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In the Literature

From: The Hospitalist, February 2007

Hospital Quality for AMI, Testing Dual Antiplatelet Therapy, Inhaled Insulin Therapy, and More

by Michael P. Phy, DO, MSc

IN THE LITERATURE

Hospital Quality for AMI: Process Measures and Their Relationship with Short-term Mortality

Bradley EH, Herrin J, Elbel B, et al. Hospital quality for acute myocardial infarction: correlation among process measures and relationship with short-term mortality. JAMA. 2006 Jul 5;296(1):72-78.

Background

The Centers for Medicare and Medicaid Services (CMS) and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) monitor and publicly report hospital performance in the treatment of acute myocardial infarction (AMI). Core process measures are considered an indicator of quality of care, but little is known about how these measures affect outcomes (mortality). Five of the seven core measures for AMI assess medication prescription practices; the other two measures are counseling on smoking cessation and timely reperfusion therapy.

Inferences about a hospital’s quality of care for AMI are created by measuring the hospital’s success at performing these measures. No previous study had evaluated a possible correlation between performance on these measures and short-term mortality. The authors of this study used National Registry of Myocardial Infarction (NRMI) and CMS databases to determine the association between hospital performance on AMI process measures and hospital-specific, risk-standardized, 30-day mortality rates.

There is a need for new research to define and study new AMI process measures that can explain more of the variance in both short- and long-term outcomes.

Methods

A cross-sectional study was performed using hospitals that reported AMI discharges to the NRMI from January 2002 through March 2003. Hospitals had to report a minimum of 10 eligible patients. Hospital performance on core measures was recorded: beta-blocker on admission, beta-blocker on dismissal, aspirin on admission, aspirin on dismissal, angiotensin-converting enzyme inhibitor (ACE) prescription on dismissal, smoking cessation counseling for smokers during admission, and time to reperfusion therapy. Risk-standardized, 30-day, all-cause mortality rates were calculated for each hospital using CMS Medicare claims for patients ages 66 and older with AMI. The primary analysis determined the association of hospital-specific, risk-standardized, 30-day mortality rates with hospital performance on the core process measures.

Results

The most successfully completed core process measure for AMI was aspirin on admission. A mean of 86.4% of participating hospitals completed this measure. The core process measure for AMI that was the least frequently documented was smoking cessation counseling; a mean of 13.9% of participating hospitals completed this measure. Notably, timely reperfusion therapy for AMI—fibrinolytic therapy within 30 minutes of arrival or percutaneous intervention within 120 minutes of arrival—was completed by only 54.5% (mean) of participating hospitals.

Each core process measure had a statistically significant but small correlation with the risk-standardized, 30-day mortality rate (explaining between 0.1% and 3.3% of variance in mortality). Of the 180 hospitals in the top quintile of risk-standardized, 30-day mortality rates, only 31% were in the top quintile of the core process measures. A composite model of all seven core process measures determined that these measures could only explain 6% of the hospital-level variation in risk-standardized, 30-day mortality rates. Secondary analyses did not differ substantially.

Conclusions

In this study, each core process measure for AMI showed a modest correlation with 30-day mortality, but accounted for only 6% of 30-day mortality. This finding highlights the fact that continued measurement of these processes is valuable, but a hospital’s short-term mortality rates for AMI cannot be reliably inferred from performance on publicly reported process measures. These measures are weighted more toward long-term outcome measures. There is a need for new research to define and study new AMI process measures that can explain more of the variance in both short- and long-term outcomes.

Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events

Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006 Apr 20;354(16):1706-1717.

Background

Atherothrombotic disorders of the circulatory system are the leading cause of death and disability in the world. Low-dose aspirin has been shown to reduce ischemic event in populations above a certain risk threshold; however, aspirin alone may be insufficient treatment to prevent ischemic events in high-risk patients. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce ischemic events in patients with unstable angina, non-ST segment elevation and ST segment elevation myocardial infarction, as well as in those undergoing angioplasty and stenting.

The risk of moderate or severe bleeding in symptomatic patients was higher in the clopidogrel plus aspirin group than in the aspirin plus placebo group.

Methods

This was a prospective, multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of aspirin plus clopidogrel in comparison with aspirin plus placebo in patients at high risk for a cardiovascular event. Patients included in the study were 45 or older and had one of the following: multiple atherothrombotic risk factors, documented coronary artery disease, documented cerebrovascular disease, or documented symptomatic peripheral vascular disease. The primary efficacy endpoint was the first occurrence of myocardial infarction (MI), stroke, or death from cardiovascular causes. The primary safety endpoint was severe bleeding.

Results

A total of 15,603 patients were enrolled in the study. Treatment was permanently discontinued by 20.4% in the clopidogrel group as compared with 18.2% in the placebo group (P<0.001). A total of 4.8% of patients in the clopidogrel group and 4.9% in the placebo group discontinued treatment because of an adverse event (P=0.67). Other than the treatment medications, concomitant medication use was similar in both groups. A median follow-up of 28 months revealed that the rates of primary efficacy events in the clopidogrel and placebo group were similar (6.8% versus 7.3%, P=0.22, respectively). The rate of primary safety events was 1.7% in the clopidogrel group and 1.3% in the placebo group, P=0.09.

Conclusions

This trial enrolled patients who either had established atherothrombotic disease or were at high risk for such disease and found that there was no significant benefit associated with the use of clopidogrel plus aspirin compared to aspirin alone in reducing myocardial infarction, stroke, or cardiovascular death. The risk of moderate or severe bleeding in symptomatic patients was higher in the clopidogrel plus aspirin group than in the aspirin plus placebo group. Overall, these findings do not support the use of dual antiplatelet therapy across this broad patient population.

D-Dimer in the Diagnosis of Pulmonary Embolism

Kearon C, Ginsberg JS, Douketis J, et al. An evaluation of D-dimer in the diagnosis of pulmonary embolism: a randomized trial. Ann Intern Med. 2006 Jun 6;144(11):812-821.

Background

The clinical usefulness of the D-dimer test in the diagnosis of pulmonary embolism (PE) has been previously studied. In patients with suspected PE, it may be safe to omit additional diagnostic testing if a patient has a negative D-dimer test; however, this approach has never been evaluated in a randomized, controlled trial.

The investigators in this trial studied two subgroups of patients with suspected PE and a negative D-dimer: patients with a low clinical probability of PE and those with a moderate or high clinical probability of PE who had a non-diagnostic ventilation perfusion scan (VQ scan) and no proximal deep vein thrombosis on venous ultrasonography. The hypothesis was that patients with a negative D-dimer who do not have further testing for PE won’t have a higher frequency of venous thromboembolism during follow-up than patients who undergo routine diagnostic testing.

Even in patients with moderate to high pretest clinical probability, a non-diagnostic VQ scan, and normal venous ultrasonography, only one patient with a negative D-dimer had a venous thromboembolic event at six months follow-up.

Methods

Before any diagnostic testing, patients were assigned a probability score, using the Wells Criteria, to categorize the probability of PE as low or moderate to high.

Patients with low probability Wells scores: D-dimer testing was done on all patients with a low clinical probability of PE. Patients with a negative D-dimer were randomly assigned either to no additional diagnostic testing and no anticoagulation treatment or to additional diagnostic testing with an initial VQ scan. If the VQ scan was negative, then PE was excluded. If the VQ scan showed one or more segmental perfusion defects that were normally ventilated, then the scan was considered diagnostic for PE. If there were perfusion defects that did not meet the criteria for a high probability scan, then the scan was considered non-diagnostic. Patients with non-diagnostic scans underwent ultrasonography of the proximal veins of the legs. If deep vein thrombosis was present, PE was diagnosed. If ultrasonography was normal, the test was repeated after seven and 14 days. In all patients with a positive D-dimer, a VQ scan was performed.

Patients with moderate to high probability Wells scores: A VQ scan was performed on all patients with a moderate to high probability for PE. Patients with high probability scans were treated; patients with normal scans were not treated. Patients with non-diagnostic scans and normal venous ultrasonography were randomly assigned to receive either no additional testing or serial ultrasonography.

Outcomes: All patients were followed for six months for the development of venous thromboembolism after initial diagnostic testing.

Results

The study enrolled 1,126 patients. Overall, 160 patients (14.2%) had PE diagnosed at initial presentation or by venous ultrasonography. Of 952 patients who did not receive an initial diagnosis of PE, 11 (1.2%) had PE diagnosed at follow-up.

Patients with low probability Wells scores: Low clinical probability was present in 670 patients (60%). In patients with low clinical probability of PE, 373 (56%) had negative D-dimer tests and 297 (44%) had positive D-dimer tests. Of the 373 patients with low probability and negative D-dimer results, 187 were randomized to no additional testing and 186 received a VQ scan. The frequency of venous thromboembolism at six-month follow-up was similar in these two groups (-0.5% [CI, -3.0% to 1.6%]). Three patients with negative D-dimer tests were diagnosed with PE by VQ scan. Results were fairly complete (five patients without a six-month follow-up in the no additional testing group and one without a follow-up in the VQ scan group).

Twenty-four patients with low clinical probability and positive D-dimer results (n=297) were diagnosed with PE. Three patients did not complete the six-month follow-up. Of the remaining 294 patients, five patients had venous thromboembolism at six months.

Patients with moderate to high probability Wells scores: There were 456 patients (40%) had moderate or high clinical probability for PE. Each of these patients had a VQ scan. Non-diagnostic VQ scans and normal venous ultrasonography were performed on 226 patients. Of these 226 patients, 86 had a negative D-dimer and 140 had a positive D-dimer. Of the 86 patients with negative VQ scans, normal venous ultrasonography, and a negative D-dimer, 83 were randomly assigned to no additional testing or serial venous ultrasonography (42 and 41 respectively). At six months follow-up, one patient assigned to no additional testing had venous thromboembolism, and no patients in the additional testing group had venous thromboembolism.

Conclusions

The results of this trial suggest that it is safe to withhold additional diagnostic testing in patients with suspected PE, low pretest clinical probability, and a negative D-dimer test. Even in patients with moderate to high pretest clinical probability, a non-diagnostic VQ scan, and normal venous ultrasonography, only one patient with a negative D-dimer had a venous thromboembolic event at six months follow-up. The assay used for this study was an erythrocyte agglutination SimpliRED assay. Reported sensitivity is approximately 90%, and specificity is approximately 75%. To the readers, it should be noted that the authors defined a low probability Wells score as 4 rather than 1.5 or lower.

Efficacy and Safety of Inhaled Insulin Therapy in Adults with Diabetes Mellitus

Ceglia L, Lau J, Pittas AG. Meta-analysis: efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus. Ann Intern Med. 2006 Nov 7;145(9):665-675.

Background

Despite its effectiveness in attaining glycemic control, there is considerable resistance to insulin use by patients and healthcare providers, primarily because of the need for subcutaneous injection. In January 2006, the U.S. Food and Drug Administration (FDA) approved the first formulation of inhaled insulin for clinical use in nonsmoking adults with type 1 or type 2 diabetes and no pulmonary disease. The authors of this paper present a systematic review to examine the efficacy, safety, and patient acceptability of inhaled insulin.

All trials reported a statistically significant increase in overall patient satisfaction with inhaled insulin over subcutaneous insulin.

Methods

The authors conducted a search of MEDLINE to find English-language, randomized, controlled trials of inhaled insulin in nonpregnant adults with diabetes. To find unpublished studies, the authors reviewed the briefing document on Exubera powder for oral inhalation (Pfizer Inc., New York). An abstract was included if it reported original data from controlled trials in patients with type 1 or 2 diabetes and hemoglobin A1C outcomes for patients receiving inhaled insulin versus outcomes for a comparison group (subcutaneous insulin or oral hypoglycemics). Studies with less than 12 weeks duration were excluded because no comparison could be made regarding glycemic efficacy. For glycemic efficacy, the primary outcome was the treatment group difference in hemoglobin A1C from baseline. Secondary outcome was the proportion of patients with hemoglobin A1C levels less than 7%. To evaluate safety, the primary outcomes were severe hypoglycemia (glucose ≤36 mg/dL), cough, and treatment group difference in pulmonary function variables.

Results

Sixteen trials involving a total of 4,023 patients met inclusion criteria. Seven trials compared inhaled insulin with various subcutaneous insulin regimens in patients with type 1 diabetes. Nine trials compared inhaled insulin with subcutaneous insulin or oral hypoglycemic agents in patients with type 2 diabetes. Inhaled insulin was given with meals and titrated according to study-specific glucose goals. Subcutaneous insulin was titrated to the same specific goals. Doses of oral hypoglycemic agents were adjusted for glycemic targets in only two of the nine trials. The combined data from the studies demonstrated a small but statistically significant decrease in the levels of baseline hemoglobin A1C levels in favor of subcutaneous insulin (weighted mean difference 0.08%, [CI 0.03% to 0.14%]) in patients with type 1 or type 2 diabetes. The greatest advantage of subcutaneous insulin was noted in the study with the longest duration (104 weeks). There was no difference between the study groups in studies with duration of 24 weeks or less. Patients with type 1 or type 2 diabetes taking inhaled insulin were no more likely to achieve hemoglobin A1C levels less than 7% than those using subcutaneous insulin.

The combined data from studies comparing inhaled insulin to oral hypoglycemic agents in patients with type 2 diabetes showed that inhaled insulin lowered hemoglobin A1C levels more effectively (weighted mean difference -1.04%, [CI -1.59% to -0.49%]). In studies in which the oral hypoglycemic agents were titrated, inhaled insulin still lowered baseline hemoglobin A1C levels but to a lesser degree (weighted mean difference -0.20%, [CI - 0.34% to -0.07%]). Patients with type 2 diabetes taking inhaled insulin were more likely to achieve hemoglobin A1C levels less than 7% than those taking oral agents.

There was no difference in episodes of severe hypoglycemia in patients using inhaled insulin compared to those using subcutaneous insulin. A higher proportion of patients using inhaled insulin reported at least one episode of severe hypoglycemia compared to those using oral agents (risk ratio, 3.06 [CI 1.03 to 9.07]; 9.4% versus 3.5%, respectively).

With respect to pulmonary safety, all trials selected patients without histories of pulmonary problems and with at least six months of nonsmoking status. Pulmonary safety was assessed by self-reported symptoms and by pulmonary function tests. The most common pulmonary symptom associated with inhaled insulin was nonproductive cough. This symptom was reported more frequently compared to patients using subcutaneous insulin or oral agents (risk ratio, 3.52 [CI 2.23 to 5.56]; 16.9% versus 5.0%). Cough was noted early in the treatment course and diminished in frequency over time. Patients receiving inhaled insulin had a greater decrease in FEV1 (forced expiratory volume in the first second) from baseline than the comparator group (weighted mean difference, -0.031 L [CI-0.043 L to -0.020 L]). This decrease progressed slowly over the first six months but stabilized in studies of up to two years’ duration.

Only four trials reported data on overall patient satisfaction for inhaled insulin versus subcutaneous insulin. All trials reported a statistically significant increase in overall patient satisfaction with inhaled insulin over subcutaneous insulin. Patients randomly assigned to inhaled insulin were more likely to continue taking inhaled insulin than to switch back to subcutaneous insulin.

Conclusions

This meta-analysis showed that inhaled insulin is comparable to subcutaneous insulin in lowering hemoglobin A1C levels in patients with type 1 or type 2 diabetes. The proportion of patients reaching a target hemoglobin A1C of less than 7% was much lower in the studies in this meta-analysis as compared to levels in trials of intensive subcutaneous insulin therapy.

It’s more difficult to compare inhaled insulin with oral hypoglycemic agents because most studies involving oral agents used fixed dosing with different types of oral agents. There was a three-fold risk of severe hypoglycemia in patients using inhaled insulin compared to those using oral hypoglycemic agents. This is probably due to overall improved glycemic control in the inhaled insulin group. Cough was more common in the inhaled insulin groups, and there were small decreases in FEV1, but these did not progress over two years. The potential for pulmonary toxicity with long-term administration has not been evaluated and deserves further study.

Classic Literature

A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care

Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-417.

Background

There are important risks and benefits of red cell transfusion in critically ill patients. One concern is that anemia may not be tolerated well in this group. Because red cell transfusions are used to augment the delivery of oxygen to avoid the harmful effects of oxygen debt, transfusing patients to keep their hemoglobin levels higher than 10.0 g per deciliter has become a routine practice. There is concern, however, that critically ill patients may be at increased risk of immunosuppressive and microcirculatory complications of red cell transfusions. Also, concern about the safety and supply of red cell transfusions has encouraged a more conservative approach to transfusion strategies.

The authors of this study conducted a randomized, controlled, clinical trial involving critically ill patients with euvolemia to determine whether a restrictive transfusion strategy that maintains hemoglobin concentrations between 7.0 and 9.0 g per deciliter was equivalent to a liberal strategy of maintaining hemoglobin concentrations between 10.0 and 12.0 g per deciliter.

Methods

Enrolled patients were admitted to 25 different intensive care units in Canada between 1994 and 1997. Included patients were expected to have an intensive care unit stay longer than 24 hours and a hemoglobin concentration of 9.0 g per deciliter or less within 72 hours after admission and were considered euvolemic after initial treatment by physicians. Critically ill patients with euvolemia were randomized to either the restrictive or the liberal strategy. Patients were given one unit at a time, and the hemoglobin concentration was measured after each unit transfused. Transfusion was stopped when the patient’s hemoglobin concentration was in the target range. The primary outcome was death from all causes within 30 days of randomization.

Results

A total of 838 patients were enrolled in the study; 418 in the restrictive group and 420 in the liberal group. The average daily hemoglobin concentrations were 8.5 g per deciliter in the restrictive group and 10.7 g per deciliter in the liberal group (P<0.01). An average of 2.6 red cell units per patient was transfused in the restrictive group, as compared to an average of 5.6 red cell units in the liberal group (P<0.01). Thirty-three percent of patients in the restrictive group did not receive any transfusion; every patient in the liberal group received at least one red cell unit.

The rate of death from all causes in the 30 days after admission was 18.7% in the restrictive group and 23.3% in the liberal group (-0.84% to 10.2%, P=0.11). The inpatient mortality rates were lower in the restrictive group (22.2% versus 28.1%, P=0.05). More patients in the liberal group had some type of cardiac complication (21.0% versus 13.2% respectively, P<0.01). Subgroup analyses demonstrated that patients with lower APACHE II scores (20 or less) and patients younger than 55 had improved survival in the restrictive strategy group. There were no significant differences in 30-day mortality between treatment groups in the subgroup of patients with a primary or secondary diagnosis of cardiac disease (20.5% in the restrictive group and 22.9% in the liberal group, P=0.69).

Conclusions

The findings in this study indicate that the use of a restrictive red cell transfusion strategy to hemoglobin levels as low as 7.0 g per deciliter, combined with the maintenance of hemoglobin concentrations between 7.0 and 9.0 g per deciliter, was at least as effective as a more liberal strategy in critically ill patients with euvolemia. All-cause 30-day mortality was no different between the groups but favored the restrictive strategy. The rates of inpatient deaths were lower in the restrictive group. There were more cardiac complications in the liberal group. An important subgroup of patients, those with a history of cardiac disease, had no differences in mortality. The use of this strategy decreased the average number of red cell transfusions by 54%. TH


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