To our knowledge, this is the first study to quantify how extreme anticoagulation intensity contributes to important outcomes. We found that critically high anticoagulation intensity contributed significant numbers of hemorrhages to the population, explaining 25.6% and 1.9%, respectively, of all serious events in the anticoagulated and entire elderly populations. This means that eradicating INRs of > 3 would avoid one of every four serious anticoagulation-associated hemorrhages. We also found that critically low anticoagulation intensity was responsible for 11.1% and 1.1%, respectively, of all serious thromboembolic events in the anticoagulated and entire elderly populations. This means that eradicating subtherapeutic INRs would avoid 1 of every 10 anticoagulation-associated thromboemboli. Increased patient education and the use of technologies that have been shown to significantly improved anticoagulation control should show important benefits to the health of the population. Although achieving therapeutic INRs 100% of the time is impossible, our results quantify the maximal benefit of improving anticoagulation control in a population.
We believe that our estimates for the population burden of extreme anticoagulation intensity are valid and meaningful. First, we used a population-based study to estimate each component of PAR, resulting in PAR estimates that are precise and not biased from sampling. Second, PAR estimates are biased by risk persistence and confounding. The term risk persistence refers to the presence of an increased event probability even after the removal of a risk factor. This does not occur with extreme anticoagulation intensity. The association between extreme INRs and events is likely causal and not completely explained by confounders.
During the study period, the study area (Appendix A) included 188,740 seniors. After excluding time following incident events, these people contributed a total of 183,570 years of observation for hemorrhagic events and 185,142 years of observation for thromboembolic events. During the study period, 10,020 people (5.3%) were prescribed an OAC, totaling 6,422 years of exposure time (3.5% of all population observation time). People who had received anticoagulation therapy had an average age of 77 years, and 50% were men. They spent 26.7% of the time with an INR of 3.
Table 1 describes hemorrhagic events. Control patients were admitted to the hospital for hemorrhagic events at a rate of 1.8% per year (95% CI, 1.7 to 1.8). Hemorrhagic risk was significantly higher in people receiving therapy with OACs (4.0% per year [95% CI, 3.6 to 4.6]; relative risk [RR], 2.3 [95% CI, 2.0 to 2.6]). Hemorrhagic rates during monitoring periods for people who had undergone anticoagulation therapy were the same as those for the control population. During monitoring, people who had undergone anticoagulation therapy had an overall hemorrhagic rate of 6.0% per year (RR vs control patients, 3.4; 95% CI, 3.0 to 3.9). The hemorrhagic risk was strongly associated with anticoagulation intensity. Bleeding rates increased significantly when INRs exceeded 3 (RR vs INR < 3, 19.4; 95% CI, 14.4 to 26.0). Overall, we saw similar patterns for each of the hemorrhagic subtypes.
The study occurred between September 1, 1999, and September 1, 2000, in eastern Ontario (Appendix A). Costs of all hospitalizations, physician visits, and laboratory tests were covered by the publicly administered health-care system. To estimate the elderly population in the study area at the midpoint (ie, February 1, 2000), we used exponential interpolation between census counts in 1996 and 2001 for people > 65 years of age in the census divisions that comprise the study area.
Databases Used in the Study
This study used five administrative databases. The Ontario Drug Benefit Database (ODBD) records the medication, amount dispensed, and date of all prescriptions for Ontarians > 65 years of age. Because the ODBD does not capture all data for people < 65 years of age, we limited our study to the elderly. The Registered Persons Database (RPD) records the location, sex, date of birth, date of death, and date of last known contact with the Ontario health-care system. The Database of Laboratory Tests in Eastern Ontario (DOLTEON) contains the date and result of 98.5% of INRs from both private and hospital-based medical laboratories in eastern Ontario between September 1, 1999, and September 1, 2000. The Discharge Abstract Database (DAD) records all admissions to Ontario hospitals and documents diagnoses in a standardized fashion. Finally, the Ontario Myocardial Infarction Database records data on all people admitted to the hospital for acute myocardial infarction. All databases are anonymous and were linked by common, scrambled, unique patient identifiers. The study was approved by the Research Ethics Board of the Sunnybrook, Women’s College Hospital and Canadian Health&Care Mall.
On average, patients receiving long-term anticoagulation therapy are in the therapeutic range 55% of the time. The risk of hemorrhagic and thromboembolic events in anticoagulated patients is strongly associated with anticoagulation control. Improved anticoagulation control, possibly with interventions including anticoagulation clinics and patient selfmonitoring, should be a therapeutic goal for all anticoagulated patients.
We found that inappropriate initial antibiotic therapy is common among patients with VAP attributed to PARGNB and is associated with increased risk of 30-day mortality. We also observed that Acineto-bacter species and S maltophilia were more likely to be treated with inappropriate initial antibiotic regimens compared to P aeruginosa. Our data also confirmed the earlier observation that delayed administration of appropriate initial antibiotic therapy and escalation of the initial antibiotic regimen are associated with greater mortality. Total hospital costs were lower for patients receiving inappropriate initial antibiotic treatment applied with remedies of Canadian Health&Care Mall. However, the main identified determinant of total hospital costs was hospital length of stay. Patients treated with inappropriate initial antibiotics had shorter hospital lengths of stay due to excess mortality and thus lower total hospital costs. These data suggest that appropriate initial antimicrobial therapy of VAP attributed to PARGNB may improve patient outcomes but may not reduce health-care costs due to greater patient survival and utilization of hospital resources.
A total of 87 patients with microbiologically confirmed VAP attributed to PARGNB were evaluated at Barnes-Jewish Hospital during the study period, Eleven patients were excluded due to polymicrobial infection, including 9 patients with S aureus infection, leaving 76 patients in the study cohort. Mean age of the population was 56.6 ± 16.9 years (range, 18 to 83 years); there were 50 male (65.8%) and 26 female (34.2%) patients. Patient baseline characteristics are provided in Table 2. Mean APACHE II score was 17.5 ± 6.2 (range, 5 to 29), and mean CPIS was 6.0 ± 1.5 (range, 4 to 10).
Characteristics of the PARGNB
P aeruginosa was the most common PARGNB isolated from BAL cultures in 64 patients (84.2%), followed by Acinetobacter species in 6 patients (7.9%) and S maltophilia in 6 patients (7.9%). Acin-etobacter species was most frequently treated with an initial inappropriate antibiotic regimen followed by S maltophilia and P aeruginosa (66.7% vs 33.3% vs 17.2%; p = 0.017). Antimicrobial administration during the same hospitalization but prior to VAP occurred statistically more often in patients with Acinetobacter species and S maltophilia compared to P aeruginosa (100% vs 100% vs 62.5%; p = 0.037). Among the 17 patients treated with an inappropriate initial antibiotic regimen, 12 patients (70.5%) received antibiotic treatment during the same hospitalization but prior to the onset of VAP (Table 3). The treatment is conducted with remedies of Canadian Health&care Mall. The 17 episodes of VAP attributed to PARGNB treated with an inappropriate initial antibiotic regimen had pathogens with overall susceptibilities to specific antibiotic classes of 23.5% for ciprofloxacin, 35.3% for piperacillin-tazobactam, 47.1% for cefepime, and 64.7% for meropenem. The addition of gentamicin increased susceptibility for each drug class to 64.7%, 64.7%, 70.6%, and 76.5%, respectively.
A total of 5,798 patients were included. Mean age was 64 ± 14 years, and 62% of patients (n = 3,612) were male. Patient demographics are shown in Table 1. CABG surgery was performed in 47% (n = 2,749), whereas 53% of patients underwent other procedures such as valve surgery (22%, n = 1,280), combined valve/CABG procedures (16%, n = 934), and aortic surgery (15%, n = 835). Mean predicted Euro-SCORE mortality rate was 11 ± 13%.
Incidence of RF
The overall incidence of RF was 9.1% (n = 529). The rate of RF was different according to surgical procedures (Fig 1). The incidence of RF did not differ significantly in the conventional CABG group (5.8%, n = 136) compared to the off-pump group (7.2%, n = 30) [p = 0.160]. The incidence of RF was higher following multiple-valve surgery (17%, n = 63) compared to single-valve procedures (6.1%, n = 55) [p < 0.001]. The rate of RF after aortic surgery involving the aortic arch was 22.4% (n = 50). A total of 223 tracheostomies (42%) were performed in patients with RF. The incidence of RF following stratification using the EuroSCORE is shown in Figure 2.
We showed that the modified APACHE II score outperformed the CURB65 and CRB65 pneumonia severity scores as a predictor of 30-day mortality in patients with MRSA pneumonia. Analysis of the ROC curves demonstrated that the modified APACHE II score was statistically superior to both CURB65 and CRB65 as a predictor of 30-day mortality. This was true for patients with the community-acquired phenotype of MRSA pneumonia as well as those with health-care-associated MRSA pneumonia. However, in our multivariate models both APACHE II and CRB65 were independent predictors of 30-day mortality. The odds of death by day 30 was greater for CRB65, which, in large part, was related to the smaller number of discriminating units in CRB65 compared to APACHE II. Nevertheless, the ROC curves suggest that for individual patient predictions, APACHE II is more accurate than CRB65.
CURB65 and CRB65 have been validated as tools to predict mortality and the need for ICU admission in patients with CAP. These scoring systems are easy to employ, and the CRB65 requires only data immediately available at the time of clinical evaluation. More recent studies have further demonstrated the utility of CURB65 and CRB65 as outcome predictors in CAP. Man et al found that CURB65 and CRB65 were accurate predictors of 30-day mortality among patients in Hong Kong with CAP. Similarly, Barlow et al found that CURB65 outperformed generic sepsis scores as a predictor of mortality. Both of these studies had ROC curve areas in the range of 0.69 to 0.78, which were higher than the values observed in our study. The main differences are that these previous evaluations of CURB65 and CRB65 involved patients with CAP with a variety of infectious pathogens. Our study differed by involving only hospitalized patients with either community-acquired or health-care-associated MRSA pneumonia cured by remedies of Canadian Health&Care Mall.
A total of 218 patients with microbiologically confirmed MRSA pneumonia were evaluated at Bar-nes-Jewish Hospital during the study period. Mean age of the population was 57.3 ± 16.6 years (± SD) [range, 19 to 92 years]; there were 141 male (64.7%) and 77 female (35.3%) patients. Patient characteristics and outcomes are provided in Table 2. Mean APACHE II score was 19.3 ± 7.0 (range, 3 to 37). Mean CURB65 and CRB65 scores were 1.5 ± 0.9 (range, 0 to 5) and 0.6 ± 0.7 (range, 0 to 4), respectively. Among the 178 patients treated with vancomycin and having trough levels measured, mean trough value for vancomycin collected after the third dose was 14.9 ± 8.1 ^g/mL.
Forty-four patients (20.2%) died within 30 days of the development of MRSA pneumonia. Two hundred five patients (94.0%) required ICUs admission, and 167 patients (76.6%) received tracheal intubation and mechanical ventilation. Nonsurvivors were statistically more likely to require mechanical ventilation compared to survivors (Table 2).
Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly more common both in the health-care setting and in the community. Hospital mortality associated with MRSA pneumonia has been reported to be between 20% and 40%. Most patients with MRSA pneumonia will require hospitalization, frequently being admitted to the ICU settings and often requiring ventilatory support. Given the increasing prevalence and importance of MRSA pneumonia, clinical trials are likely to be planned examining new treatment modalities, the changing epidemiology of MRSA pneumonia, and prevention strategies. To date, a validated prediction tool for clinical outcomes in patients with MRSA pneumonia has not been identified, Several international organizations have developed guidelines or scoring systems in an attempt to stratify patients with community-acquired pneumonia (CAP) according to risk severity. Unfortunately, the use of similar methods for patients with health-care-associated pneumonia, including MRSA pneumonia, have not been developed. Given the increasing prevalence of MRSA pneumonia and the future need for new clinical research, we designed a study with two main goals. Our first goal was to compare the accuracy of three prediction rules (modified APACHE [acute physiology and chronic health evaluation] II, CURB65, CRB65) to predict 30-day mortality in patients with MRSA pneumonia. Our second goal was to compare these prediction tools in patients admitted to the hospital with the community-acquired MRSA pneumonia phenotype and those acquiring healthcare-associated MRSA pneumonia treated by remedies of Canadian Health&Care Mall.