Improving Reperfusion in Patients with Myocardial Infarction doc

Improving Reperfusion in Patients with Myocardial Infarction e d i t o r i a l s n engl j med 358;6 www.nejm.org february 7, 2008 634 T h e n e w e ngl a n d j o u r na l o f me dicine Improving Reperfusion in Patients with Myocardial Infarction George W. Vetrovec, M.D. A little over 50 years ago, my father had a heart attack. He was driven to the hospital by friends after having “indigestion” for 2 days. He spent 2 weeks as an inpatient on an unmonitored reha- bilitation ward and was treated principally with warfarin and digitalis. He was lucky and sur- vived, but in that era, more than 20% of patients with an acute myocardial infarction died. Fast- forward to today, when public education about early recognition of symptoms, emergency trans- port, monitored coronary care units, and early reperfusion by means of primary percutaneous coronary intervention (PCI) have markedly re- duced mortality from acute myocardial infarction to less than 5%. Major contributors to this remarkable im- provement in outcome are based on pathologi- cal studies 1,2 showing thrombotic occlusion of an artery associated with acute myocardial infarc- tion (Fig. 1A), in parallel with diagnostic and therapeutic advances from cardiac catheteriza- tion laboratories. By performing coronary angi- ography during evolving myocardial infarction, DeWood et al. 3 observed total coronary-artery occlusion in patients with acute myocardial in- farction, with frequent, early, spontaneous re- perfusion. Coincidentally, angiographic features of the thrombus were characterized, helping to identify the role of clots in acute coronary syn- dromes. 4,5 Most of the remarkable improvements have occurred over the 30 years since the introduction of coronary angioplasty. 6 Rentrop et al. 7 demon- strated that reperfusion with the use of mechani- cal or thrombolytic revascularization could avert evolving infarction. Most recently, the recognized importance of early and complete reperfusion by means of PCI has led to a strategy of using PCI as the preferred therapy for acute myocar- dial infarction, with a goal of reestablishing flow within 90 minutes after presentation (i.e., a door-to-balloon time of <90 minutes), provid- ed that this can be achieved without major de- lays in transport. 8 Thus, the improvement in outcomes for patients with acute myocardial in- farction is principally due to earlier, more effec- tive mechanical resolution of thrombotic occlu- sion of a coronary artery to maximally and quickly restore effective myocardial perfusion. Technically, the current method of primary PCI is to cross the occlusion with a balloon catheter, which, after a brief period of inflation, reestablishes flow. Subsequently, one or more stents are placed to provide stable revasculariza- tion ( Fig. 1B ). The initial inflation expedites reper- fusion and provides visualization of the occlud- ed segment for accurate stent sizing. However, as a consequence of manipulations of the bal- loon and stent, distal clot embolization occurs, at times visibly reducing distal reperfusion through the occlusion of macrovessels and micro- vessels. Reduced distal flow is indicated by slow coronary flow (Thrombolysis in Myocardial In- farction flow grade 2), incomplete resolution of the injury seen on the electrocardiogram, ab- normal myocardial blush, or any combination of these. Abnormal blush (represented by a low blush grade) reflects slow or absent washout of injected contrast medium within the reperfused arterial system. Each of these indicators has been associated with a less favorable long-term prognosis. 9 In this issue of the Journal, Svilaas et al. 10 de- scribe passing a guidewire through the occluded infarct-related artery, but instead of then open- ing the artery with a balloon, a small catheter is Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 . editorials n engl j med 358;6 www.nejm.org february 7, 2008 635 advanced into the occluded segment. Direct as- piration of the occluding thrombus is then per- formed ( Fig. 1C ; also see the animated illustra- tion available with the full text of this article at www.nejm.org). After aspiration, stenting was performed, without balloon dilation beforehand in the majority of patients, unless the stent could not be delivered. Conceptually, this tech- nique limits the embolization of distal clots, thus improving distal myocardial perfusion. To test this hypothesis, Svilaas et al. ran- domly assigned 1071 patients to undergo initial aspiration with stenting or conventional primary PCI with the use of a balloon and stent. They 01/23/08 AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully Author Fig # Title ME DE Artist Issue date COLOR FIGURE Version 7 Vetrovec 1 LAM 02/07/08 Refining reperfusion GDC JL Thrombus occluding vessel Area of potential infarct Blockage within branch of left anterior descending coronary artery B Standard approach to revascularization A C Revascularization using a thrombectomy aspiration catheter Guidewire Aspiration catheter Nonoccluding plaque Thrombus occluding vessel Thrombus occluding blood flow No blood flow Blood flow Guidewire Aspiration catheter suctions thrombotic material Balloon angioplasty catheter Stent deployed Stent deployed after removal of thrombus Balloon inflated to restore blood flow Lumen of vessel Thrombus occluding blood flow Figure 1. Thrombotic Occlusion of an Artery Associated with Acute Myocardial Infarction and Subsequent Percutaneous Coronary Inter- vention (PCI). In an occluded infarct-related artery (Panel A), reperfusion can be achieved by the standard means of primary PCI (Panel B) or by the new method of thrombus aspiration (Panel C), followed by stenting. Also see the animated illustration, available with the full text of this article at www.nejm.org. Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 . T h e n e w e ngl a n d j o u r na l o f me dicine n engl j med 358;6 www.nejm.org february 7, 2008 636 used the ST-segment characteristics on electro- cardiography as well as the myocardial blush grade to assess the efficacy of clot extraction before stenting on distal perfusion. There was a clear correlation between the resolution of elec- trocardiographic changes and improvement in myocardial blush scores: complete resolution of ST-segment elevation, the absence of persistent ST-segment deviation, and myocardial blush grade of 0 or 1 were all significantly more frequent in the patients who underwent aspiration than in those who underwent conventional PCI. In addi- tion, histological assessment of the aspirate from nearly three quarters of the patients who under- went aspiration revealed platelet thrombi, consis- tent with current understanding of the role of such thrombi in the pathophysiological charac- teristics of acute myocardial infarction. Clinical outcome at 30 days was significantly related to the extent of myocardial reperfusion. Mortality was higher among patients with per- sistent abnormalities in myocardial blush than among patients with improved myocardial distal- bed perfusion. The frequencies of other adverse events were similar to that of death. Reasons for the reported benefit of reduced embolization in patients who underwent aspira- tion seem related to enhanced distal-bed perfu- sion. Neumann et al. 11 showed that increases in ejection fraction correlated with improved peak Doppler flow velocity in patients receiving a platelet glycoprotein IIb/IIIa inhibitor that mini- mizes distal thrombotic occlusion of small ves- sels. The significance may be that maintaining arterial flow limits apoptosis and potentially adverse remodeling, 12 thus providing a mecha- nism for the favorable outcomes associated with improved microvascular reperfusion. Although the study by Svilaas et al. reports encouraging results for coronary-thrombus ex- traction, previous extraction trials of different designs have had various results. Caveats re- garding the trial by Svilaas et al. include the fact that it was a single-center study performed by highly experienced interventionalists who had a low failure rate with regard to delivering the catheter. It is unknown whether more general use will demonstrate similar safety and favorable out- comes. Furthermore, there is concern that such catheters can dissect or damage the arterial seg- ment, necessitating longer stents, which could increase the risk of late restenosis. In addition, some operators believe that direct stenting with- out multiple balloon inflations reduces the risk of distal emboli. In the trial by Svilaas et al., the majority of patients in the thrombus-aspiration group had stents placed directly, whereas the majority in the conventional-PCI group had bal- loon angioplasty followed by stenting, which might have increased the relative incidence of embolization in the conventional-PCI group. In addition, current guidelines of the Ameri- can College of Cardiology, the American Heart Association, and the Society for Cardiovascular Angiography and Interventions emphasize the door-to-balloon time as the primary temporal marker of quality. If strategies involving throm- bus extraction evolve to become a primary re- perfusion strategy, quality indicators must en- compass reperfusion by multiple methods, specifically balloon inflation or catheter place- ment through the occlusion as interchangeable markers of reperfusion. Potential adverse issues aside, on the basis of the data of Svilaas et al., thrombus extraction is conceptually sound and appears to reduce the risk among patients undergoing primary PCI. With the current low risk of death associated with early reperfusion in patients with acute myo- cardial infarction, refinements can be expected to make only small, albeit clinically significant, improvements in outcome. Thrombus aspiration appears to be such a favorable improvement. No potential conflict of interest relevant to this article was re- ported. From the Virginia Commonwealth University Pauley Heart Cen- ter, Medical College of Virginia Hospitals, Virginia Common- wealth University, Richmond. Falk E. Plaque rupture with severe pre-existing stenosis pre- cipitating coronary thrombosis: characteristics of coronary ath- erosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983;50:127-34. Davies MJ, Thomas A. Thrombosis and acute coronary- related lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137-40. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myo- cardial infarction. N Engl J Med 1980;303:897-902. Vetrovec GW, Cowley MJ, Overton H, Richardson DW. Intra- coronary thrombus in syndromes of unstable myocardial ische- mia. Am Heart J 1981;102:1202-8. Vetrovec GW, Leinbach RC, Gold HK, Cowley MJ. Intracoro- nary thrombolysis in syndromes of unstable ischemia: angio- graphic and clinical results. Am Heart J 1982;104:946-52. Gruntzig A. Transluminal dilatation of coronary-artery ste- nosis. Lancet 1978;1:263. Rentrop KP, Blanke H, Karsch KR, Kreuzer H. Initial experi- ence with transluminal recanalization of the recently occluded infarct-related coronary artery in acute myocardial infarction — comparison with conventionally treated patients. Clin Car- diol 1979;2:92-105. 1. 2. 3. 4. 5. 6. 7. Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 . editorials n engl j med 358;6 www.nejm.org february 7, 2008 637 Nallamothu BK, Bradley EH, Krumholtz HM. Time to treat- ment in primary percutaneous coronary intervention. N Engl J Med 2007;357:1631-8. Poli A, Fetiveau R, Vandoni P, et al. Integrated analysis of myocardial blush and ST-segment elevation recovery after suc- cessful primary angioplasty: real-time grading of microvascular reperfusion and prediction of early and late recovery of left ven- tricular function. Circulation 2002;106:313-8. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspira- tion during primary percutaneous coronary intervention. N Engl J Med 2008;358:557-67. 8. 9. 10. Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycopro- tein Ib/IIIa receptor blockade on recovery of coronary flow and left ventricular function after placement of coronary-artery stents in acute myocardial infarction. Circulation 1998;98: 2695-701. Abbate A, Bussani R, Biondi-Zoccai GG, et al. Infarct-related artery occlusion, tissue markers of ischaemia, and increased ap- optosis in the peri-infarct viable myocardium. Eur Heart J 2005; 26:2039-45. Copyright © 2008 Massachusetts Medical Society. 11. 12. Pharmacogenomic Biomarkers for Prediction of Severe Adverse Drug Reactions Magnus Ingelman-Sundberg, Ph.D., B.Sc.Med. The accumulating knowledge of human genomic variation is being used for the development of personalized medicine, with the aims of de- creasing the number of adverse drug reactions and increasing the efficacy of drug treatment. Considerable pharmacogenomic research has fo- cused on understanding the molecular mecha- nisms behind adverse drug reactions and find- ing biomarkers that identify people at risk. Serious adverse drug reactions have been shown to cause or contribute to 6 to 7% of all hospitalizations, a 2-day increase in the average length of hospitalization, and 100,000 deaths annually in the United States — and may, ac- cording to some estimates, cost about as much as the drug treatment itself. 1 During the period 1998–2005, the numbers of reported adverse drug reactions and deaths related to such reactions have increased, both by a factor of about 2.6. 2 Adverse drug reactions are also a major problem during the development of a drug. In total, ap- proximately 4% of all new medical agents are withdrawn from the market owing to adverse drug reactions. 1 During the period 1995–2005, at least 34 drugs were withdrawn, mainly as a result of hepatotoxic or cardiotoxic effects — no- tably, cerivastatin, nefazodone, rofecoxib (Vioxx), terfenadine, and troglitazone. 3 The search for pharmacogenomic biomarkers that could be used to identify patients at increased risk for drug-related toxic effects has often focused on variation within genes encoding drug-metab- olizing enzymes. Altered enzymatic activity can lead to elevated levels of the substrate drug, or alternatively, increased amounts of a reactive me- tabolite, either of which could have toxic effects. For immune-mediated toxic effects, much fo- cus has been placed on the major-histocompati- bility-complex class I genes. A review of pharma- cogenomic biomarkers reveals only a limited number of potentially useful examples ( Table 1 ), with the highest specificity seen among the HLA allelic variants. Thus, many more biomarkers remain to be identified. Unfortunately, much of the existing research in this area has been hampered by limitations in study design, such as poorly defined case and control groups, the use of retrospective and nonblind study protocols, and nonoptimal selection of gene variants. In addition, polygenic influences on many adverse drug reactions, instances of treatment with mul- tiple drugs, and variation in the severity of clini- Table 1. Pharmacogenomic Biomarkers as Predictors of Adverse Drug Reactions. Gene or Allele Relevant Drug Specificity of Biomarker Percent of Patients with an Adverse Reaction to Drug* TPMT (mutant) 6-Mercaptopurines Very good 1–10 UGT1A1*28 Irinotecan Good 30–40 CYP2C9 and VKORC1 Warfarin† Good 5–40 CYP2D6 (mutant) Tricyclic anti- depressants Relatively good 5–7 HLA-B*5701 Abacavir Very good 5–8 HLA-B*1502 Carbamazepine Very good 10 HLA-DRB1*07 and DQA1*02 Ximelagatran Good 5–7 * Percentages are of affected whites except that for HLA-B*1502, which is the percentage of affected Asians. † Carriage of the CYP2C9 and VKORC1 alleles affects warfarin dosing. Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at RIKSHOSPITALET HF on February 18, 2008 . The new england journal of medicine n engl j med 352;16 www.nejm.org april 21, 2005 1706 editorial Infection, Antibiotics, and Atherothrombosis — End of the Road or New Beginnings? Jeffrey L. Anderson, M.D. Two large, high-quality, and convincingly negative clinical trials for the secondary prevention of coro- nary heart disease, 1,2 published in this issue of the Journal, raise questions as to whether we are at the end of the road or should move on to new begin- nings as we explore the hypothesis that infection plays a role in atherosclerosis. Evidence that vascu- lar inflammation is an important mechanism in- volved in all stages of atherogenesis continues to accumulate. Such evidence has legitimately raised the question of whether infection is one of the in- flammatory stimuli that operate in the pathophysi- ology of atherothrombosis, either locally, within vascular tissue, or systemically, through inflamma- tory mediators. 3 Furthermore, data from animal models and seroepidemiologic and pathological observations have raised the possibility that Chla- mydia pneumoniae, a species of intracellular gram- negative bacterium, might be an infectious vector of atherogenesis and, hence, a target for therapy. C. pneumoniae is an obligate microbe that common- ly causes respiratory infection, is frequently found in atherosclerotic plaque, and is susceptible to mac- rolide and quinolone antibiotics. 3 Indeed, studies in animal models have demonstrated that C. pneu- moniae can accelerate atherogenesis and that anti- biotics can suppress it. 3 Initial clinical studies from the United King- dom 4 and Argentina 5 reported that antibiotic ther- apy might lead to large reductions in secondary cardiovascular risk in patients with stable coronary heart disease or acute coronary syndromes. Subse- quent work by my colleagues and me 6 and, later, by others in studies of intermediate size 7-10 failed to confirm a large benefit (Table 1). However, these studies left open the possibility of limited-to-mod- erate clinical benefits (i.e., risk reductions of 20 to 30 percent), which would require testing in trials involving several thousand patients. Subsequently, the Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders (WIZARD) study, a megatrial involving 7724 patients with stable disease who had a histo- ry of myocardial infarction and serologic evidence of C. pneumoniae, failed to find a long-term benefit, even though a favorable trend was noted during and shortly after a three-month course of treatment with azithromycin. 11 Similarly, with regard to acute cor- onary syndromes, the Azithromycin in Acute Cor- onary Syndromes study (AZACS), a moderately large trial involving 1439 patients, did not show a bene- fit, but its conclusions were limited by its short du- ration of therapy (azithromycin for five days). 10 To these earlier trials, the Azithromycin and Coronary Events Study (ACES) 1 and the Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction (PROVE IT– TIMI) trial 2 add major new information. The ACES trial 1 which was sponsored by the National Insti- tutes of Health, was a randomized, double-blind, placebo-controlled trial involving 4012 adults with stable coronary heart disease who were enrolled without regard to their serologic C. pneumoniae sta- tus. Participants received weekly azithromycin or placebo for one year. The mean period of follow- up was four years. The primary end point, a compos- ite of death due to coronary heart disease, nonfatal myocardial infarction, hospitalization for unstable angina, or coronary revascularization, occurred in 22.4 percent of the patients who received placebo and 22.3 percent of those who received azithromy- cin — a relative-risk reduction of less than 1 per- cent, with narrow confidence intervals (¡13 percent to 13 percent). Furthermore, unlike the WIZARD Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2005 Massachusetts Medical Society. All rights reserved. n engl j med 352;16 www.nejm.org april 21, 2005 editorial 1707 trial, ACES showed no trend toward an early bene- fit during the period of active therapy. Individual components of the primary end point and the sec- ondary end points were unaffected. The frequency of gastrointestinal side effects increased to some extent. The investigators concluded that azithromy- cin, even when given regularly for one year, is inef- fective for the prevention of secondary cardiovas- cular events. The PROVE IT–TIMI study, 2 a double-blind, randomized, two-by-two factorial trial involving 4162 patients at multiple centers, addressed two complementary issues: the secondary prevention of cardiovascular events after acute coronary syn- dromes and, in addition, antibiotic therapy with gatifloxacin, a potentially more efficacious antibi- otic than azithromycin. Results of the first random- ization, which involved intensive as compared with moderate reductions in lipid levels, have been re- ported previously. The second randomization com- pared the results of treatment with gatifloxacin and placebo, given, after initial dosing, for 10 days each month during a follow-up period of 18 to 32 months (mean, 24 months). The primary end point — a composite of death from any cause, myocardial infarction, unstable angina requiring hospitalization, revascularization performed at least 30 days after randomization, or stroke — occurred in 25.1 percent of the patients who received placebo and 23.7 percent of those who received gatifloxacin; this represented a 5 per- cent reduction in the hazard ratio, an insignificant difference with narrow confidence intervals (¡8 per- cent to 16 percent). No benefits were noted in any major subgroup, including those stratified accord- ing to the level of C-reactive protein or C. pneumoniae seropositivity. Antibiotic therapy reduced the inci- dence of upper respiratory infection, but it caused more gastrointestinal side effects, and it did not reduce C-reactive protein levels. The investigators concluded that gatifloxacin, even when given over the long term, is ineffective for the secondary pre- vention of cardiovascular events after acute coro- nary syndromes. The expectation that these antibiotic trials might provide insight into the validity (or fallacy) of the infection hypothesis must be tempered by consider- ation of important limitations and uncertainties. Such drawbacks suggest that the hypothesis does not easily lend itself to proof or disproof accord- ing to Koch’s classic postulates. Even if studies yield positive results, the hypothesis is not entirely proved, because nonspecific antiinflammatory ef- fects or antiinfective actions against other organ- isms might be operative. Antibiotic intervention targeted to C. pneumoniae through the prevention of * The studies used a variety of inclusion criteria and exclusion criteria and tested various doses and durations of therapy. † ACADEMIC denotes Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infarction with Chlamydia, ISAR-3 Intracoronary Stenting and Antibiotic Regimen 3, CLARIFY Clarithromycin in Acute Coronary Syndrome Patients in Finland, ANTIBIO Antibiotic Therapy after Acute Myocardial Infarction, AZACS Azithromycin in Acute Coronary Syn- drome, WIZARD Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, ACES Azithromycin and Coronary Events Study, and PROVE IT–TIMI Pravastatin or Atorvastatin Evaluation and Infection Therapy–Throm- bolysis in Myocardial Infarction. Table 1. Large and Intermediate-Size Trials of Antibiotics for the Secondary Prevention of Coronary Heart Disease.* Trial† Year No. of Patients Indication or Setting Antibiotic Duration of Therapy and Follow-up Result ACADEMIC 6 2000 302 Coronary heart disease Azithromycin 3 mo; 2 yr Negative ISAR-3 7 2001 1020 Post–percutaneous coronary intervention Roxithromycin 1 mo; 6–12 mo Negative CLARIFY 8 2002 148 Acute coronary syndromes Clarithromycin 3 mo; 18 mo Trend ANTIBIO 9 2003 872 Myocardial infarction Roxithromycin 6 wk; 12 mo Negative AZACS 10 2003 1450 Acute coronary syndromes Azithromycin 5 days; 6 mo Negative WIZARD 11 2003 7724 Coronary heart disease Azithromycin 3 mo; 3 yr Negative ACES 1 2005 4012 Coronary heart disease Azithromycin 12 mo; 4 yr Negative PROVE IT–TIMI 2 2005 4162 Acute coronary syndromes Gatifloxacin 18 mo; 24 mo Negative Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 1708 n engl j med 352;16 www.nejm.org april 21, 2005 typical periodontal, respiratory tract, and urinary tract infections could prevent the progression of cardiovascular disease if the treatment suppressed infection-related, circulating inflammatory media- tors of atherothrombosis. Indeed, that there is an infection-related increase in the risk of myocardial infarction and stroke was strongly supported by a recent study in the Journal . 12 Moreover, tetracyclines (e.g., minocycline and doxycycline), which have been touted for the treatment of a variety of inflam- matory conditions, including rheumatoid arthri- tis, chronic periodontitis, and acute coronary syn- dromes, may have anti–matrix metalloproteinase activity in doses even lower than those for antimi- crobial uses; this activity could represent a mecha- nism of potential benefit unrelated to antibiotic effects. Negative outcomes, which have been noted in most of the recent studies (Table 1), might be ex- plained not only by the use of an incorrect hypoth- esis (i.e., that infection is not atherogenic) but also by an inadequate sample size or by the use of an ineffective antibiotic regimen. The ACES and PROVE IT–TIMI trials address most of the concerns about study design, including sample size (and its effect on the power of the study) and the duration of therapy, but they leave open the possibility of ineffectiveness. Indeed, Gieffers et al. found that C. pneumoniae infection in vitro in monocytes from healthy volunteers or in vivo in circulating mono- cytes from patients who had been treated for coro- nary heart disease was refractory to azithromycin 13 : antibiotic treatment did not inhibit chlamydial growth within monocytes, and after withdrawal of antibiotic therapy, C. pneumoniae could be cultured from monocyte cell lines. In contrast, antibiotics eliminated C. pneumoniae from epithelial cells. 13 Whether gatifloxacin would perform better is un- certain. Hence, whereas ACES and PROVE IT–TIMI, together with other studies (Table 1), appear con- clusively to eliminate azithromycin, gatifloxacin, and related agents as useful preventive therapies for secondary cardiovascular events, they leave open the possibility that novel antibiotics with more potent bactericidal activity against intracellular microbes could lead to a different outcome. 14 However, event rates in ACES and PROVE IT–TIMI were unaffected even during the long periods of ongoing (and pre- sumably suppressive) therapy. Hence, another rea- son for a negative trial result should be considered: that an advanced, unmodifiable stage of disease was chosen for study. A large body of negative clinical-trial results sug- gests that antibiotics effective for clinical C. pneu- moniae infection are not useful for secondary pre- vention (Table 1). The testing of these agents for the treatment of advanced coronary heart disease appears to be at the end of the road. On the other hand, evidence that infection can be a stimulus for atherothrombosis continues to mount. 3,12,15 These positive observations suggest that we should re- think, revise, and reformulate hypotheses and re- search strategies — that is, that we should begin anew, rather than discard the possibility of infec- tion as an etiologic factor. We should focus on ex- panding our limited knowledge base with regard to proatherogenic mechanisms (including viral vec- tors); we should include sophisticated preclinical models in our research plans; and, when appro- priate, we should return to the clinical arena with trials that better select target patients (e.g., those at an earlier stage of atherosclerosis or those with bet- ter markers of latent or active infection or with a high total or viral burden 3 ) and interventions, including novel antiinfective agents and vaccines. 3,14,15 Mean- while, standard antibiotics do not work for the sec- ondary prevention of cardiovascular heart disease. From the University of Utah School of Medicine, LDS Hospital, Salt Lake City. 1. Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005; 352:1637-45. 2. Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treat- ment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005;352:1646-54. 3. Anderson JL, Muhlestein JB. The role of infection. In: Theroux P, ed. Acute coronary syndromes: a companion to Braunwald’s Heart Disease. Philadelphia: Saunders, 2003:88-107. 4. Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovas- cular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997;96:404-7. 5. Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Ran- domised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. Lancet 1997;350:404-7. 6. Muhlestein JB, Anderson JL, Carlquist JF, et al. Randomized 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. 7. Neumann F, Kastrati A, Miethke T, et al. Treatment of 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. 8. Sinisalo J, Mattila K, Valtonen V, et al. Effect of 3 months of antimicrobial treatment with clarithromycin in acute non-Q-wave coronary syndrome. Circulation 2002;105:1555-60. 9. Zahn R, Schneider S, Frilling B, et al. Antibiotic therapy after acute myocardial infarction: a prospective randomized study. Circu- lation 2003;107:1253-9. 10. Cercek B, Shah PK, Noc M, et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2005 Massachusetts Medical Society. All rights reserved. n engl j med 352;16 www.nejm.org april 21, 2005 editorial 1709 acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003; 361:809-13. 11. O’Connor CM, Dunne MW, Pfeffer MA, et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 2003;290: 1459-66. 12. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Val- lance P. Risk of myocardial infarction and stroke after acute infec- tion or vaccination. N Engl J Med 2004;351:2611-8. 13. Gieffers J, Fullgraf H, Jahn J, et al. Chlamydia pneumoniae in- fection in circulating human monocytes is refractory to antibiotic treatment. Circulation 2001;103:351-6. 14. Roblin PM, Reznik T, Kutlin A, Hammerschlag MR. In vitro 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. 15. Madjid M, Naghavi M, Litovsky SA, Casscells SW. Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies. Circulation 2003;108:2730-6. Copyright © 2005 Massachusetts Medical Society. Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2005 Massachusetts Medical Society. All rights reserved. . 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,. Improving Reperfusion in Patients with Myocardial Infarction e d i t o r i a l s n engl j med 358;6 www.nejm.org february 7, 2008 634 T h e n e w e ngl a n d j o u r na l o f me dicine Improving. 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