Atherothrombosis — Wave Goodbye to Combined Anticoagulation and Antiplatelet Therapy? n engl j med 357;3 www.nejm.org july 19, 2007 293 e d i t o r i a l s T h e n e w e ngl a n d j o u r na l o f m e d icine 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 guidelines 6 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-analysis 8 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 ve- 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 throm- Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a n d j o u r na l o f m e d icine n engl j med 357;3 www.nejm.org july 19, 2007 294 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- COL O R F I G URE AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully 07/02/07Draft 3 1 SBL Mohler Author Fig # Title ME DE Artist Issue date Activated platelet 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 A 2 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. Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. editorials n engl j med 357;3 www.nejm.org july 19, 2007 295 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, Society 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. Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ngl a n d j o u r na l o f m e d icine n engl j med 357;3 www.nejm.org july 19, 2007 296 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. Copyright © 2007 Massachusetts Medical Society. 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 Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. n engl j med 357;15 www.nejm.org october 11, 2007 1543 e d i t o r i a l s T h e n e w e ngl a n d j o u r na l o f me dicine 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 colleagues 4 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 Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. 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 357;15 www.nejm.org october 11, 2007 1544 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- leagues 5 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 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. Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. editorials n engl j med 357;15 www.nejm.org october 11, 2007 1545 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 concentrations. 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. Copyright © 2007 Massachusetts Medical Society. 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 infection 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- leagues 7 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 Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. . icine Atherothrombosis — Wave Goodbye to Combined Anticoagulation and Antiplatelet Therapy? Emile R. Mohler III, M.D. Atherothrombosis describes the occurrence of both atherosclerosis and thrombosis. Atherothrombosis — Wave Goodbye to Combined Anticoagulation and Antiplatelet Therapy? n engl j med 357;3 www.nejm.org july 19, 2007 293 e. 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