Opinion
LESS IS MORE PERSPECTIVE
Allison M. Wolfe, MD Department of Medicine, University of Colorado, Aurora. Mim Ari, MD Department of Medicine, University of Colorado, Aurora.
Patent Foramen Ovale and Stroke Prevention— To Close or Not to Close A Teachable Moment Story From the Front Lines A 65-year-old man with a history of chronic obstructive pulmonary disease, hyperlipidemia, and hypertension was seen in clinic for hospital follow-up. He had previously been admitted to the hospital with slurred speech and aphasia and diagnosed as having a left middle cerebral artery ischemic infarct. Tissue plasminogen activator was administered with a positive neurologic outcome. His only residual deficit was numbness in 3 digits in his right hand impacting his dexterity, which was improving with therapy. Initial workup to determine the cause of his stroke was unrevealing: no deep venous thrombosis (DVT) was seen on lower extremity ultrasonography; normal arteries were seen on carotid ultrasonography; and there was no thrombus in his left atrium. However, transesophageal echocardiography revealed a patent foramen ovale (PFO). He reported that the cardiologist wanted to close his PFO percutaneously to prevent future strokes. He was enthusiastic about pursuing this course of treatment and unaware of the data surrounding the efficacy, as well as the risks, of the procedure.
Teachable Moment
Corresponding Author: Allison M. Wolfe, MD, Department of Medicine, University of Colorado, 12631 E 17th Ave, PO Box B178, Academic Office 1, Aurora, CO 80045 (Allison.Wolfe @ucdenver.edu). jamainternalmedicine.com
Cerebral vascular accidents (CVAs) are a major cause of morbidity and mortality in the United States. In approximately one-third of CVAs, a cause is not determined, leaving patients and physicians with the frustrating diagnosis of cryptogenic stroke.1 It is hypothesized that some cryptogenic strokes may be caused by a venous embolism passing through a PFO and into the systemic circulation.2 While mechanically plausible, the role of PFO in CVA remains unclear. However, a wide range of therapies to address secondary prevention in patients with PFOs have been proposed and adopted, including percutaneous closure, antiplatelet therapy, and anticoagulation. These therapies have varying degrees of potential harm. Initial observational studies and meta-analyses have indicated decreased recurrent CVAs with PFO closure. However, 3 randomized clinical trials have not borne out this same conclusion. In CLOSURE-I,2 researchers compared medical therapy and PFO closure using the STARFlex Septal Closure System in patients with cryptogenic stroke or transient ischemic attack (TIA) and a PFO. They found no significant difference in the secondary end point of recurrent stroke: 2.9% vs 3.1% (95% CI, 0.41-1.98). Two other randomized trials in 2013, PC 3 and RESPECT, 4 also
failed to show clear benefit with PFO closure using the Amplatzer PFO Occluder. In PC, the recurrent stroke rate was 0.5% vs 2.4% (95% CI, 0.02-1.72). 3 In RESPECT, there was no difference in the primary composite outcome of nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization (0.66 events per 100 patient-years vs 1.38 events per 100 patient-years [95% CI, 0.22-1.11]).4 Despite the study population being limited to those with CVA only, and not those with CVA or TIA, the results did not reach statistical significance. Closure of a PFO is also not without risks. In CLOSURE-I, 2 PFO closure was associated with increased rates of atrial fibrillation (5.7% vs 0.7%). The higher risk of atrial fibrillation was not duplicated in either RESPECT3 or PC.4 Though the findings did not reach statistical significance, all 3 randomized clinical trials demonstrated a trend toward increased risk of serious adverse events in the procedural arm compared with medical therapy. It is not known how the risks of closure will compare with medical therapy in actual practice, since randomized clinical trials are generally not powered to detect important harms. Though without clear benefit in every case, PFO closure may be beneficial for certain patients. Subgroup analysis of the RESPECT trial indicated improved outcomes with PFO closure when atrial septal aneurysm was present and shunt size was substantial.4 Additionally, current guidelines recommend consideration of PFO closure in 2 circumstances (recommendations classified by the American College of Chest Physicians as grade 2C): recurrent cryptogenic stroke through aspirin therapy and cryptogenic stroke in the setting of both PFO and DVT.5 The role of PFO in cryptogenic stroke remains unclear. Existing evidence does not show a clear benefit in recurrent CVA prevention with PFO closure compared with medical therapy alone. Additional randomized trials currently ongoing may be able to more definitively answer this question through pooled meta-analysis, and they might better identify high-risk patients most likely to derive benefit from closure. The perils associated with PFO closure, while uncommon, can be serious and may well outweigh the benefits of closure in many patients. Our patient decided to pursue closure despite knowing that there is no research showing definitive decreased recurrent stroke risk. He desired to do “everything possible to stay alive” and concluded that the risks of the procedure were miniJAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Birmingham User on 05/29/2015
1545
Opinion Perspective
mal. It is imperative that physicians present to their patients the growing body of evidence, including the uncertainty of clinical ef-
fectiveness of PFO closure, to engage them in shared decision making and prevent preference misdiagnosis.
Published Online: August 25, 2014. doi:10.1001/jamainternmed.2014.3923.
cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991-999.
Conflict of Interest Disclosures: None reported.
3. Meier B, Kalesan B, Mattle HP, et al; PC Trial Investigators. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368(12):1083-1091.
1. Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke. 2009;40(4):1195-1203. 2. Furlan AJ, Reisman M, Massaro J, et al; CLOSURE I Investigators. Closure or medical therapy for
4. Carroll JD, Saver JL, Thaler DE, et al; RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092-1100.
5. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):7S-47S.
LESS IS MORE PERSPECTIVE
Bryan LeBude, MD Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. Gretchen Diemer, MD Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
CME Quiz at jamanetworkcme.com and CME Questions page 1712
Corresponding Author: Bryan LeBude, MD, Department of Medicine, Thomas Jefferson University Hospital, 1025 Walnut St, Ste 805, Philadelphia, PA 19107 (bryanlebude@gmail .com). 1546
Routine Blood Cultures for the Febrile Inpatient A Teachable Moment Story From the Front Lines A 67-year-old woman with a history of hypertension presentedtothehospitalafter1weekoffever,cough,anddyspnea. Physical examination demonstrated a temperature of39°C,respiratoryrateof24breaths/min,andinspiratory crackles auscultated at the left lung base. A chest radiograph showed a left lower lobe infiltrate. Findings from laboratory studies were notable for a blood urea nitrogen level of 21 mg/dL (to convert to millimoles per liter, multiply by 0.357). The patient was admitted to the general medicine inpatient service and started on ceftriaxone and azithromycin therapies for community-acquired pneumonia. During hospital day 1, the patient noted improvement in her symptoms. On attending physician rounds, a plan was made for transition to oral antibiotics on the following day, with consideration for discharge. Just prior to midnight on hospital day 1, the night coverage resident was called because the patient was found to have a temperature of 38.3°C. At this time she was asymptomatic, and the remainder of her examination findings were normal. The resident instructed the nurse to draw 2 sets of blood cultures. On hospital day 2, the patient noted continued improvement in her symptoms and remained afebrile since the previous night. Blood cultures drawn the night prior resulted as preliminarily positive for gram-positive cocci in clusters from 1 of 2 sets. The team subsequently started vancomycin therapy for possible methicillin-resistant Staphylococcus aureus bacteremia. This regimen was continued awaiting organism identification. On hospital day 4, the positive blood culture was reported as Staphylococcus epidermidis. Owing to the absence of signs or symptoms consistent with active infection by this organism, the result was concluded to be a contaminant. Vancomycin therapy was discontinued, and antibiotics were narrowed to azithromycin to complete a 7-day course. Following evaluation by physical therapy,
the patient was deemed safe for discharge on hospital day 5. The patient described anxiety regarding her diminished physical strength following a 5-day inpatient stay, in addition to concern that the added interventions and length of stay would result in financial hardship.
Teachable Moment Blood cultures have been the “gold standard” for detecting bacteremia since their earliest application, when Streptococcus viridans was identified as the cause of malignant endocarditis.1 With approximately 200 000 cases of bacteremia occurring in the United States each year and an associated mortality approaching 50% in certain populations, physicians carry a low index of suspicion for ordering blood cultures. As a result, a low percentage (4%-7%) of blood cultures are positive.2 Published guidelines do not specifically state when blood cultures should be drawn for most clinical conditions.3 Unfortunately a large portion (approximately half) of positive blood cultures are subsequently determined to be contaminants—skin flora inoculated into culture bottles.4 These false positives lead to inappropriate tests and interventions. Compared with truenegative results, false-positive results are independently correlated with a 39% increase in charged amounts for antibiotics and a 20% increase in total subsequent laboratory charges, in addition to an average increased length of stay of 4.5 days.4 Other potential harms for the patient include adverse effects of the unnecessary antibiotics, as well as concerns for increasing antibiotic resistance patterns in the setting of overuse as exemplified by the emergence of vancomycin-resistant organisms. The decision to obtain blood cultures for the febrile inpatient should consider the pretest probability of bacteremia, in addition to the likelihood that the results will influence management. A review by Coburn et al2 demonstrated that the pretest probability of bacter-
JAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Birmingham User on 05/29/2015
jamainternalmedicine.com
LESS IS MORE PERSPECTIVE
Allison M. Wolfe, MD Department of Medicine, University of Colorado, Aurora. Mim Ari, MD Department of Medicine, University of Colorado, Aurora.
Patent Foramen Ovale and Stroke Prevention— To Close or Not to Close A Teachable Moment Story From the Front Lines A 65-year-old man with a history of chronic obstructive pulmonary disease, hyperlipidemia, and hypertension was seen in clinic for hospital follow-up. He had previously been admitted to the hospital with slurred speech and aphasia and diagnosed as having a left middle cerebral artery ischemic infarct. Tissue plasminogen activator was administered with a positive neurologic outcome. His only residual deficit was numbness in 3 digits in his right hand impacting his dexterity, which was improving with therapy. Initial workup to determine the cause of his stroke was unrevealing: no deep venous thrombosis (DVT) was seen on lower extremity ultrasonography; normal arteries were seen on carotid ultrasonography; and there was no thrombus in his left atrium. However, transesophageal echocardiography revealed a patent foramen ovale (PFO). He reported that the cardiologist wanted to close his PFO percutaneously to prevent future strokes. He was enthusiastic about pursuing this course of treatment and unaware of the data surrounding the efficacy, as well as the risks, of the procedure.
Teachable Moment
Corresponding Author: Allison M. Wolfe, MD, Department of Medicine, University of Colorado, 12631 E 17th Ave, PO Box B178, Academic Office 1, Aurora, CO 80045 (Allison.Wolfe @ucdenver.edu). jamainternalmedicine.com
Cerebral vascular accidents (CVAs) are a major cause of morbidity and mortality in the United States. In approximately one-third of CVAs, a cause is not determined, leaving patients and physicians with the frustrating diagnosis of cryptogenic stroke.1 It is hypothesized that some cryptogenic strokes may be caused by a venous embolism passing through a PFO and into the systemic circulation.2 While mechanically plausible, the role of PFO in CVA remains unclear. However, a wide range of therapies to address secondary prevention in patients with PFOs have been proposed and adopted, including percutaneous closure, antiplatelet therapy, and anticoagulation. These therapies have varying degrees of potential harm. Initial observational studies and meta-analyses have indicated decreased recurrent CVAs with PFO closure. However, 3 randomized clinical trials have not borne out this same conclusion. In CLOSURE-I,2 researchers compared medical therapy and PFO closure using the STARFlex Septal Closure System in patients with cryptogenic stroke or transient ischemic attack (TIA) and a PFO. They found no significant difference in the secondary end point of recurrent stroke: 2.9% vs 3.1% (95% CI, 0.41-1.98). Two other randomized trials in 2013, PC 3 and RESPECT, 4 also
failed to show clear benefit with PFO closure using the Amplatzer PFO Occluder. In PC, the recurrent stroke rate was 0.5% vs 2.4% (95% CI, 0.02-1.72). 3 In RESPECT, there was no difference in the primary composite outcome of nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization (0.66 events per 100 patient-years vs 1.38 events per 100 patient-years [95% CI, 0.22-1.11]).4 Despite the study population being limited to those with CVA only, and not those with CVA or TIA, the results did not reach statistical significance. Closure of a PFO is also not without risks. In CLOSURE-I, 2 PFO closure was associated with increased rates of atrial fibrillation (5.7% vs 0.7%). The higher risk of atrial fibrillation was not duplicated in either RESPECT3 or PC.4 Though the findings did not reach statistical significance, all 3 randomized clinical trials demonstrated a trend toward increased risk of serious adverse events in the procedural arm compared with medical therapy. It is not known how the risks of closure will compare with medical therapy in actual practice, since randomized clinical trials are generally not powered to detect important harms. Though without clear benefit in every case, PFO closure may be beneficial for certain patients. Subgroup analysis of the RESPECT trial indicated improved outcomes with PFO closure when atrial septal aneurysm was present and shunt size was substantial.4 Additionally, current guidelines recommend consideration of PFO closure in 2 circumstances (recommendations classified by the American College of Chest Physicians as grade 2C): recurrent cryptogenic stroke through aspirin therapy and cryptogenic stroke in the setting of both PFO and DVT.5 The role of PFO in cryptogenic stroke remains unclear. Existing evidence does not show a clear benefit in recurrent CVA prevention with PFO closure compared with medical therapy alone. Additional randomized trials currently ongoing may be able to more definitively answer this question through pooled meta-analysis, and they might better identify high-risk patients most likely to derive benefit from closure. The perils associated with PFO closure, while uncommon, can be serious and may well outweigh the benefits of closure in many patients. Our patient decided to pursue closure despite knowing that there is no research showing definitive decreased recurrent stroke risk. He desired to do “everything possible to stay alive” and concluded that the risks of the procedure were miniJAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Birmingham User on 05/29/2015
1545
Opinion Perspective
mal. It is imperative that physicians present to their patients the growing body of evidence, including the uncertainty of clinical ef-
fectiveness of PFO closure, to engage them in shared decision making and prevent preference misdiagnosis.
Published Online: August 25, 2014. doi:10.1001/jamainternmed.2014.3923.
cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991-999.
Conflict of Interest Disclosures: None reported.
3. Meier B, Kalesan B, Mattle HP, et al; PC Trial Investigators. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368(12):1083-1091.
1. Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke. 2009;40(4):1195-1203. 2. Furlan AJ, Reisman M, Massaro J, et al; CLOSURE I Investigators. Closure or medical therapy for
4. Carroll JD, Saver JL, Thaler DE, et al; RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092-1100.
5. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):7S-47S.
LESS IS MORE PERSPECTIVE
Bryan LeBude, MD Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. Gretchen Diemer, MD Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
CME Quiz at jamanetworkcme.com and CME Questions page 1712
Corresponding Author: Bryan LeBude, MD, Department of Medicine, Thomas Jefferson University Hospital, 1025 Walnut St, Ste 805, Philadelphia, PA 19107 (bryanlebude@gmail .com). 1546
Routine Blood Cultures for the Febrile Inpatient A Teachable Moment Story From the Front Lines A 67-year-old woman with a history of hypertension presentedtothehospitalafter1weekoffever,cough,anddyspnea. Physical examination demonstrated a temperature of39°C,respiratoryrateof24breaths/min,andinspiratory crackles auscultated at the left lung base. A chest radiograph showed a left lower lobe infiltrate. Findings from laboratory studies were notable for a blood urea nitrogen level of 21 mg/dL (to convert to millimoles per liter, multiply by 0.357). The patient was admitted to the general medicine inpatient service and started on ceftriaxone and azithromycin therapies for community-acquired pneumonia. During hospital day 1, the patient noted improvement in her symptoms. On attending physician rounds, a plan was made for transition to oral antibiotics on the following day, with consideration for discharge. Just prior to midnight on hospital day 1, the night coverage resident was called because the patient was found to have a temperature of 38.3°C. At this time she was asymptomatic, and the remainder of her examination findings were normal. The resident instructed the nurse to draw 2 sets of blood cultures. On hospital day 2, the patient noted continued improvement in her symptoms and remained afebrile since the previous night. Blood cultures drawn the night prior resulted as preliminarily positive for gram-positive cocci in clusters from 1 of 2 sets. The team subsequently started vancomycin therapy for possible methicillin-resistant Staphylococcus aureus bacteremia. This regimen was continued awaiting organism identification. On hospital day 4, the positive blood culture was reported as Staphylococcus epidermidis. Owing to the absence of signs or symptoms consistent with active infection by this organism, the result was concluded to be a contaminant. Vancomycin therapy was discontinued, and antibiotics were narrowed to azithromycin to complete a 7-day course. Following evaluation by physical therapy,
the patient was deemed safe for discharge on hospital day 5. The patient described anxiety regarding her diminished physical strength following a 5-day inpatient stay, in addition to concern that the added interventions and length of stay would result in financial hardship.
Teachable Moment Blood cultures have been the “gold standard” for detecting bacteremia since their earliest application, when Streptococcus viridans was identified as the cause of malignant endocarditis.1 With approximately 200 000 cases of bacteremia occurring in the United States each year and an associated mortality approaching 50% in certain populations, physicians carry a low index of suspicion for ordering blood cultures. As a result, a low percentage (4%-7%) of blood cultures are positive.2 Published guidelines do not specifically state when blood cultures should be drawn for most clinical conditions.3 Unfortunately a large portion (approximately half) of positive blood cultures are subsequently determined to be contaminants—skin flora inoculated into culture bottles.4 These false positives lead to inappropriate tests and interventions. Compared with truenegative results, false-positive results are independently correlated with a 39% increase in charged amounts for antibiotics and a 20% increase in total subsequent laboratory charges, in addition to an average increased length of stay of 4.5 days.4 Other potential harms for the patient include adverse effects of the unnecessary antibiotics, as well as concerns for increasing antibiotic resistance patterns in the setting of overuse as exemplified by the emergence of vancomycin-resistant organisms. The decision to obtain blood cultures for the febrile inpatient should consider the pretest probability of bacteremia, in addition to the likelihood that the results will influence management. A review by Coburn et al2 demonstrated that the pretest probability of bacter-
JAMA Internal Medicine October 2014 Volume 174, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a University of Birmingham User on 05/29/2015
jamainternalmedicine.com
