Journal watch: recent studies of note

Recent studies about warfarin use in elderly AF patients, ticagrelor vs. clopidogrel in ACS patients, and other topics.


Benefits may outweigh risks for elderly AF patients on warfarin, study concludes

The risk of major bleeding is higher in elderly patients than in younger patients with atrial fibrillation taking warfarin, but careful management can keep the risks acceptably low, a recent study concluded.

In the prospective observational study, researchers looked at 783 patients with AF on warfarin who spent (respectively) a median of 14%, 71% and 15% of time below, within and above the intended therapeutic range. There was no difference in treatment quality between patients younger than or older than 80 years, but bleeding risk was higher in patients with a history of previous cerebral ischemic event and patients age 80 or older. The study appeared in the Journal of the American College of Cardiology.

The findings indicate that the absolute risk of major bleeding in patients aged 80 or older is acceptably low (2.5 × 100 patient/years), the authors concluded. While a previous study found a fivefold increase in major bleeding among elderly AF patients, that study included more patients with coronary artery disease and concomitant use of aspirin, they said.

The authors noted that using computer-assisted systems for dose adjustment may have helped achieve the low bleeding rates found in the study. Overall, the findings suggest that elderly patients can benefit from warfarin therapy provided that good-quality anticoagulation can be obtained based on ranges set by the international normalized ratio.

Warfarin lowers stroke risk in older AF patients but risk may rise in patients with ESRD

Elderly adults at high risk for stroke benefit most from the use of warfarin for atrial fibrillation (AF) according to one study, but another study warns that warfarin may increase the risk of stroke in AF patients on hemodialysis.

In the first study, published in the Sept. 1 Annals of Internal Medicine, researchers studied six-year rates of ischemic stroke and intracranial hemorrhage in more than 13,000 adults with nonvalvular AF. The adjusted net clinical benefit of warfarin overall was 0.68% per year and was greatest among patients who had a history of ischemic stroke or were 85 years or older. The authors concluded that risk assessment for prescribing anticoagulants in AF patients should incorporate risks for both thromboembolism and intracranial hemorrhage.

The authors noted that patients with the highest CHADS-2 scores (one point for each of congestive heart failure, hypertension, age and diabetes and two points for stroke) benefited most from anticoagulation while those in the lowest-risk categories showed little benefit, findings that validate recent guidelines restricting recommendations for anticoagulant therapy to patients with a CHADS-2 score of two or more. They concluded that their findings highlight the potentially significant net clinical benefit of warfarin anticoagulation for patients with AF at high risk for ischemic strokes.

In the second study, published in the Journal of the American Society of Nephrology, researchers studied the association between the use of warfarin, clopidogrel or aspirin and new stroke, mortality and hospitalization in a retrospective cohort of 1,671 hemodialysis patients with pre-existing AF. After an average follow-up of 1.6 years, warfarin use (compared with non-use) was associated with a significantly increased risk of new stroke (both ischemic and hemorrhagic), but not of all-cause mortality or hospitalization. The risk was greatest among patients who did not receive international normalized ratio monitoring in the first 90 days of dialysis. Clopidogrel or aspirin use was not associated with an increased risk of new stroke.

The findings, combined with the results of a previous study that found increased mortality risk with anticoagulation use in end-stage renal disease (ESRD) patients, should raise concern about the use of warfarin in dialysis patients, the authors noted, but they cautioned that large randomized trials are needed before changing recommendations. For now, they said, physicians should conduct careful risk evaluations and ensure close monitoring of ESRD patients on warfarin to minimize risks of hemorrhagic complications.

Ticagrelor led to lower mortality rates than clopidogrel in ACS patients

Treatment with ticagrelor in patients with acute coronary syndrome (ACS) significantly reduced the rate of death from cardiovascular causes compared with clopidogrel, without raising the rate of overall major bleeding, a recent study concluded.

The multicenter, double-blind, industry-sponsored randomized trial compared outcomes in 18,624 patients admitted with ACS, with or without ST-segment elevation, who were treated with either ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg thereafter). After 12 months, the primary end point of death from vascular causes, myocardial infarction or stroke had occurred in 9.8% of ticagrelor patients compared with 11.7% in the clopidogrel group. Patients taking ticagrelor had significantly lower rates of myocardial infarction alone and death from vascular causes alone as well as from all causes, but there was no difference in stroke rates. There was also no significant difference in the rate of major bleeding between the two groups, but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting, including fatal intracranial bleeding. In addition, there were side effects that included dyspnea, bradyarrhythmias and increased serum creatinine. The results appear in the Sept. 10 New England Journal of Medicine.

An accompanying editorial noted that the availability of three agents for antagonizing platelet ADP receptors gives physicians more options, such as switching patients from clopidogrel or prasugrel to ticagrelor five to seven days before elective surgery. However, ticagrelor, like prasugrel, should likely be avoided in patients with a history of stroke or transient ischemic attacks and in patients with an excessively high risk of bleeding, as well as in those with chronic obstructive pulmonary disease, moderate or severe renal failure or a history of syncope.

Ticagrelor or prasugrel may be the preferred treatments for all remaining patients with ACS, the editorial continued, until there are data comparing these two agents. Future studies should evaluate the adverse effects of ticagrelor in a much larger number of patients, and patients who are given this drug should be carefully monitored for side effects, the editorialist said.

Procalcitonin test can be used to guide antibiotic use

Fewer antibiotics were used to treat lower respiratory infections when treatment decisions were based on a measurement of procalcitonin instead of standard guidelines, a recent study found.

The randomized controlled trial included 1,359 patients seen in Swiss emergency departments for lower respiratory tract infections. Physicians treated the patients according to either standard guidelines or a new algorithm that used serum procalcitonin (PCT) levels to determine the likelihood of a bacterial infection. Patients who were admitted to the hospital received repeat PCT tests to determine when to discontinue antibiotic therapy.

The intervention group had a lower mean duration of exposure to antibiotics (5.7 days vs. 8.7; 95% CI for difference, −40.3% to −28.7%). Even greater relative differences in treatment duration were seen in the subgroups of patients who had exacerbation of chronic obstructive pulmonary disease and acute bronchitis. Antibiotic-associated adverse events were less frequent in the PCT group (19.8% vs. 28.1%; 95% CI, −12.7% to −3.7%), but overall adverse events were similar and the PCT patients had a slightly higher mortality rate (5.1% vs. 4.8%).

The use of the PCT algorithm had different effects depending on the patients' diagnoses, the researchers noted. In patients with community-acquired pneumonia, the algorithm was expected to shorten treatment duration, while antibiotics were less likely to be used at all in treatment of acute bronchitis. A reduction in antibiotic use would help to reduce individual antibiotic-associated costs and adverse events as well as discourage the growth of drug-resistant organisms, the researchers concluded. They noted that point-of-care testing for PCT is becoming more available in the U.S.

An accompanying editorial cautioned that more generalizable data on effectiveness and safety will be needed before the algorithm can be widely adopted. The editorialist expressed concern about the mortality difference between the groups, and noted that the study did not assess the cost-effectiveness of PCT testing as a means to reduce antibiotic overuse. The research was published in the Sept. 9 Journal of the American Medical Association.

Protein may be marker for circulatory failure in sepsis patients

High plasma levels of heparin-binding protein (HBP) may be a marker for identifying patients at risk for sepsis with circulatory failure, a study found.

Researchers studied 233 febrile adult patients with suspected infection and classified them based on systemic inflammatory response syndrome criteria, organ failure and final diagnosis. Blood samples were analyzed for HBP, procalcitonin, interleukin-6, C-reactive protein and number of white blood cells. They found that a plasma HBP level of 15 ng/mL or was a significant indicator of severe sepsis and eventual circulatory failure. The study was published online Sept. 2 in Clinical Infectious Diseases and appears in the Oct. 1 issue.

The results show a close correlation between increased HBP plasma levels and the development of hypotension, organ failure and septic shock, the authors said. Of the 26 patients with septic shock, 24 had increased plasma HBP at enrollment while 37 of the remaining 44 patients with severe sepsis had elevated HBP levels. In contrast, only seven patients among the 100 with nonsevere sepsis had increased HBP.

The findings suggest that a normal HBP level in a febrile patient with suspected infection would likely rule out the risk of severe sepsis, the authors said. The results have important clinical implications since delay of proper treatment has a large impact on mortality in patients with septic shock. The authors noted that in the study, a high HBP level preceded circulatory failure by several hours in many patients.

The findings indicate that intensifying fluid resuscitation and beginning proper antibiotic treatment in febrile patients with high HBP levels has the potential to prevent circulatory failure, the authors said. However, they noted that HBP is not a marker for bacterial infection because patients with some invasive bacterial infections had normal HBP levels.

Study identifies potential markers of adverse outcomes following liver transplant

History of stroke, coronary artery disease, postoperative sepsis and increased interventricular septal thickness were markers of adverse cardiac outcomes after liver transplantation in a retrospective study of older patients at intermediate cardiac risk.

Researchers retrospectively studied patients (mean age 52±9 years, 67% male) who had liver transplants between 2001 and 2005 and analyzed outcomes of nonfatal myocardial infarction (MI), death and either outcome within the first 30 days after surgery. During this perioperative period, 7% of patients suffered MIs and 9% died. Using a multivariate model, researchers determined that history of coronary artery disease (CAD), prior stroke and postoperative sepsis predicted greater risk while the use of perioperative beta-blockers was protective for combined cardiac outcomes. The study was published online Sept. 14 in Circulation and appears in the November issue.

Although the study analyzed many cardiac risk factors, including diabetes, hypertension and age, only history of CAD and stroke significantly increased perioperative cardiac outcomes in the 30-day period, the authors said. Increased intraventricular septal thickness—likely a surrogate marker for left ventricular hypertrophy—also increased risk of death, they added.

The study also found that a normal stress test had a very high negative predictive value (>90%) in all transplant patients, the authors noted. However, an abnormal stress echocardiography was not associated with adverse cardiac outcomes, suggesting that only patients at low risk for negative cardiac outcomes would benefit from noninvasive stress testing.

Current guidelines recommend perioperative beta-blockers during noncardiac surgery in high-risk patients but not lower-risk patients, the authors noted. The protective effect of beta-blockers found in this study likely reflects its high-risk population, they noted, adding that the finding needs to be further evaluated in randomized trials.

The authors emphasized that the results provide insight into this specific population, and future prospective randomized trials are needed that analyze the role of stress testing, use of beta-blockers, and identification of variables associated with adverse cardiac outcomes before firm conclusions or recommendations can be made.

Tip location may affect thromboembolic risk in peripherally inserted central catheters

The location of the catheter tip during placement of a peripherally inserted central catheter may affect thromboembolic risk, according to a new study.

Researchers performed a retrospective chart review at a single hospital in Memphis, Tenn., to determine rates of venous thromboembolism (VTE) after placement of a peripherally inserted central catheter (PICC). The primary outcome measures were upper-extremity deep venous thrombosis, defined as a symptomatic event in the ipsilateral extremity subsequently confirmed by duplex ultrasonography, and pulmonary embolism, defined as a symptomatic event leading to ventilation-perfusion lung scan or spiral CT. The study results are in the September Journal of Hospital Medicine.

Nine hundred fifty-four PICCs were inserted in 777 patients from Aug. 1 to Nov. 1, 2005. Thirty-eight patients (4.89%) developed one or more VTEs while in the hospital (total PICC-days, 7,444; 5.10 VTEs/1,000 PICC-days). Twenty-seven patients (3.47%) developed upper-extremity deep venous thrombosis, four (0.51%) developed superficial upper-extremity thrombosis and eight (1.03%) developed pulmonary embolism. The PICC was inserted in the superior vena cava (SVC) in 85.3% of patients; VTE risk was higher in those whose PICC was inserted at a different location from the SVC or SVC/right atrial junction (odds ratio, 2.61 [95% CI, 1.28 to 5.35]). Patients with a history of VTE were more likely to develop PICC-related VTE (odds ratio, 10.83 [95% CI, 4.89 to 23.95]), as were patients who had a longer length of stay (odds ratio, 1.21 [95% CI, 1.07 to 1.37]). Duration of PICC use also seemed to be associated with VTE risk, but the relationship was not statistically significant.

The authors acknowledged the limitations of their study, including an inability to determine independent risk factors and a possible underestimation of PICC-associated VTE rates. However, they concluded that approximately 5% of patients who receive PICCs while hospitalized will develop VTEs, especially those with a history of the condition, and that current use of large (5 French) double-lumen catheters may be more likely to cause thrombosis. They suggested that the location of the catheter tip at insertion “may be an important modifiable risk factor.”

Warfarin still underused at discharge for heart failure and atrial fibrillation

Warfarin continues to be widely underused at discharge for patients with heart failure and atrial fibrillation, and compliance with guidelines varies significantly among hospitals and geographic areas, a recent study concluded.

Researchers analyzed 72,534 heart failure (HF) admissions over three years at 255 hospitals participating in the American Heart Association's Get with the Guidelines HF program. Among eligible HF patients with atrial fibrillation (AF) without contraindications, the median prevalence of warfarin therapy at discharge was 64.9%. Increasing age, nonwhite race, anemia and treatment in the South were associated with not receiving warfarin, as was CHADS-2 risk (congestive heart failure, hypertension, age >75 years, diabetes, and prior stroke or transient ischemic attack). The study appears in the Sept. 29 Journal of the American College of Cardiology.

Guidelines have recommended using warfarin to treat HF patients with AF since 2005, the authors noted. However, rates of warfarin use did not improve over the course of the study. Another concerning finding, they added, was the variation in warfarin use among hospitals, with warfarin less likely to be used at smaller hospitals and hospitals in the South.

Underuse of warfarin has significant clinical implications, the authors continued. They estimated the risk of stroke or transient ischemic attack in the study's hospitalized cohort at 5.9% per year, based on a mean CHADS-2 score of 3. Failure to prescribe warfarin in the 5,475 HF admissions could have led to between 110 and 216 preventable thromboembolic events, they said. Generalized to the U.S. population of HF and AF, that would mean 7,000 preventable events per year.

An accompanying editorial noted that while registries are valuable tools for managing evidence-based care, they often do not consider “real life” issues, such as physical, social and mental vulnerabilities, that might influence a physician's decision about warfarin use. For example, while the population of the registry was elderly, common geriatric problems such as cognitive impairment and fall risk were not recorded.

The current study's findings, while not a substitute for evidence from a randomized trial, should lead to more research into the root causes of warfarin underuse in HF patients with AF, and to quality improvement interventions to address the problem, the editorial concluded.

At-home treatment for heart failure matches hospital

Heart failure patients who were treated at home for acute decompensation of chronic heart failure (CHF) had similar outcomes to those admitted to the hospital, a new study found.

The Italian study was a randomized, controlled trial of the Geriatric Home Hospitalization Service, in which hospital professionals (including geriatricians, nurses, physiotherapists and a social worker and counselor) treated patients at their homes. The study participants were at least 75 years old and were admitted to the study hospital's emergency department for acute decompensation of CHF. They were then either admitted to the general medicine ward (n=53) or the hospital-at-home program (which included education for patients and families and frequent physician and nurse visits) (n=48).

The primary outcome, six-month mortality, was the same in the two groups, as was the number of hospital admissions during six-month follow-up. The patients treated at home had a longer mean time to their next admission (84.3 days vs. 69.8 days, P=0.02). The home group also showed improvements in depression, nutritional status and quality of life. Four of the home patients were transferred to the hospital during the study, but after discharge, all were at home, while 16% of the hospital group were discharged to long-term care facilities.

The study demonstrates that hospital-at-home care is a viable, efficacious alternative to hospitalization for acutely decompensated CHF, the study authors concluded. They noted that although the home patients were on average treated for longer than the inpatients, the mean total cost was lower for patients treated at home $2,604 vs. $3,028). The study was published in the Sept. 28 Archives of Internal Medicine.

Despite its successes, wider dissemination of the hospital-at-home model is impeded by many factors, including Medicare reimbursements, hospital incentives, geriatrician shortages, and adaptability, according to an accompanying editorial that called for a broadening of the availability of these models and awareness campaigns to educate consumers about their benefits, since 46% of patients eligible for the study declined to be assigned to hospital-at-home care.

Three-point risk score predicts mortality in patients admitted for acute COPD

A simple risk scoring system may help predict the severity of acute exacerbations of chronic obstructive pulmonary disease (COPD) at admission, a new study found.

Researchers analyzed more than 88,000 patients admitted with acute exacerbations of COPD over two years and used recursive partition to create risk classifications for in-hospital mortality, with need for mechanical ventilation as a secondary endpoint. Three variables proved to be predictive of mortality: serum urea nitrogen level greater than 25 mg/dL, acute mental status change, and pulse greater than 109 beats per minute.

For patients with all three risk factors, the mortality rates were 13.1% and 14.6% in the derivation and validation cohorts, respectively, compared with 0.3% in both cohorts among patients who did not have the risk factors and were younger than 65 years. The area under the receiver-operating curve in the two cohorts was 0.72 and 0.71, respectively, for mortality, and 0.77 (both cohorts) for mechanical ventilation. The study appears in the Sept. 28 Archives of Internal Medicine.

The assessment tool may be especially valuable because it relies on information that is easily obtainable in the emergency department, the authors said. The existing assessment tool for COPD, the BODE score (body mass index, degree of airflow obstruction and dyspnea and exercise capacity), requires extensive assessment of many risk factors and is difficult to implement in the ED, they noted.

The authors acknowledged possible limitations of the study, including reliance on administrative data for diagnosis of acute exacerbations of COPD; exclusion of patients with a principal diagnosis of acute respiratory failure; and lack of information on certain COPD-specific covariates, especially forced expiratory volume in the first second of expiration. However, they emphasized that the goal of the study was to create a score that could be easily used with routinely available data.

The authors concluded that while no assessment tool is infallible, applying the risk score might enhance care of patients with acute exacerbations of COPD by predicting risk of death and need for mechanical ventilation.