Antibiotics in CHD prevention: End in sight or a new beginning?

April 20, 2005

Boston, MA - The negative results of two trials of antibiotics for the secondary prevention of coronary heart disease—ACES and PROVE-IT TIMI 22—have been published in the April 21, 2005 issue of the New England Journal of Medicine[1,2].

In an accompanying editorial, Dr Jeffrey L Anderson (LDS Hospital, Salt Lake City, UT), examines where to go from here, given the number of failed studies reported to date.[3]

ACES and PROVE-IT TIMI 22 were first reported at the European Society of Cardiology meeting in Munich last year, by Dr J Thomas Grayston (University of Washington, Seattle) and Dr Chris P Cannon (Brigham and Women's Hospital, Boston, MA), respectively; these two are also the lead authors of the papers published this week.

In his editorial, Anderson says that although the two studies raise questions as to whether the end of the road in this field has been reached, this is unlikely given the accumulating evidence that infection can be a stimulus for atherothrombosis.

Both trials show antibiotics ineffective for secondary prevention

Both ACES and PROVE-IT TIMI 22 examined the effects of antibiotic treatment of Chlamydia pneumoniaeACES looked at the use of azithromycin (Zithromax®; Pfizer) in patients with stable coronary artery disease, while PROVE-IT TIMI 22 used gatifloxacin (Tequin®; Bristol-Myers Squibb/Sankyo) in patients immediately after acute coronary syndrome.

ACES was a randomized, double-blind, placebo-controlled trial involving 4012 adults who were enrolled without regard to their serologic C pneumoniae status. Participants received 600 mg of azithromycin or placebo weekly 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% of the patients who received placebo and 22.3% of those who received azithromycina relative-risk reduction of less than 1%, with narrow confidence intervals.

PROVE IT-TIMI 22 was a double-blind, randomized, placebo-controlled trial involving 4162 patients who had been hospitalized with ACS in the preceding 10 days. They were treated with 400 mg of gatifloxacin or 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 pointa composite of death from any cause, myocardial infarction, unstable angina requiring hospitalization, revascularization performed at least 30 days after randomization, or strokeoccurred in 25.1% of placebo patients and 23.7% of those who received gatifloxacin; this represented a 5% reduction in the hazard ratio, an insignificant difference with narrow confidence intervals.

Not the end of the story
The ACES results do not tell us anything about a possible role of C pneumoniae in the early development or acceleration of disease in the coronary arteries.

The investigators of both trials conclude that the two antibiotics, even when given long term, were ineffective for the secondary prevention of cardiovascular events. However, both research teams caution that this is not the end of the story.

"Since the trial was not designed to study the role of C pneumoniae in causing CHD, the ACES results do not tell us anything about a possible role of C pneumoniae in the early development or acceleration of disease in the coronary arteries," says Grayston in a University of Washington media release. "More study is needed to determine the role of C pneumoniae in heart disease."

Cannon and colleagues say: "It is possible that C pneumoniae is a cause of early atherosclerosis but that once the process is established, with the appearance of cholesterol-laden plaque and inflammation, therapy with antichlamydial antibiotics is not effective."

A new beginning

In his editorial, Anderson lists all the large and intermediate-size trials of antibiotics for secondary prevention of coronary heart disease that have been conducted to date. With the exception of one, all the studies were negative, including the mega WIZARD trial.

Large and intermediate-size trials of antibiotics for secondary prevention of CHD

Trial Year Patients (n) Indication or setting Antibiotic Duration of therapy and follow-up Result
ACADEMIC 2000 302 CHD Azithromycin 3 months; 2 years Negative
ISAR-3 2001 1020 Post-PCI Roxithromycin 1 month; 6-12 months Negative
CLARIFY 2002 148 ACS Clarithromycin 3 months; 18 months Trend
ANTIBIO 2003 872 MI Roxithromycin 6 weeks; 12 months Negative
AZACS 2003 1450 ACS Azithromycin 5 days; 6 months Negative
WIZARD 2003 7724 CHD Azithromycin 3 months; 3 years Negative
ACES 2005 4012 CHD Azithromycin 12 months; 4 years Negative
PROVE-IT TIMI 2005 4162 ACS Gatifloxacin 18 months; 24 months Negative
We should begin anew, rather than discard the possibility of infection as an etiologic factor.

"A large body of negative clinical-trial results suggests that antibiotics effective for clinical C pneumoniae infection are not useful for secondary prevention. The testing of these agents for the treatment of advanced coronary heart disease appears to be at the end of the road," Anderson says. But, he notes, "On the other hand, evidence that infection can be a stimulus for atherothrombosis continues to mount."

These positive observations suggest that researchers should "rethink, revise, and reformulate hypotheses and research strategiesthat is, that we should begin anew, rather than discard the possibility of infection as an etiologic factor," Anderson continues.

Clinical trials needed at earlier stage of disease, with new antibiotics and vaccines

Just last week, a new seroepidemiologic study reported by heart wire showed that C pneumoniae was linked to MI in young men. Importantly, this research looked at the timing of infection, suggesting that a recent or chronic active C pneumoniae infection could contribute to a cardiac event. And other pathogens, such as Helicobacter pylori, have been associated with endothelial dysfunction and inflammation.

Anderson says efforts should now focus on expanding the limited knowledge base with regard to proatherogenic mechanisms (including viral vectors) and sophisticated preclinical models should be included in research plans.

"When appropriate, we should return to the clinical arena with trials that better select target patientsfor example, those at an earlier stage of atherosclerosis or those with better markers of latent or active infection or with a high total or viral burdenand interventions, including novel anti-infective agents and vaccines.

"Meanwhile, standard antibiotics do not work for the secondary prevention of cardiovascular disease," he concludes.

The National Heart, Lung, and Blood Institute and Pfizer funded ACES. Grayston has received grant support from Pfizer for ACES. CoauthorsDr Alfred F Parisi> has equity ownership in Pfizer, Dr John R Crouse has received consulting fees and grant support from Pfizer, and Dr Charles Knirsch is employed by Pfizer and has equity interest in the company. Bristol-Myers Squibb and Sankyo supported PROVE-IT TIMI 22. Cannon has received grant support from Astra-Zeneca, Bristol-Myers Squibb, Merck, and Sanofi-Aventis and has served on paid advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Sanofi-Aventis, and the Merck-Schering-Plough partnership. Coauthors Dr Eugene Braunwald has received grant support from Sanofi-Aventis and Bristol-Myers Squibb; Carolyn H McCabe has received grant support from AstraZeneca, Sanofi-Aventis, and Bristol-Myers Squibb; Dr Brent Muhlestein has received grant support from and served on paid advisory boards for Bristol-Myers Squibb; and Dr Robert P Giugliano has received lecture fees from Bristol-Myers Squibb.


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