Insulin Therapy, C. Diff Update, LMWH or UFH for Acute Coronary Syndrome

C. Difficile Update

1. Loo VG, Poirier L, Miller MA, et al. A Predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005 Dec 8;353(23):2442-2449.
2. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005 Dec 8;353(23):2433-2441.
3. Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North American and Europe. Lancet. 2005 Sep 24-30;366(9491):1079-1084.

In 1978, Clostridium difficile was linked to antibiotic-associated diarrhea and pseudomembranous colitis. This spore-forming gram-positive rod causes disease through two toxins—A and B—which can be detected with cytotoxin assays. It colonizes a significant proportion of hospitalized patients, but causes disease in less than 1%. The primary risk factor for developing disease is antibiotic exposure, presumably through disruption of normal gut flora. Outcomes range from mild diarrhea to life-threatening pseudomembranous colitis requiring colectomy.

Since 2000 a number of hospitals in the United States and Canada have witnessed outbreaks of C. difficile characterized by increases in both the incidence and severity of disease. Three recent publications have shed light on the changes in microbiology that have contributed to those findings. All of the studies characterized C. difficile isolates from these outbreaks, and one included information about patient outcomes.

When isolates from the outbreaks were collected, all three studies identified a predominant strain of C. difficile known as NAP1/027. It accounted for 50%-82% of isolates from the outbreaks in these studies. In contrast, NAP1/027 was present in only 14 isolates from a database of more than 6,000 strains isolated in the United States prior to 2001.

NAP1/027 has a number of concerning microbiologic characteristics. It contains a deletion in the gene tcdC, which normally suppresses the production of toxins A and B. Warny, et al. found that the NAP1/027 strain produces levels of toxins A and B that are 16 and 23 times higher, respectively, than a historically dominant strain. NAP1/027 also produces a binary toxin previously uncommon in C. difficile isolates. The role of binary toxin is not well understood, but it may mediate increased pathogenicity. Finally, the NAP1/027 strain displays high levels of fluoroquinolone resistance, which is uncommon in previous strains of C. difficile.

Loo, et al. also studied patient outcomes in 1,703 patients with C. difficile disease outbreaks in 12 Canadian hospitals. The 30-day mortality rate attributable to C. difficile infection was 6.9%, compared with 0.5-5.5% in previous studies. Patients older than 80 had a higher risk of developing C. difficile infection. For those who did, the 30-day mortality rate attributable to C. difficile was more than 10%.

The discovery of the NAP1/027 strain should strengthen our resolve to use antibiotics judiciously, to recognize and treat C. difficile infections promptly, and to implement strict isolation when cases are discovered. Special attention should be given to elderly patients, who may be at higher risk. Finally, it stresses the importance of hospital epidemiology and infection control, areas in which hospitalists can take an active role.—SM

The Controversy of Thrombolytic Therapy in Hemodynamically Stable Patients with Acute PE

Söhne M, Ten Wolde M Boomsma F, et al. Brain natriuretic peptide in hemodynamically stable acute pulmonary embolism. J Thromb Haemost. 2006 Mar;4(3):552-526.

The role of thrombolytic therapy in hemodynamically stable patients with acute pulmonary embolism is controversial. Right ventricular dysfunction can be an indication for thrombolytics in some patients, but clinical examination is limited and emergent echocardiography is unavailable in many institutions. Rapid measurement of brain natriuretic peptide (BNP) as a marker of right ventricular strain may assist with decision-making in the management of acute PE. Söhne, et al, hypothesized that BNP at presentation would predict the risk of recurrent venous thromboembolism (VTE), including fatal pulmonary embolism.

A nested-case control study was performed within a large, randomized-controlled study of initial treatment of pulmonary embolism. Patients with recurrent VTE within three months were each matched to three controls. BNP levels were drawn at baseline, and both hypertension and congestive heart failure were evaluated as potential confounders.

Cases had significantly higher baseline BNP values than controls (2.45 pmol/L versus 0.80 pmol/L). The odds ratio for each unit increase in the (log) BNP was 2.4 (95% CI: 1.5-3.7). Hypertension was not a confounding factor, but patients with a history of congestive heart failure had no association between elevated BNP and recurrent VTE. Using receiver-operating characteristic analysis, the optimal BNP cut-off of 1.25 pmol/L resulted in a sensitivity and specificity for recurrent VTE of 60% and 62%, respectively.

Three recent studies have suggested that BNP can be used to predict adverse outcomes in patients with pulmonary embolism, including mortality and eventual need for mechanical ventilation, cardiopulmonary resuscitation or thrombolysis. In this study, which included only hemodynamically stable patients with acute pulmonary embolism, however, BNP did not independently predict adverse outcomes. Nonetheless, BNP may be a useful adjunct to other clinical data in deciding whether or not to initiate thrombolytic therapy in pulmonary embolism patients without a history of congestive heart failure.—CR

Insulin Therapy in the ICU

Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-461.

A landmark 2001 study by Van den Berghe, et al. compared tight versus liberal control of blood sugars in surgical ICU patients. The authors found that patients randomized to intensive insulin therapy had decreased mortality during intensive care compared to those receiving conventional treatment (ARR 3.4%, NNT 29).

In this follow-up study, Van den Berghe, et al., shifted the focus toward medical ICU patients. As their previous results were most dramatic in patients who stayed in the ICU for at least five days, they recruited patients expected to require at least three ICU days.

Twelve hundred patients were randomized to receive either conventional (goal BG 180-200 mg/dl) or intensive (goal BG 80-110 mg/dl) insulin treatment. The primary end point was all-cause mortality in the hospital. Secondary outcomes were also defined, including ICU mortality, 90-day mortality, days to weaning from mechanical ventilation, days in the ICU and in the hospital, renal failure, and incidence of bacteremia.

In the intention-to-treat analysis, there was no statistically significant difference in the primary end point of in-hospital mortality. Predefined subgroup analysis of patients who stayed in the ICU longer than three days showed a significant mortality benefit for the intensive insulin regimen (ARR 6.8%, NNT 15). However, in the subgroup of patients staying less than three days in the ICU, there was increased risk of death from all causes (ARI 8.2%, NNH 12). This finding did or did not meet statistical significance depending on the statistical method employed. Some secondary outcome measures assessing morbidity suggested a benefit of intensive insulin therapy. These included a reduction in kidney failure (ARR 3%, NNT 33), earlier weaning from mechanical ventilation, and earlier discharge from the ICU and from the hospital.

The results of this important study are sure to fuel more debate on ideal goals for blood sugar control in the critically ill. The study confirms previous findings that intensive insulin management improves mortality in patients with longer stays in the ICU. As length of stay in the ICU is difficult to predict in advance, the possibility of tight glycemic control increasing mortality in patients with short ICU stays complicates the decision to implement intensive insulin therapy. These results should especially give us pause in extrapolating the original study results to our sick floor patients.—RH

LMWH or UFH for High-Risk Patients with ACS

Mahaffey KW, Cohen M, Garg J, et al. High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial. JAMA. 2005 Nov 23;294(20):2594-2600.

In July 2004 the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial reported 30-day post hospitalization data. This study compared low molecular weight heparin (LMWH) to unfractionated heparin (UFH) during acute coronary syndrome (ACS) and found it “at least as effective” as UFH. Further data extending to six months and 12 months was reported in November.

This prospective, randomized, open-labeled multicentered trial enrolled 9,978 patients and compared LMWH versus UFH in ACS. Enrolled patients had had active ischemic symptoms within 24 hours of enrollment, and met two of the following three criteria:

1. Age 60 or older;
2. Elevated cardiac enzymes; and
3. Ischemic ECG changes other than ST elevations.

All patients were treated with standard medical therapy with 50% in both groups receiving GIIb/IIIa inhibitors. Interventions were pursued equally in both groups of patients; 92% had angiograms within 24 hours, 47% had percutaneous interventions, and 19% underwent coronary artery bypass grafting during the index hospitalization.

Six-month and 12-month data confirmed that LMWH use was noninferior to UFH. At six months there was no significant difference between the groups in frequency of nonfatal MI, further revascularization, CVA, or hospitalization. At 12 months, all cause mortality was found to be equivalent between the two groups. Interestingly, nearly 18% died or experienced nonfatal MI through six months of follow-up and 7.4% died by one-year follow-up, despite aggressive coronary revascularization and high use of evidence-based therapies at the time of hospital discharge.

When compared with other trials, these higher than “normal” rates of death and MI were believed related to the high-risk patient population and a lower threshold of cardiac enzyme abnormality. In this high-risk group of patients, LMWH and UFH appear to be equally safe and efficacious for the treatment of ACS, with equivalent long-term outcomes.—RM TH