first question

The fact that the group originally assigned to pravastatin had better outcomes, even after years

of similar statin treatment of the placebo group during the post-trial period, suggests the impor-tance of duration of therapy in determining out-come Earlier initiation of therapy appears to have durably mitigated the atherosclerotic process

Recently published data from Cohen and col-leagues5 provide strong support for the notion that earlier treatment, even among asymptomatic indi-viduals, may reduce the incidence of clinical coro-nary heart disease These investigators examined the effect of two nonsense mutations of the gene coding for the serine protease PCSK9, the result-ing inactivation of which lowers the level of LDL cholesterol One of these mutations was found in 2.6% of blacks in the Atherosclerosis Risk in Communities Study 6,7 and was associated with a 28% reduction in serum LDL cholesterol The other was found in 3.2% of white subjects and was associated with a 15% reduction in serum LDL cholesterol In the black subjects, there was

an 88% reduction in the 15-year coronary event rate, and in the white subjects, a 50% decrease

The decrease in coronary events is far greater than would be expected (on the basis of data from clin-ical trials) from the moderate reductions in cho-lesterol that resulted from mutation of the gene

The data from Cohen and colleagues underscore the possibility that very large reductions in coro-nary heart disease event rates might be achieved, even with modest LDL cholesterol reductions, if brought about early enough in life

What is the optimal target for LDL cholester-ol? Epidemiologic studies demonstrate a strong, graded association of serum LDL cholesterol and the coronary heart disease event rate without any clear indication of a level below which further lowering of LDL cholesterol fails to further re-duce coronary events.8-11 Consistent with the epi-demiologic observations, clinical trials have dem-onstrated a strong, graded relationship between serum LDL cholesterol and coronary events.10 However, even though the few major primary pre-vention trials show a progressive reduction in event rate with decreasing LDL cholesterol, no pri-mary prevention trial provides information about events below an LDL cholesterol level of about

90 mg per deciliter (2.3 mmol per liter), and none

of the trials address the issue in adults in their early to middle years

Interesting data come from studies of hunter-gatherers, Arctic Eskimos, and other civilizations not exposed to the diets and lifestyles of the

“modern” industrialized world In these societies, cholesterol levels remain quite low (with LDL cholesterol in the range of 50 to 70 mg per deci-liter [1.3 to 1.8 mmol per deci-liter]),9 and clinical and postmortem studies show an absence of both the early indications of chronic disease seen in young people in Western societies and the athero-sclerosis seen in older people.12-15 The “Western-ization” of such societies results in development of the same diseases that affect our own,12 a finding that suggests that genetic differences are not the primary reason for the disparity The lowest-risk segment of the population in the Framingham Heart Study is sometimes cited to support the occasionally offered suggestion that only about half of the risk for coronary events results from known coronary risk factors This is somewhat akin to comparing cancer rates in heavy smokers with rates in those who smoke less The “tradi-tional” societies discussed above are far more appropriate comparators Comparisons with these societies offer the intriguing notion that very large reductions in coronary disease might attend pharmacologic achievement of the LDL cholesterol levels characteristic of those popu-lations

Is there an LDL cholesterol level below which incident coronary heart disease is essentially eliminated, or does the relationship approach an asymptote at some nonzero risk level? The geom-etry of the relationship of clinical coronary events and LDL cholesterol, in patients without prior coronary events, has not been studied at LDL cholesterol levels anywhere close to those achiev-able with modern therapy If there is a nonzero asymptote, what is it? We can delineate the geom-etry by performing clinical trials with existing medications The geometry of the relationship will determine the ultimate impact of lowering LDL cholesterol One possible result is that suffi-cient lowering will reduce the incidence of coro-nary disease to the point that it becomes a rela-tively uncommon diagnosis

The views expressed in this editorial are those of the author and do not necessarily reflect those of the National Heart, Lung, and Blood Institute.

No potential conflict of interest relevant to this article was re-ported.

From the Atherothrombosis and Coronary Artery Disease Branch, National Heart, Lung, and Blood Institute, Bethesda, MD.

Trang 8

Shepherd J, Cobbe S, Ford I, et al Prevention of coronary

heart disease with pravastatin in men with

hypercholesterole-mia N Engl J Med 1995;333:1301-7.

Downs JR, Clearfield M, Weis S, et al Primary prevention of

acute coronary events with lovastatin in men and women with

average cholesterol levels: results of AFCAPS/TexCaPS JAMA

1998;279:1615-22.

Sever PS, Dahlöf B, Poulter NR, et al Prevention of coronary

and stroke events with atorvastatin in hypertensive patients who

have average or lower-than-average cholesterol concentrations,

in the Anglo-Scandinavian Cardiac Outcomes Trial — Lipid

Lower-ing Arm (ASCOT-LLA): a multicentre randomised controlled trial

Lancet 2003;361:1149-58.

Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW,

Cobbe SM Long-term follow-up of the West of Scotland

Coro-nary Prevention Study N Engl J Med 2007;357:1477-86.

Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH Sequence

variations in PCSK9, low LDL, and protection against coronary

heart disease N Engl J Med 2006;354:1264-72.

The ARIC Investigators The Atherosclerosis Risk in

Commu-nities (ARIC) Study: design and objectives Am J Epidemiol 1989;

129:687-702.

Chambless LE, Folsom AR, Sharrett AR, et al Coronary

heart disease risk prediction in the Atherosclerosis Risk in

Com-munities (ARIC) study J Clin Epidemiol 2003;56:880-90.

1.

2.

3.

4.

5.

6.

7.

Stamler J, Daviglus ML, Garside DB, Dyer AR, Greenland P, Neaton JD Relationship of baseline serum cholesterol levels in three large cohorts of younger men to long-term coronary, cardio-vascular, and all-cause mortality and to longevity JAMA 2000;

284:311-8.

O’Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R Op-timal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal J Am Coll Cardiol 2004;43:2142-6.

Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W Serum cholesterol concentration and coronary heart disease in popula-tion with low cholesterol concentrapopula-tions BMJ 1991;303:276-82.

Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial Lancet 2002;360:7-22.

Eaton SB, Konner M, Shostak M Stone agers in the fast lane:

chronic degenerative diseases in evolutionary perspective Am J Med 1988;84:739-49.

Vint F Post-mortem findings in the natives of Kenya E Afr Med J 1937;13:332-40.

Gottmann AW A report of one hundred three autopsies on Alaskan natives Arch Pathol 1960;70:117-24.

Arthaud JB Cause of death in 339 Alaskan natives as deter-mined by autopsy Arch Pathol 1970;90:433-8.

8.

9.

10.

11.

12.

13.

14.

15.

Of Attraction and Rejection — Asthma and the Microbial World

Erika von Mutius, M.D., M.Sc

In the first half of the past century, it was thought

that asthma was precipitated or prolonged by

in-fection and that inin-fection with several bacteria,

including Streptococcus pneumoniae and Haemophilus

influenzae, had a role in asthma.1 Some

investiga-tors had suggested that bacterial allergy or

chron-ic focal infection could be a cause of asthma.2

More recently, population-based studies relating

infections with Chlamydia pneumoniae and

Myco-plasma pneumoniae to asthma severity encouraged

a resurgent debate, but clinical trials involving

various antibiotics failed to demonstrate sustained

clinical benefit.1

To understand this debate we need to consider

asthma and wheeze in children The greatest

in-cidence of wheeze occurs in children under the

age of 4 years.3 A significant proportion of

in-fants with wheeze outgrow symptoms between

2 and 3 years of age, and this wheezing

pheno-type has therefore been referred to as “transient

wheeze.” The remaining children with wheeze

have repeated episodes of airway obstruction

un-til school age, in about half the cohort in

con-junction with allergen sensitization to food and

inhalants.4 In school-age children, eosinophilic

inflammation in the airway is a characteristic

feature of asthma, as it is in adults.5

Because of the difficulty in performing

com-plex physiological studies in young children, we know very little about the pathogenetic processes occurring in the airways of infants and toddlers with wheeze Even less is known about the rela-tion between the progression and remission of symptoms and underlying mechanisms How-ever, some light is shed from studies in which bronchoalveolar lavage was performed in young children with severe wheeze; it is notable that neutrophilic rather than eosinophilic inflamma-tion in the airway has been found at this age.6 Whether these findings reflect certain phenotypes

of severe wheeze that justify invasive bronchos-copy or whether they reflect features of develop-ing asthma is unknown In adults, neutrophilic inflammation in the airway is seen in the context

of asthma exacerbations due to viral infections and in some patients with severe asthma Since viral infections are the predominant triggers of wheeze in young children, they may induce neutro-philic inflammation in the airway and thereby contribute to the development of asthma in chil-dren up to school age

In this issue of the Journal, Bisgaard and

col-leagues7 propose an alternative explanation; that

is, that bacterial colonization of the airways may induce neutrophilic inflammation in the airways and thereby cause asthma In their prospective

Định dạng
Số trang	8
Dung lượng	308,38 KB