Persons exposed to smallpox should be vaccinated with a replication-competent vaccine, unless they are severely immunodeficient, according to a guideline from the Centers for Disease Control and Prevention.

© CDC

Severely immunodeficient persons won’t benefit from a smallpox vaccination because there will likely be a poor immune response and heightened risk of negative events. These include bone marrow transplant recipients within 4 months of transplantation, people infected with HIV with CD4 cell counts <50 cells/mm³, persons with severe combined immunodeficiency, complete DiGeorge syndrome patients, and people with other severely immunocompromised states requiring isolation.

“If antivirals are not immediately available, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in persons with severe immunodeficiency,” the CDC added.

Find the full guideline in the MMWR (February 20, 2015 / 64(RR02);1-26).

Persons exposed to smallpox should be vaccinated with a replication-competent vaccine, unless they are severely immunodeficient, according to a guideline from the Centers for Disease Control and Prevention.

© CDC

Severely immunodeficient persons won’t benefit from a smallpox vaccination because there will likely be a poor immune response and heightened risk of negative events. These include bone marrow transplant recipients within 4 months of transplantation, people infected with HIV with CD4 cell counts <50 cells/mm³, persons with severe combined immunodeficiency, complete DiGeorge syndrome patients, and people with other severely immunocompromised states requiring isolation.

“If antivirals are not immediately available, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in persons with severe immunodeficiency,” the CDC added.

Find the full guideline in the MMWR (February 20, 2015 / 64(RR02);1-26).

Persons exposed to smallpox should be vaccinated with a replication-competent vaccine, unless they are severely immunodeficient, according to a guideline from the Centers for Disease Control and Prevention.

© CDC

Severely immunodeficient persons won’t benefit from a smallpox vaccination because there will likely be a poor immune response and heightened risk of negative events. These include bone marrow transplant recipients within 4 months of transplantation, people infected with HIV with CD4 cell counts <50 cells/mm³, persons with severe combined immunodeficiency, complete DiGeorge syndrome patients, and people with other severely immunocompromised states requiring isolation.

“If antivirals are not immediately available, it is reasonable to consider the use of Imvamune in the setting of a smallpox virus exposure in persons with severe immunodeficiency,” the CDC added.

Find the full guideline in the MMWR (February 20, 2015 / 64(RR02);1-26).

Bleeding complications following angiographic interventions have recently become an increasing cause of medical malpractice litigation. The reason for this increase is likely a result of several factors including the controversy surrounding the multiple approaches that are currently employed for the treatment of this type of bleeding, as well as the significant morbidity and mortality associated with these treatment paradigms. Allegations in these lawsuits usually include failure to diagnose, failure to treat, failure to transfuse, negligence in the use of an endovascular approach, and negligence in open surgical treatment. Physical examination, close observation, and an aggressive approach to intervention are necessary if litigation is to be avoided in this patient population.

Case 1

The patient underwent cardiac catheterization with placement of a coronary stent. The patient was placed on Integrilin. Following the catheterization, the patient had multiple episodes of hypotension. Each episode responded to fluid boluses and transfusion. No surgical consultation was obtained. The patient’s hemoglobin never fell below 8 grams. The patient was transfused approximately 8 units of blood. The patient’s Integrilin was discontinued. However, the patient progressed to multisystem organ failure and died. Autopsy revealed a massive hematoma of the retroperitoneum and a patent coronary stent. A medical malpractice suit was filed. The case was settled.

Case 2

A patient underwent cardiac catheterization and subsequently developed severe bleeding. She received approximately 10 units of blood prior to vascular surgical consultation. By the time the vascular surgeon saw the patient, the patient was intubated and on vasopressors. The vascular surgeon stated that the patient was not a candidate for surgery. The patient subsequently died. A lawsuit was filed against both the cardiologist and the vascular surgeon. This case was settled by both physicians.

Case 3

A cardiologist calls a vascular surgeon who is at home at 10 p.m. to let her know that he has a patient with a retroperitoneal hematoma following a cardiac cath. He informs the surgeon that the patient is stable. He “just wants her to be aware in case the patient’s condition deteriorates.”

During the night the patient has repeated hypotensive episodes which the cardiologist manages with transfusions. At 5 a.m. the patient arrests and is resuscitated. The surgeon is called, and she takes the patient to surgery but the patient succumbs. The surgeon is sued for not coming in to see the patient and being more involved during the night.

The jury finds in favor of the surgeon. However, the trial took 2 weeks during which time the surgeon had to attend the deliberations and so she was unable work.

Discussion

Unfortunately, the above examples represent the all too often complication of postprocedure bleeding following femoral access.

In case 1, early exploration would more likely than not, and within a reasonable degree of medical certainty, prevented the patient’s death. The presumption is that the patient died from the untreated complication of postcatheterization hemorrhage. The defendant’s claim that the patient’s hemoglobin was never lower than 8 mg did not serve as an adequate defense. Even if the patient was found at autopsy to have an occluded stent which caused an acute MI, the plaintiff’s attorney would likely argue successfully that if the bleeding had been appropriately treated, the stent would have remained patent. The cardiologist was found culpable for not consulting a vascular surgeon.

In the second example, the plaintiff’s expert explained to the jury that without surgery, the patient would continue to bleed and certainly die. He went on to opine that the only possible chance of the patient surviving was with surgical intervention, and this chance was denied to the patient by the vascular surgeon who refused to operate. In these types of cases, the surgeon incorrectly believes that he/she can avoid liability and involvement in the case by not operating on the patient. However, as this case demonstrated, the surgeon is still likely to be named as a defendant in the law suit.

The third case illustrates two common pitfalls for the vascular surgeon and perhaps represents the most dangerous situation for the vascular surgeon. The first pitfall occurs when the vascular surgeon relies on telephone information without examining the patient. Secondly, as in this case, a formal consult was never initiated by the cardiologist. The surgeon incorrectly assumed that because no formal consult was placed she had no liability. However, according to the plaintiff’s expert, since she had been informed about the patient she should have come in to see the patient.

Had she done so, he alleged she would have realized that the patient required an intervention either with a covered stent or a surgical repair of the bleeding external iliac artery. Clearly, the fact that no formal consult was placed in the chart did not prevent the vascular surgeon from being a named defendant in this case.

Several steps should be taken if a physician is to minimize the risk of being named as a defendant in a lawsuit involving postangiographic intervention bleeding. First, if the physician is a not a surgeon, surgical consultation should be obtained as soon as postprocedure bleeding is suspected. Second, surgeons should pursue an aggressive approach to the treatment of this complication. Whereas it may be reasonable to treat a single episode of hypotension with fluid or blood transfusion, unless there are mitigating circumstances, any patient who develops a second episode of hypotension in the face of ongoing bleeding should undergo intervention. Furthermore, there must be clear documentation as to why a particular approach (endovascular versus open repair) was chosen. A medical physician’s inability to perform an open approach or a surgeon’s inability to perform an endovascular approach are not sustainable defenses.

Surgeons who are consulted late in the patient’s clinical course, prior to intervention, should document the patient’s poor prognosis and make it clear that no matter what is done the patient is unlikely to survive.

However, in most situations, the defense that a patient with ongoing bleeding was too unstable to treat is likely to fail.

Access site bleeding following percutaneous interventions is often a readily treatable complication. A low threshold for intervention, cooperation among vascular specialists, and, as always, clear documentation will go a long way to keep physicians working and out of the courtroom.

Dr. Brown is associate editor of Vascular Specialist. Dr. Samson is the medical editor, Vascular Specialist.

 The opinions expressed by the authors neither imply nor establish a standard 
of care.

Bleeding complications following angiographic interventions have recently become an increasing cause of medical malpractice litigation. The reason for this increase is likely a result of several factors including the controversy surrounding the multiple approaches that are currently employed for the treatment of this type of bleeding, as well as the significant morbidity and mortality associated with these treatment paradigms. Allegations in these lawsuits usually include failure to diagnose, failure to treat, failure to transfuse, negligence in the use of an endovascular approach, and negligence in open surgical treatment. Physical examination, close observation, and an aggressive approach to intervention are necessary if litigation is to be avoided in this patient population.

Case 1

The patient underwent cardiac catheterization with placement of a coronary stent. The patient was placed on Integrilin. Following the catheterization, the patient had multiple episodes of hypotension. Each episode responded to fluid boluses and transfusion. No surgical consultation was obtained. The patient’s hemoglobin never fell below 8 grams. The patient was transfused approximately 8 units of blood. The patient’s Integrilin was discontinued. However, the patient progressed to multisystem organ failure and died. Autopsy revealed a massive hematoma of the retroperitoneum and a patent coronary stent. A medical malpractice suit was filed. The case was settled.

Case 2

A patient underwent cardiac catheterization and subsequently developed severe bleeding. She received approximately 10 units of blood prior to vascular surgical consultation. By the time the vascular surgeon saw the patient, the patient was intubated and on vasopressors. The vascular surgeon stated that the patient was not a candidate for surgery. The patient subsequently died. A lawsuit was filed against both the cardiologist and the vascular surgeon. This case was settled by both physicians.

Case 3

A cardiologist calls a vascular surgeon who is at home at 10 p.m. to let her know that he has a patient with a retroperitoneal hematoma following a cardiac cath. He informs the surgeon that the patient is stable. He “just wants her to be aware in case the patient’s condition deteriorates.”

During the night the patient has repeated hypotensive episodes which the cardiologist manages with transfusions. At 5 a.m. the patient arrests and is resuscitated. The surgeon is called, and she takes the patient to surgery but the patient succumbs. The surgeon is sued for not coming in to see the patient and being more involved during the night.

The jury finds in favor of the surgeon. However, the trial took 2 weeks during which time the surgeon had to attend the deliberations and so she was unable work.

Discussion

Unfortunately, the above examples represent the all too often complication of postprocedure bleeding following femoral access.

In case 1, early exploration would more likely than not, and within a reasonable degree of medical certainty, prevented the patient’s death. The presumption is that the patient died from the untreated complication of postcatheterization hemorrhage. The defendant’s claim that the patient’s hemoglobin was never lower than 8 mg did not serve as an adequate defense. Even if the patient was found at autopsy to have an occluded stent which caused an acute MI, the plaintiff’s attorney would likely argue successfully that if the bleeding had been appropriately treated, the stent would have remained patent. The cardiologist was found culpable for not consulting a vascular surgeon.

In the second example, the plaintiff’s expert explained to the jury that without surgery, the patient would continue to bleed and certainly die. He went on to opine that the only possible chance of the patient surviving was with surgical intervention, and this chance was denied to the patient by the vascular surgeon who refused to operate. In these types of cases, the surgeon incorrectly believes that he/she can avoid liability and involvement in the case by not operating on the patient. However, as this case demonstrated, the surgeon is still likely to be named as a defendant in the law suit.

The third case illustrates two common pitfalls for the vascular surgeon and perhaps represents the most dangerous situation for the vascular surgeon. The first pitfall occurs when the vascular surgeon relies on telephone information without examining the patient. Secondly, as in this case, a formal consult was never initiated by the cardiologist. The surgeon incorrectly assumed that because no formal consult was placed she had no liability. However, according to the plaintiff’s expert, since she had been informed about the patient she should have come in to see the patient.

Had she done so, he alleged she would have realized that the patient required an intervention either with a covered stent or a surgical repair of the bleeding external iliac artery. Clearly, the fact that no formal consult was placed in the chart did not prevent the vascular surgeon from being a named defendant in this case.

Several steps should be taken if a physician is to minimize the risk of being named as a defendant in a lawsuit involving postangiographic intervention bleeding. First, if the physician is a not a surgeon, surgical consultation should be obtained as soon as postprocedure bleeding is suspected. Second, surgeons should pursue an aggressive approach to the treatment of this complication. Whereas it may be reasonable to treat a single episode of hypotension with fluid or blood transfusion, unless there are mitigating circumstances, any patient who develops a second episode of hypotension in the face of ongoing bleeding should undergo intervention. Furthermore, there must be clear documentation as to why a particular approach (endovascular versus open repair) was chosen. A medical physician’s inability to perform an open approach or a surgeon’s inability to perform an endovascular approach are not sustainable defenses.

Surgeons who are consulted late in the patient’s clinical course, prior to intervention, should document the patient’s poor prognosis and make it clear that no matter what is done the patient is unlikely to survive.

However, in most situations, the defense that a patient with ongoing bleeding was too unstable to treat is likely to fail.

Access site bleeding following percutaneous interventions is often a readily treatable complication. A low threshold for intervention, cooperation among vascular specialists, and, as always, clear documentation will go a long way to keep physicians working and out of the courtroom.

Dr. Brown is associate editor of Vascular Specialist. Dr. Samson is the medical editor, Vascular Specialist.

 The opinions expressed by the authors neither imply nor establish a standard 
of care.

Bleeding complications following angiographic interventions have recently become an increasing cause of medical malpractice litigation. The reason for this increase is likely a result of several factors including the controversy surrounding the multiple approaches that are currently employed for the treatment of this type of bleeding, as well as the significant morbidity and mortality associated with these treatment paradigms. Allegations in these lawsuits usually include failure to diagnose, failure to treat, failure to transfuse, negligence in the use of an endovascular approach, and negligence in open surgical treatment. Physical examination, close observation, and an aggressive approach to intervention are necessary if litigation is to be avoided in this patient population.

Case 1

The patient underwent cardiac catheterization with placement of a coronary stent. The patient was placed on Integrilin. Following the catheterization, the patient had multiple episodes of hypotension. Each episode responded to fluid boluses and transfusion. No surgical consultation was obtained. The patient’s hemoglobin never fell below 8 grams. The patient was transfused approximately 8 units of blood. The patient’s Integrilin was discontinued. However, the patient progressed to multisystem organ failure and died. Autopsy revealed a massive hematoma of the retroperitoneum and a patent coronary stent. A medical malpractice suit was filed. The case was settled.

Case 2

A patient underwent cardiac catheterization and subsequently developed severe bleeding. She received approximately 10 units of blood prior to vascular surgical consultation. By the time the vascular surgeon saw the patient, the patient was intubated and on vasopressors. The vascular surgeon stated that the patient was not a candidate for surgery. The patient subsequently died. A lawsuit was filed against both the cardiologist and the vascular surgeon. This case was settled by both physicians.

Case 3

A cardiologist calls a vascular surgeon who is at home at 10 p.m. to let her know that he has a patient with a retroperitoneal hematoma following a cardiac cath. He informs the surgeon that the patient is stable. He “just wants her to be aware in case the patient’s condition deteriorates.”

During the night the patient has repeated hypotensive episodes which the cardiologist manages with transfusions. At 5 a.m. the patient arrests and is resuscitated. The surgeon is called, and she takes the patient to surgery but the patient succumbs. The surgeon is sued for not coming in to see the patient and being more involved during the night.

The jury finds in favor of the surgeon. However, the trial took 2 weeks during which time the surgeon had to attend the deliberations and so she was unable work.

Discussion

Unfortunately, the above examples represent the all too often complication of postprocedure bleeding following femoral access.

In case 1, early exploration would more likely than not, and within a reasonable degree of medical certainty, prevented the patient’s death. The presumption is that the patient died from the untreated complication of postcatheterization hemorrhage. The defendant’s claim that the patient’s hemoglobin was never lower than 8 mg did not serve as an adequate defense. Even if the patient was found at autopsy to have an occluded stent which caused an acute MI, the plaintiff’s attorney would likely argue successfully that if the bleeding had been appropriately treated, the stent would have remained patent. The cardiologist was found culpable for not consulting a vascular surgeon.

In the second example, the plaintiff’s expert explained to the jury that without surgery, the patient would continue to bleed and certainly die. He went on to opine that the only possible chance of the patient surviving was with surgical intervention, and this chance was denied to the patient by the vascular surgeon who refused to operate. In these types of cases, the surgeon incorrectly believes that he/she can avoid liability and involvement in the case by not operating on the patient. However, as this case demonstrated, the surgeon is still likely to be named as a defendant in the law suit.

The third case illustrates two common pitfalls for the vascular surgeon and perhaps represents the most dangerous situation for the vascular surgeon. The first pitfall occurs when the vascular surgeon relies on telephone information without examining the patient. Secondly, as in this case, a formal consult was never initiated by the cardiologist. The surgeon incorrectly assumed that because no formal consult was placed she had no liability. However, according to the plaintiff’s expert, since she had been informed about the patient she should have come in to see the patient.

Had she done so, he alleged she would have realized that the patient required an intervention either with a covered stent or a surgical repair of the bleeding external iliac artery. Clearly, the fact that no formal consult was placed in the chart did not prevent the vascular surgeon from being a named defendant in this case.

Several steps should be taken if a physician is to minimize the risk of being named as a defendant in a lawsuit involving postangiographic intervention bleeding. First, if the physician is a not a surgeon, surgical consultation should be obtained as soon as postprocedure bleeding is suspected. Second, surgeons should pursue an aggressive approach to the treatment of this complication. Whereas it may be reasonable to treat a single episode of hypotension with fluid or blood transfusion, unless there are mitigating circumstances, any patient who develops a second episode of hypotension in the face of ongoing bleeding should undergo intervention. Furthermore, there must be clear documentation as to why a particular approach (endovascular versus open repair) was chosen. A medical physician’s inability to perform an open approach or a surgeon’s inability to perform an endovascular approach are not sustainable defenses.

Surgeons who are consulted late in the patient’s clinical course, prior to intervention, should document the patient’s poor prognosis and make it clear that no matter what is done the patient is unlikely to survive.

However, in most situations, the defense that a patient with ongoing bleeding was too unstable to treat is likely to fail.

Access site bleeding following percutaneous interventions is often a readily treatable complication. A low threshold for intervention, cooperation among vascular specialists, and, as always, clear documentation will go a long way to keep physicians working and out of the courtroom.

Dr. Brown is associate editor of Vascular Specialist. Dr. Samson is the medical editor, Vascular Specialist.

 The opinions expressed by the authors neither imply nor establish a standard 
of care.

POINT: Medical treatment ends need for CEA or CAS.

By Anne L. Abbott, M.D.

The medical profession and the wider community must be congratulated upon their sustained efforts over recent decades that have seen an 80% fall in the average annual risk of stroke associated with moderate and severe (50%-99%) asymptomatic carotid stenosis (ACS).^1-6 This has been achieved by better medical treatment which consists of encouraging healthy lifestyle habits and appropriate use of medication. This major impact results from the combined effect of addressing all vascular risk factors in individual patients and efforts to use the best medical treatment available at the time. Rates are now so low (around 0.5% per year for ipsilateral stroke) that procedures, such as carotid endarterectomy (CEA), are now more likely to harm than help patients.⁷

Even if procedures were always completely risk-free, improved medical treatment may mean we have now reached the point where carotid procedures for ACS are safe but essentially ineffective for reducing stroke risk. The latest measurements of stroke risk using medical treatment alone indicate that only about 2.5% of patients with 50%-99% ACS will have a an ipsilateral stroke due to the carotid lesion during their remaining lifetime if they are receiving pretty good quality, current medical treatment alone. This is because the average age of identifying patients with ACS in past studies was about 70 years and the average survival following diagnosis was 10 years.¹ Further, only about half the strokes occurring in the distribution of an internal carotid artery with >60% proximal stenosis are due to the carotid lesion.⁸

Guidelines recommendations for CEA for 50%-99% or 60%-99% ACS rely on marginal, 20- to 30-year-old differences in stroke rates between patients given medical treatment alone versus those given additional CEA in best practice settings.^9-11  Such recommendations are not relevant to current clinical practice largely because the medical treatment used in these studies is obsolete. Multiple independent observations regarding the improved stroke prevention efficacy of medical treatment,^1-6,12 and the additional observations below, provide ample evidence that current medical treatment alone is the only routine-practice (nontrial) approach we should use for  patients with 50%-99% ACS and any future role of carotid procedures in these patients could only apply to very small minority subgroups:

i. Current optimal medical treatment for patients with ACS has not been defined nor its impact measured. This means that it is likely we can lower the risk of stroke and other vascular complications in patients with ACS stenosis even further than has been achieved in the most recent studies. The definition of current optimal medical treatment will vary from patient to patient depending on which vascular risk factors they have and what has been shown effective in modifying these to reduce the risk of any complications of vascular disease.

ii. The 30-day peri-operative risk of stroke or death (and other significant complications) remains above 0% in the most recent results of trials and registries^13-15 and is usually not measured in routine practice. Latest measurements of average annual ipsilateral stroke risk with medical treatment alone are about 2-3 times lower than for patients who had CEA or CAS in the Asymp tomatic Carotid Atherosclerosis Study (ACAS)10 or the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).^{7, 13}

iii. Patients with 50%-99% ACS receiving current optimal medical treatment and with a sufficiently high average annual risk of ipsilateral stroke, indicating they may benefit from CEA, have not been identified. This rate would need to be in excess of at least 2.5%-3.0%, using results from ACAS,¹⁰ to expect any surgical benefit in routine practice. Studies of baseline degree of  ACS within the 50%-99% range,^10,11,16 plaque echolucency¹⁷ and most studies of detecting asymptomatic stenosis progression18-21 show that these parameters (used separately) confer a relative risk of stroke of only about 2.0-2.5. Therefore, a higher degree of baseline stenosis within the 50%-99% range, the detection of predominantly echolucent carotid plaques  or asymptomatic progression are too weak on their own to identity patients likely to benefit from an additional carotid procedure. Combinations of risk markers are required for sufficient risk discrimination. For instance, results from the Asymptomatic Carotid Stenosis and Risk of Stroke Study (largest study so far of medically managed patients with moderate or severe ACS) showed that a combination of clinical features, baseline degree of stenosis and standardized ultrasonic plaque characteristics can achieve average annual ipsilateral stroke risk stratification ranging  from <1.0% to 10%.¹⁶ However, like all stroke risk stratification studies performed so far, this study was performed before the era of current medical treatment and the results have not been independently tested.

iv. Even if patients with sufficiently higher than average annual risk of ipsilateral stroke are one day reliably identified, randomized trials of an additional carotid procedure will be required to determine if, and to what extent, that procedure is likely to reduce ipsilateral stroke risk in routine practice.

v. The available evidence from randomized trials and registries indicates that CAS causes about twice as many strokes or deaths as surgery (just like it does for symptomatic carotid stenosis). Therefore, currently CAS cannot be recommended.⁷  In conclusion, the available evidence clearly indicates that current medical treatment alone now offers the best chance of reducing the risk of ipsilateral stroke in patients with 50%-99% ACS. There is no current evidence of benefit from CEA or CAS in these patients overall, or in any particular subgroups. However, there is much evidence regarding procedural risk and unaffordable cost.  Risk of ipsilateral stroke is now so low without carotid procedures it is time to shift from the historic approach of identifying ACS primarily to administer CEA. Rather, it is time to properly recognize that carotid stenosis is a risk factor of all complications of vascular disease, more than it is for ipsilateral stroke.²²

The priority is to define current optimal medical treatment as best we can, recognising that patients with ACS are a risk-heterogenous population. Then we need quality independent measurements of its impact on risk of all vascular disease complications using quality prospective cohort studies. Risk stratification models should be used to identify those who may benefit from trials of more intensive medical treatment, motivational strategies, plus/minus the safest carotid procedures. If identifying patients with ACS for CEA in routine practice is to be feasible, this needs to be done within well organized environments that support patients with a wide range of stenosis severity with the primary aim of implementing current optimal medical treatment to prevent all vascular complications. Finally, it must be accepted that as medical treatment and its implementation continue to improve, the added value of carotid procedures, including for symptomatic carotid stenosis, will continue to recede until we can say, ‘good job - it is finally fixed and it is time to move on to other major health issues.’

Dr. Abbott is a neurologist and an associate professor at Monash University, Melbourne, Australia.

References

1. Stroke. 2009;40:e573-583
2. Eur J Vasc Endovasc Surg. 2009;37:625-632
3. Nat Rev Cardiol. 2011;9:116-124
4. Stroke. 2013;44
5. Management of asymptomatic carotid stenosis: Technology assessment report. 2012:83
6. Annals of Internal Medicine. 2013;158:676-685
7. Stroke. 2013;44:1186-1190
8. N Engl J Med. 2000;342:1693-1700
9. N Engl J Med. 1993;328:221-227.
10.JAMA. 1995;273:1421-1428
11. Lancet. 2004;363:1491-1502
12. Arch Neurol. 2010;67:180-186
13. N Engl J Med. 2010;363:11-23
14. J Vasc Surg. 2009;49:71-79
15. J Vasc Surg. 2011;53:307-315
16. J Vasc Surg. 2010;52:1486-1496 e1481-1485
17. Gupta A, Kesavabhotla K, Barbadaran H, Kamel H, Panda A, Giambrone A, et al. Plaque echolucency and stroke risk in asymptoamtioc carotid stenosis: A systematic review and meta-analysis. Stroke. 2014 in press.
18. J Vasc Surg. 1999;29:208-214; discussion 214-206
19. J Vasc Surg. 2013;58:128-135 e121
20  Stroke. 2013;44:792-794
21. J Vasc Surg. 2014;59:956-967
22. N Engl J Med. 1986;315:860-865.

COUNTERPOINT: Medical therapy alone is not always enough.

By Mark F. Conrad, M.D., M.MSc., and Richard P. Cambria M.D.

Stroke remains the 3rd leading cause of death in the United States.¹  It is estimated that 10% to 20% of ischemic strokes can be attributed to an ipsilateral, typically high-grade carotid stenosis, thus, asymptomatic carotid bifurcation stenosis remains a potentially significant public health problem.²  Epidemiologic studies indicate that 5% to 6% of the population >65 years of age will harbor an asymptomatic and potentially surgically significant carotid stenosis.¹  The modern literature linking the degree of stenosis of the internal carotid artery and risk of ipsilateral stroke dates to the natural history studies of Chambers and Norris published in the New England Journal of Medicine in 1986.³  These investigators demonstrated a significant correlation of stroke risk with a >70% ipsilateral carotid artery stenosis and progression under observation. 

Carotid endarterectomy (CEA) has been the standard of care for the prevention of stroke in patients with severe (>70%) asymptomatic carotid artery stenosis (ACS) for five decades.  This is supported by level 1 evidence from multiple randomized trials^{4, 5} and consensus guideline recommendations.^{2, 6}  Yet the use of CEA in patients with ACS has been recently challenged by a widely publicized review article⁷ whose author has embarked upon an anti-CEA crusade with the zealous fervor of one who worships at the altar of the statin.  In this review, 11 prospective studies of medical therapy of patients with ACS (defined by the author as >50% stenosis) were stratified by date of publication such that the four series published from 2000-2007 had a lower raw data stroke rate with medical management (.6- 1.3%) than the 1.5% stroke rate reported after CEA in the ACAS study.^4,7  The authors concluded that medical management alone is “at least 3-8” times more cost effective than CEA despite a complete lack of cost data in the cited articles.   In an effort to debunk this revisionist history, we will begin by addressing the four aforementioned trials and finish with a discussion of the recent literature including an observational study from our own institution.

The first study of the four followed the asymptomatic contralateral carotid artery of all patients enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) for 5 years to determine the risk of stroke in medically managed patients.⁸  There were 2,377 patients of whom 216 (9%) had a stenosis >60% but only 113 (4.7%) had a stenosis of 75-99%.  The 5-year risk of ipsilateral stroke in the 75-99% asymptomatic stenosis cohort was 18.5% or 3.7% per year (this did not include other neurologic events such as TIA or amaurosis fugax).⁸  However, in the meta-analysis, no stroke rate was included in the raw data column (which was the basis of the final calculated overall stroke risk) and the final estimate quoted used the 60%-99% cohort such that the annual stroke rate was reported as 3.2%.⁷

The Asymptomatic Carotid Stenosis and Risk of Ipsilateral Hemispheric Ischemic Events Study (ACSRS) was a multicenter study that followed 1,115 patients with ACS >50% by duplex scanning for 6-84 months (mean 37.1) with the goal of stratifying patients into cohorts of high and low risk for future neurologic events.⁹  They concluded that the annual stroke rate in high-risk patients was 4.3% versus 0.7% in low-risk patients.  There were 453 patients with 70%-99% stenosis by NASCET criteria with a raw stroke rate of 5.7% (1.9%/ year over an average 3-year follow-up) and a 5-year ipsilateral event rate of about 18%.⁹  However, when the patients with 50-69% were added, the raw stroke rate decreased to 1.3%.⁷

The Asymptomatic Stenosis Embolus Detection (ASED) study was a prospective trial that tested the theory that transcranial Doppler embolic signal detection would identify increased risk of ipsilateral neurologic events in patients with >60% ACS.¹⁰  Of the 240 arteries studied, 115 (48%) had a stenosis of 70%-99% but 10 of these patients were censored because they underwent CEA during the follow-up period.  Their outcomes were not further stratified by degree of stenosis but the average ipsilateral carotid event rate was 3.1% per year with a 1% stroke risk per year.^{7, 10}

The final, and most damning study in the meta-analysis, included a cohort of patients from the Second Manifestations of Arterial disease (SMART) study which is a registry of patients from the Netherlands with risk factors for, or symptoms of, arterial disease.

 This study attempted to determine the risk of new vascular event in patients with ACS but 996 (27% of the registry) patients with a history of cerebrovascular disease (undefined) were excluded from analysis.¹¹  They identified 221 patients (8% of 2684 eligible patients) with ACS >50% and reported an ipsilateral stroke event rate of .6%/year.⁷ 

However, in the 147 patients with a 70-99% stenosis, the hazard ratio for ischemic stroke was 1.7 but it was not possible to separate the patients with a moderate (50-69%) stenosis from the outcomes of those with more severe (>70%) disease.¹¹ 

The major flaw with this study is that the authors excluded the 996 patients with a history of cerebrovascular disease who were at highest risk of having an ACS and subsequently suffering a stroke.

The flaw with combining the results of the above studies to conclude that medical therapy is the best way to prevent stroke in patients with severe ACS is that only half (828/1,754, 47%) of the patients included had a severe (70-99%) stenosis that would warrant CEA in the United States.^{6, 7}

The majority of the patients studied would have been treated with best medical therapy and serial Duplex scanning. Indeed, when the moderate patients were excluded, the yearly stroke rates for patients with actual severe stenosis ranged from 2.0%-3.7%; substantially higher than the 1.5% stroke rate associated with CEA.^{8, 9}

Randomized prospective trials such as the asymptomatic carotid artery stenosis (ACAS) study published in 1995 and the more recently updated asymptomatic carotid surgery trial (ACST) indicated a quite similar annual stroke risk in the 2% range for patients treated with medical therapy as opposed to those randomized to carotid endarterectomy (this study was excluded from the meta-analysis because patients with a remote (>6 months before entry) history of neurologic events were included).^4,12 In addition, the 10-year follow-up data in the ACST trial demonstrated a sustained benefit for endarterectomy over optimal medical therapy.⁵ It is important to emphasize that in this trial some 80% of patients were on optimal medical therapy (aspirin plus statin agents) in the later years of the trial.

These long-term data indicate that while the protective effect of endarterectomy was more pronounced in those not on appropriate lipid-lowering therapy (the 10-year advantage of endarterectomy over medical therapy in the prevention of stroke was 5.8% in patients taking a statin and 6.2% in those who were not)  the protective effect of endarterectomy over optimal medical therapy was statistically significant (P=0.002).⁵

This is of course relevant because clinicians in the modern era have typically used data from ACST to counsel patients about the stroke risk of asymptomatic high-grade carotid stenosis.

Finally, we followed at a cohort of 115 patients with severe (>70%) ACS who did not undergo CEA for a variety of reasons.

The average follow-up was 27 months and 86% of patients were on statin therapy. 

The 5-year ipsilateral ischemic event rate was 30%, and 48% of these were strokes.  When stratified by degree of stenosis, the patients with a 90%-99% stenosis had an ipsilateral neurologic event rate of 55%. This is a single center experience but the stroke rate of 3% per year is consistent with contemporary series and reiterates the reality of this risk for medically treated patients.

The question remains. When the efficacy of a CEA for the prevention of stroke in patients with ACS is supported by level 1 evidence from multiple prospective, randomized trials, why would anyone who treats patients with carotid disease allow a meta-analysis of natural history studies (that redefines a severe stenosis as >50%) convince them otherwise?

We believe that the answer lies in the unsubstantiated conclusion that “current medical intervention was estimated at least 3 to 8 times more cost effective” than CEA.⁷ 

As health care in the United States continues to evolve, we are faced with the issue of how best to spend limited resource dollars.

Is it practical or cost efficient to perform preventative surgery?

In England, an annual stroke rate of 2%-3% in a small subset of the population may be acceptable but we are not ready to concede that in the United States.  
For now, we will follow the SVS practice guidelines for the management of ACS as they are evidenced based and definitive.

CEA in conjunction with medical therapy remains the best way to prevent stroke in patients with severe  (>70%) ACS.

Dr. Conrad is  an assistant professor of surgery, Harvard Medical School, Boston. Dr. Cambria is The Robert R. Linton MD Professor of Vascular and Endovascular Surgery, Harvard Medical School, Boston.

References

1.Neurology. 2006;67:1390-1395
2.Circulation. 2012;125:188-197
3.N Engl J of Med. 1986;315:860-865
4.JAMA. 1995;273:1421-1428
5.Lancet. 2010;376:1074-1084
6.Journal of Vascular Surgery. 2011;54:e1-31
7.Stroke. 2009;40:e573-583
8.N Engl J Med. 2000;342:1693-1700
9. Eur J Vasc Endovasc Surg. 2005;30:275-284
10.Stroke. 2005;36:1128-1133
11. Stroke. 2007;38:1470-1475
12. Lancet. 2004;363:1491-1502

POINT: Medical treatment ends need for CEA or CAS.

By Anne L. Abbott, M.D.

The medical profession and the wider community must be congratulated upon their sustained efforts over recent decades that have seen an 80% fall in the average annual risk of stroke associated with moderate and severe (50%-99%) asymptomatic carotid stenosis (ACS).^1-6 This has been achieved by better medical treatment which consists of encouraging healthy lifestyle habits and appropriate use of medication. This major impact results from the combined effect of addressing all vascular risk factors in individual patients and efforts to use the best medical treatment available at the time. Rates are now so low (around 0.5% per year for ipsilateral stroke) that procedures, such as carotid endarterectomy (CEA), are now more likely to harm than help patients.⁷

Even if procedures were always completely risk-free, improved medical treatment may mean we have now reached the point where carotid procedures for ACS are safe but essentially ineffective for reducing stroke risk. The latest measurements of stroke risk using medical treatment alone indicate that only about 2.5% of patients with 50%-99% ACS will have a an ipsilateral stroke due to the carotid lesion during their remaining lifetime if they are receiving pretty good quality, current medical treatment alone. This is because the average age of identifying patients with ACS in past studies was about 70 years and the average survival following diagnosis was 10 years.¹ Further, only about half the strokes occurring in the distribution of an internal carotid artery with >60% proximal stenosis are due to the carotid lesion.⁸

Guidelines recommendations for CEA for 50%-99% or 60%-99% ACS rely on marginal, 20- to 30-year-old differences in stroke rates between patients given medical treatment alone versus those given additional CEA in best practice settings.^9-11  Such recommendations are not relevant to current clinical practice largely because the medical treatment used in these studies is obsolete. Multiple independent observations regarding the improved stroke prevention efficacy of medical treatment,^1-6,12 and the additional observations below, provide ample evidence that current medical treatment alone is the only routine-practice (nontrial) approach we should use for  patients with 50%-99% ACS and any future role of carotid procedures in these patients could only apply to very small minority subgroups:

i. Current optimal medical treatment for patients with ACS has not been defined nor its impact measured. This means that it is likely we can lower the risk of stroke and other vascular complications in patients with ACS stenosis even further than has been achieved in the most recent studies. The definition of current optimal medical treatment will vary from patient to patient depending on which vascular risk factors they have and what has been shown effective in modifying these to reduce the risk of any complications of vascular disease.

ii. The 30-day peri-operative risk of stroke or death (and other significant complications) remains above 0% in the most recent results of trials and registries^13-15 and is usually not measured in routine practice. Latest measurements of average annual ipsilateral stroke risk with medical treatment alone are about 2-3 times lower than for patients who had CEA or CAS in the Asymp tomatic Carotid Atherosclerosis Study (ACAS)10 or the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).^{7, 13}

iii. Patients with 50%-99% ACS receiving current optimal medical treatment and with a sufficiently high average annual risk of ipsilateral stroke, indicating they may benefit from CEA, have not been identified. This rate would need to be in excess of at least 2.5%-3.0%, using results from ACAS,¹⁰ to expect any surgical benefit in routine practice. Studies of baseline degree of  ACS within the 50%-99% range,^10,11,16 plaque echolucency¹⁷ and most studies of detecting asymptomatic stenosis progression18-21 show that these parameters (used separately) confer a relative risk of stroke of only about 2.0-2.5. Therefore, a higher degree of baseline stenosis within the 50%-99% range, the detection of predominantly echolucent carotid plaques  or asymptomatic progression are too weak on their own to identity patients likely to benefit from an additional carotid procedure. Combinations of risk markers are required for sufficient risk discrimination. For instance, results from the Asymptomatic Carotid Stenosis and Risk of Stroke Study (largest study so far of medically managed patients with moderate or severe ACS) showed that a combination of clinical features, baseline degree of stenosis and standardized ultrasonic plaque characteristics can achieve average annual ipsilateral stroke risk stratification ranging  from <1.0% to 10%.¹⁶ However, like all stroke risk stratification studies performed so far, this study was performed before the era of current medical treatment and the results have not been independently tested.

iv. Even if patients with sufficiently higher than average annual risk of ipsilateral stroke are one day reliably identified, randomized trials of an additional carotid procedure will be required to determine if, and to what extent, that procedure is likely to reduce ipsilateral stroke risk in routine practice.

v. The available evidence from randomized trials and registries indicates that CAS causes about twice as many strokes or deaths as surgery (just like it does for symptomatic carotid stenosis). Therefore, currently CAS cannot be recommended.⁷  In conclusion, the available evidence clearly indicates that current medical treatment alone now offers the best chance of reducing the risk of ipsilateral stroke in patients with 50%-99% ACS. There is no current evidence of benefit from CEA or CAS in these patients overall, or in any particular subgroups. However, there is much evidence regarding procedural risk and unaffordable cost.  Risk of ipsilateral stroke is now so low without carotid procedures it is time to shift from the historic approach of identifying ACS primarily to administer CEA. Rather, it is time to properly recognize that carotid stenosis is a risk factor of all complications of vascular disease, more than it is for ipsilateral stroke.²²

The priority is to define current optimal medical treatment as best we can, recognising that patients with ACS are a risk-heterogenous population. Then we need quality independent measurements of its impact on risk of all vascular disease complications using quality prospective cohort studies. Risk stratification models should be used to identify those who may benefit from trials of more intensive medical treatment, motivational strategies, plus/minus the safest carotid procedures. If identifying patients with ACS for CEA in routine practice is to be feasible, this needs to be done within well organized environments that support patients with a wide range of stenosis severity with the primary aim of implementing current optimal medical treatment to prevent all vascular complications. Finally, it must be accepted that as medical treatment and its implementation continue to improve, the added value of carotid procedures, including for symptomatic carotid stenosis, will continue to recede until we can say, ‘good job - it is finally fixed and it is time to move on to other major health issues.’

Dr. Abbott is a neurologist and an associate professor at Monash University, Melbourne, Australia.

References

1. Stroke. 2009;40:e573-583
2. Eur J Vasc Endovasc Surg. 2009;37:625-632
3. Nat Rev Cardiol. 2011;9:116-124
4. Stroke. 2013;44
5. Management of asymptomatic carotid stenosis: Technology assessment report. 2012:83
6. Annals of Internal Medicine. 2013;158:676-685
7. Stroke. 2013;44:1186-1190
8. N Engl J Med. 2000;342:1693-1700
9. N Engl J Med. 1993;328:221-227.
10.JAMA. 1995;273:1421-1428
11. Lancet. 2004;363:1491-1502
12. Arch Neurol. 2010;67:180-186
13. N Engl J Med. 2010;363:11-23
14. J Vasc Surg. 2009;49:71-79
15. J Vasc Surg. 2011;53:307-315
16. J Vasc Surg. 2010;52:1486-1496 e1481-1485
17. Gupta A, Kesavabhotla K, Barbadaran H, Kamel H, Panda A, Giambrone A, et al. Plaque echolucency and stroke risk in asymptoamtioc carotid stenosis: A systematic review and meta-analysis. Stroke. 2014 in press.
18. J Vasc Surg. 1999;29:208-214; discussion 214-206
19. J Vasc Surg. 2013;58:128-135 e121
20  Stroke. 2013;44:792-794
21. J Vasc Surg. 2014;59:956-967
22. N Engl J Med. 1986;315:860-865.

COUNTERPOINT: Medical therapy alone is not always enough.

By Mark F. Conrad, M.D., M.MSc., and Richard P. Cambria M.D.

Stroke remains the 3rd leading cause of death in the United States.¹  It is estimated that 10% to 20% of ischemic strokes can be attributed to an ipsilateral, typically high-grade carotid stenosis, thus, asymptomatic carotid bifurcation stenosis remains a potentially significant public health problem.²  Epidemiologic studies indicate that 5% to 6% of the population >65 years of age will harbor an asymptomatic and potentially surgically significant carotid stenosis.¹  The modern literature linking the degree of stenosis of the internal carotid artery and risk of ipsilateral stroke dates to the natural history studies of Chambers and Norris published in the New England Journal of Medicine in 1986.³  These investigators demonstrated a significant correlation of stroke risk with a >70% ipsilateral carotid artery stenosis and progression under observation. 

Carotid endarterectomy (CEA) has been the standard of care for the prevention of stroke in patients with severe (>70%) asymptomatic carotid artery stenosis (ACS) for five decades.  This is supported by level 1 evidence from multiple randomized trials^{4, 5} and consensus guideline recommendations.^{2, 6}  Yet the use of CEA in patients with ACS has been recently challenged by a widely publicized review article⁷ whose author has embarked upon an anti-CEA crusade with the zealous fervor of one who worships at the altar of the statin.  In this review, 11 prospective studies of medical therapy of patients with ACS (defined by the author as >50% stenosis) were stratified by date of publication such that the four series published from 2000-2007 had a lower raw data stroke rate with medical management (.6- 1.3%) than the 1.5% stroke rate reported after CEA in the ACAS study.^4,7  The authors concluded that medical management alone is “at least 3-8” times more cost effective than CEA despite a complete lack of cost data in the cited articles.   In an effort to debunk this revisionist history, we will begin by addressing the four aforementioned trials and finish with a discussion of the recent literature including an observational study from our own institution.

The first study of the four followed the asymptomatic contralateral carotid artery of all patients enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) for 5 years to determine the risk of stroke in medically managed patients.⁸  There were 2,377 patients of whom 216 (9%) had a stenosis >60% but only 113 (4.7%) had a stenosis of 75-99%.  The 5-year risk of ipsilateral stroke in the 75-99% asymptomatic stenosis cohort was 18.5% or 3.7% per year (this did not include other neurologic events such as TIA or amaurosis fugax).⁸  However, in the meta-analysis, no stroke rate was included in the raw data column (which was the basis of the final calculated overall stroke risk) and the final estimate quoted used the 60%-99% cohort such that the annual stroke rate was reported as 3.2%.⁷

The Asymptomatic Carotid Stenosis and Risk of Ipsilateral Hemispheric Ischemic Events Study (ACSRS) was a multicenter study that followed 1,115 patients with ACS >50% by duplex scanning for 6-84 months (mean 37.1) with the goal of stratifying patients into cohorts of high and low risk for future neurologic events.⁹  They concluded that the annual stroke rate in high-risk patients was 4.3% versus 0.7% in low-risk patients.  There were 453 patients with 70%-99% stenosis by NASCET criteria with a raw stroke rate of 5.7% (1.9%/ year over an average 3-year follow-up) and a 5-year ipsilateral event rate of about 18%.⁹  However, when the patients with 50-69% were added, the raw stroke rate decreased to 1.3%.⁷

The Asymptomatic Stenosis Embolus Detection (ASED) study was a prospective trial that tested the theory that transcranial Doppler embolic signal detection would identify increased risk of ipsilateral neurologic events in patients with >60% ACS.¹⁰  Of the 240 arteries studied, 115 (48%) had a stenosis of 70%-99% but 10 of these patients were censored because they underwent CEA during the follow-up period.  Their outcomes were not further stratified by degree of stenosis but the average ipsilateral carotid event rate was 3.1% per year with a 1% stroke risk per year.^{7, 10}

The final, and most damning study in the meta-analysis, included a cohort of patients from the Second Manifestations of Arterial disease (SMART) study which is a registry of patients from the Netherlands with risk factors for, or symptoms of, arterial disease.

 This study attempted to determine the risk of new vascular event in patients with ACS but 996 (27% of the registry) patients with a history of cerebrovascular disease (undefined) were excluded from analysis.¹¹  They identified 221 patients (8% of 2684 eligible patients) with ACS >50% and reported an ipsilateral stroke event rate of .6%/year.⁷ 

However, in the 147 patients with a 70-99% stenosis, the hazard ratio for ischemic stroke was 1.7 but it was not possible to separate the patients with a moderate (50-69%) stenosis from the outcomes of those with more severe (>70%) disease.¹¹ 

The major flaw with this study is that the authors excluded the 996 patients with a history of cerebrovascular disease who were at highest risk of having an ACS and subsequently suffering a stroke.

The flaw with combining the results of the above studies to conclude that medical therapy is the best way to prevent stroke in patients with severe ACS is that only half (828/1,754, 47%) of the patients included had a severe (70-99%) stenosis that would warrant CEA in the United States.^{6, 7}

The majority of the patients studied would have been treated with best medical therapy and serial Duplex scanning. Indeed, when the moderate patients were excluded, the yearly stroke rates for patients with actual severe stenosis ranged from 2.0%-3.7%; substantially higher than the 1.5% stroke rate associated with CEA.^{8, 9}

Randomized prospective trials such as the asymptomatic carotid artery stenosis (ACAS) study published in 1995 and the more recently updated asymptomatic carotid surgery trial (ACST) indicated a quite similar annual stroke risk in the 2% range for patients treated with medical therapy as opposed to those randomized to carotid endarterectomy (this study was excluded from the meta-analysis because patients with a remote (>6 months before entry) history of neurologic events were included).^4,12 In addition, the 10-year follow-up data in the ACST trial demonstrated a sustained benefit for endarterectomy over optimal medical therapy.⁵ It is important to emphasize that in this trial some 80% of patients were on optimal medical therapy (aspirin plus statin agents) in the later years of the trial.

These long-term data indicate that while the protective effect of endarterectomy was more pronounced in those not on appropriate lipid-lowering therapy (the 10-year advantage of endarterectomy over medical therapy in the prevention of stroke was 5.8% in patients taking a statin and 6.2% in those who were not)  the protective effect of endarterectomy over optimal medical therapy was statistically significant (P=0.002).⁵

This is of course relevant because clinicians in the modern era have typically used data from ACST to counsel patients about the stroke risk of asymptomatic high-grade carotid stenosis.

Finally, we followed at a cohort of 115 patients with severe (>70%) ACS who did not undergo CEA for a variety of reasons.

The average follow-up was 27 months and 86% of patients were on statin therapy. 

The 5-year ipsilateral ischemic event rate was 30%, and 48% of these were strokes.  When stratified by degree of stenosis, the patients with a 90%-99% stenosis had an ipsilateral neurologic event rate of 55%. This is a single center experience but the stroke rate of 3% per year is consistent with contemporary series and reiterates the reality of this risk for medically treated patients.

The question remains. When the efficacy of a CEA for the prevention of stroke in patients with ACS is supported by level 1 evidence from multiple prospective, randomized trials, why would anyone who treats patients with carotid disease allow a meta-analysis of natural history studies (that redefines a severe stenosis as >50%) convince them otherwise?

We believe that the answer lies in the unsubstantiated conclusion that “current medical intervention was estimated at least 3 to 8 times more cost effective” than CEA.⁷ 

As health care in the United States continues to evolve, we are faced with the issue of how best to spend limited resource dollars.

Is it practical or cost efficient to perform preventative surgery?

In England, an annual stroke rate of 2%-3% in a small subset of the population may be acceptable but we are not ready to concede that in the United States.  
For now, we will follow the SVS practice guidelines for the management of ACS as they are evidenced based and definitive.

CEA in conjunction with medical therapy remains the best way to prevent stroke in patients with severe  (>70%) ACS.

Dr. Conrad is  an assistant professor of surgery, Harvard Medical School, Boston. Dr. Cambria is The Robert R. Linton MD Professor of Vascular and Endovascular Surgery, Harvard Medical School, Boston.

References

1.Neurology. 2006;67:1390-1395
2.Circulation. 2012;125:188-197
3.N Engl J of Med. 1986;315:860-865
4.JAMA. 1995;273:1421-1428
5.Lancet. 2010;376:1074-1084
6.Journal of Vascular Surgery. 2011;54:e1-31
7.Stroke. 2009;40:e573-583
8.N Engl J Med. 2000;342:1693-1700
9. Eur J Vasc Endovasc Surg. 2005;30:275-284
10.Stroke. 2005;36:1128-1133
11. Stroke. 2007;38:1470-1475
12. Lancet. 2004;363:1491-1502

POINT: Medical treatment ends need for CEA or CAS.

By Anne L. Abbott, M.D.

The medical profession and the wider community must be congratulated upon their sustained efforts over recent decades that have seen an 80% fall in the average annual risk of stroke associated with moderate and severe (50%-99%) asymptomatic carotid stenosis (ACS).^1-6 This has been achieved by better medical treatment which consists of encouraging healthy lifestyle habits and appropriate use of medication. This major impact results from the combined effect of addressing all vascular risk factors in individual patients and efforts to use the best medical treatment available at the time. Rates are now so low (around 0.5% per year for ipsilateral stroke) that procedures, such as carotid endarterectomy (CEA), are now more likely to harm than help patients.⁷

Even if procedures were always completely risk-free, improved medical treatment may mean we have now reached the point where carotid procedures for ACS are safe but essentially ineffective for reducing stroke risk. The latest measurements of stroke risk using medical treatment alone indicate that only about 2.5% of patients with 50%-99% ACS will have a an ipsilateral stroke due to the carotid lesion during their remaining lifetime if they are receiving pretty good quality, current medical treatment alone. This is because the average age of identifying patients with ACS in past studies was about 70 years and the average survival following diagnosis was 10 years.¹ Further, only about half the strokes occurring in the distribution of an internal carotid artery with >60% proximal stenosis are due to the carotid lesion.⁸

Guidelines recommendations for CEA for 50%-99% or 60%-99% ACS rely on marginal, 20- to 30-year-old differences in stroke rates between patients given medical treatment alone versus those given additional CEA in best practice settings.^9-11  Such recommendations are not relevant to current clinical practice largely because the medical treatment used in these studies is obsolete. Multiple independent observations regarding the improved stroke prevention efficacy of medical treatment,^1-6,12 and the additional observations below, provide ample evidence that current medical treatment alone is the only routine-practice (nontrial) approach we should use for  patients with 50%-99% ACS and any future role of carotid procedures in these patients could only apply to very small minority subgroups:

i. Current optimal medical treatment for patients with ACS has not been defined nor its impact measured. This means that it is likely we can lower the risk of stroke and other vascular complications in patients with ACS stenosis even further than has been achieved in the most recent studies. The definition of current optimal medical treatment will vary from patient to patient depending on which vascular risk factors they have and what has been shown effective in modifying these to reduce the risk of any complications of vascular disease.

ii. The 30-day peri-operative risk of stroke or death (and other significant complications) remains above 0% in the most recent results of trials and registries^13-15 and is usually not measured in routine practice. Latest measurements of average annual ipsilateral stroke risk with medical treatment alone are about 2-3 times lower than for patients who had CEA or CAS in the Asymp tomatic Carotid Atherosclerosis Study (ACAS)10 or the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).^{7, 13}

iii. Patients with 50%-99% ACS receiving current optimal medical treatment and with a sufficiently high average annual risk of ipsilateral stroke, indicating they may benefit from CEA, have not been identified. This rate would need to be in excess of at least 2.5%-3.0%, using results from ACAS,¹⁰ to expect any surgical benefit in routine practice. Studies of baseline degree of  ACS within the 50%-99% range,^10,11,16 plaque echolucency¹⁷ and most studies of detecting asymptomatic stenosis progression18-21 show that these parameters (used separately) confer a relative risk of stroke of only about 2.0-2.5. Therefore, a higher degree of baseline stenosis within the 50%-99% range, the detection of predominantly echolucent carotid plaques  or asymptomatic progression are too weak on their own to identity patients likely to benefit from an additional carotid procedure. Combinations of risk markers are required for sufficient risk discrimination. For instance, results from the Asymptomatic Carotid Stenosis and Risk of Stroke Study (largest study so far of medically managed patients with moderate or severe ACS) showed that a combination of clinical features, baseline degree of stenosis and standardized ultrasonic plaque characteristics can achieve average annual ipsilateral stroke risk stratification ranging  from <1.0% to 10%.¹⁶ However, like all stroke risk stratification studies performed so far, this study was performed before the era of current medical treatment and the results have not been independently tested.

iv. Even if patients with sufficiently higher than average annual risk of ipsilateral stroke are one day reliably identified, randomized trials of an additional carotid procedure will be required to determine if, and to what extent, that procedure is likely to reduce ipsilateral stroke risk in routine practice.

v. The available evidence from randomized trials and registries indicates that CAS causes about twice as many strokes or deaths as surgery (just like it does for symptomatic carotid stenosis). Therefore, currently CAS cannot be recommended.⁷  In conclusion, the available evidence clearly indicates that current medical treatment alone now offers the best chance of reducing the risk of ipsilateral stroke in patients with 50%-99% ACS. There is no current evidence of benefit from CEA or CAS in these patients overall, or in any particular subgroups. However, there is much evidence regarding procedural risk and unaffordable cost.  Risk of ipsilateral stroke is now so low without carotid procedures it is time to shift from the historic approach of identifying ACS primarily to administer CEA. Rather, it is time to properly recognize that carotid stenosis is a risk factor of all complications of vascular disease, more than it is for ipsilateral stroke.²²

The priority is to define current optimal medical treatment as best we can, recognising that patients with ACS are a risk-heterogenous population. Then we need quality independent measurements of its impact on risk of all vascular disease complications using quality prospective cohort studies. Risk stratification models should be used to identify those who may benefit from trials of more intensive medical treatment, motivational strategies, plus/minus the safest carotid procedures. If identifying patients with ACS for CEA in routine practice is to be feasible, this needs to be done within well organized environments that support patients with a wide range of stenosis severity with the primary aim of implementing current optimal medical treatment to prevent all vascular complications. Finally, it must be accepted that as medical treatment and its implementation continue to improve, the added value of carotid procedures, including for symptomatic carotid stenosis, will continue to recede until we can say, ‘good job - it is finally fixed and it is time to move on to other major health issues.’

Dr. Abbott is a neurologist and an associate professor at Monash University, Melbourne, Australia.

References

1. Stroke. 2009;40:e573-583
2. Eur J Vasc Endovasc Surg. 2009;37:625-632
3. Nat Rev Cardiol. 2011;9:116-124
4. Stroke. 2013;44
5. Management of asymptomatic carotid stenosis: Technology assessment report. 2012:83
6. Annals of Internal Medicine. 2013;158:676-685
7. Stroke. 2013;44:1186-1190
8. N Engl J Med. 2000;342:1693-1700
9. N Engl J Med. 1993;328:221-227.
10.JAMA. 1995;273:1421-1428
11. Lancet. 2004;363:1491-1502
12. Arch Neurol. 2010;67:180-186
13. N Engl J Med. 2010;363:11-23
14. J Vasc Surg. 2009;49:71-79
15. J Vasc Surg. 2011;53:307-315
16. J Vasc Surg. 2010;52:1486-1496 e1481-1485
17. Gupta A, Kesavabhotla K, Barbadaran H, Kamel H, Panda A, Giambrone A, et al. Plaque echolucency and stroke risk in asymptoamtioc carotid stenosis: A systematic review and meta-analysis. Stroke. 2014 in press.
18. J Vasc Surg. 1999;29:208-214; discussion 214-206
19. J Vasc Surg. 2013;58:128-135 e121
20  Stroke. 2013;44:792-794
21. J Vasc Surg. 2014;59:956-967
22. N Engl J Med. 1986;315:860-865.

COUNTERPOINT: Medical therapy alone is not always enough.

By Mark F. Conrad, M.D., M.MSc., and Richard P. Cambria M.D.

Stroke remains the 3rd leading cause of death in the United States.¹  It is estimated that 10% to 20% of ischemic strokes can be attributed to an ipsilateral, typically high-grade carotid stenosis, thus, asymptomatic carotid bifurcation stenosis remains a potentially significant public health problem.²  Epidemiologic studies indicate that 5% to 6% of the population >65 years of age will harbor an asymptomatic and potentially surgically significant carotid stenosis.¹  The modern literature linking the degree of stenosis of the internal carotid artery and risk of ipsilateral stroke dates to the natural history studies of Chambers and Norris published in the New England Journal of Medicine in 1986.³  These investigators demonstrated a significant correlation of stroke risk with a >70% ipsilateral carotid artery stenosis and progression under observation. 

Carotid endarterectomy (CEA) has been the standard of care for the prevention of stroke in patients with severe (>70%) asymptomatic carotid artery stenosis (ACS) for five decades.  This is supported by level 1 evidence from multiple randomized trials^{4, 5} and consensus guideline recommendations.^{2, 6}  Yet the use of CEA in patients with ACS has been recently challenged by a widely publicized review article⁷ whose author has embarked upon an anti-CEA crusade with the zealous fervor of one who worships at the altar of the statin.  In this review, 11 prospective studies of medical therapy of patients with ACS (defined by the author as >50% stenosis) were stratified by date of publication such that the four series published from 2000-2007 had a lower raw data stroke rate with medical management (.6- 1.3%) than the 1.5% stroke rate reported after CEA in the ACAS study.^4,7  The authors concluded that medical management alone is “at least 3-8” times more cost effective than CEA despite a complete lack of cost data in the cited articles.   In an effort to debunk this revisionist history, we will begin by addressing the four aforementioned trials and finish with a discussion of the recent literature including an observational study from our own institution.

The first study of the four followed the asymptomatic contralateral carotid artery of all patients enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) for 5 years to determine the risk of stroke in medically managed patients.⁸  There were 2,377 patients of whom 216 (9%) had a stenosis >60% but only 113 (4.7%) had a stenosis of 75-99%.  The 5-year risk of ipsilateral stroke in the 75-99% asymptomatic stenosis cohort was 18.5% or 3.7% per year (this did not include other neurologic events such as TIA or amaurosis fugax).⁸  However, in the meta-analysis, no stroke rate was included in the raw data column (which was the basis of the final calculated overall stroke risk) and the final estimate quoted used the 60%-99% cohort such that the annual stroke rate was reported as 3.2%.⁷

The Asymptomatic Carotid Stenosis and Risk of Ipsilateral Hemispheric Ischemic Events Study (ACSRS) was a multicenter study that followed 1,115 patients with ACS >50% by duplex scanning for 6-84 months (mean 37.1) with the goal of stratifying patients into cohorts of high and low risk for future neurologic events.⁹  They concluded that the annual stroke rate in high-risk patients was 4.3% versus 0.7% in low-risk patients.  There were 453 patients with 70%-99% stenosis by NASCET criteria with a raw stroke rate of 5.7% (1.9%/ year over an average 3-year follow-up) and a 5-year ipsilateral event rate of about 18%.⁹  However, when the patients with 50-69% were added, the raw stroke rate decreased to 1.3%.⁷

The Asymptomatic Stenosis Embolus Detection (ASED) study was a prospective trial that tested the theory that transcranial Doppler embolic signal detection would identify increased risk of ipsilateral neurologic events in patients with >60% ACS.¹⁰  Of the 240 arteries studied, 115 (48%) had a stenosis of 70%-99% but 10 of these patients were censored because they underwent CEA during the follow-up period.  Their outcomes were not further stratified by degree of stenosis but the average ipsilateral carotid event rate was 3.1% per year with a 1% stroke risk per year.^{7, 10}

The final, and most damning study in the meta-analysis, included a cohort of patients from the Second Manifestations of Arterial disease (SMART) study which is a registry of patients from the Netherlands with risk factors for, or symptoms of, arterial disease.

 This study attempted to determine the risk of new vascular event in patients with ACS but 996 (27% of the registry) patients with a history of cerebrovascular disease (undefined) were excluded from analysis.¹¹  They identified 221 patients (8% of 2684 eligible patients) with ACS >50% and reported an ipsilateral stroke event rate of .6%/year.⁷ 

However, in the 147 patients with a 70-99% stenosis, the hazard ratio for ischemic stroke was 1.7 but it was not possible to separate the patients with a moderate (50-69%) stenosis from the outcomes of those with more severe (>70%) disease.¹¹ 

The major flaw with this study is that the authors excluded the 996 patients with a history of cerebrovascular disease who were at highest risk of having an ACS and subsequently suffering a stroke.

The flaw with combining the results of the above studies to conclude that medical therapy is the best way to prevent stroke in patients with severe ACS is that only half (828/1,754, 47%) of the patients included had a severe (70-99%) stenosis that would warrant CEA in the United States.^{6, 7}

The majority of the patients studied would have been treated with best medical therapy and serial Duplex scanning. Indeed, when the moderate patients were excluded, the yearly stroke rates for patients with actual severe stenosis ranged from 2.0%-3.7%; substantially higher than the 1.5% stroke rate associated with CEA.^{8, 9}

Randomized prospective trials such as the asymptomatic carotid artery stenosis (ACAS) study published in 1995 and the more recently updated asymptomatic carotid surgery trial (ACST) indicated a quite similar annual stroke risk in the 2% range for patients treated with medical therapy as opposed to those randomized to carotid endarterectomy (this study was excluded from the meta-analysis because patients with a remote (>6 months before entry) history of neurologic events were included).^4,12 In addition, the 10-year follow-up data in the ACST trial demonstrated a sustained benefit for endarterectomy over optimal medical therapy.⁵ It is important to emphasize that in this trial some 80% of patients were on optimal medical therapy (aspirin plus statin agents) in the later years of the trial.

These long-term data indicate that while the protective effect of endarterectomy was more pronounced in those not on appropriate lipid-lowering therapy (the 10-year advantage of endarterectomy over medical therapy in the prevention of stroke was 5.8% in patients taking a statin and 6.2% in those who were not)  the protective effect of endarterectomy over optimal medical therapy was statistically significant (P=0.002).⁵

This is of course relevant because clinicians in the modern era have typically used data from ACST to counsel patients about the stroke risk of asymptomatic high-grade carotid stenosis.

Finally, we followed at a cohort of 115 patients with severe (>70%) ACS who did not undergo CEA for a variety of reasons.

The average follow-up was 27 months and 86% of patients were on statin therapy. 

The 5-year ipsilateral ischemic event rate was 30%, and 48% of these were strokes.  When stratified by degree of stenosis, the patients with a 90%-99% stenosis had an ipsilateral neurologic event rate of 55%. This is a single center experience but the stroke rate of 3% per year is consistent with contemporary series and reiterates the reality of this risk for medically treated patients.

The question remains. When the efficacy of a CEA for the prevention of stroke in patients with ACS is supported by level 1 evidence from multiple prospective, randomized trials, why would anyone who treats patients with carotid disease allow a meta-analysis of natural history studies (that redefines a severe stenosis as >50%) convince them otherwise?

We believe that the answer lies in the unsubstantiated conclusion that “current medical intervention was estimated at least 3 to 8 times more cost effective” than CEA.⁷ 

As health care in the United States continues to evolve, we are faced with the issue of how best to spend limited resource dollars.

Is it practical or cost efficient to perform preventative surgery?

In England, an annual stroke rate of 2%-3% in a small subset of the population may be acceptable but we are not ready to concede that in the United States.  
For now, we will follow the SVS practice guidelines for the management of ACS as they are evidenced based and definitive.

CEA in conjunction with medical therapy remains the best way to prevent stroke in patients with severe  (>70%) ACS.

Dr. Conrad is  an assistant professor of surgery, Harvard Medical School, Boston. Dr. Cambria is The Robert R. Linton MD Professor of Vascular and Endovascular Surgery, Harvard Medical School, Boston.

References

1.Neurology. 2006;67:1390-1395
2.Circulation. 2012;125:188-197
3.N Engl J of Med. 1986;315:860-865
4.JAMA. 1995;273:1421-1428
5.Lancet. 2010;376:1074-1084
6.Journal of Vascular Surgery. 2011;54:e1-31
7.Stroke. 2009;40:e573-583
8.N Engl J Med. 2000;342:1693-1700
9. Eur J Vasc Endovasc Surg. 2005;30:275-284
10.Stroke. 2005;36:1128-1133
11. Stroke. 2007;38:1470-1475
12. Lancet. 2004;363:1491-1502

On January 30, the New York Times published “Medicare Payments Surge for Stents to Unblock Blood Vessels in Limbs,” which questioned the medical necessity of many in-office interventions for peripheral artery disease and the motives of some doctors who perform them. (If you haven’t already, I encourage you to read the article at http://vsweb.org/NYTstents.)

Times reporters Julie Creswell and Reed Abelson analyzed Medicare payments, finding that the top 10 billing cardiologists made about half their Medicare reimbursements from office-based peripheral arterial procedures, with the implication that some doctors were taking advantage of an unregulated site-of-service.

The problem, though, goes beyond a handful of top billers. According to a citation from the Advisory Board Company, while the “number of procedures to open blockages in heart vessels fell by about 30 percent from 2005 to 2013…[o]ver the same time, the number of similar procedures for vessels outside the heart soared by almost 70 percent.”

The article struck a nerve. For several days, it was one of the most emailed articles on the New York Times website, and hundreds of SVS members throughout the world emailed us. Members were particularly outraged at the financial abuses reported. Many mentioned that they themselves had witnessed inappropriate care for asymptomatic PAD patients.

It was clear from the emails I received that our members want SVS to be on the right side of this issue, advocating for appropriate treatment of patients with PAD, and it makes me proud to be part of this community.

Over the past year, SVS has taken steps to address the issue of appropriateness.

Last June at our Vascular Annual Meeting, SVS held the Crawford Forum to discuss how we as a society can develop mechanisms to support appropriate vascular care and ethical decision-making. If you missed it, you can watch the entire symposium online at http://vsweb.org/Crawford.

Our Clinical Practice Council has seized upon appropriate care in office-based facilities as its current project and is working on constructive suggestions to ensure that site-of-service is not only convenient to patients but also provides high-quality, appropriate care.

Last month, we published in the Journal for Vascular Surgery “Practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudication,” which emphasize inexpensive physiologic testing in diagnosing PAD and conservative measures such as risk-factor modification and exercise in treating asymptomatic patients and claudicants. You can review the guidelines at http://vsweb.org/LEguidelines.

In addition, our recommendations for Choosing Wisely, a program of the American Board of Internal Medicine Foundation to curb unnecessary tests and treatment, warns against stents and other non-surgical and surgical interventions in asymptomatic patients and claudicants until conservative treatments have been tried. SVS is also partnering with Consumer Reports to educate patients about this issue this spring.

Finally, SVS has partnered with several international vascular societies on the Global Vascular Guidelines for critical limb ischemia and recently agreed to participate in a multi-societal collaboration to develop guidelines for the management of PAD.

There is more work to do. Next month’s Vascular Specialist will include some of the feedback we received from our members as well as suggestions on how SVS can develop criteria for appropriateness. To share your thoughts, please email me at [email protected].

What follows is the text of the Lawrence letter to the New York Times:

To the Editor:

Most of my colleagues in vascular medicine want to provide the best treatment for their patients, but those who don’t should be exposed, as was done in “Medicare Bills Rise for Stents Put Into Limbs” (front page, Jan. 30). This article shows how inappropriate care can harm a patient and greatly increase the cost of health care, while grossly enhancing the income of those who overuse procedures.

Office-based procedures are not inherently bad, if standards for appropriate care are followed. The Society for Vascular Surgery recently held a national symposium to discuss ways to discourage inappropriate use of vascular procedures, and recently, we published evidence-based practice guidelines to encourage appropriate care of peripheral arterial disease.

These guidelines emphasize conservative measures as the first line of treatment for patients without symptoms or with vascular pain only when walking, reserving interventions and surgery for those with more severe problems. They also recommend inexpensive, noninvasive tests to determine whether the pain is truly vascular. These tests should be used in every patient.

Practice guidelines set standards for our members, but all physicians treating patients with vascular disease should also use them. Vascular specialists need an in-depth understanding of vascular disease, as well as technical skill, but they also need the ethics to treat patients like a brother or a sister, not the source of payment for a new car.

PETER F. LAWRENCE, Los Angeles

The writer, chief of vascular surgery at U.C.L.A., is president of the Society for Vascular Surgery.

On January 30, the New York Times published “Medicare Payments Surge for Stents to Unblock Blood Vessels in Limbs,” which questioned the medical necessity of many in-office interventions for peripheral artery disease and the motives of some doctors who perform them. (If you haven’t already, I encourage you to read the article at http://vsweb.org/NYTstents.)

Times reporters Julie Creswell and Reed Abelson analyzed Medicare payments, finding that the top 10 billing cardiologists made about half their Medicare reimbursements from office-based peripheral arterial procedures, with the implication that some doctors were taking advantage of an unregulated site-of-service.

The problem, though, goes beyond a handful of top billers. According to a citation from the Advisory Board Company, while the “number of procedures to open blockages in heart vessels fell by about 30 percent from 2005 to 2013…[o]ver the same time, the number of similar procedures for vessels outside the heart soared by almost 70 percent.”

The article struck a nerve. For several days, it was one of the most emailed articles on the New York Times website, and hundreds of SVS members throughout the world emailed us. Members were particularly outraged at the financial abuses reported. Many mentioned that they themselves had witnessed inappropriate care for asymptomatic PAD patients.

It was clear from the emails I received that our members want SVS to be on the right side of this issue, advocating for appropriate treatment of patients with PAD, and it makes me proud to be part of this community.

Over the past year, SVS has taken steps to address the issue of appropriateness.

Last June at our Vascular Annual Meeting, SVS held the Crawford Forum to discuss how we as a society can develop mechanisms to support appropriate vascular care and ethical decision-making. If you missed it, you can watch the entire symposium online at http://vsweb.org/Crawford.

Our Clinical Practice Council has seized upon appropriate care in office-based facilities as its current project and is working on constructive suggestions to ensure that site-of-service is not only convenient to patients but also provides high-quality, appropriate care.

Last month, we published in the Journal for Vascular Surgery “Practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudication,” which emphasize inexpensive physiologic testing in diagnosing PAD and conservative measures such as risk-factor modification and exercise in treating asymptomatic patients and claudicants. You can review the guidelines at http://vsweb.org/LEguidelines.

In addition, our recommendations for Choosing Wisely, a program of the American Board of Internal Medicine Foundation to curb unnecessary tests and treatment, warns against stents and other non-surgical and surgical interventions in asymptomatic patients and claudicants until conservative treatments have been tried. SVS is also partnering with Consumer Reports to educate patients about this issue this spring.

Finally, SVS has partnered with several international vascular societies on the Global Vascular Guidelines for critical limb ischemia and recently agreed to participate in a multi-societal collaboration to develop guidelines for the management of PAD.

There is more work to do. Next month’s Vascular Specialist will include some of the feedback we received from our members as well as suggestions on how SVS can develop criteria for appropriateness. To share your thoughts, please email me at [email protected].

What follows is the text of the Lawrence letter to the New York Times:

To the Editor:

Most of my colleagues in vascular medicine want to provide the best treatment for their patients, but those who don’t should be exposed, as was done in “Medicare Bills Rise for Stents Put Into Limbs” (front page, Jan. 30). This article shows how inappropriate care can harm a patient and greatly increase the cost of health care, while grossly enhancing the income of those who overuse procedures.

Office-based procedures are not inherently bad, if standards for appropriate care are followed. The Society for Vascular Surgery recently held a national symposium to discuss ways to discourage inappropriate use of vascular procedures, and recently, we published evidence-based practice guidelines to encourage appropriate care of peripheral arterial disease.

These guidelines emphasize conservative measures as the first line of treatment for patients without symptoms or with vascular pain only when walking, reserving interventions and surgery for those with more severe problems. They also recommend inexpensive, noninvasive tests to determine whether the pain is truly vascular. These tests should be used in every patient.

Practice guidelines set standards for our members, but all physicians treating patients with vascular disease should also use them. Vascular specialists need an in-depth understanding of vascular disease, as well as technical skill, but they also need the ethics to treat patients like a brother or a sister, not the source of payment for a new car.

PETER F. LAWRENCE, Los Angeles

The writer, chief of vascular surgery at U.C.L.A., is president of the Society for Vascular Surgery.

On January 30, the New York Times published “Medicare Payments Surge for Stents to Unblock Blood Vessels in Limbs,” which questioned the medical necessity of many in-office interventions for peripheral artery disease and the motives of some doctors who perform them. (If you haven’t already, I encourage you to read the article at http://vsweb.org/NYTstents.)

Times reporters Julie Creswell and Reed Abelson analyzed Medicare payments, finding that the top 10 billing cardiologists made about half their Medicare reimbursements from office-based peripheral arterial procedures, with the implication that some doctors were taking advantage of an unregulated site-of-service.

The problem, though, goes beyond a handful of top billers. According to a citation from the Advisory Board Company, while the “number of procedures to open blockages in heart vessels fell by about 30 percent from 2005 to 2013…[o]ver the same time, the number of similar procedures for vessels outside the heart soared by almost 70 percent.”

The article struck a nerve. For several days, it was one of the most emailed articles on the New York Times website, and hundreds of SVS members throughout the world emailed us. Members were particularly outraged at the financial abuses reported. Many mentioned that they themselves had witnessed inappropriate care for asymptomatic PAD patients.

It was clear from the emails I received that our members want SVS to be on the right side of this issue, advocating for appropriate treatment of patients with PAD, and it makes me proud to be part of this community.

Over the past year, SVS has taken steps to address the issue of appropriateness.

Last June at our Vascular Annual Meeting, SVS held the Crawford Forum to discuss how we as a society can develop mechanisms to support appropriate vascular care and ethical decision-making. If you missed it, you can watch the entire symposium online at http://vsweb.org/Crawford.

Our Clinical Practice Council has seized upon appropriate care in office-based facilities as its current project and is working on constructive suggestions to ensure that site-of-service is not only convenient to patients but also provides high-quality, appropriate care.

Last month, we published in the Journal for Vascular Surgery “Practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudication,” which emphasize inexpensive physiologic testing in diagnosing PAD and conservative measures such as risk-factor modification and exercise in treating asymptomatic patients and claudicants. You can review the guidelines at http://vsweb.org/LEguidelines.

In addition, our recommendations for Choosing Wisely, a program of the American Board of Internal Medicine Foundation to curb unnecessary tests and treatment, warns against stents and other non-surgical and surgical interventions in asymptomatic patients and claudicants until conservative treatments have been tried. SVS is also partnering with Consumer Reports to educate patients about this issue this spring.

Finally, SVS has partnered with several international vascular societies on the Global Vascular Guidelines for critical limb ischemia and recently agreed to participate in a multi-societal collaboration to develop guidelines for the management of PAD.

There is more work to do. Next month’s Vascular Specialist will include some of the feedback we received from our members as well as suggestions on how SVS can develop criteria for appropriateness. To share your thoughts, please email me at [email protected].

What follows is the text of the Lawrence letter to the New York Times:

To the Editor:

Most of my colleagues in vascular medicine want to provide the best treatment for their patients, but those who don’t should be exposed, as was done in “Medicare Bills Rise for Stents Put Into Limbs” (front page, Jan. 30). This article shows how inappropriate care can harm a patient and greatly increase the cost of health care, while grossly enhancing the income of those who overuse procedures.

Office-based procedures are not inherently bad, if standards for appropriate care are followed. The Society for Vascular Surgery recently held a national symposium to discuss ways to discourage inappropriate use of vascular procedures, and recently, we published evidence-based practice guidelines to encourage appropriate care of peripheral arterial disease.

These guidelines emphasize conservative measures as the first line of treatment for patients without symptoms or with vascular pain only when walking, reserving interventions and surgery for those with more severe problems. They also recommend inexpensive, noninvasive tests to determine whether the pain is truly vascular. These tests should be used in every patient.

Practice guidelines set standards for our members, but all physicians treating patients with vascular disease should also use them. Vascular specialists need an in-depth understanding of vascular disease, as well as technical skill, but they also need the ethics to treat patients like a brother or a sister, not the source of payment for a new car.

PETER F. LAWRENCE, Los Angeles

The writer, chief of vascular surgery at U.C.L.A., is president of the Society for Vascular Surgery.

Diagnosis: Bullous impetigo

Bullous impetigo is a superficial skin infection that is most commonly seen in children (especially under the age of 2 years). It accounts for 10% of all pediatric skin disease and 25% of all impetigo.

Bullous impetigo is a variant of impetigo that produces exfoliative or epidermolytic toxins (ETA and ETB) in response to a staphylococcal infection. ETA and ETB are glutamate-specific serine proteases that bind and cleave desmoglein-1, a glycoprotein integral to intraepidermal keratinocyte adhesion. ETA and ETB produced at the site of a staphylococcal infection drive a cutaneous blistering response caused by intraepidermal cleavage below or within the stratum granulosum.  While toxins typically act locally, they can spread systemically and produce generalized blistering. Therefore, lesions may be few and localized, or numerous and widespread.

A patient with bullous impetigo typically presents with a history of vesicular lesions that progress to flaccid bullae with little/no surrounding erythema. The color of the fluid contents can change from clear to cloudy/yellow. These bullae can easily rupture and leave a moist, erythematous base with surrounding honey-colored crust. Sometimes only the central portion of the bullae will drain, leaving a surrounding rim that retains fluid for days. Bullous impetigo most commonly affects moist, intertriginous areas. Most bullae heal without scarring, although hyperpigmentation has been reported in patients with darker skin types. Fever and other constitutional symptoms are uncommon.

The differential diagnosis of bullous impetigo includes contact dermatitis, bullous insect bites, thermal burns, pemphigus vulgaris, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis. It is especially important to rule out herpes simplex, varicella, bullous tinea, bullous fixed drug reaction, bullous drug eruption, and staphylococcal scalded skin syndrome.

The diagnosis of bullous impetigo is usually based upon clinical presentation. However, the diagnosis can easily be confirmed through bacterial culture of blister fluid that isolates Staphylococcus. Nikolsky’s sign is usually negative.

Bullous impetigo is self-limiting and, if left untreated, will typically resolve in weeks to months. The treatment of choice includes topical mupirocin ointment, along with local cleansing and crust removal. Oral antistaphylococcal drugs for 7-10 days are prescribed in the setting of widespread or complicated disease. Penicillinase-resistant penicillins and cephalosporins are effective against methicillin-susceptible Staphylococcus aureus. It is also important to consider methicillin-resistant S. aureus  and treat with trimethoprim-sulfamethoxazole, clindamycin, or linezolid. Intravenous vancomycin should be reserved for patients with severe, widespread disease.

This patient was treated with cephalexin and mupirocin. Her lesions began drying up 2 days after the initiation of antibiotics. Bacterial culture results were positive for Staphylococcus. 

Diagnosis: Bullous impetigo

Bullous impetigo is a superficial skin infection that is most commonly seen in children (especially under the age of 2 years). It accounts for 10% of all pediatric skin disease and 25% of all impetigo.

Bullous impetigo is a variant of impetigo that produces exfoliative or epidermolytic toxins (ETA and ETB) in response to a staphylococcal infection. ETA and ETB are glutamate-specific serine proteases that bind and cleave desmoglein-1, a glycoprotein integral to intraepidermal keratinocyte adhesion. ETA and ETB produced at the site of a staphylococcal infection drive a cutaneous blistering response caused by intraepidermal cleavage below or within the stratum granulosum.  While toxins typically act locally, they can spread systemically and produce generalized blistering. Therefore, lesions may be few and localized, or numerous and widespread.

A patient with bullous impetigo typically presents with a history of vesicular lesions that progress to flaccid bullae with little/no surrounding erythema. The color of the fluid contents can change from clear to cloudy/yellow. These bullae can easily rupture and leave a moist, erythematous base with surrounding honey-colored crust. Sometimes only the central portion of the bullae will drain, leaving a surrounding rim that retains fluid for days. Bullous impetigo most commonly affects moist, intertriginous areas. Most bullae heal without scarring, although hyperpigmentation has been reported in patients with darker skin types. Fever and other constitutional symptoms are uncommon.

The differential diagnosis of bullous impetigo includes contact dermatitis, bullous insect bites, thermal burns, pemphigus vulgaris, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis. It is especially important to rule out herpes simplex, varicella, bullous tinea, bullous fixed drug reaction, bullous drug eruption, and staphylococcal scalded skin syndrome.

The diagnosis of bullous impetigo is usually based upon clinical presentation. However, the diagnosis can easily be confirmed through bacterial culture of blister fluid that isolates Staphylococcus. Nikolsky’s sign is usually negative.

Bullous impetigo is self-limiting and, if left untreated, will typically resolve in weeks to months. The treatment of choice includes topical mupirocin ointment, along with local cleansing and crust removal. Oral antistaphylococcal drugs for 7-10 days are prescribed in the setting of widespread or complicated disease. Penicillinase-resistant penicillins and cephalosporins are effective against methicillin-susceptible Staphylococcus aureus. It is also important to consider methicillin-resistant S. aureus  and treat with trimethoprim-sulfamethoxazole, clindamycin, or linezolid. Intravenous vancomycin should be reserved for patients with severe, widespread disease.

This patient was treated with cephalexin and mupirocin. Her lesions began drying up 2 days after the initiation of antibiotics. Bacterial culture results were positive for Staphylococcus. 

Diagnosis: Bullous impetigo

Bullous impetigo is a superficial skin infection that is most commonly seen in children (especially under the age of 2 years). It accounts for 10% of all pediatric skin disease and 25% of all impetigo.

Bullous impetigo is a variant of impetigo that produces exfoliative or epidermolytic toxins (ETA and ETB) in response to a staphylococcal infection. ETA and ETB are glutamate-specific serine proteases that bind and cleave desmoglein-1, a glycoprotein integral to intraepidermal keratinocyte adhesion. ETA and ETB produced at the site of a staphylococcal infection drive a cutaneous blistering response caused by intraepidermal cleavage below or within the stratum granulosum.  While toxins typically act locally, they can spread systemically and produce generalized blistering. Therefore, lesions may be few and localized, or numerous and widespread.

A patient with bullous impetigo typically presents with a history of vesicular lesions that progress to flaccid bullae with little/no surrounding erythema. The color of the fluid contents can change from clear to cloudy/yellow. These bullae can easily rupture and leave a moist, erythematous base with surrounding honey-colored crust. Sometimes only the central portion of the bullae will drain, leaving a surrounding rim that retains fluid for days. Bullous impetigo most commonly affects moist, intertriginous areas. Most bullae heal without scarring, although hyperpigmentation has been reported in patients with darker skin types. Fever and other constitutional symptoms are uncommon.

The differential diagnosis of bullous impetigo includes contact dermatitis, bullous insect bites, thermal burns, pemphigus vulgaris, bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis. It is especially important to rule out herpes simplex, varicella, bullous tinea, bullous fixed drug reaction, bullous drug eruption, and staphylococcal scalded skin syndrome.

The diagnosis of bullous impetigo is usually based upon clinical presentation. However, the diagnosis can easily be confirmed through bacterial culture of blister fluid that isolates Staphylococcus. Nikolsky’s sign is usually negative.

Bullous impetigo is self-limiting and, if left untreated, will typically resolve in weeks to months. The treatment of choice includes topical mupirocin ointment, along with local cleansing and crust removal. Oral antistaphylococcal drugs for 7-10 days are prescribed in the setting of widespread or complicated disease. Penicillinase-resistant penicillins and cephalosporins are effective against methicillin-susceptible Staphylococcus aureus. It is also important to consider methicillin-resistant S. aureus  and treat with trimethoprim-sulfamethoxazole, clindamycin, or linezolid. Intravenous vancomycin should be reserved for patients with severe, widespread disease.

This patient was treated with cephalexin and mupirocin. Her lesions began drying up 2 days after the initiation of antibiotics. Bacterial culture results were positive for Staphylococcus. 

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.

One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.

Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).

David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.

Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).

High response rate

The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.

All 16 patients analyzed had prior allogeneic

hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.

Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.

The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.

The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.

Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.

Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.

And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).

‘Promising’ donor immune modulation

Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.

Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.

Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.

The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.

Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.

And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.

Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.

*Information in the abstract differs from that presented at the meeting.

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.

One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.

Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).

David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.

Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).

High response rate

The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.

All 16 patients analyzed had prior allogeneic

hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.

Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.

The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.

The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.

Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.

Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.

And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).

‘Promising’ donor immune modulation

Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.

Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.

Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.

The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.

Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.

And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.

Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.

*Information in the abstract differs from that presented at the meeting.

Prescription medications

Photo courtesy of CDC

SAN DIEGO—Ibrutinib can produce favorable results in heavily pretreated patients with chronic lymphocytic leukemia (CLL) who have undergone allogeneic transplant, according to studies presented at the 2015 BMT Tandem Meetings.

One study showed that ibrutinib prompted an 88% overall response rate (ORR) in 16 patients with relapsed/refractory CLL.

Another analysis showed that ibrutinib can promote full donor chimerism and resolution of chronic graft-vs-host disease (GVHD).

David B. Miklos, MD, PhD, of the Stanford University Medical Center in California, presented the outcomes in 16 patients as abstract 75.

Christine E. Ryan, also of the Stanford University Medical Center, and her colleagues presented the other analysis, which included 5 patients, in a poster at the meeting (abstract 444*).

High response rate

The data Dr Miklos presented were collected from 4 clinical trials (phases 2 and 3) in relapsed/refractory CLL. The research was sponsored by Pharmacyclics, the company co-developing ibrutinib with Janssen Biotech, Inc.

All 16 patients analyzed had prior allogeneic

hematopoietic stem cell transplant (allo-HSCT). They had a median of 5 prior therapies, 12 (75%) had received 4 or more prior therapies, and 10 (63%) had del 17p.

Patients received ibrutinib as a single agent or in combination with ofatumumab. The study endpoints were investigator-assessed ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

The ORR was 88%, with 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis.

The median duration of response, PFS, and OS were not reached at a median follow-up of 23 months. The estimated PFS at 24 months was 77%, and the estimated OS at that time point was 75%.

The median time on ibrutinib was 18 months (range, 0.4 to 38.8 months), with 69% (n=11) of patients continuing on treatment.

Five (31%) patients discontinued ibrutinib—2 due to disease progression, 2 due to pneumonia, and 1 as a voluntary patient withdrawal. Both patients who developed pneumonia died.

Grade 3 or higher treatment-emergent severe adverse events occurred in 11 patients. Six patients had infections.

And there was 1 case each of febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea (some patients had more than 1 event).

‘Promising’ donor immune modulation

Ryan and her colleagues presented data from 5 patients with relapsed/refractory CLL. They had relapsed 1 to 8.5 years after allo-HSCT.

Four patients had never achieved donor CD3 T-cell chimerism greater than 95%. And 1 patient had chronic GVHD when ibrutinib treatment began.

Patients received single-agent ibrutinib at 420 mg daily, starting 1 month to 2 years after relapse. Four patients remain on treatment, with courses ranging from 3 to 17 months.

The researchers reported that all patients showed sustained disease response and promising donor immune modulation. Four patients with abnormal lymph nodes prior to ibrutinib treatment experienced a “dramatic” reduction in lymph node size—a 68% reduction after 3 months.

Two patients achieved undetectable minimal residual disease (MRD) after 39 months and 8 months, respectively. One of these patients achieved full donor CD3 chimerism after 1 year of ibrutinib treatment and has maintained undetectable MRD for more than 10 months after stopping therapy.

And the patient with chronic GVHD achieved complete resolution of the condition after 6 months of ibrutinib treatment.

Three investigators involved in this research work for Sequenta, Inc., the company developing the ClonoSIGHT MRD test, which was used to detect MRD in this study.

*Information in the abstract differs from that presented at the meeting.

Scientist in the lab

Photo by Darren Baker

By tracking the evolution of Abl and Src, investigators have made discoveries that may aid the design of highly specific cancer drugs.

Abl and Src are 2 nearly identical protein kinases with a predilection to cause cancer in humans, mainly chronic myeloid leukemia and colon cancer.

The proteins are separated by 146 amino acids and one big difference: Abl is susceptible to treatment with the tyrosine kinase inhibitor imatinib (Gleevec), but Src is not.

Dorothee Kern, PhD, of Brandeis University in Waltham, Massachusetts, and her colleagues traced the journey of these 2 proteins over 1 billion years of evolution, pinpointing the exact evolutionary shifts that caused imatinib to bind well with one protein and poorly with the other.

This new approach to researching enzymes and their binding sites may have a major impact on the development of cancer drugs, the investigators said.

They published their findings in Science.

To determine why imatinib binds with Abl but not Src, Dr Kern and her colleagues turned back the evolutionary clock 1 billion years.

This revealed Abl and Src’s common ancestor, a primitive protein in yeast the team dubbed “ANC-AS.” They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids, and we were looking for the handful that dictate Gleevec specificity,” Dr Kern said. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles, and catalysis processes—creating Abl and Src.

By following this progression, while testing the proteins’ affinity to imatinib along the way, the investigators were able to whittle down the 146 different amino acids to 15 that are responsible for imatinib specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium—a process in which the protein transitions between 2 structures. The main difference between Abl and Src, when it comes to binding with imatinib, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why imatinib works on Abl—and doesn’t work on Src—scientists have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity has opened the door wider to designing good drugs,” Dr Kern said. “Our results pave the way for a different approach to rational drug design.”

Scientist in the lab

Photo by Darren Baker

By tracking the evolution of Abl and Src, investigators have made discoveries that may aid the design of highly specific cancer drugs.

Abl and Src are 2 nearly identical protein kinases with a predilection to cause cancer in humans, mainly chronic myeloid leukemia and colon cancer.

The proteins are separated by 146 amino acids and one big difference: Abl is susceptible to treatment with the tyrosine kinase inhibitor imatinib (Gleevec), but Src is not.

Dorothee Kern, PhD, of Brandeis University in Waltham, Massachusetts, and her colleagues traced the journey of these 2 proteins over 1 billion years of evolution, pinpointing the exact evolutionary shifts that caused imatinib to bind well with one protein and poorly with the other.

This new approach to researching enzymes and their binding sites may have a major impact on the development of cancer drugs, the investigators said.

They published their findings in Science.

To determine why imatinib binds with Abl but not Src, Dr Kern and her colleagues turned back the evolutionary clock 1 billion years.

This revealed Abl and Src’s common ancestor, a primitive protein in yeast the team dubbed “ANC-AS.” They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids, and we were looking for the handful that dictate Gleevec specificity,” Dr Kern said. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles, and catalysis processes—creating Abl and Src.

By following this progression, while testing the proteins’ affinity to imatinib along the way, the investigators were able to whittle down the 146 different amino acids to 15 that are responsible for imatinib specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium—a process in which the protein transitions between 2 structures. The main difference between Abl and Src, when it comes to binding with imatinib, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why imatinib works on Abl—and doesn’t work on Src—scientists have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity has opened the door wider to designing good drugs,” Dr Kern said. “Our results pave the way for a different approach to rational drug design.”

Scientist in the lab

Photo by Darren Baker

By tracking the evolution of Abl and Src, investigators have made discoveries that may aid the design of highly specific cancer drugs.

Abl and Src are 2 nearly identical protein kinases with a predilection to cause cancer in humans, mainly chronic myeloid leukemia and colon cancer.

The proteins are separated by 146 amino acids and one big difference: Abl is susceptible to treatment with the tyrosine kinase inhibitor imatinib (Gleevec), but Src is not.

Dorothee Kern, PhD, of Brandeis University in Waltham, Massachusetts, and her colleagues traced the journey of these 2 proteins over 1 billion years of evolution, pinpointing the exact evolutionary shifts that caused imatinib to bind well with one protein and poorly with the other.

This new approach to researching enzymes and their binding sites may have a major impact on the development of cancer drugs, the investigators said.

They published their findings in Science.

To determine why imatinib binds with Abl but not Src, Dr Kern and her colleagues turned back the evolutionary clock 1 billion years.

This revealed Abl and Src’s common ancestor, a primitive protein in yeast the team dubbed “ANC-AS.” They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids, and we were looking for the handful that dictate Gleevec specificity,” Dr Kern said. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles, and catalysis processes—creating Abl and Src.

By following this progression, while testing the proteins’ affinity to imatinib along the way, the investigators were able to whittle down the 146 different amino acids to 15 that are responsible for imatinib specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium—a process in which the protein transitions between 2 structures. The main difference between Abl and Src, when it comes to binding with imatinib, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why imatinib works on Abl—and doesn’t work on Src—scientists have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity has opened the door wider to designing good drugs,” Dr Kern said. “Our results pave the way for a different approach to rational drug design.”

Thrombus

Image by Kevin MacKenzie

Teva Pharmaceutical Industries Ltd. has launched the generic equivalent of the low-molecular-weight heparin Lovenox (enoxaparin sodium injection) in 7 dosage strengths in the US.

Enoxaparin can be used to prevent deep vein thrombosis (DVT) in patients undergoing abdominal surgery, those receiving a hip or knee replacement, and patients at risk of thromboembolic complications due to severely restricted mobility during acute illness.

When administered with warfarin, enoxaparin can be used for inpatient treatment of acute DVT, with or without pulmonary embolism (PE). Enoxaparin given in conjunction with warfarin may also be used for outpatient treatment of acute DVT without PE.

When given concurrently with aspirin, enoxaparin can be used to prevent ischemic complications of unstable angina and non-Q-wave myocardial infarction. Enoxaparin may also be used to treat acute ST-segment elevation myocardial infarction that is managed medically or with subsequent percutaneous coronary intervention.

Teva’s Enoxaparin Sodium Injection USP is available in the following doses:

• 30 mg/0.3 mL syringe, 10 x 0.3 mL
• 40 mg/0.4 mL syringe, 10 x 0.4 mL
• 60 mg/0.6 mL syringe, 10 x 0.6 mL
• 80 mg/0.8 mL syringe, 10 x 0.8 mL
• 100 mg/mL syringe, 10 x 1 mL
• 120 mg/0.8 mL syringe, 10 x 0.8 mL
• 150 mg/mL syringe, 10 x 1 mL.

Safety information

Enoxaparin’s label contains a boxed warning detailing the risk of epidural or spinal hematomas that can occur in patients who are anticoagulated with low-molecular-weight heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. The hematomas may result in long-term or permanent paralysis.

Enoxaparin is contraindicated in patients with active major bleeding, thrombocytopenia with a positive in vitro test for antiplatelet antibody in the presence of enoxaparin, or known hypersensitivity to enoxaparin, heparin, or pork products.

Serious adverse reactions reported with enoxaparin include increased risk of hemorrhage and thrombocytopenia.

Enoxaparin should be used with extreme caution in patients who have conditions with an increased risk of hemorrhage or in patients treated concomitantly with platelet inhibitors. Major hemorrhages, including retroperitoneal and intracranial bleeding, have been reported with enoxaparin. Some of these cases have been fatal.

Bleeding can occur at any site during enoxaparin treatment. The drug should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, and hemorrhage.

In clinical trials, the most common adverse reactions associated with enoxaparin (occurring in more than 1% of patients) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea. Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection.

For additional information on enoxaparin, see the full prescribing information.

Thrombus

Image by Kevin MacKenzie

Teva Pharmaceutical Industries Ltd. has launched the generic equivalent of the low-molecular-weight heparin Lovenox (enoxaparin sodium injection) in 7 dosage strengths in the US.

Enoxaparin can be used to prevent deep vein thrombosis (DVT) in patients undergoing abdominal surgery, those receiving a hip or knee replacement, and patients at risk of thromboembolic complications due to severely restricted mobility during acute illness.

When administered with warfarin, enoxaparin can be used for inpatient treatment of acute DVT, with or without pulmonary embolism (PE). Enoxaparin given in conjunction with warfarin may also be used for outpatient treatment of acute DVT without PE.

When given concurrently with aspirin, enoxaparin can be used to prevent ischemic complications of unstable angina and non-Q-wave myocardial infarction. Enoxaparin may also be used to treat acute ST-segment elevation myocardial infarction that is managed medically or with subsequent percutaneous coronary intervention.

Teva’s Enoxaparin Sodium Injection USP is available in the following doses:

• 30 mg/0.3 mL syringe, 10 x 0.3 mL
• 40 mg/0.4 mL syringe, 10 x 0.4 mL
• 60 mg/0.6 mL syringe, 10 x 0.6 mL
• 80 mg/0.8 mL syringe, 10 x 0.8 mL
• 100 mg/mL syringe, 10 x 1 mL
• 120 mg/0.8 mL syringe, 10 x 0.8 mL
• 150 mg/mL syringe, 10 x 1 mL.

Safety information

Enoxaparin’s label contains a boxed warning detailing the risk of epidural or spinal hematomas that can occur in patients who are anticoagulated with low-molecular-weight heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. The hematomas may result in long-term or permanent paralysis.

Enoxaparin is contraindicated in patients with active major bleeding, thrombocytopenia with a positive in vitro test for antiplatelet antibody in the presence of enoxaparin, or known hypersensitivity to enoxaparin, heparin, or pork products.

Serious adverse reactions reported with enoxaparin include increased risk of hemorrhage and thrombocytopenia.

Enoxaparin should be used with extreme caution in patients who have conditions with an increased risk of hemorrhage or in patients treated concomitantly with platelet inhibitors. Major hemorrhages, including retroperitoneal and intracranial bleeding, have been reported with enoxaparin. Some of these cases have been fatal.

Bleeding can occur at any site during enoxaparin treatment. The drug should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, and hemorrhage.

In clinical trials, the most common adverse reactions associated with enoxaparin (occurring in more than 1% of patients) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea. Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection.

For additional information on enoxaparin, see the full prescribing information.

Thrombus

Image by Kevin MacKenzie

Teva Pharmaceutical Industries Ltd. has launched the generic equivalent of the low-molecular-weight heparin Lovenox (enoxaparin sodium injection) in 7 dosage strengths in the US.

Enoxaparin can be used to prevent deep vein thrombosis (DVT) in patients undergoing abdominal surgery, those receiving a hip or knee replacement, and patients at risk of thromboembolic complications due to severely restricted mobility during acute illness.

When administered with warfarin, enoxaparin can be used for inpatient treatment of acute DVT, with or without pulmonary embolism (PE). Enoxaparin given in conjunction with warfarin may also be used for outpatient treatment of acute DVT without PE.

When given concurrently with aspirin, enoxaparin can be used to prevent ischemic complications of unstable angina and non-Q-wave myocardial infarction. Enoxaparin may also be used to treat acute ST-segment elevation myocardial infarction that is managed medically or with subsequent percutaneous coronary intervention.

Teva’s Enoxaparin Sodium Injection USP is available in the following doses:

• 30 mg/0.3 mL syringe, 10 x 0.3 mL
• 40 mg/0.4 mL syringe, 10 x 0.4 mL
• 60 mg/0.6 mL syringe, 10 x 0.6 mL
• 80 mg/0.8 mL syringe, 10 x 0.8 mL
• 100 mg/mL syringe, 10 x 1 mL
• 120 mg/0.8 mL syringe, 10 x 0.8 mL
• 150 mg/mL syringe, 10 x 1 mL.

Safety information

Enoxaparin’s label contains a boxed warning detailing the risk of epidural or spinal hematomas that can occur in patients who are anticoagulated with low-molecular-weight heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. The hematomas may result in long-term or permanent paralysis.

Enoxaparin is contraindicated in patients with active major bleeding, thrombocytopenia with a positive in vitro test for antiplatelet antibody in the presence of enoxaparin, or known hypersensitivity to enoxaparin, heparin, or pork products.

Serious adverse reactions reported with enoxaparin include increased risk of hemorrhage and thrombocytopenia.

Enoxaparin should be used with extreme caution in patients who have conditions with an increased risk of hemorrhage or in patients treated concomitantly with platelet inhibitors. Major hemorrhages, including retroperitoneal and intracranial bleeding, have been reported with enoxaparin. Some of these cases have been fatal.

Bleeding can occur at any site during enoxaparin treatment. The drug should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, and hemorrhage.

In clinical trials, the most common adverse reactions associated with enoxaparin (occurring in more than 1% of patients) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea. Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection.

For additional information on enoxaparin, see the full prescribing information.

Chlamydomonas reinhardtii

Image from Bielefeld University

A vaccine candidate generated using algae may be able to prevent the transmission of malaria from infected hosts to mosquitoes, preclinical research suggests.

Researchers used Chlamydomonas reinhardtii microalgae to produce recombinant Pfs25 protein.

When paired with human-compatible adjuvants—glucopyranosal lipid A (GLA) plus squalene oil-in-water emulsion—the protein generated antibodies that nearly eliminated malaria infection in mosquitoes.

The researchers reported these results in Infection and Immunity.

“Most malaria vaccine approaches are aimed at preventing humans from becoming infected when bitten by mosquitoes that carry the parasite,” said study author Joseph Vinetz, MD, of the University of California, San Diego.

“Our approach is to prevent transmission of the malaria parasite from infected humans to mosquitoes. This approach is similar to that of the current measles vaccine, which is such a hot topic of discussion these days, because the goal is to generate herd immunity in a population. We think that this approach is key to global malaria elimination too.”

Dr Vinetz and his colleagues wanted to produce a large quantity of properly folded Pfs25, a protein found on the surface of the malaria parasite’s reproductive cells, which are only present within the mosquito’s gut after it feeds on a malaria-infected blood meal.

Since antibodies against Pfs25 can halt the parasite’s lifecycle in the mosquito, they might also block transmission of the parasite to the next host. However, properly folded Pfs25 that induces transmission-blocking antibodies has been difficult to produce in the lab.

To overcome this problem, the researchers turned to Chlamydomonas reinhardtii. They introduced the Pfs25 gene into the algae by shooting the DNA into the plant cell’s nucleus.

After they let the algae do the work of replicating, building, and folding the protein, the team was able to purify enough functional Pfs25 for testing.

They also tested different adjuvants, which help stimulate the immune system’s response to Pfs25. They tested alum alone, GLA plus alum, squalene oil-in-water emulsion, and GLA plus squalene oil-in-water emulsion.

The best Pfs25/adjuvant combination—GLA plus squalene oil-in-water emulsion—elicited a uniquely robust antibody response in mice with high affinity and avidity—antibodies that specifically and strongly reacted with the malaria parasite’s reproductive cells.

The researchers then fed mosquitoes malaria parasites in the presence of control serum or immune serum collected from mice vaccinated with algae-produced Pfs25 in the presence of the adjuvants.

Eight days later, the team examined the mosquitoes’ guts for the presence of the malaria parasite. And they found that 4.2% (1/24) of mosquitoes that consumed the Pfs25/adjuvant-treated mouse serum were positive for the malaria parasite, compared to 70% (28/40) of control mosquitoes.

“We are really excited to see that Pfs25 produced by algae can effectively prevent malaria parasites from developing within the mosquito,” said study author Stephen Mayfield, PhD, of the University of California, San Diego.

“With the low cost of algal production, this may be the only system that can make an economic malaria vaccine. Now, we’re looking forward to comparing algae-produced Pfs25 and adjuvant head-to-head against other approaches to malaria vaccine production and administration.”

Chlamydomonas reinhardtii

Image from Bielefeld University

A vaccine candidate generated using algae may be able to prevent the transmission of malaria from infected hosts to mosquitoes, preclinical research suggests.

Researchers used Chlamydomonas reinhardtii microalgae to produce recombinant Pfs25 protein.

When paired with human-compatible adjuvants—glucopyranosal lipid A (GLA) plus squalene oil-in-water emulsion—the protein generated antibodies that nearly eliminated malaria infection in mosquitoes.

The researchers reported these results in Infection and Immunity.

“Most malaria vaccine approaches are aimed at preventing humans from becoming infected when bitten by mosquitoes that carry the parasite,” said study author Joseph Vinetz, MD, of the University of California, San Diego.

“Our approach is to prevent transmission of the malaria parasite from infected humans to mosquitoes. This approach is similar to that of the current measles vaccine, which is such a hot topic of discussion these days, because the goal is to generate herd immunity in a population. We think that this approach is key to global malaria elimination too.”

Dr Vinetz and his colleagues wanted to produce a large quantity of properly folded Pfs25, a protein found on the surface of the malaria parasite’s reproductive cells, which are only present within the mosquito’s gut after it feeds on a malaria-infected blood meal.

Since antibodies against Pfs25 can halt the parasite’s lifecycle in the mosquito, they might also block transmission of the parasite to the next host. However, properly folded Pfs25 that induces transmission-blocking antibodies has been difficult to produce in the lab.

To overcome this problem, the researchers turned to Chlamydomonas reinhardtii. They introduced the Pfs25 gene into the algae by shooting the DNA into the plant cell’s nucleus.

After they let the algae do the work of replicating, building, and folding the protein, the team was able to purify enough functional Pfs25 for testing.

They also tested different adjuvants, which help stimulate the immune system’s response to Pfs25. They tested alum alone, GLA plus alum, squalene oil-in-water emulsion, and GLA plus squalene oil-in-water emulsion.

The best Pfs25/adjuvant combination—GLA plus squalene oil-in-water emulsion—elicited a uniquely robust antibody response in mice with high affinity and avidity—antibodies that specifically and strongly reacted with the malaria parasite’s reproductive cells.

The researchers then fed mosquitoes malaria parasites in the presence of control serum or immune serum collected from mice vaccinated with algae-produced Pfs25 in the presence of the adjuvants.

Eight days later, the team examined the mosquitoes’ guts for the presence of the malaria parasite. And they found that 4.2% (1/24) of mosquitoes that consumed the Pfs25/adjuvant-treated mouse serum were positive for the malaria parasite, compared to 70% (28/40) of control mosquitoes.

“We are really excited to see that Pfs25 produced by algae can effectively prevent malaria parasites from developing within the mosquito,” said study author Stephen Mayfield, PhD, of the University of California, San Diego.

“With the low cost of algal production, this may be the only system that can make an economic malaria vaccine. Now, we’re looking forward to comparing algae-produced Pfs25 and adjuvant head-to-head against other approaches to malaria vaccine production and administration.”

Chlamydomonas reinhardtii

Image from Bielefeld University

A vaccine candidate generated using algae may be able to prevent the transmission of malaria from infected hosts to mosquitoes, preclinical research suggests.

Researchers used Chlamydomonas reinhardtii microalgae to produce recombinant Pfs25 protein.

When paired with human-compatible adjuvants—glucopyranosal lipid A (GLA) plus squalene oil-in-water emulsion—the protein generated antibodies that nearly eliminated malaria infection in mosquitoes.

The researchers reported these results in Infection and Immunity.

“Most malaria vaccine approaches are aimed at preventing humans from becoming infected when bitten by mosquitoes that carry the parasite,” said study author Joseph Vinetz, MD, of the University of California, San Diego.

“Our approach is to prevent transmission of the malaria parasite from infected humans to mosquitoes. This approach is similar to that of the current measles vaccine, which is such a hot topic of discussion these days, because the goal is to generate herd immunity in a population. We think that this approach is key to global malaria elimination too.”

Dr Vinetz and his colleagues wanted to produce a large quantity of properly folded Pfs25, a protein found on the surface of the malaria parasite’s reproductive cells, which are only present within the mosquito’s gut after it feeds on a malaria-infected blood meal.

Since antibodies against Pfs25 can halt the parasite’s lifecycle in the mosquito, they might also block transmission of the parasite to the next host. However, properly folded Pfs25 that induces transmission-blocking antibodies has been difficult to produce in the lab.

To overcome this problem, the researchers turned to Chlamydomonas reinhardtii. They introduced the Pfs25 gene into the algae by shooting the DNA into the plant cell’s nucleus.

After they let the algae do the work of replicating, building, and folding the protein, the team was able to purify enough functional Pfs25 for testing.

They also tested different adjuvants, which help stimulate the immune system’s response to Pfs25. They tested alum alone, GLA plus alum, squalene oil-in-water emulsion, and GLA plus squalene oil-in-water emulsion.

The best Pfs25/adjuvant combination—GLA plus squalene oil-in-water emulsion—elicited a uniquely robust antibody response in mice with high affinity and avidity—antibodies that specifically and strongly reacted with the malaria parasite’s reproductive cells.

The researchers then fed mosquitoes malaria parasites in the presence of control serum or immune serum collected from mice vaccinated with algae-produced Pfs25 in the presence of the adjuvants.

Eight days later, the team examined the mosquitoes’ guts for the presence of the malaria parasite. And they found that 4.2% (1/24) of mosquitoes that consumed the Pfs25/adjuvant-treated mouse serum were positive for the malaria parasite, compared to 70% (28/40) of control mosquitoes.

“We are really excited to see that Pfs25 produced by algae can effectively prevent malaria parasites from developing within the mosquito,” said study author Stephen Mayfield, PhD, of the University of California, San Diego.

“With the low cost of algal production, this may be the only system that can make an economic malaria vaccine. Now, we’re looking forward to comparing algae-produced Pfs25 and adjuvant head-to-head against other approaches to malaria vaccine production and administration.”

MAUI, HAWAII – Rheumatologists and other providers need to ask patients if they’ve had metal-on-metal hip implants.

That goes for hip resurfacing – which by definition is metal on metal – as well as actual metal-on-metal hips. Signs of trouble can be as subtle as mental status changes, and they go well beyond the traditional issues with worn-out artificial joints.

During a video interview at the 2015 Rheumatology Winter Clinical Symposium, Dr. Bill Bugbee, an orthopedic surgeon and professor at the University of California, San Diego, explained the problems and the warning signs for which physicians should watch.

[email protected]

MAUI, HAWAII – Rheumatologists and other providers need to ask patients if they’ve had metal-on-metal hip implants.

That goes for hip resurfacing – which by definition is metal on metal – as well as actual metal-on-metal hips. Signs of trouble can be as subtle as mental status changes, and they go well beyond the traditional issues with worn-out artificial joints.

During a video interview at the 2015 Rheumatology Winter Clinical Symposium, Dr. Bill Bugbee, an orthopedic surgeon and professor at the University of California, San Diego, explained the problems and the warning signs for which physicians should watch.

[email protected]

MAUI, HAWAII – Rheumatologists and other providers need to ask patients if they’ve had metal-on-metal hip implants.

That goes for hip resurfacing – which by definition is metal on metal – as well as actual metal-on-metal hips. Signs of trouble can be as subtle as mental status changes, and they go well beyond the traditional issues with worn-out artificial joints.

During a video interview at the 2015 Rheumatology Winter Clinical Symposium, Dr. Bill Bugbee, an orthopedic surgeon and professor at the University of California, San Diego, explained the problems and the warning signs for which physicians should watch.

[email protected]