Giuseppe
Emeritus
[Source: JAMA, full page: (LINK). Abstract, edited.]
Online First / Original Investigation | October 09, 2013 Caring for the Critically Ill Patient
Effect of Statin Therapy on Mortality in Patients With Ventilator-Associated Pneumonia: A Randomized Clinical Trial
FREE ONLINE FIRST
Laurent Papazian, MD, PhD<SUP>1</SUP>; Antoine Roch, MD, PhD<SUP>1</SUP>; Pierre-Emmanuel Charles, MD, PhD<SUP>2</SUP>; Christine Penot-Ragon, PharmD<SUP>3</SUP>; Gilles Perrin, MD<SUP>4</SUP>; Philippe Roulier, MD<SUP>5</SUP>; Philippe Goutorbe, MD<SUP>6</SUP>; Jean-Yves Lefrant, MD, PhD<SUP>7</SUP>; Sandrine Wiramus, MD, PhD<SUP>8</SUP>; Boris Jung, MD, PhD<SUP>9</SUP>; ?bastien Perbet, MD<SUP>10</SUP>; Romain Hernu, MD<SUP>11</SUP>; Andr? Nau, MD<SUP>12</SUP>; Olivier Baldesi, MD<SUP>13</SUP>; Jerome Allardet-Servent, MD<SUP>14</SUP>; Karine Baumstarck, MD, PhD<SUP>15</SUP>; Elisabeth Jouve, PhD<SUP>16</SUP>; Myriam Moussa, PhD<SUP>1</SUP>; Sami Hraiech, MD<SUP>1</SUP>; Christophe Guervilly, MD<SUP>1</SUP>; Jean-Marie Forel, MD<SUP>1</SUP>; for the STATIN-VAP Study Group
Author Affiliations: <SUP>1</SUP>Assistance Publique?H?pitaux de Marseille, H?pital Nord, R?animation des D?tresses Respiratoires et des Infections S?v?res UMR-CNRS 7278, Aix-Marseile Universit?, Marseille, France <SUP>2</SUP>CHU de Dijon, Service de r?animation m?dicale, Dijon, France <SUP>3</SUP>Assistance Publique - H?pitaux de Marseille, H?pitaux Sud, Pharmacie des H?pitaux Sud, Marseille, France <SUP>4</SUP>Assistance Publique?H?pitaux de Marseille, H?pital de la Timone, R?animation des Urgences et M?dicale, Marseille, France <SUP>5</SUP>Centre Hospitalier de Perpignan, Service de R?animation, Perpignan, France <SUP>6</SUP>H?pital d?Instruction des Arm?es, H?pital Sainte-Anne, Service de r?animation, Toulon, France <SUP>7</SUP>CHU de Nimes, service des r?animations, Division anesth?sie, r?animation, douleur, urgence, N?mes, France <SUP>8</SUP>Assistance Publique - H?pitaux de Marseille, H?pital Nord, R?animation polyvalente, Marseille, France <SUP>9</SUP>D?partment d?Anesth?sie R?animation Saint Eloi, Centre Hospitalier Universit? de Montellier et Institut National de la Sant? et de la Recherche M?dicale U-1046 (INSERM U-1046), Montpellier, France <SUP>10</SUP>H?pital Estaing, Service de r?animation adulte, Clermont-Ferrand, France <SUP>11</SUP>Hospices Civils de Lyon, H?pital Edouard-Herriot, Service de r?animation m?dicale, Lyon, France <SUP>12</SUP>H?pital d?Instruction des Arm?es, H?pital Laveran, Service de r?animation, Marseille, France <SUP>13</SUP>Centre Hospitalier d?Aix-en-Provence, Service de r?animation, Aix-en-Provence, France <SUP>14</SUP>H?pital Ambroise Par?, Service de r?animation, Marseille, France <SUP>15</SUP>Unit? d?Aide M?thodologique ? la Recherche Clinique?Assistance Publique?H?pitaux de Marseille; Aix-Marseille Universit?, Facult? de m?decine, Marseille, France <SUP>16</SUP>CIC-Centre de Pharmacologie Clinique et d?Evaluations Th?rapeutiques; H?pital de la Timone, Assistance Publique?H?pitaux de Marseille, Marseille, France
JAMA. Published online October 09, 2013. doi:10.1001/jama.2013.280031
ABSTRACT
Importance
Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality.
Objective
To determine whether statin therapy can decrease day-28 mortality in patients with VAP.
Design, Setting, and Participants
Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients.
Interventions
Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.
Main Outcomes and Measures
Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14.
Results
The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, −3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, −1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score.
Conclusions and Relevance
In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.
Trial Registration clinicaltrials.gov Identifier: NCT01057758
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Online First / Original Investigation | October 09, 2013 Caring for the Critically Ill Patient
Effect of Statin Therapy on Mortality in Patients With Ventilator-Associated Pneumonia: A Randomized Clinical Trial
FREE ONLINE FIRST
Laurent Papazian, MD, PhD<SUP>1</SUP>; Antoine Roch, MD, PhD<SUP>1</SUP>; Pierre-Emmanuel Charles, MD, PhD<SUP>2</SUP>; Christine Penot-Ragon, PharmD<SUP>3</SUP>; Gilles Perrin, MD<SUP>4</SUP>; Philippe Roulier, MD<SUP>5</SUP>; Philippe Goutorbe, MD<SUP>6</SUP>; Jean-Yves Lefrant, MD, PhD<SUP>7</SUP>; Sandrine Wiramus, MD, PhD<SUP>8</SUP>; Boris Jung, MD, PhD<SUP>9</SUP>; ?bastien Perbet, MD<SUP>10</SUP>; Romain Hernu, MD<SUP>11</SUP>; Andr? Nau, MD<SUP>12</SUP>; Olivier Baldesi, MD<SUP>13</SUP>; Jerome Allardet-Servent, MD<SUP>14</SUP>; Karine Baumstarck, MD, PhD<SUP>15</SUP>; Elisabeth Jouve, PhD<SUP>16</SUP>; Myriam Moussa, PhD<SUP>1</SUP>; Sami Hraiech, MD<SUP>1</SUP>; Christophe Guervilly, MD<SUP>1</SUP>; Jean-Marie Forel, MD<SUP>1</SUP>; for the STATIN-VAP Study Group
Author Affiliations: <SUP>1</SUP>Assistance Publique?H?pitaux de Marseille, H?pital Nord, R?animation des D?tresses Respiratoires et des Infections S?v?res UMR-CNRS 7278, Aix-Marseile Universit?, Marseille, France <SUP>2</SUP>CHU de Dijon, Service de r?animation m?dicale, Dijon, France <SUP>3</SUP>Assistance Publique - H?pitaux de Marseille, H?pitaux Sud, Pharmacie des H?pitaux Sud, Marseille, France <SUP>4</SUP>Assistance Publique?H?pitaux de Marseille, H?pital de la Timone, R?animation des Urgences et M?dicale, Marseille, France <SUP>5</SUP>Centre Hospitalier de Perpignan, Service de R?animation, Perpignan, France <SUP>6</SUP>H?pital d?Instruction des Arm?es, H?pital Sainte-Anne, Service de r?animation, Toulon, France <SUP>7</SUP>CHU de Nimes, service des r?animations, Division anesth?sie, r?animation, douleur, urgence, N?mes, France <SUP>8</SUP>Assistance Publique - H?pitaux de Marseille, H?pital Nord, R?animation polyvalente, Marseille, France <SUP>9</SUP>D?partment d?Anesth?sie R?animation Saint Eloi, Centre Hospitalier Universit? de Montellier et Institut National de la Sant? et de la Recherche M?dicale U-1046 (INSERM U-1046), Montpellier, France <SUP>10</SUP>H?pital Estaing, Service de r?animation adulte, Clermont-Ferrand, France <SUP>11</SUP>Hospices Civils de Lyon, H?pital Edouard-Herriot, Service de r?animation m?dicale, Lyon, France <SUP>12</SUP>H?pital d?Instruction des Arm?es, H?pital Laveran, Service de r?animation, Marseille, France <SUP>13</SUP>Centre Hospitalier d?Aix-en-Provence, Service de r?animation, Aix-en-Provence, France <SUP>14</SUP>H?pital Ambroise Par?, Service de r?animation, Marseille, France <SUP>15</SUP>Unit? d?Aide M?thodologique ? la Recherche Clinique?Assistance Publique?H?pitaux de Marseille; Aix-Marseille Universit?, Facult? de m?decine, Marseille, France <SUP>16</SUP>CIC-Centre de Pharmacologie Clinique et d?Evaluations Th?rapeutiques; H?pital de la Timone, Assistance Publique?H?pitaux de Marseille, Marseille, France
JAMA. Published online October 09, 2013. doi:10.1001/jama.2013.280031
ABSTRACT
Importance
Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality.
Objective
To determine whether statin therapy can decrease day-28 mortality in patients with VAP.
Design, Setting, and Participants
Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients.
Interventions
Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.
Main Outcomes and Measures
Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14.
Results
The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, −3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, −1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score.
Conclusions and Relevance
In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.
Trial Registration clinicaltrials.gov Identifier: NCT01057758
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