Antibiotic After Primary PCI Helps Reduce LV Remodeling After STEMI

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Administration of the tetracycline antibiotic doxycycline immediately after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) and low ejection fraction reduces adverse left ventricular (LV) remodeling.

For the TIPTOP trial, researchers led by Giampaolo Cerisano, MD, of the University of Florence (Florence, Italy), looked at 110 patients with a first STEMI and LVEF less than 40% who were treated with primary PCI between May 2007 and February 2011. Patients were randomized to doxycycline treatment (n = 55; 100 mg oral dose immediately after primary PCI and then every 12 hours for 7 days) or a control group (n =  55).

Doxycycline is a potent matrix metalloproteinase (MMP) inhibitor that has been shown in preclinical studies to attenuate post-infarct LV remodeling, the authors note.

The groups were well matched in terms of baseline characteristics. On echocardiography (baseline and 6 months), doxycycline patients showed positive results in terms of percent change in LV end diastolic volume index (LVEDVi; primary endpoint), LV end systolic volume index (LVESVi), and LVEF while the control group did not (table 1).

Table 1. Echocardiographic Outcomes at 6 Months

 

Doxycycline Group
(n = 55)

Controls
(n = 55)

P Value

Mean LVEDVi, mL

0.3

8.7

0.004

Mean LVESVi, mL

-4.5

1.3

0.02

Mean Increase in LVEF

12.1%

7.5%

0.04

Median Change in LVEDVia

0.4%

13.4%

0.012

a Primary endpoint.

On single-photon emission computed tomography (SPECT), performed in 84% of the doxycycline group and 82% of controls, final infarct size was smaller in doxycycline patients (median of 5.5% vs. 10.4%; P = 0.052) as was infarct severity index (median of 0.53 vs. 0.44; P = 0.014).

Infarct-related artery patency on follow-up angiography was observed in all doxycycline patients and all but 1 control, and there was no difference in binary restenosis greater than 50% between groups (26% in both). In the control group, there was a significant correlation between percentage change in LVEDVi and final infarct size on SPECT (r = 0.65; P < 0.001), with a smaller slope of the regression line for the doxycycline group than for the control group (P = 0.01 by analysis of covariance).

Clinical Results, Safety Promising with Antibiotic

Mean length of hospital stay was similar for the doxycycline group (6.1 days) and the control group (6.3 days; P = 0.75). The 6-month incidence of death, MI, congestive heart failure, and stroke was lower among doxycycline patients than among controls (10.9% vs. 25.5%; P = 0.04). Mortality at 6 months was 4.6% overall, 1.8% in the doxycycline group, and 7.3% in controls. Ischemic stroke occurred at a rate of 1.8% in the doxycycline group and 3.6% in the control group. Worsening of NYHA class III-IV and/or hospital readmission for congestive heart failure occurred in 7.4% of doxycycline patients and 13.7% of control patients.

“This study shows that in patients with a first STEMI and LV dysfunction treated with primary PCI, a timely short-term treatment with doxycycline significantly reduces LV remodeling,” Dr. Cerisano and colleagues conclude. They note that the magnitude of the change in LVEDVi obtained with doxycycline compared with controls reflects the high-risk profile of the study patients and confirms the principle that it is “precisely” in the higher-risk patients that a benefit from additional therapy can clearly be detected.

The study authors point out that there were no side effects attributable to doxycycline therapy. “We believe that this is largely due to the relatively small number of patients studied, the short duration of treatment (7 days), and the safety of the dosage used (100 mg twice daily),” they write. “This result is even less surprising when one considers that ~47 million new doxycycline prescriptions were dispensed over 5 years in the late 1990s in the [United State] with an event rate of 13 per million.”

Nevertheless, the authors stress that the results should be considered preliminary “and require confirmation in a larger clinical study.”

Doxycycline Mechanism Makes Sense, Worth Study

“This open-label pilot study appears promising and suggests a role for doxycycline in ameliorating left ventricular remodeling after a STEMI,” commented Debabrata Mukherjee, MD, of Texas Tech University Health Sciences Center (El Paso, TX), in an e-mail communication with TCTMD. “Future larger blinded studies with longer term follow up incorporating magnetic resonance imaging are indicated to objectively assess benefits versus potential risks of this therapy. Such studies should also use optimal guideline-based therapies including mineralocorticoid antagonists.”

Dr. Mukherjee added that the proposed mechanism of action for doxycycline is plausible. “Yes, mechanistically it makes sense,” he said. “The rationale for use of doxycycline to reduce post-MI remodeling is based on its ability to inhibit members of the MMP family of endopeptidases, preferentially MMP-9 and -2 which are increased in the setting of remodeled hearts after MI. In addition to inhibiting MMPs directly, doxycycline also inhibits MMP synthesis by modulating cytokine cascade, which plays an important role in the post-infarct remodeling process.”

 


Source:
Cerisano G, Buonamici P, Valenti R, et al. Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodeling: The TIPTOP trial. Eur Heart J. 2013;Epub ahead of print.

 

 

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Disclosures
  • Drs. Cerisano and Mukherjee report no relevant conflicts of interest.

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