Infection, Antibiotics, and Atherothrombosis — End of the Road or New Beginnings?
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《新英格兰医药杂志》
Two large, high-quality, and convincingly negative clinical trials for the secondary prevention of coronary 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 beginnings as we explore the hypothesis that infection plays a role in atherosclerosis. Evidence that vascular inflammation is an important mechanism involved in all stages of atherogenesis continues to accumulate. Such evidence has legitimately raised the question of whether infection is one of the inflammatory stimuli that operate in the pathophysiology of atherothrombosis, either locally, within vascular tissue, or systemically, through inflammatory mediators.3 Furthermore, data from animal models and seroepidemiologic and pathological observations have raised the possibility that Chlamydia 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 commonly causes respiratory infection, is frequently found in atherosclerotic plaque, and is susceptible to macrolide and quinolone antibiotics.3 Indeed, studies in animal models have demonstrated that C. pneumoniae can accelerate atherogenesis and that antibiotics can suppress it.3
Initial clinical studies from the United Kingdom4 and Argentina5 reported that antibiotic therapy might lead to large reductions in secondary cardiovascular risk in patients with stable coronary heart disease or acute coronary syndromes. Subsequent work by my colleagues and me6 and, later, by others in studies of intermediate size7,8,9,10 failed to confirm a large benefit (Table 1). However, these studies left open the possibility of limited-to-moderate clinical benefits (i.e., risk reductions of 20 to 30 percent), which would require testing in trials involving several thousand patients.
Table 1. Large and Intermediate-Size Trials of Antibiotics for the Secondary Prevention of Coronary Heart Disease.
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 history 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 coronary syndromes, the Azithromycin in Acute Coronary Syndromes study (AZACS), a moderately large trial involving 1439 patients, did not show a benefit, but its conclusions were limited by its short duration of therapy (azithromycin for five days).10
To these earlier trials, the Azithromycin and Coronary Events Study (ACES)1 and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction (PROVE IT–TIMI) trial2 add major new information. The ACES trial1 which was sponsored by the National Institutes 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 status. Participants received weekly azithromycin or placebo for one year. The mean period of follow-up was four years. The primary end point, a composite 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 azithromycin — a relative-risk reduction of less than 1 percent, with narrow confidence intervals (–13 percent to 13 percent). Furthermore, unlike the WIZARD trial, ACES showed no trend toward an early benefit during the period of active therapy. Individual components of the primary end point and the secondary end points were unaffected. The frequency of gastrointestinal side effects increased to some extent. The investigators concluded that azithromycin, even when given regularly for one year, is ineffective for the prevention of secondary cardiovascular 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 syndromes and, in addition, antibiotic therapy with gatifloxacin, a potentially more efficacious antibiotic than azithromycin. Results of the first randomization, which involved intensive as compared with moderate reductions in lipid levels, have been reported previously. The second randomization compared 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 percent reduction in the hazard ratio, an insignificant difference with narrow confidence intervals (–8 percent to 16 percent). No benefits were noted in any major subgroup, including those stratified according to the level of C-reactive protein or C. pneumoniae seropositivity. Antibiotic therapy reduced the incidence 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 prevention of cardiovascular events after acute coronary syndromes.
The expectation that these antibiotic trials might provide insight into the validity (or fallacy) of the infection hypothesis must be tempered by consideration of important limitations and uncertainties. Such drawbacks suggest that the hypothesis does not easily lend itself to proof or disproof according to Koch's classic postulates. Even if studies yield positive results, the hypothesis is not entirely proved, because nonspecific antiinflammatory effects or antiinfective actions against other organisms might be operative. Antibiotic intervention targeted to C. pneumoniae through the prevention of typical periodontal, respiratory tract, and urinary tract infections could prevent the progression of cardiovascular disease if the treatment suppressed infection-related, circulating inflammatory mediators 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 inflammatory conditions, including rheumatoid arthritis, chronic periodontitis, and acute coronary syndromes, may have anti–matrix metalloproteinase activity in doses even lower than those for antimicrobial uses; this activity could represent a mechanism of potential benefit unrelated to antibiotic effects.
Negative outcomes, which have been noted in most of the recent studies (Table 1), might be explained not only by the use of an incorrect hypothesis (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 monocytes from patients who had been treated for coronary heart disease was refractory to azithromycin13: antibiotic treatment did not inhibit chlamydial growth within monocytes, and after withdrawal of antibiotic therapy, C. pneumoniae could be cultured from monocyte cell lines. In contrast, antibiotics eliminated C. pneumoniae from epithelial cells.13 Whether gatifloxacin would perform better is uncertain. Hence, whereas ACES and PROVE IT–TIMI, together with other studies (Table 1), appear conclusively 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 presumably suppressive) therapy. Hence, another reason 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 suggests that antibiotics effective for clinical C. pneumoniae infection are not useful for secondary prevention (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 rethink, revise, and reformulate hypotheses and research strategies — that is, that we should begin anew, rather than discard the possibility of infection as an etiologic factor. We should focus on expanding our limited knowledge base with regard to proatherogenic mechanisms (including viral vectors); we should include sophisticated preclinical models in our research plans; and, when appropriate, 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 better markers of latent or active infection or with a high total or viral burden3) and interventions, including novel antiinfective agents and vaccines.3,14,15 Meanwhile, standard antibiotics do not work for the secondary prevention of cardiovascular heart disease.
Source Information
From the University of Utah School of Medicine, LDS Hospital, Salt Lake City.
References
Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005;352:1637-1645.
Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005;352:1646-1654.
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.
Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997;96:404-407.
Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. Lancet 1997;350:404-407.
Muhlestein JB, Anderson JL, Carlquist JF, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study. Circulation 2000;102:1755-1760.
Neumann F, Kastrati A, Miethke T, et al. Treatment of Chlamydia pneumoniae infection with roxithromycin and effect on neointima proliferation after coronary stent placement (ISAR-3): a randomised, double-blind, placebo-controlled trial. Lancet 2001;357:2085-2089.
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;105:1555-1560.
Zahn R, Schneider S, Frilling B, et al. Antibiotic therapy after acute myocardial infarction: a prospective randomized study. Circulation 2003;107:1253-1259.
Cercek B, Shah PK, Noc M, et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003;361:809-813.
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;290:1459-1466.
Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611-2618.
Gieffers J, Fullgraf H, Jahn J, et al. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation 2001;103:351-356.
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;47:1135-1136.
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;108:2730-2736.(Jeffrey L. Anderson, M.D.)
Initial clinical studies from the United Kingdom4 and Argentina5 reported that antibiotic therapy might lead to large reductions in secondary cardiovascular risk in patients with stable coronary heart disease or acute coronary syndromes. Subsequent work by my colleagues and me6 and, later, by others in studies of intermediate size7,8,9,10 failed to confirm a large benefit (Table 1). However, these studies left open the possibility of limited-to-moderate clinical benefits (i.e., risk reductions of 20 to 30 percent), which would require testing in trials involving several thousand patients.
Table 1. Large and Intermediate-Size Trials of Antibiotics for the Secondary Prevention of Coronary Heart Disease.
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 history 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 coronary syndromes, the Azithromycin in Acute Coronary Syndromes study (AZACS), a moderately large trial involving 1439 patients, did not show a benefit, but its conclusions were limited by its short duration of therapy (azithromycin for five days).10
To these earlier trials, the Azithromycin and Coronary Events Study (ACES)1 and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction (PROVE IT–TIMI) trial2 add major new information. The ACES trial1 which was sponsored by the National Institutes 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 status. Participants received weekly azithromycin or placebo for one year. The mean period of follow-up was four years. The primary end point, a composite 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 azithromycin — a relative-risk reduction of less than 1 percent, with narrow confidence intervals (–13 percent to 13 percent). Furthermore, unlike the WIZARD trial, ACES showed no trend toward an early benefit during the period of active therapy. Individual components of the primary end point and the secondary end points were unaffected. The frequency of gastrointestinal side effects increased to some extent. The investigators concluded that azithromycin, even when given regularly for one year, is ineffective for the prevention of secondary cardiovascular 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 syndromes and, in addition, antibiotic therapy with gatifloxacin, a potentially more efficacious antibiotic than azithromycin. Results of the first randomization, which involved intensive as compared with moderate reductions in lipid levels, have been reported previously. The second randomization compared 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 percent reduction in the hazard ratio, an insignificant difference with narrow confidence intervals (–8 percent to 16 percent). No benefits were noted in any major subgroup, including those stratified according to the level of C-reactive protein or C. pneumoniae seropositivity. Antibiotic therapy reduced the incidence 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 prevention of cardiovascular events after acute coronary syndromes.
The expectation that these antibiotic trials might provide insight into the validity (or fallacy) of the infection hypothesis must be tempered by consideration of important limitations and uncertainties. Such drawbacks suggest that the hypothesis does not easily lend itself to proof or disproof according to Koch's classic postulates. Even if studies yield positive results, the hypothesis is not entirely proved, because nonspecific antiinflammatory effects or antiinfective actions against other organisms might be operative. Antibiotic intervention targeted to C. pneumoniae through the prevention of typical periodontal, respiratory tract, and urinary tract infections could prevent the progression of cardiovascular disease if the treatment suppressed infection-related, circulating inflammatory mediators 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 inflammatory conditions, including rheumatoid arthritis, chronic periodontitis, and acute coronary syndromes, may have anti–matrix metalloproteinase activity in doses even lower than those for antimicrobial uses; this activity could represent a mechanism of potential benefit unrelated to antibiotic effects.
Negative outcomes, which have been noted in most of the recent studies (Table 1), might be explained not only by the use of an incorrect hypothesis (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 monocytes from patients who had been treated for coronary heart disease was refractory to azithromycin13: antibiotic treatment did not inhibit chlamydial growth within monocytes, and after withdrawal of antibiotic therapy, C. pneumoniae could be cultured from monocyte cell lines. In contrast, antibiotics eliminated C. pneumoniae from epithelial cells.13 Whether gatifloxacin would perform better is uncertain. Hence, whereas ACES and PROVE IT–TIMI, together with other studies (Table 1), appear conclusively 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 presumably suppressive) therapy. Hence, another reason 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 suggests that antibiotics effective for clinical C. pneumoniae infection are not useful for secondary prevention (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 rethink, revise, and reformulate hypotheses and research strategies — that is, that we should begin anew, rather than discard the possibility of infection as an etiologic factor. We should focus on expanding our limited knowledge base with regard to proatherogenic mechanisms (including viral vectors); we should include sophisticated preclinical models in our research plans; and, when appropriate, 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 better markers of latent or active infection or with a high total or viral burden3) and interventions, including novel antiinfective agents and vaccines.3,14,15 Meanwhile, standard antibiotics do not work for the secondary prevention of cardiovascular heart disease.
Source Information
From the University of Utah School of Medicine, LDS Hospital, Salt Lake City.
References
Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005;352:1637-1645.
Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005;352:1646-1654.
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.
Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997;96:404-407.
Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. Lancet 1997;350:404-407.
Muhlestein JB, Anderson JL, Carlquist JF, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study. Circulation 2000;102:1755-1760.
Neumann F, Kastrati A, Miethke T, et al. Treatment of Chlamydia pneumoniae infection with roxithromycin and effect on neointima proliferation after coronary stent placement (ISAR-3): a randomised, double-blind, placebo-controlled trial. Lancet 2001;357:2085-2089.
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;105:1555-1560.
Zahn R, Schneider S, Frilling B, et al. Antibiotic therapy after acute myocardial infarction: a prospective randomized study. Circulation 2003;107:1253-1259.
Cercek B, Shah PK, Noc M, et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003;361:809-813.
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;290:1459-1466.
Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611-2618.
Gieffers J, Fullgraf H, Jahn J, et al. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation 2001;103:351-356.
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;47:1135-1136.
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;108:2730-2736.(Jeffrey L. Anderson, M.D.)