Research on symptom management and monitoring of health-related quality of life (HRQOL) among cancer patients has typically focused on the active treatment phase.^1-7 More recently, greater attention has been given to the psychosocial needs and follow-up care plans for survivors.⁸ Several technology-assisted symptom/HRQOL monitoring systems with routine assessments have been shown to be easy to use,^1,3,5,9-16 readily accepted by patients,^{3,9,11,14,15,17,18} helpful in communication between patients and providers, ^3,9,11,13,15 and a means of overcoming numerous barriers to conducting routine assessments.^16,19-23 Real-time clinician feedback at the point-of-care appears to be a crucial component of these systems, giving patients and providers a systematic way of discussing symptoms and aspects of HRQOL that are often addressed only informally or not at all.

To date, 6 randomized controlled trials (RCTs) have assessed the impact of technology-assisted interventions among cancer patients.^6,23-27 There was significant variability across these studies, including differing sample sizes, number of intervention contacts, tumor site (eg, breast, lung, colon), outcomes assessed (eg, symptom distress, communication, and HRQOL), and types of technology used (eg, touch-screen computers, telephone systems). The methodological differences make it difficult to compare these studies, although a common thread was that patients found the systems easy to use and they generally perceived the systems as beneficial.^6,23-27 

Despite the positive response from participants, only 2 of the 6 RCTs demonstrated positive outcomes for the intervention over the control group.^23,25 In a study of 286 cancer patients and 28 oncologists, Velikova et al (2004) found that both the intervention and the attentioncontrol groups had better HRQOL than the control group over a 6-month period.²³ Among the intervention patients, the HRQOL improvement was related to clear use of the HRQOL data by physicians, and to physician/ patient discussion of pain and role function. A positive effect on emotional well-being was associated with feedback of the data to physicians. However, there were no significant differences between the intervention and attention-control groups.

Research on symptom management and monitoring of health-related quality of life (HRQOL) among cancer patients has typically focused on the active treatment phase.^1-7 More recently, greater attention has been given to the psychosocial needs and follow-up care plans for survivors.⁸ Several technology-assisted symptom/HRQOL monitoring systems with routine assessments have been shown to be easy to use,^1,3,5,9-16 readily accepted by patients,^{3,9,11,14,15,17,18} helpful in communication between patients and providers, ^3,9,11,13,15 and a means of overcoming numerous barriers to conducting routine assessments.^16,19-23 Real-time clinician feedback at the point-of-care appears to be a crucial component of these systems, giving patients and providers a systematic way of discussing symptoms and aspects of HRQOL that are often addressed only informally or not at all.

To date, 6 randomized controlled trials (RCTs) have assessed the impact of technology-assisted interventions among cancer patients.^6,23-27 There was significant variability across these studies, including differing sample sizes, number of intervention contacts, tumor site (eg, breast, lung, colon), outcomes assessed (eg, symptom distress, communication, and HRQOL), and types of technology used (eg, touch-screen computers, telephone systems). The methodological differences make it difficult to compare these studies, although a common thread was that patients found the systems easy to use and they generally perceived the systems as beneficial.^6,23-27 

Despite the positive response from participants, only 2 of the 6 RCTs demonstrated positive outcomes for the intervention over the control group.^23,25 In a study of 286 cancer patients and 28 oncologists, Velikova et al (2004) found that both the intervention and the attentioncontrol groups had better HRQOL than the control group over a 6-month period.²³ Among the intervention patients, the HRQOL improvement was related to clear use of the HRQOL data by physicians, and to physician/ patient discussion of pain and role function. A positive effect on emotional well-being was associated with feedback of the data to physicians. However, there were no significant differences between the intervention and attention-control groups.

Research on symptom management and monitoring of health-related quality of life (HRQOL) among cancer patients has typically focused on the active treatment phase.^1-7 More recently, greater attention has been given to the psychosocial needs and follow-up care plans for survivors.⁸ Several technology-assisted symptom/HRQOL monitoring systems with routine assessments have been shown to be easy to use,^1,3,5,9-16 readily accepted by patients,^{3,9,11,14,15,17,18} helpful in communication between patients and providers, ^3,9,11,13,15 and a means of overcoming numerous barriers to conducting routine assessments.^16,19-23 Real-time clinician feedback at the point-of-care appears to be a crucial component of these systems, giving patients and providers a systematic way of discussing symptoms and aspects of HRQOL that are often addressed only informally or not at all.

To date, 6 randomized controlled trials (RCTs) have assessed the impact of technology-assisted interventions among cancer patients.^6,23-27 There was significant variability across these studies, including differing sample sizes, number of intervention contacts, tumor site (eg, breast, lung, colon), outcomes assessed (eg, symptom distress, communication, and HRQOL), and types of technology used (eg, touch-screen computers, telephone systems). The methodological differences make it difficult to compare these studies, although a common thread was that patients found the systems easy to use and they generally perceived the systems as beneficial.^6,23-27 

Despite the positive response from participants, only 2 of the 6 RCTs demonstrated positive outcomes for the intervention over the control group.^23,25 In a study of 286 cancer patients and 28 oncologists, Velikova et al (2004) found that both the intervention and the attentioncontrol groups had better HRQOL than the control group over a 6-month period.²³ Among the intervention patients, the HRQOL improvement was related to clear use of the HRQOL data by physicians, and to physician/ patient discussion of pain and role function. A positive effect on emotional well-being was associated with feedback of the data to physicians. However, there were no significant differences between the intervention and attention-control groups.

Background Patients with late-stage cancer are living longer, making it important to understand factors that contribute to maintaining quality of life (QOL) and completing advanced illness behaviors (eg, advance directives).

Objective To examine whether illness perceptions—the cognitive beliefs that patients form about their cancer—may be more important guides to adjustment than clinical characteristics of the cancer.

Methods In a cross-sectional study, 105 female patients diagnosed with stage III (n 66) or IV (n 39) breast (n 44), gynecological (n 38), or lung (n 23) cancer completed self-report measures of illness perceptions, QOL, and advanced illness behaviors. Clinical data was obtained from medical records.

Results Despite modest associations, patients’ beliefs about the cancer were clearly unique from the clinical characteristics of the cancer. Illness perception variables accounted for a large portion of the variance (PS .01) for QOL and advanced illness behaviors, whereas clinical characteristics did not. QOL scores were predicted by patients’ reports of experiencing more cancer related symptoms (ie, illness identity), believing that their cancer is central to their self-identity, and higher income. Higher completion of advanced illness behaviors was predicted by higher income, the cancer being recurrent, and participants perceiving their cancer as more severe but also more understandable.

Limitations This study was limited by a cross-sectional design, small sample size, and focus on female patients.

Conclusion Addressing patients’ beliefs about their cancer diagnosis may provide important targets for intervention to improve QOL and illness behaviors in patients with late-stage cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Background Patients with late-stage cancer are living longer, making it important to understand factors that contribute to maintaining quality of life (QOL) and completing advanced illness behaviors (eg, advance directives).

Objective To examine whether illness perceptions—the cognitive beliefs that patients form about their cancer—may be more important guides to adjustment than clinical characteristics of the cancer.

Methods In a cross-sectional study, 105 female patients diagnosed with stage III (n 66) or IV (n 39) breast (n 44), gynecological (n 38), or lung (n 23) cancer completed self-report measures of illness perceptions, QOL, and advanced illness behaviors. Clinical data was obtained from medical records.

Results Despite modest associations, patients’ beliefs about the cancer were clearly unique from the clinical characteristics of the cancer. Illness perception variables accounted for a large portion of the variance (PS .01) for QOL and advanced illness behaviors, whereas clinical characteristics did not. QOL scores were predicted by patients’ reports of experiencing more cancer related symptoms (ie, illness identity), believing that their cancer is central to their self-identity, and higher income. Higher completion of advanced illness behaviors was predicted by higher income, the cancer being recurrent, and participants perceiving their cancer as more severe but also more understandable.

Limitations This study was limited by a cross-sectional design, small sample size, and focus on female patients.

Conclusion Addressing patients’ beliefs about their cancer diagnosis may provide important targets for intervention to improve QOL and illness behaviors in patients with late-stage cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Background Patients with late-stage cancer are living longer, making it important to understand factors that contribute to maintaining quality of life (QOL) and completing advanced illness behaviors (eg, advance directives).

Objective To examine whether illness perceptions—the cognitive beliefs that patients form about their cancer—may be more important guides to adjustment than clinical characteristics of the cancer.

Methods In a cross-sectional study, 105 female patients diagnosed with stage III (n 66) or IV (n 39) breast (n 44), gynecological (n 38), or lung (n 23) cancer completed self-report measures of illness perceptions, QOL, and advanced illness behaviors. Clinical data was obtained from medical records.

Results Despite modest associations, patients’ beliefs about the cancer were clearly unique from the clinical characteristics of the cancer. Illness perception variables accounted for a large portion of the variance (PS .01) for QOL and advanced illness behaviors, whereas clinical characteristics did not. QOL scores were predicted by patients’ reports of experiencing more cancer related symptoms (ie, illness identity), believing that their cancer is central to their self-identity, and higher income. Higher completion of advanced illness behaviors was predicted by higher income, the cancer being recurrent, and participants perceiving their cancer as more severe but also more understandable.

Limitations This study was limited by a cross-sectional design, small sample size, and focus on female patients.

Conclusion Addressing patients’ beliefs about their cancer diagnosis may provide important targets for intervention to improve QOL and illness behaviors in patients with late-stage cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 develop a VTE in the Western countries. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of patients diagnosed with thrombotic events will die within the first month after diagnosis. PE is a common consequence of DVT; 40% of patients who are diagnosed with a DVT will be subsequently found to have a PE upon further imaging. The high rate of association is also seen in those who present with a PE, 70% of whom will also be found to have a concomitant DVT.

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Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 develop a VTE in the Western countries. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of patients diagnosed with thrombotic events will die within the first month after diagnosis. PE is a common consequence of DVT; 40% of patients who are diagnosed with a DVT will be subsequently found to have a PE upon further imaging. The high rate of association is also seen in those who present with a PE, 70% of whom will also be found to have a concomitant DVT.

To read the full article in PDF:

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Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 develop a VTE in the Western countries. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of patients diagnosed with thrombotic events will die within the first month after diagnosis. PE is a common consequence of DVT; 40% of patients who are diagnosed with a DVT will be subsequently found to have a PE upon further imaging. The high rate of association is also seen in those who present with a PE, 70% of whom will also be found to have a concomitant DVT.

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After a stroke, an important goal is to prevent another one.^1,2 And for patients who have had an ischemic stroke or transient ischemic attack (TIA) due to atherosclerosis, an important part of secondary preventive therapy is a drug that inhibits platelets—ie, aspirin, extended-release dipyridamole, or clopidogrel. This has taken years to establish.

In the following pages, we discuss the antiplatelet agents that have been shown to be beneficial after stroke of atherosclerotic origin, and we briefly review the indications for surgery and stenting for the subset of patients whose strokes are caused by symptomatic carotid disease.

(Although managing modifiable risk factors such as smoking, hypertension, diabetes, and dyslipidemia is also important, we will not cover this topic here, nor will we talk about hemorrhagic stroke or stroke due to atrial fibrillation. Also not discussed here is cilostazol, which, although shown to be effective in preventing recurrent stroke when compared with placebo and aspirin,^3,4 has not been approved for this use by the US Food and Drug Administration, as of this writing.)

HOW WE REVIEWED THE LITERATURE

We searched PubMed using the terms aspirin, acetylsalicylic acid, clopidogrel, and/or dipyridamole, in combination with stroke, cerebral ische(ae)mia, transient ische(ae)mic attacks, or retinal artery occlusion. We reviewed only clinical trials or meta-analyses of these drugs for either primary or secondary prevention of cerebrovascular disease.

As our aim was to review the topic and not to perform a meta-analysis, no cutoffs were used to exclude trials. The references in the selected papers were also reviewed to expand the articles. Finally, the references in the current American Heart Association and American Stroke Association secondary stroke prevention guideline were also reviewed.

For a summary of the trials included in our review, see the Data Supplement as an appendix to the online version of this article.

ASPIRIN: THE GOLD STANDARD

Prescribed by Hippocrates in the form of willow bark extract, aspirin has long been known for its antipyretic and anti-inflammatory properties. Its antiplatelet and antithrombotic properties, first described in 1967 by Weiss and Aledort,⁵ are mediated by irreversible inhibition of cyclooxygenase, leading to decreased thromboxane A2, a platelet-aggregation activator.

Fields et al,^6,7 in 1977 and 1978, reported that in a controlled trial in patients with TIA or monocular blindness, fewer subsequent TIAs occurred in patients who received aspirin, although the difference was not statistically significant, with lower rates of events only in nonsurgical patients. Over the next 20 years, the results remained mixed.

The Danish Cooperative study⁸ (1983) found no significant difference in the rate of recurrent stroke with aspirin vs placebo.

AICLA.⁹ The Accidents Ischémiques Cérébraux Liés à l’Athérosclérose study of 1983 did find a difference. However, both the Danish Cooperative study and the AICLA were limited by lacking standardized computed tomographic imaging to rule out hemorrhagic stroke and by being relatively small.

The Swedish Cooperative Study¹⁰ (1987) found no statistical difference between high-dose aspirin and placebo in preventing recurrent vascular events (stroke, TIA, or myocardial infarction [MI]) 1 to 3 weeks after a stroke. However, it had several limitations: the aspirin group contained more patients with ischemic heart disease (who are more likely to die of cardiac causes), there were significantly more men in the aspirin group, and nearly one-fourth of the deaths were a result of the initial stroke, potentially masking the effect of aspirin in secondary prevention.

Later studies began to show a consistently favorable effect of aspirin.

Boysen et al¹¹ in 1988 reported a nonsignificant trend toward fewer adverse events with aspirin.

UK-TIA.¹² The United Kingdom Transient Ischaemic Attack trial in 1991 found a similar trend.

SALT.¹³ The Swedish Aspirin Low-dose Trial, also in 1991, showed a significant 18% lower rate of stroke or death in patients with recent TIA, minor stroke, or retinal occlusion treated with low-dose aspirin. The inclusion of patients with TIA helped broaden the population that might benefit. However, the study may have favored the aspirin group by having a run-in period in which patients were nonrandomly treated either with aspirin or with anticoagulation at the discretion of the patient’s physician and, if they suffered “several” TIAs, a stroke, retinal artery occlusion, or MI, were removed from the study.

ESPS-2.¹⁴ The second European Stroke Prevention Study in 1996 added to the evidence that aspirin prevents recurrent stroke. Patients with a history of TIA or stroke were randomized in double-blind fashion to four treatment groups: placebo, low-dose aspirin, dipyridamole, or aspirin plus dipyridamole. At 2 years, strokes had occurred in 18% fewer patients in the aspirin group than in the placebo group, and TIAs had occurred in 21.9% fewer. However, aspirin was associated with an absolute 0.5% increase in severe and fatal bleeding. The power of the study was limited because patients from one center were excluded because of “serious inconsistencies in patient case record forms and compliance assay determinations.” ¹⁴

Comment. The mixed results with aspirin in studies predating ESPS-2 were partly because the study populations were too small to show benefit.

ATT.¹⁵ The Antithrombotic Trialists’ Collaboration performed a meta-analysis that conclusively confirmed the benefit of aspirin after stroke or TIA. The investigators analyzed individual patient data pooled from randomized controlled trials published before 1997 that compared antiplatelet regimens (mostly aspirin) against placebo and against each other. The rates of vascular events were 10.7% with treatment vs 13.2% with placebo (P < .0001). Antiplatelet therapy was particularly effective in preventing ischemic stroke, with a 25% reduction in the rate of nonfatal stroke, and with an overall absolute benefit in stroke prevention across all high-risk patient groups. This translated to 25 fewer nonfatal strokes per 1,000 patients treated with antiplatelet therapy.

Studies of aspirin have used different daily doses—the earliest studies used large doses of 1,000 to 1,500 mg.^6–10

Boysen et al¹¹ in 1988 found a trend toward benefit (not statistically significant) with doses ranging from 50 mg to 100 mg.

In 1991, three separate studies found that higher doses of aspirin were no more effective than lower doses.

The UK-TIA trial¹² compared aspirin 300 mg vs 1,200 mg and found a higher risk of gastrointestinal bleeding with the higher dose.

The SALT Collaborative Group¹³ found 75 mg to be effective.

The Dutch TIA trial¹⁶ compared 30 mg vs 283 mg; end point outcomes were similar but the rate of adverse events was higher with 283 mg.

ESPS-2 was able to show efficacy at a dose of only 50 mg.¹⁴

Taylor et al¹⁷ compared lower doses (81 or 325 mg) vs higher doses (650 or 1,300 mg) for patients undergoing carotid endarterectomy and found that the risk of adverse events was twice as high with the higher doses.

The ATT Collaboration¹⁵ found that efficacy was 40% lower with the highest dose of aspirin than with the lowest doses.

Algra and van Gijn¹⁸ performed a meta-analysis of all these studies and found no difference in risk reduction between low-dose and high-dose aspirin, with an overall relative risk reduction of 13% at any dose above 30 mg.

Campbell et al,¹⁹ in a 2007 review, found that doses greater than 300 mg conferred no benefit, and that rapid and maximum suppression of thromboxane A2 can be achieved by chewing or ingesting dissolved forms of aspirin 162 mg.

Conclusion. Aspirin doses higher than 81 mg (the US standard) confer no greater benefit and may even decrease the efficacy of aspirin. In an emergency, rapid suppression of thromboxane A2 can be achieved by chewing a minimum dose of 162 mg.

DIPYRIDAMOLE CAN BE ADDED TO ASPIRIN

In 1967, Weiss and Aledort⁵ found that aspirin’s antiplatelet effect could be blocked by adenosine diphosphate, which is released by activated platelet cells and is an essential part of thrombus formation. Adjacent platelets are then activated, leading to up-regulation of thromboxane A2 and glycoprotein IIb/IIIa receptors and resulting in a cascade of platelet activation and clot formation.²⁰ Dipyridamole inhibits aggregation of platelets by inhibiting their ability to take up adenosine diphosphate.

Studies of dipyridamole

AICLA.⁹ Bousser et al⁹ randomized patients who suffered one or more cerebral or retinal infarctions to receive placebo, aspirin 1 g, or aspirin 1 g plus dipyridamole 225 mg. Aspirin was significantly better than placebo in preventing a recurrence of stroke. The event rate with aspirin plus dipyridamole was similar to the rate with aspirin alone, although on 2-by-2 analysis, the difference between placebo and aspirin plus dipyridamole did not reach statistical significance. However, the rate of carotid-origin stroke was 17% with aspirin alone and 6% with aspirin plus dipyridamole, a statistically significant difference.

Thus, this study confirmed the benefit of aspirin in preventing ischemic events but did not fully support the addition of dipyridamole, except in preventing stroke of carotid origin. The study had a number of limitations: the sample size was small, TIA was not included as an end point, computed tomography was not required for entry, and many patients were lost to follow-up, decreasing the statistical power of the trial.

The ESPS study²¹ was also a randomized controlled trial of aspirin plus dipyridamole vs placebo. But unlike AICLA, ESPS included patients with TIA.

ESPS found a 38.1% relative risk reduction in stroke with aspirin plus dipyridamole compared with placebo, and a 30.6% reduction in death from all causes. Interestingly, patients who had a TIA as the qualifying event had a lower end-point incidence and larger end-point reduction than those who had a stroke as the qualifying event. However, ESPS did not resolve the question of whether adding dipyridamole to aspirin affords any benefit over aspirin alone.

ESPS-2¹⁴ hoped to answer this question. Patients were randomized to placebo, aspirin, dipyridamole, or aspirin plus dipyridamole. On 2 × 2 analysis, the dipyridamole group had a 16% lower rate of recurrent stroke than the placebo group, and patients on aspirin plus dipyridamole had a 37% lower rate. Aspirin plus dipyridamole yielded a 23.1% reduction compared with aspirin alone, and a 24.7% reduction compared with dipyridamole alone. Similar benefit was reported for the end point of TIA with combination therapy compared with either agent alone.

However, nearly 25% of patients had to withdraw because of side effects, particularly in the dipyridamole-alone and aspirin-dipyridamole groups, and, as mentioned above, verification of compliance in the aspirin group was an issue.^14,22 Nevertheless, ESPS-2 clearly showed that aspirin plus dipyridamole was better than either drug alone in preventing recurrent stroke. It also showed the effectiveness of dipyridamole, which AICLA and ESPS could not do, because it had a larger study population, used a lower dose of aspirin, and perhaps because it used an extended-release form of dipyridamole.²³

The ATT meta-analysis¹⁵ showed a clear benefit of antiplatelet therapy. However, much of this benefit was derived from aspirin therapy, with the addition of dipyridamole resulting in a nonsignificant 6% reduction of vascular events. Most of the patients on dipyridamole were from the ESPS-2 study. In effect, the ATT was a meta-analysis of aspirin, as aspirin studies dominated at that time.

A Cochrane review²⁴ publsihed in 2003 attempted to rectify this by analyzing randomized controlled trials of dipyridamole vs placebo.²⁴ Like the ATT meta-analysis, it did not bear out the benefits of dipyridamole: compared with placebo, there was no effect on the rate of vascular death, and only a minimal benefit in reduction of vascular events—and this latter point is only because of the inclusion of ESPS-2.

Directly comparing aspirin plus dipyridamole vs aspirin alone, the reviewers found no effect on the rate of vascular death, and with the exclusion of ESPS-2, no effect on vascular events.

The Cochrane review had the same limitation as the ATT meta-analysis, ie, dependence on a single trial (ESPS-2) to show benefit, and perhaps the fact that ESPS-2 was the only study that used an extended-release form of dipyridamole.

Leonardi-Bee et al²⁵ performed a meta-analysis that overcame the limitation of ESPS-2 being the only study at the time with positive findings: they used pooled individual patient data from randomized trials and analyzed them en masse. Patients on aspirin plus dipyridamole had a 39% lower risk than with placebo and a 22% lower risk than with aspirin alone. Unlike the ATT and the Cochrane review, excluding ESPS-2 did not alter the statistically significant lower stroke rate with aspirin plus dipyridamole compared with controls. This meta-analysis helped to confirm ESPS-2’s finding of the additive effect of aspirin plus dipyridamole compared with aspirin and placebo control.

ESPRIT.^26,27 The European/Australasian Stroke Prevention in Reversible Ischaemia Trial confirmed these findings. This randomized controlled trial compared aspirin plus dipyridamole against aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the past 6 months. For the primary end point (death from all vascular causes, nonfatal stroke, nonfatal MI, nonfatal major bleeding complication), the hazard ratio was 0.80 favoring aspirin plus dipyridamole, with a number needed to treat of 104 over a mean of 3.5 years (absolute risk reduction of 1% per year). Importantly, twice as many patients taking aspirin plus dipyridamole discontinued the medication.

Caveats to interpreting this study are that it was not blinded, the aspirin doses varied (although the median aspirin dose—75 mg—was the same between the two groups), and not all patients received the extended-release form of dipyridamole.

ESPS-2, ESPRIT, and the meta-analysis by Leonardi-Bee et al showed that aspirin plus dipyridamole is more effective than placebo or aspirin alone in secondary prevention of vascular events, including stroke. Also, extended-release dipyridamole appears to be more effective.

Unfortunately, many patients stop taking dipyridamole because of side effects (primarily headache).

Based on the results of ESPRIT, the absolute benefit of dipyridamole used alone may be small.

CLOPIDOGREL: SIMILAR TO ASPIRIN IN EFFICACY?

Like dipyridamole, clopidogrel targets adenosine diphosphate to prevent clot formation, blocking its ability to bind to its receptor on platelets. It is a thienopyridine and, unlike its sister drug ticlopidine, does not seem to be associated with the potentially serious side effects of neutropenia. However, a few cases of thrombotic thrombocytopenic purpura have been reported.²⁸ The other drugs in this class have not been evaluated in clinical trials for secondary stroke prophylaxis.

Trials of clopidogrel

CAPRIE.²⁹ The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, in 1996, was one of the first to compare the clinical use of clopidogrel against aspirin. It was a randomized controlled noninferiority trial in patients over age 21 (inclusion criteria: ischemic stroke, MI, or peripheral arterial disease) randomized to aspirin 325 mg once daily or clopidogrel 75 mg once daily. Patients were followed for 1 to 3 years.

Patients on clopidogrel had a relative risk reduction of 8.7% in primary events (ischemic stroke, MI, or vascular death); patients on aspirin were at significantly higher risk of gastrointestinal hemorrhage. Patients with peripheral arterial disease as the qualifying event did particularly well on clopidogrel, with a significant relative risk reduction of 23.8%.

Limitations of the CAPRIE trial included its inability to measure the effect of treatment on individual outcomes, particularly stroke, and the fact that the relative risk reduction for patients with stroke as the qualifying event was not significant (P = .66). Another limitation was that it did not use TIA as an entry criterion or as part of the composite outcome. Also, the relative risk reduction had a wide confidence interval, and a large number of patients discontinued therapy for reasons other than the defined outcomes.

Nevertheless, the CAPRIE trial showed clopidogrel to be an effective antiplatelet prophylactic, particularly in patients with peripheral artery disease, but with no discernible difference from aspirin for those patients with MI or stroke as a qualifying event.

MATCH.³⁰ The Management of Atherothrombosis With Clopidogrel in High-risk Patients trial hoped to better assess clopidogrel’s efficacy, particularly in patients with ischemic cerebral events. Cardiac studies leading up to MATCH suggested that adding a thienopyridine to aspirin might offer additive benefit in reducing the rate of vascular outcomes.^15,31 MATCH randomized high-risk patients (inclusion criteria were ischemic stroke or TIA and a history of vascular disease) to clopidogrel or to aspirin plus clopidogrel.

There was a nonsignificant 6.4% relative risk reduction in the combined primary outcome of MI, ischemic stroke, vascular death, other vascular death, and re-hospitalization for acute ischemic events in the aspirin-plus-clopidogrel group compared with clopidogrel alone. However, this came at the cost of double the number of bleeding events in the combination group, mitigating most of the benefit of combination therapy.

An important caveat in interpreting the results of MATCH, as compared with the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, is that aspirin was being added to clopidogrel, not vice versa. CURE, which looked at the addition of clopidogrel to aspirin vs aspirin alone in cardiac patients, found a significant reduction of ischemic events taken as a group (relative risk 0.8), and a trend toward a lower rate of stroke (relative risk 0.86, but 95% confidence interval encompassing 1) for aspirin plus clopidogrel vs aspirin alone.³¹ However, patients in the CURE trial did not have high-risk vasculopathy per se but rather non-ST-elevation MI, perhaps skewing the benefit of combination therapy and lessening the risk of intracranial bleeding.

CHARISMA.³² The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, like the CURE trial, compared aspirin plus clopidogrel vs aspirin in patients with established cardiovascular, cerebrovascular, or peripheral arterial disease, or who were at high risk of events. As in the MATCH study, the findings for combination therapy were a nonsignificant relative risk of 0.93 for primary events (MI, stroke, or death from cardiovascular causes), and a significant reduction of secondary end points (primary end point event plus TIA or hospitalization for unstable angina) (relative risk 0.92, P = .04).

Importantly, combination therapy significantly increased the rate of bleeding events. In asymptomatic patients (those without documented vascular disease but with multiple atherothrombotic risk factors), there was actually harm with combined treatment. Conversely, for symptomatic patients (those with documented vascular disease), there was a negligible, but significant reduction in primary end points.

The result was that in patients with documented vascular disease, aspirin plus clopidogrel combination therapy provided little or no benefit over aspirin alone. For patients with elevated risk factors but no documented vascular burden, there may actually be harm from combination therapy.

PRoFESS.³³ Logically following is the question of whether aspirin plus dipyridamole offers any benefit over clopidogrel as a stroke prophylactic. The Prevention Regimen for Effectively Avoiding Second Strokes trial hoped to answer this by comparing clopidogrel against aspirin plus dipyridamole, both with and without telmisartan, in patients with recent stroke.

The rate of recurrent stroke was similar in the two groups, but there were 25 fewer ischemic strokes in patients on aspirin plus dipyridamole, offset by an increase in hemorrhagic strokes. Rates of secondary outcomes of stroke, death, or MI were nearly identical between the groups. Early discontinuation of treatment was significantly more frequent in those patients taking aspirin plus dipyridamole, meaning better compliance for those taking clopidogrel.

Initially, patients were to be randomized to either aspirin plus dipyridamole or aspirin plus clopidogrel. However, after MATCH³⁰ demonstrated a significantly higher bleeding risk with aspirin plus clopidogrel, patients were changed to clopidogrel alone. But despite this, the bleeding risk was still higher with aspirin plus dipyridamole.

During the trial, the entry criteria were expanded, allowing for the inclusion of younger patients and those with less recent strokes; but despite this change, the study remained underpowered to demonstrate its goal of noninferiority. Thus, it showed only a trend of noninferiority of clopidogrel vs aspirin plus dipyridamole.

What the clopidogrel trials tell us

Clopidogrel confers a benefit similar to that of aspirin (as shown in the CAPRIE study).²⁹ Although aspirin plus dipyridamole confers greater benefit than aspirin alone (as shown in the ESPS-2,¹⁴ Leonardi-Bee,²⁵ and ESPRIT²⁶ studies), aspirin plus dipyridamole is not superior to clopidogrel, and may even be inferior.³⁴

WARFARIN FOR ATRIAL FIBRILLATION ONLY

Warfarin acts by disrupting the coagulation cascade rather than acting at the site of platelet plug formation. In theory, warfarin should be as effective as the antiplatelet drugs in preventing clot formation, and so it was thought to possibly be effective in preventing stroke of arterial origin.

However, in at least three studies, warfarin increased the risk of death, MI, and hemorrhage, with perhaps a slight decrease in the risk of recurrent stroke in patients with suspected stroke or TIA.^35–37 This should be differentiated from stroke originating from cardiac dysrhythmias, for which warfarin has clearly been shown to be beneficial.²⁸

THREE GOOD MEDICAL OPTIONS FOR PREVENTING STROKE RECURRENCE

Antiplatelet therapy offers benefit in the primary and secondary prevention of stroke, with a 25% reduction in the rate of nonfatal stroke and a 17% reduction in the rate of death due to vascular causes.¹⁵

Aspirin is the best established, best tolerated, and least expensive of the three contemporary agents. Further, it is also the agent of choice for acute stroke care, to be given within 48 hours of a stroke to mitigate the risk of death and morbidity. The data for other agents in acute stroke management remain limited.³⁸

Aspirin plus dipyridamole

Aspirin plus dipyridamole is slightly more efficacious than aspirin alone, and it is an alternative when aspirin is ineffective and when the patient can afford the additional cost. Aspirin plus dipyridamole offers up to a 22% relative risk reduction (but a small reduction in absolute risk) of stroke compared with aspirin alone, as demonstrated by ESPS-2,¹⁴ Leonardi-Bee et al,²⁵ and ESPRIT.²⁶

When is clopidogrel appropriate?

Up to one-third of patients may not tolerate aspirin plus dipyridamole because of side effects. Clopidogrel is an option for these patients. The CAPRIE study²⁹ showed clopidogrel similar in efficacy to aspirin.

In contrast to aspirin plus dipyridamole, there is clearly no benefit to combining aspirin and clopidogrel for ischemic stroke prophylaxis. And data from PRoFESS³³ suggested the combination was qualitatively inferior to aspirin plus dipyridamole. However, the PRoFESS trial was underpowered to fully bear this out.

Therefore, current guidelines consider all three agents as appropriate for secondary prevention of stroke. One is not preferred over another, and the selection should be based on individual patient characteristics and affordability.²⁸

CAROTID SURGERY OR STENTING: BENEFITS AND LIMITATIONS

Atherosclerosis is the most common cause of stroke, and atherosclerosis of the common carotid bifurcation accounts for a small but significant percentage of all strokes.^39–41

The degree of carotid stenosis and whether it is producing symptoms influence how it should be managed. For patients with symptomatic carotid stenosis of more than 70%, multicenter randomized trials have shown that surgery (ie, carotid endarterectomy) added to medical therapy decreases the rate of recurrent stroke by up to 17% and the rate of combined stroke and death by 10% to 12% over a 2- to 3-year follow-up period (level of evidence A).^42–44 No study has proven the efficacy of surgery in patients with symptomatic stenosis of less than 50%.^43,44

Similarly, in asymptomatic carotid disease, preventive surgery is a beneficial adjunct to medical therapy in certain patients. An approximate 6% reduction in the rate of stroke or death over 5 years has been shown in patients with moderate stenosis (> 60%), with men younger than age 75 and with greater than 70% stenosis deriving the most benefit.^45–47

However, these robust, positive results with surgical intervention should not overshadow the importance of intensive and guided medical therapy, which has been shown to mitigate the risk of stroke.^48,49

Is stenting as good as surgery? In the multicenter randomized Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), stenting resulted in similar rates of stroke and MI in patients with symptomatic and asymptomatic disease.⁵⁰ However, stenting carried a greater risk of perioperative stroke, and endarterectomy carried a greater risk of MI. Those under age 70 benefited more from stenting, and those over age 70 benefited more from endarterectomy.

But another fact to keep in mind is that the relationship between carotid narrowing and an ipsilateral stroke is not necessarily direct. Two follow-up studies in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found that up to 45% of strokes that occurred after intervention in the distribution of the asymptomatic stenosed carotid artery were unrelated to the stenosis.^51,52 Moreover, up to 20% of subsequent strokes in the distribution of the symptomatic artery were not of large-artery origin, increasing up to 35% for those with stenosis of less than 70%.⁵¹ Clearly, thorough screening of those with presumed symptomatic stenosis is needed to eliminate other possible causes.

After a stroke, an important goal is to prevent another one.^1,2 And for patients who have had an ischemic stroke or transient ischemic attack (TIA) due to atherosclerosis, an important part of secondary preventive therapy is a drug that inhibits platelets—ie, aspirin, extended-release dipyridamole, or clopidogrel. This has taken years to establish.

In the following pages, we discuss the antiplatelet agents that have been shown to be beneficial after stroke of atherosclerotic origin, and we briefly review the indications for surgery and stenting for the subset of patients whose strokes are caused by symptomatic carotid disease.

(Although managing modifiable risk factors such as smoking, hypertension, diabetes, and dyslipidemia is also important, we will not cover this topic here, nor will we talk about hemorrhagic stroke or stroke due to atrial fibrillation. Also not discussed here is cilostazol, which, although shown to be effective in preventing recurrent stroke when compared with placebo and aspirin,^3,4 has not been approved for this use by the US Food and Drug Administration, as of this writing.)

HOW WE REVIEWED THE LITERATURE

We searched PubMed using the terms aspirin, acetylsalicylic acid, clopidogrel, and/or dipyridamole, in combination with stroke, cerebral ische(ae)mia, transient ische(ae)mic attacks, or retinal artery occlusion. We reviewed only clinical trials or meta-analyses of these drugs for either primary or secondary prevention of cerebrovascular disease.

As our aim was to review the topic and not to perform a meta-analysis, no cutoffs were used to exclude trials. The references in the selected papers were also reviewed to expand the articles. Finally, the references in the current American Heart Association and American Stroke Association secondary stroke prevention guideline were also reviewed.

For a summary of the trials included in our review, see the Data Supplement as an appendix to the online version of this article.

ASPIRIN: THE GOLD STANDARD

Prescribed by Hippocrates in the form of willow bark extract, aspirin has long been known for its antipyretic and anti-inflammatory properties. Its antiplatelet and antithrombotic properties, first described in 1967 by Weiss and Aledort,⁵ are mediated by irreversible inhibition of cyclooxygenase, leading to decreased thromboxane A2, a platelet-aggregation activator.

Fields et al,^6,7 in 1977 and 1978, reported that in a controlled trial in patients with TIA or monocular blindness, fewer subsequent TIAs occurred in patients who received aspirin, although the difference was not statistically significant, with lower rates of events only in nonsurgical patients. Over the next 20 years, the results remained mixed.

The Danish Cooperative study⁸ (1983) found no significant difference in the rate of recurrent stroke with aspirin vs placebo.

AICLA.⁹ The Accidents Ischémiques Cérébraux Liés à l’Athérosclérose study of 1983 did find a difference. However, both the Danish Cooperative study and the AICLA were limited by lacking standardized computed tomographic imaging to rule out hemorrhagic stroke and by being relatively small.

The Swedish Cooperative Study¹⁰ (1987) found no statistical difference between high-dose aspirin and placebo in preventing recurrent vascular events (stroke, TIA, or myocardial infarction [MI]) 1 to 3 weeks after a stroke. However, it had several limitations: the aspirin group contained more patients with ischemic heart disease (who are more likely to die of cardiac causes), there were significantly more men in the aspirin group, and nearly one-fourth of the deaths were a result of the initial stroke, potentially masking the effect of aspirin in secondary prevention.

Later studies began to show a consistently favorable effect of aspirin.

Boysen et al¹¹ in 1988 reported a nonsignificant trend toward fewer adverse events with aspirin.

UK-TIA.¹² The United Kingdom Transient Ischaemic Attack trial in 1991 found a similar trend.

SALT.¹³ The Swedish Aspirin Low-dose Trial, also in 1991, showed a significant 18% lower rate of stroke or death in patients with recent TIA, minor stroke, or retinal occlusion treated with low-dose aspirin. The inclusion of patients with TIA helped broaden the population that might benefit. However, the study may have favored the aspirin group by having a run-in period in which patients were nonrandomly treated either with aspirin or with anticoagulation at the discretion of the patient’s physician and, if they suffered “several” TIAs, a stroke, retinal artery occlusion, or MI, were removed from the study.

ESPS-2.¹⁴ The second European Stroke Prevention Study in 1996 added to the evidence that aspirin prevents recurrent stroke. Patients with a history of TIA or stroke were randomized in double-blind fashion to four treatment groups: placebo, low-dose aspirin, dipyridamole, or aspirin plus dipyridamole. At 2 years, strokes had occurred in 18% fewer patients in the aspirin group than in the placebo group, and TIAs had occurred in 21.9% fewer. However, aspirin was associated with an absolute 0.5% increase in severe and fatal bleeding. The power of the study was limited because patients from one center were excluded because of “serious inconsistencies in patient case record forms and compliance assay determinations.” ¹⁴

Comment. The mixed results with aspirin in studies predating ESPS-2 were partly because the study populations were too small to show benefit.

ATT.¹⁵ The Antithrombotic Trialists’ Collaboration performed a meta-analysis that conclusively confirmed the benefit of aspirin after stroke or TIA. The investigators analyzed individual patient data pooled from randomized controlled trials published before 1997 that compared antiplatelet regimens (mostly aspirin) against placebo and against each other. The rates of vascular events were 10.7% with treatment vs 13.2% with placebo (P < .0001). Antiplatelet therapy was particularly effective in preventing ischemic stroke, with a 25% reduction in the rate of nonfatal stroke, and with an overall absolute benefit in stroke prevention across all high-risk patient groups. This translated to 25 fewer nonfatal strokes per 1,000 patients treated with antiplatelet therapy.

Studies of aspirin have used different daily doses—the earliest studies used large doses of 1,000 to 1,500 mg.^6–10

Boysen et al¹¹ in 1988 found a trend toward benefit (not statistically significant) with doses ranging from 50 mg to 100 mg.

In 1991, three separate studies found that higher doses of aspirin were no more effective than lower doses.

The UK-TIA trial¹² compared aspirin 300 mg vs 1,200 mg and found a higher risk of gastrointestinal bleeding with the higher dose.

The SALT Collaborative Group¹³ found 75 mg to be effective.

The Dutch TIA trial¹⁶ compared 30 mg vs 283 mg; end point outcomes were similar but the rate of adverse events was higher with 283 mg.

ESPS-2 was able to show efficacy at a dose of only 50 mg.¹⁴

Taylor et al¹⁷ compared lower doses (81 or 325 mg) vs higher doses (650 or 1,300 mg) for patients undergoing carotid endarterectomy and found that the risk of adverse events was twice as high with the higher doses.

The ATT Collaboration¹⁵ found that efficacy was 40% lower with the highest dose of aspirin than with the lowest doses.

Algra and van Gijn¹⁸ performed a meta-analysis of all these studies and found no difference in risk reduction between low-dose and high-dose aspirin, with an overall relative risk reduction of 13% at any dose above 30 mg.

Campbell et al,¹⁹ in a 2007 review, found that doses greater than 300 mg conferred no benefit, and that rapid and maximum suppression of thromboxane A2 can be achieved by chewing or ingesting dissolved forms of aspirin 162 mg.

Conclusion. Aspirin doses higher than 81 mg (the US standard) confer no greater benefit and may even decrease the efficacy of aspirin. In an emergency, rapid suppression of thromboxane A2 can be achieved by chewing a minimum dose of 162 mg.

DIPYRIDAMOLE CAN BE ADDED TO ASPIRIN

In 1967, Weiss and Aledort⁵ found that aspirin’s antiplatelet effect could be blocked by adenosine diphosphate, which is released by activated platelet cells and is an essential part of thrombus formation. Adjacent platelets are then activated, leading to up-regulation of thromboxane A2 and glycoprotein IIb/IIIa receptors and resulting in a cascade of platelet activation and clot formation.²⁰ Dipyridamole inhibits aggregation of platelets by inhibiting their ability to take up adenosine diphosphate.

Studies of dipyridamole

AICLA.⁹ Bousser et al⁹ randomized patients who suffered one or more cerebral or retinal infarctions to receive placebo, aspirin 1 g, or aspirin 1 g plus dipyridamole 225 mg. Aspirin was significantly better than placebo in preventing a recurrence of stroke. The event rate with aspirin plus dipyridamole was similar to the rate with aspirin alone, although on 2-by-2 analysis, the difference between placebo and aspirin plus dipyridamole did not reach statistical significance. However, the rate of carotid-origin stroke was 17% with aspirin alone and 6% with aspirin plus dipyridamole, a statistically significant difference.

Thus, this study confirmed the benefit of aspirin in preventing ischemic events but did not fully support the addition of dipyridamole, except in preventing stroke of carotid origin. The study had a number of limitations: the sample size was small, TIA was not included as an end point, computed tomography was not required for entry, and many patients were lost to follow-up, decreasing the statistical power of the trial.

The ESPS study²¹ was also a randomized controlled trial of aspirin plus dipyridamole vs placebo. But unlike AICLA, ESPS included patients with TIA.

ESPS found a 38.1% relative risk reduction in stroke with aspirin plus dipyridamole compared with placebo, and a 30.6% reduction in death from all causes. Interestingly, patients who had a TIA as the qualifying event had a lower end-point incidence and larger end-point reduction than those who had a stroke as the qualifying event. However, ESPS did not resolve the question of whether adding dipyridamole to aspirin affords any benefit over aspirin alone.

ESPS-2¹⁴ hoped to answer this question. Patients were randomized to placebo, aspirin, dipyridamole, or aspirin plus dipyridamole. On 2 × 2 analysis, the dipyridamole group had a 16% lower rate of recurrent stroke than the placebo group, and patients on aspirin plus dipyridamole had a 37% lower rate. Aspirin plus dipyridamole yielded a 23.1% reduction compared with aspirin alone, and a 24.7% reduction compared with dipyridamole alone. Similar benefit was reported for the end point of TIA with combination therapy compared with either agent alone.

However, nearly 25% of patients had to withdraw because of side effects, particularly in the dipyridamole-alone and aspirin-dipyridamole groups, and, as mentioned above, verification of compliance in the aspirin group was an issue.^14,22 Nevertheless, ESPS-2 clearly showed that aspirin plus dipyridamole was better than either drug alone in preventing recurrent stroke. It also showed the effectiveness of dipyridamole, which AICLA and ESPS could not do, because it had a larger study population, used a lower dose of aspirin, and perhaps because it used an extended-release form of dipyridamole.²³

The ATT meta-analysis¹⁵ showed a clear benefit of antiplatelet therapy. However, much of this benefit was derived from aspirin therapy, with the addition of dipyridamole resulting in a nonsignificant 6% reduction of vascular events. Most of the patients on dipyridamole were from the ESPS-2 study. In effect, the ATT was a meta-analysis of aspirin, as aspirin studies dominated at that time.

A Cochrane review²⁴ publsihed in 2003 attempted to rectify this by analyzing randomized controlled trials of dipyridamole vs placebo.²⁴ Like the ATT meta-analysis, it did not bear out the benefits of dipyridamole: compared with placebo, there was no effect on the rate of vascular death, and only a minimal benefit in reduction of vascular events—and this latter point is only because of the inclusion of ESPS-2.

Directly comparing aspirin plus dipyridamole vs aspirin alone, the reviewers found no effect on the rate of vascular death, and with the exclusion of ESPS-2, no effect on vascular events.

The Cochrane review had the same limitation as the ATT meta-analysis, ie, dependence on a single trial (ESPS-2) to show benefit, and perhaps the fact that ESPS-2 was the only study that used an extended-release form of dipyridamole.

Leonardi-Bee et al²⁵ performed a meta-analysis that overcame the limitation of ESPS-2 being the only study at the time with positive findings: they used pooled individual patient data from randomized trials and analyzed them en masse. Patients on aspirin plus dipyridamole had a 39% lower risk than with placebo and a 22% lower risk than with aspirin alone. Unlike the ATT and the Cochrane review, excluding ESPS-2 did not alter the statistically significant lower stroke rate with aspirin plus dipyridamole compared with controls. This meta-analysis helped to confirm ESPS-2’s finding of the additive effect of aspirin plus dipyridamole compared with aspirin and placebo control.

ESPRIT.^26,27 The European/Australasian Stroke Prevention in Reversible Ischaemia Trial confirmed these findings. This randomized controlled trial compared aspirin plus dipyridamole against aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the past 6 months. For the primary end point (death from all vascular causes, nonfatal stroke, nonfatal MI, nonfatal major bleeding complication), the hazard ratio was 0.80 favoring aspirin plus dipyridamole, with a number needed to treat of 104 over a mean of 3.5 years (absolute risk reduction of 1% per year). Importantly, twice as many patients taking aspirin plus dipyridamole discontinued the medication.

Caveats to interpreting this study are that it was not blinded, the aspirin doses varied (although the median aspirin dose—75 mg—was the same between the two groups), and not all patients received the extended-release form of dipyridamole.

ESPS-2, ESPRIT, and the meta-analysis by Leonardi-Bee et al showed that aspirin plus dipyridamole is more effective than placebo or aspirin alone in secondary prevention of vascular events, including stroke. Also, extended-release dipyridamole appears to be more effective.

Unfortunately, many patients stop taking dipyridamole because of side effects (primarily headache).

Based on the results of ESPRIT, the absolute benefit of dipyridamole used alone may be small.

CLOPIDOGREL: SIMILAR TO ASPIRIN IN EFFICACY?

Like dipyridamole, clopidogrel targets adenosine diphosphate to prevent clot formation, blocking its ability to bind to its receptor on platelets. It is a thienopyridine and, unlike its sister drug ticlopidine, does not seem to be associated with the potentially serious side effects of neutropenia. However, a few cases of thrombotic thrombocytopenic purpura have been reported.²⁸ The other drugs in this class have not been evaluated in clinical trials for secondary stroke prophylaxis.

Trials of clopidogrel

CAPRIE.²⁹ The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, in 1996, was one of the first to compare the clinical use of clopidogrel against aspirin. It was a randomized controlled noninferiority trial in patients over age 21 (inclusion criteria: ischemic stroke, MI, or peripheral arterial disease) randomized to aspirin 325 mg once daily or clopidogrel 75 mg once daily. Patients were followed for 1 to 3 years.

Patients on clopidogrel had a relative risk reduction of 8.7% in primary events (ischemic stroke, MI, or vascular death); patients on aspirin were at significantly higher risk of gastrointestinal hemorrhage. Patients with peripheral arterial disease as the qualifying event did particularly well on clopidogrel, with a significant relative risk reduction of 23.8%.

Limitations of the CAPRIE trial included its inability to measure the effect of treatment on individual outcomes, particularly stroke, and the fact that the relative risk reduction for patients with stroke as the qualifying event was not significant (P = .66). Another limitation was that it did not use TIA as an entry criterion or as part of the composite outcome. Also, the relative risk reduction had a wide confidence interval, and a large number of patients discontinued therapy for reasons other than the defined outcomes.

Nevertheless, the CAPRIE trial showed clopidogrel to be an effective antiplatelet prophylactic, particularly in patients with peripheral artery disease, but with no discernible difference from aspirin for those patients with MI or stroke as a qualifying event.

MATCH.³⁰ The Management of Atherothrombosis With Clopidogrel in High-risk Patients trial hoped to better assess clopidogrel’s efficacy, particularly in patients with ischemic cerebral events. Cardiac studies leading up to MATCH suggested that adding a thienopyridine to aspirin might offer additive benefit in reducing the rate of vascular outcomes.^15,31 MATCH randomized high-risk patients (inclusion criteria were ischemic stroke or TIA and a history of vascular disease) to clopidogrel or to aspirin plus clopidogrel.

There was a nonsignificant 6.4% relative risk reduction in the combined primary outcome of MI, ischemic stroke, vascular death, other vascular death, and re-hospitalization for acute ischemic events in the aspirin-plus-clopidogrel group compared with clopidogrel alone. However, this came at the cost of double the number of bleeding events in the combination group, mitigating most of the benefit of combination therapy.

An important caveat in interpreting the results of MATCH, as compared with the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, is that aspirin was being added to clopidogrel, not vice versa. CURE, which looked at the addition of clopidogrel to aspirin vs aspirin alone in cardiac patients, found a significant reduction of ischemic events taken as a group (relative risk 0.8), and a trend toward a lower rate of stroke (relative risk 0.86, but 95% confidence interval encompassing 1) for aspirin plus clopidogrel vs aspirin alone.³¹ However, patients in the CURE trial did not have high-risk vasculopathy per se but rather non-ST-elevation MI, perhaps skewing the benefit of combination therapy and lessening the risk of intracranial bleeding.

CHARISMA.³² The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, like the CURE trial, compared aspirin plus clopidogrel vs aspirin in patients with established cardiovascular, cerebrovascular, or peripheral arterial disease, or who were at high risk of events. As in the MATCH study, the findings for combination therapy were a nonsignificant relative risk of 0.93 for primary events (MI, stroke, or death from cardiovascular causes), and a significant reduction of secondary end points (primary end point event plus TIA or hospitalization for unstable angina) (relative risk 0.92, P = .04).

Importantly, combination therapy significantly increased the rate of bleeding events. In asymptomatic patients (those without documented vascular disease but with multiple atherothrombotic risk factors), there was actually harm with combined treatment. Conversely, for symptomatic patients (those with documented vascular disease), there was a negligible, but significant reduction in primary end points.

The result was that in patients with documented vascular disease, aspirin plus clopidogrel combination therapy provided little or no benefit over aspirin alone. For patients with elevated risk factors but no documented vascular burden, there may actually be harm from combination therapy.

PRoFESS.³³ Logically following is the question of whether aspirin plus dipyridamole offers any benefit over clopidogrel as a stroke prophylactic. The Prevention Regimen for Effectively Avoiding Second Strokes trial hoped to answer this by comparing clopidogrel against aspirin plus dipyridamole, both with and without telmisartan, in patients with recent stroke.

The rate of recurrent stroke was similar in the two groups, but there were 25 fewer ischemic strokes in patients on aspirin plus dipyridamole, offset by an increase in hemorrhagic strokes. Rates of secondary outcomes of stroke, death, or MI were nearly identical between the groups. Early discontinuation of treatment was significantly more frequent in those patients taking aspirin plus dipyridamole, meaning better compliance for those taking clopidogrel.

Initially, patients were to be randomized to either aspirin plus dipyridamole or aspirin plus clopidogrel. However, after MATCH³⁰ demonstrated a significantly higher bleeding risk with aspirin plus clopidogrel, patients were changed to clopidogrel alone. But despite this, the bleeding risk was still higher with aspirin plus dipyridamole.

During the trial, the entry criteria were expanded, allowing for the inclusion of younger patients and those with less recent strokes; but despite this change, the study remained underpowered to demonstrate its goal of noninferiority. Thus, it showed only a trend of noninferiority of clopidogrel vs aspirin plus dipyridamole.

What the clopidogrel trials tell us

Clopidogrel confers a benefit similar to that of aspirin (as shown in the CAPRIE study).²⁹ Although aspirin plus dipyridamole confers greater benefit than aspirin alone (as shown in the ESPS-2,¹⁴ Leonardi-Bee,²⁵ and ESPRIT²⁶ studies), aspirin plus dipyridamole is not superior to clopidogrel, and may even be inferior.³⁴

WARFARIN FOR ATRIAL FIBRILLATION ONLY

Warfarin acts by disrupting the coagulation cascade rather than acting at the site of platelet plug formation. In theory, warfarin should be as effective as the antiplatelet drugs in preventing clot formation, and so it was thought to possibly be effective in preventing stroke of arterial origin.

However, in at least three studies, warfarin increased the risk of death, MI, and hemorrhage, with perhaps a slight decrease in the risk of recurrent stroke in patients with suspected stroke or TIA.^35–37 This should be differentiated from stroke originating from cardiac dysrhythmias, for which warfarin has clearly been shown to be beneficial.²⁸

THREE GOOD MEDICAL OPTIONS FOR PREVENTING STROKE RECURRENCE

Antiplatelet therapy offers benefit in the primary and secondary prevention of stroke, with a 25% reduction in the rate of nonfatal stroke and a 17% reduction in the rate of death due to vascular causes.¹⁵

Aspirin is the best established, best tolerated, and least expensive of the three contemporary agents. Further, it is also the agent of choice for acute stroke care, to be given within 48 hours of a stroke to mitigate the risk of death and morbidity. The data for other agents in acute stroke management remain limited.³⁸

Aspirin plus dipyridamole

Aspirin plus dipyridamole is slightly more efficacious than aspirin alone, and it is an alternative when aspirin is ineffective and when the patient can afford the additional cost. Aspirin plus dipyridamole offers up to a 22% relative risk reduction (but a small reduction in absolute risk) of stroke compared with aspirin alone, as demonstrated by ESPS-2,¹⁴ Leonardi-Bee et al,²⁵ and ESPRIT.²⁶

When is clopidogrel appropriate?

Up to one-third of patients may not tolerate aspirin plus dipyridamole because of side effects. Clopidogrel is an option for these patients. The CAPRIE study²⁹ showed clopidogrel similar in efficacy to aspirin.

In contrast to aspirin plus dipyridamole, there is clearly no benefit to combining aspirin and clopidogrel for ischemic stroke prophylaxis. And data from PRoFESS³³ suggested the combination was qualitatively inferior to aspirin plus dipyridamole. However, the PRoFESS trial was underpowered to fully bear this out.

Therefore, current guidelines consider all three agents as appropriate for secondary prevention of stroke. One is not preferred over another, and the selection should be based on individual patient characteristics and affordability.²⁸

CAROTID SURGERY OR STENTING: BENEFITS AND LIMITATIONS

Atherosclerosis is the most common cause of stroke, and atherosclerosis of the common carotid bifurcation accounts for a small but significant percentage of all strokes.^39–41

The degree of carotid stenosis and whether it is producing symptoms influence how it should be managed. For patients with symptomatic carotid stenosis of more than 70%, multicenter randomized trials have shown that surgery (ie, carotid endarterectomy) added to medical therapy decreases the rate of recurrent stroke by up to 17% and the rate of combined stroke and death by 10% to 12% over a 2- to 3-year follow-up period (level of evidence A).^42–44 No study has proven the efficacy of surgery in patients with symptomatic stenosis of less than 50%.^43,44

Similarly, in asymptomatic carotid disease, preventive surgery is a beneficial adjunct to medical therapy in certain patients. An approximate 6% reduction in the rate of stroke or death over 5 years has been shown in patients with moderate stenosis (> 60%), with men younger than age 75 and with greater than 70% stenosis deriving the most benefit.^45–47

However, these robust, positive results with surgical intervention should not overshadow the importance of intensive and guided medical therapy, which has been shown to mitigate the risk of stroke.^48,49

Is stenting as good as surgery? In the multicenter randomized Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), stenting resulted in similar rates of stroke and MI in patients with symptomatic and asymptomatic disease.⁵⁰ However, stenting carried a greater risk of perioperative stroke, and endarterectomy carried a greater risk of MI. Those under age 70 benefited more from stenting, and those over age 70 benefited more from endarterectomy.

But another fact to keep in mind is that the relationship between carotid narrowing and an ipsilateral stroke is not necessarily direct. Two follow-up studies in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found that up to 45% of strokes that occurred after intervention in the distribution of the asymptomatic stenosed carotid artery were unrelated to the stenosis.^51,52 Moreover, up to 20% of subsequent strokes in the distribution of the symptomatic artery were not of large-artery origin, increasing up to 35% for those with stenosis of less than 70%.⁵¹ Clearly, thorough screening of those with presumed symptomatic stenosis is needed to eliminate other possible causes.

After a stroke, an important goal is to prevent another one.^1,2 And for patients who have had an ischemic stroke or transient ischemic attack (TIA) due to atherosclerosis, an important part of secondary preventive therapy is a drug that inhibits platelets—ie, aspirin, extended-release dipyridamole, or clopidogrel. This has taken years to establish.

In the following pages, we discuss the antiplatelet agents that have been shown to be beneficial after stroke of atherosclerotic origin, and we briefly review the indications for surgery and stenting for the subset of patients whose strokes are caused by symptomatic carotid disease.

(Although managing modifiable risk factors such as smoking, hypertension, diabetes, and dyslipidemia is also important, we will not cover this topic here, nor will we talk about hemorrhagic stroke or stroke due to atrial fibrillation. Also not discussed here is cilostazol, which, although shown to be effective in preventing recurrent stroke when compared with placebo and aspirin,^3,4 has not been approved for this use by the US Food and Drug Administration, as of this writing.)

HOW WE REVIEWED THE LITERATURE

We searched PubMed using the terms aspirin, acetylsalicylic acid, clopidogrel, and/or dipyridamole, in combination with stroke, cerebral ische(ae)mia, transient ische(ae)mic attacks, or retinal artery occlusion. We reviewed only clinical trials or meta-analyses of these drugs for either primary or secondary prevention of cerebrovascular disease.

As our aim was to review the topic and not to perform a meta-analysis, no cutoffs were used to exclude trials. The references in the selected papers were also reviewed to expand the articles. Finally, the references in the current American Heart Association and American Stroke Association secondary stroke prevention guideline were also reviewed.

For a summary of the trials included in our review, see the Data Supplement as an appendix to the online version of this article.

ASPIRIN: THE GOLD STANDARD

Prescribed by Hippocrates in the form of willow bark extract, aspirin has long been known for its antipyretic and anti-inflammatory properties. Its antiplatelet and antithrombotic properties, first described in 1967 by Weiss and Aledort,⁵ are mediated by irreversible inhibition of cyclooxygenase, leading to decreased thromboxane A2, a platelet-aggregation activator.

Fields et al,^6,7 in 1977 and 1978, reported that in a controlled trial in patients with TIA or monocular blindness, fewer subsequent TIAs occurred in patients who received aspirin, although the difference was not statistically significant, with lower rates of events only in nonsurgical patients. Over the next 20 years, the results remained mixed.

The Danish Cooperative study⁸ (1983) found no significant difference in the rate of recurrent stroke with aspirin vs placebo.

AICLA.⁹ The Accidents Ischémiques Cérébraux Liés à l’Athérosclérose study of 1983 did find a difference. However, both the Danish Cooperative study and the AICLA were limited by lacking standardized computed tomographic imaging to rule out hemorrhagic stroke and by being relatively small.

The Swedish Cooperative Study¹⁰ (1987) found no statistical difference between high-dose aspirin and placebo in preventing recurrent vascular events (stroke, TIA, or myocardial infarction [MI]) 1 to 3 weeks after a stroke. However, it had several limitations: the aspirin group contained more patients with ischemic heart disease (who are more likely to die of cardiac causes), there were significantly more men in the aspirin group, and nearly one-fourth of the deaths were a result of the initial stroke, potentially masking the effect of aspirin in secondary prevention.

Later studies began to show a consistently favorable effect of aspirin.

Boysen et al¹¹ in 1988 reported a nonsignificant trend toward fewer adverse events with aspirin.

UK-TIA.¹² The United Kingdom Transient Ischaemic Attack trial in 1991 found a similar trend.

SALT.¹³ The Swedish Aspirin Low-dose Trial, also in 1991, showed a significant 18% lower rate of stroke or death in patients with recent TIA, minor stroke, or retinal occlusion treated with low-dose aspirin. The inclusion of patients with TIA helped broaden the population that might benefit. However, the study may have favored the aspirin group by having a run-in period in which patients were nonrandomly treated either with aspirin or with anticoagulation at the discretion of the patient’s physician and, if they suffered “several” TIAs, a stroke, retinal artery occlusion, or MI, were removed from the study.

ESPS-2.¹⁴ The second European Stroke Prevention Study in 1996 added to the evidence that aspirin prevents recurrent stroke. Patients with a history of TIA or stroke were randomized in double-blind fashion to four treatment groups: placebo, low-dose aspirin, dipyridamole, or aspirin plus dipyridamole. At 2 years, strokes had occurred in 18% fewer patients in the aspirin group than in the placebo group, and TIAs had occurred in 21.9% fewer. However, aspirin was associated with an absolute 0.5% increase in severe and fatal bleeding. The power of the study was limited because patients from one center were excluded because of “serious inconsistencies in patient case record forms and compliance assay determinations.” ¹⁴

Comment. The mixed results with aspirin in studies predating ESPS-2 were partly because the study populations were too small to show benefit.

ATT.¹⁵ The Antithrombotic Trialists’ Collaboration performed a meta-analysis that conclusively confirmed the benefit of aspirin after stroke or TIA. The investigators analyzed individual patient data pooled from randomized controlled trials published before 1997 that compared antiplatelet regimens (mostly aspirin) against placebo and against each other. The rates of vascular events were 10.7% with treatment vs 13.2% with placebo (P < .0001). Antiplatelet therapy was particularly effective in preventing ischemic stroke, with a 25% reduction in the rate of nonfatal stroke, and with an overall absolute benefit in stroke prevention across all high-risk patient groups. This translated to 25 fewer nonfatal strokes per 1,000 patients treated with antiplatelet therapy.

Studies of aspirin have used different daily doses—the earliest studies used large doses of 1,000 to 1,500 mg.^6–10

Boysen et al¹¹ in 1988 found a trend toward benefit (not statistically significant) with doses ranging from 50 mg to 100 mg.

In 1991, three separate studies found that higher doses of aspirin were no more effective than lower doses.

The UK-TIA trial¹² compared aspirin 300 mg vs 1,200 mg and found a higher risk of gastrointestinal bleeding with the higher dose.

The SALT Collaborative Group¹³ found 75 mg to be effective.

The Dutch TIA trial¹⁶ compared 30 mg vs 283 mg; end point outcomes were similar but the rate of adverse events was higher with 283 mg.

ESPS-2 was able to show efficacy at a dose of only 50 mg.¹⁴

Taylor et al¹⁷ compared lower doses (81 or 325 mg) vs higher doses (650 or 1,300 mg) for patients undergoing carotid endarterectomy and found that the risk of adverse events was twice as high with the higher doses.

The ATT Collaboration¹⁵ found that efficacy was 40% lower with the highest dose of aspirin than with the lowest doses.

Algra and van Gijn¹⁸ performed a meta-analysis of all these studies and found no difference in risk reduction between low-dose and high-dose aspirin, with an overall relative risk reduction of 13% at any dose above 30 mg.

Campbell et al,¹⁹ in a 2007 review, found that doses greater than 300 mg conferred no benefit, and that rapid and maximum suppression of thromboxane A2 can be achieved by chewing or ingesting dissolved forms of aspirin 162 mg.

Conclusion. Aspirin doses higher than 81 mg (the US standard) confer no greater benefit and may even decrease the efficacy of aspirin. In an emergency, rapid suppression of thromboxane A2 can be achieved by chewing a minimum dose of 162 mg.

DIPYRIDAMOLE CAN BE ADDED TO ASPIRIN

In 1967, Weiss and Aledort⁵ found that aspirin’s antiplatelet effect could be blocked by adenosine diphosphate, which is released by activated platelet cells and is an essential part of thrombus formation. Adjacent platelets are then activated, leading to up-regulation of thromboxane A2 and glycoprotein IIb/IIIa receptors and resulting in a cascade of platelet activation and clot formation.²⁰ Dipyridamole inhibits aggregation of platelets by inhibiting their ability to take up adenosine diphosphate.

Studies of dipyridamole

AICLA.⁹ Bousser et al⁹ randomized patients who suffered one or more cerebral or retinal infarctions to receive placebo, aspirin 1 g, or aspirin 1 g plus dipyridamole 225 mg. Aspirin was significantly better than placebo in preventing a recurrence of stroke. The event rate with aspirin plus dipyridamole was similar to the rate with aspirin alone, although on 2-by-2 analysis, the difference between placebo and aspirin plus dipyridamole did not reach statistical significance. However, the rate of carotid-origin stroke was 17% with aspirin alone and 6% with aspirin plus dipyridamole, a statistically significant difference.

Thus, this study confirmed the benefit of aspirin in preventing ischemic events but did not fully support the addition of dipyridamole, except in preventing stroke of carotid origin. The study had a number of limitations: the sample size was small, TIA was not included as an end point, computed tomography was not required for entry, and many patients were lost to follow-up, decreasing the statistical power of the trial.

The ESPS study²¹ was also a randomized controlled trial of aspirin plus dipyridamole vs placebo. But unlike AICLA, ESPS included patients with TIA.

ESPS found a 38.1% relative risk reduction in stroke with aspirin plus dipyridamole compared with placebo, and a 30.6% reduction in death from all causes. Interestingly, patients who had a TIA as the qualifying event had a lower end-point incidence and larger end-point reduction than those who had a stroke as the qualifying event. However, ESPS did not resolve the question of whether adding dipyridamole to aspirin affords any benefit over aspirin alone.

ESPS-2¹⁴ hoped to answer this question. Patients were randomized to placebo, aspirin, dipyridamole, or aspirin plus dipyridamole. On 2 × 2 analysis, the dipyridamole group had a 16% lower rate of recurrent stroke than the placebo group, and patients on aspirin plus dipyridamole had a 37% lower rate. Aspirin plus dipyridamole yielded a 23.1% reduction compared with aspirin alone, and a 24.7% reduction compared with dipyridamole alone. Similar benefit was reported for the end point of TIA with combination therapy compared with either agent alone.

However, nearly 25% of patients had to withdraw because of side effects, particularly in the dipyridamole-alone and aspirin-dipyridamole groups, and, as mentioned above, verification of compliance in the aspirin group was an issue.^14,22 Nevertheless, ESPS-2 clearly showed that aspirin plus dipyridamole was better than either drug alone in preventing recurrent stroke. It also showed the effectiveness of dipyridamole, which AICLA and ESPS could not do, because it had a larger study population, used a lower dose of aspirin, and perhaps because it used an extended-release form of dipyridamole.²³

The ATT meta-analysis¹⁵ showed a clear benefit of antiplatelet therapy. However, much of this benefit was derived from aspirin therapy, with the addition of dipyridamole resulting in a nonsignificant 6% reduction of vascular events. Most of the patients on dipyridamole were from the ESPS-2 study. In effect, the ATT was a meta-analysis of aspirin, as aspirin studies dominated at that time.

A Cochrane review²⁴ publsihed in 2003 attempted to rectify this by analyzing randomized controlled trials of dipyridamole vs placebo.²⁴ Like the ATT meta-analysis, it did not bear out the benefits of dipyridamole: compared with placebo, there was no effect on the rate of vascular death, and only a minimal benefit in reduction of vascular events—and this latter point is only because of the inclusion of ESPS-2.

Directly comparing aspirin plus dipyridamole vs aspirin alone, the reviewers found no effect on the rate of vascular death, and with the exclusion of ESPS-2, no effect on vascular events.

The Cochrane review had the same limitation as the ATT meta-analysis, ie, dependence on a single trial (ESPS-2) to show benefit, and perhaps the fact that ESPS-2 was the only study that used an extended-release form of dipyridamole.

Leonardi-Bee et al²⁵ performed a meta-analysis that overcame the limitation of ESPS-2 being the only study at the time with positive findings: they used pooled individual patient data from randomized trials and analyzed them en masse. Patients on aspirin plus dipyridamole had a 39% lower risk than with placebo and a 22% lower risk than with aspirin alone. Unlike the ATT and the Cochrane review, excluding ESPS-2 did not alter the statistically significant lower stroke rate with aspirin plus dipyridamole compared with controls. This meta-analysis helped to confirm ESPS-2’s finding of the additive effect of aspirin plus dipyridamole compared with aspirin and placebo control.

ESPRIT.^26,27 The European/Australasian Stroke Prevention in Reversible Ischaemia Trial confirmed these findings. This randomized controlled trial compared aspirin plus dipyridamole against aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the past 6 months. For the primary end point (death from all vascular causes, nonfatal stroke, nonfatal MI, nonfatal major bleeding complication), the hazard ratio was 0.80 favoring aspirin plus dipyridamole, with a number needed to treat of 104 over a mean of 3.5 years (absolute risk reduction of 1% per year). Importantly, twice as many patients taking aspirin plus dipyridamole discontinued the medication.

Caveats to interpreting this study are that it was not blinded, the aspirin doses varied (although the median aspirin dose—75 mg—was the same between the two groups), and not all patients received the extended-release form of dipyridamole.

ESPS-2, ESPRIT, and the meta-analysis by Leonardi-Bee et al showed that aspirin plus dipyridamole is more effective than placebo or aspirin alone in secondary prevention of vascular events, including stroke. Also, extended-release dipyridamole appears to be more effective.

Unfortunately, many patients stop taking dipyridamole because of side effects (primarily headache).

Based on the results of ESPRIT, the absolute benefit of dipyridamole used alone may be small.

CLOPIDOGREL: SIMILAR TO ASPIRIN IN EFFICACY?

Like dipyridamole, clopidogrel targets adenosine diphosphate to prevent clot formation, blocking its ability to bind to its receptor on platelets. It is a thienopyridine and, unlike its sister drug ticlopidine, does not seem to be associated with the potentially serious side effects of neutropenia. However, a few cases of thrombotic thrombocytopenic purpura have been reported.²⁸ The other drugs in this class have not been evaluated in clinical trials for secondary stroke prophylaxis.

Trials of clopidogrel

CAPRIE.²⁹ The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, in 1996, was one of the first to compare the clinical use of clopidogrel against aspirin. It was a randomized controlled noninferiority trial in patients over age 21 (inclusion criteria: ischemic stroke, MI, or peripheral arterial disease) randomized to aspirin 325 mg once daily or clopidogrel 75 mg once daily. Patients were followed for 1 to 3 years.

Patients on clopidogrel had a relative risk reduction of 8.7% in primary events (ischemic stroke, MI, or vascular death); patients on aspirin were at significantly higher risk of gastrointestinal hemorrhage. Patients with peripheral arterial disease as the qualifying event did particularly well on clopidogrel, with a significant relative risk reduction of 23.8%.

Limitations of the CAPRIE trial included its inability to measure the effect of treatment on individual outcomes, particularly stroke, and the fact that the relative risk reduction for patients with stroke as the qualifying event was not significant (P = .66). Another limitation was that it did not use TIA as an entry criterion or as part of the composite outcome. Also, the relative risk reduction had a wide confidence interval, and a large number of patients discontinued therapy for reasons other than the defined outcomes.

Nevertheless, the CAPRIE trial showed clopidogrel to be an effective antiplatelet prophylactic, particularly in patients with peripheral artery disease, but with no discernible difference from aspirin for those patients with MI or stroke as a qualifying event.

MATCH.³⁰ The Management of Atherothrombosis With Clopidogrel in High-risk Patients trial hoped to better assess clopidogrel’s efficacy, particularly in patients with ischemic cerebral events. Cardiac studies leading up to MATCH suggested that adding a thienopyridine to aspirin might offer additive benefit in reducing the rate of vascular outcomes.^15,31 MATCH randomized high-risk patients (inclusion criteria were ischemic stroke or TIA and a history of vascular disease) to clopidogrel or to aspirin plus clopidogrel.

There was a nonsignificant 6.4% relative risk reduction in the combined primary outcome of MI, ischemic stroke, vascular death, other vascular death, and re-hospitalization for acute ischemic events in the aspirin-plus-clopidogrel group compared with clopidogrel alone. However, this came at the cost of double the number of bleeding events in the combination group, mitigating most of the benefit of combination therapy.

An important caveat in interpreting the results of MATCH, as compared with the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, is that aspirin was being added to clopidogrel, not vice versa. CURE, which looked at the addition of clopidogrel to aspirin vs aspirin alone in cardiac patients, found a significant reduction of ischemic events taken as a group (relative risk 0.8), and a trend toward a lower rate of stroke (relative risk 0.86, but 95% confidence interval encompassing 1) for aspirin plus clopidogrel vs aspirin alone.³¹ However, patients in the CURE trial did not have high-risk vasculopathy per se but rather non-ST-elevation MI, perhaps skewing the benefit of combination therapy and lessening the risk of intracranial bleeding.

CHARISMA.³² The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, like the CURE trial, compared aspirin plus clopidogrel vs aspirin in patients with established cardiovascular, cerebrovascular, or peripheral arterial disease, or who were at high risk of events. As in the MATCH study, the findings for combination therapy were a nonsignificant relative risk of 0.93 for primary events (MI, stroke, or death from cardiovascular causes), and a significant reduction of secondary end points (primary end point event plus TIA or hospitalization for unstable angina) (relative risk 0.92, P = .04).

Importantly, combination therapy significantly increased the rate of bleeding events. In asymptomatic patients (those without documented vascular disease but with multiple atherothrombotic risk factors), there was actually harm with combined treatment. Conversely, for symptomatic patients (those with documented vascular disease), there was a negligible, but significant reduction in primary end points.

The result was that in patients with documented vascular disease, aspirin plus clopidogrel combination therapy provided little or no benefit over aspirin alone. For patients with elevated risk factors but no documented vascular burden, there may actually be harm from combination therapy.

PRoFESS.³³ Logically following is the question of whether aspirin plus dipyridamole offers any benefit over clopidogrel as a stroke prophylactic. The Prevention Regimen for Effectively Avoiding Second Strokes trial hoped to answer this by comparing clopidogrel against aspirin plus dipyridamole, both with and without telmisartan, in patients with recent stroke.

The rate of recurrent stroke was similar in the two groups, but there were 25 fewer ischemic strokes in patients on aspirin plus dipyridamole, offset by an increase in hemorrhagic strokes. Rates of secondary outcomes of stroke, death, or MI were nearly identical between the groups. Early discontinuation of treatment was significantly more frequent in those patients taking aspirin plus dipyridamole, meaning better compliance for those taking clopidogrel.

Initially, patients were to be randomized to either aspirin plus dipyridamole or aspirin plus clopidogrel. However, after MATCH³⁰ demonstrated a significantly higher bleeding risk with aspirin plus clopidogrel, patients were changed to clopidogrel alone. But despite this, the bleeding risk was still higher with aspirin plus dipyridamole.

During the trial, the entry criteria were expanded, allowing for the inclusion of younger patients and those with less recent strokes; but despite this change, the study remained underpowered to demonstrate its goal of noninferiority. Thus, it showed only a trend of noninferiority of clopidogrel vs aspirin plus dipyridamole.

What the clopidogrel trials tell us

Clopidogrel confers a benefit similar to that of aspirin (as shown in the CAPRIE study).²⁹ Although aspirin plus dipyridamole confers greater benefit than aspirin alone (as shown in the ESPS-2,¹⁴ Leonardi-Bee,²⁵ and ESPRIT²⁶ studies), aspirin plus dipyridamole is not superior to clopidogrel, and may even be inferior.³⁴

WARFARIN FOR ATRIAL FIBRILLATION ONLY

Warfarin acts by disrupting the coagulation cascade rather than acting at the site of platelet plug formation. In theory, warfarin should be as effective as the antiplatelet drugs in preventing clot formation, and so it was thought to possibly be effective in preventing stroke of arterial origin.

However, in at least three studies, warfarin increased the risk of death, MI, and hemorrhage, with perhaps a slight decrease in the risk of recurrent stroke in patients with suspected stroke or TIA.^35–37 This should be differentiated from stroke originating from cardiac dysrhythmias, for which warfarin has clearly been shown to be beneficial.²⁸

THREE GOOD MEDICAL OPTIONS FOR PREVENTING STROKE RECURRENCE

Antiplatelet therapy offers benefit in the primary and secondary prevention of stroke, with a 25% reduction in the rate of nonfatal stroke and a 17% reduction in the rate of death due to vascular causes.¹⁵

Aspirin is the best established, best tolerated, and least expensive of the three contemporary agents. Further, it is also the agent of choice for acute stroke care, to be given within 48 hours of a stroke to mitigate the risk of death and morbidity. The data for other agents in acute stroke management remain limited.³⁸

Aspirin plus dipyridamole

Aspirin plus dipyridamole is slightly more efficacious than aspirin alone, and it is an alternative when aspirin is ineffective and when the patient can afford the additional cost. Aspirin plus dipyridamole offers up to a 22% relative risk reduction (but a small reduction in absolute risk) of stroke compared with aspirin alone, as demonstrated by ESPS-2,¹⁴ Leonardi-Bee et al,²⁵ and ESPRIT.²⁶

When is clopidogrel appropriate?

Up to one-third of patients may not tolerate aspirin plus dipyridamole because of side effects. Clopidogrel is an option for these patients. The CAPRIE study²⁹ showed clopidogrel similar in efficacy to aspirin.

In contrast to aspirin plus dipyridamole, there is clearly no benefit to combining aspirin and clopidogrel for ischemic stroke prophylaxis. And data from PRoFESS³³ suggested the combination was qualitatively inferior to aspirin plus dipyridamole. However, the PRoFESS trial was underpowered to fully bear this out.

Therefore, current guidelines consider all three agents as appropriate for secondary prevention of stroke. One is not preferred over another, and the selection should be based on individual patient characteristics and affordability.²⁸

CAROTID SURGERY OR STENTING: BENEFITS AND LIMITATIONS

Atherosclerosis is the most common cause of stroke, and atherosclerosis of the common carotid bifurcation accounts for a small but significant percentage of all strokes.^39–41

The degree of carotid stenosis and whether it is producing symptoms influence how it should be managed. For patients with symptomatic carotid stenosis of more than 70%, multicenter randomized trials have shown that surgery (ie, carotid endarterectomy) added to medical therapy decreases the rate of recurrent stroke by up to 17% and the rate of combined stroke and death by 10% to 12% over a 2- to 3-year follow-up period (level of evidence A).^42–44 No study has proven the efficacy of surgery in patients with symptomatic stenosis of less than 50%.^43,44

Similarly, in asymptomatic carotid disease, preventive surgery is a beneficial adjunct to medical therapy in certain patients. An approximate 6% reduction in the rate of stroke or death over 5 years has been shown in patients with moderate stenosis (> 60%), with men younger than age 75 and with greater than 70% stenosis deriving the most benefit.^45–47

However, these robust, positive results with surgical intervention should not overshadow the importance of intensive and guided medical therapy, which has been shown to mitigate the risk of stroke.^48,49

Is stenting as good as surgery? In the multicenter randomized Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), stenting resulted in similar rates of stroke and MI in patients with symptomatic and asymptomatic disease.⁵⁰ However, stenting carried a greater risk of perioperative stroke, and endarterectomy carried a greater risk of MI. Those under age 70 benefited more from stenting, and those over age 70 benefited more from endarterectomy.

But another fact to keep in mind is that the relationship between carotid narrowing and an ipsilateral stroke is not necessarily direct. Two follow-up studies in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found that up to 45% of strokes that occurred after intervention in the distribution of the asymptomatic stenosed carotid artery were unrelated to the stenosis.^51,52 Moreover, up to 20% of subsequent strokes in the distribution of the symptomatic artery were not of large-artery origin, increasing up to 35% for those with stenosis of less than 70%.⁵¹ Clearly, thorough screening of those with presumed symptomatic stenosis is needed to eliminate other possible causes.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

A 42-year-old woman is admitted to the hospital with worsening shortness of breath on exertion, poor exercise tolerance, leg edema, and swelling of the abdomen. Her symptoms have been getting worse over the last 4 months. She reports no history of fever, chills, night sweats, bleeding disorder, joint pain, weight loss, or loss of appetite.

She has type 2 diabetes mellitus and hypothyroidism. She had rheumatoid arthritis but said it was “inactive,” not requiring treatment for the last 18 years. Three months ago, she underwent a total hysterectomy and salpingo-oophorectomy for a complex adnexal mass, biopsy of which revealed a benign mucinous ovarian cyst.

Her current medications include furosemide, levothyroxine, and metformin. She is an ex-smoker with a 7 pack-year history. She drinks a glass of wine on social occasions only. Her family history is unremarkable.

On examination, she is not in distress and she has no fever. She has jugular venous distention of 5 cm, tense ascites, and marked edema of the legs, as well as hyperpigmented patches and erythematous plaques over both shins. Neck palpation reveals no lymphadenopathy or thyromegaly.

Her liver and the tip of the spleen are palpable following paracentesis, once ascitic fluid is removed.

The cardiovascular examination is normal. Chest auscultation reveals decreased breath sounds at the right lung base with bibasilar crackles. No focal neurologic deficit is noted on clinical examination.

Laboratory testing at the time of hospital admission (Table 1) includes a hepatitis panel (negative for exposure to hepatitis A, B, and C) and ascitic fluid studies. Chest radiography shows a right pleural effusion. Echocardiography demonstrates moderate pericardial effusion without tamponade; left and right ventricular function is normal. Cardiac magnetic resonance imaging finds no evidence of pericardial constriction or restrictive cardiomyopathy. Pressures are normal on pulmonary artery catheterization.

FINDING THE CAUSE OF ASCITES

1. What is the most likely cause of ascites in this patient?

• Cirrhosis
• Recent abdominal surgery
• Congestive heart failure
• Abdominal malignancy
• Nephrotic syndrome

The serum-ascites albumin gradient—ie, the serum albumin concentration minus the ascitic fluid albumin concentration—helps determine whether ascites is related to portal hypertension.¹ A high gradient (ie, above 1.1 g/dL) is seen in cirrhosis, alcoholic hepatitis, congestive heart failure, vascular occlusion syndromes (eg, Budd-Chiari syndrome), and metastatic liver disease.

From the values in Table 1, our patient’s gradient is 0.8 g/dL, which is considered low. However, we cannot completely rule out cirrhosis as the cause of her ascites because she was taking a diuretic, and diuretics can falsely decrease the gradient. Heart failure is unlikely, based on the results of echocardiography and catheterization. In addition, the 24-hour urinary protein concentration is normal, as is alpha-1 antitrypsin secretion in the stool, ruling out protein-losing nephropathy or enteropathy as the cause of her low albumin and ascites.

A high triglyceride content in her ascitic fluid (> 150 mg/dL) is consistent with chylous ascites, which is seen in patients with previous abdominal surgery or with lymphatic obstruction due to malignancy. A high neutrophil count in the ascitic fluid and a negative culture are also consistent with chylous ascites. However, in this patient, recent surgery as the cause of chylous ascites does not explain the systemic features of hepatosplenomegaly, anemia, thrombocytosis, and low albumin. Moreover, her high C-reactive protein value suggests an ongoing inflammatory process, although her erythrocyte sedimentation rate is not significantly elevated.

Therefore, the most likely cause of ascites in this patient is abdominal malignancy.

WHAT SHOULD BE DONE NEXT?

2. Which of the following studies is reasonable in this patient at this point?

• Serum protein electrophoresis
• Computed tomography (CT) of the chest, abdomen, and pelvis
• Liver biopsy
• Cytologic study of the ascitic fluid

All of these studies would be reasonable and in fact were done in this patient.

Serum protein electrophoresis (Table 2) identified a monoclonal protein band in the immunoglobulin G (IgG) kappa region.

Cytologic study of the ascitic fluid was negative for malignant cells.

Chest CT revealed bilateral pleural effusions, pericardial effusion, and bilateral axillary lymphadenopathy. CT of the abdomen and pelvis was normal, except for ascites, and no pelvic tumor was noted.

Liver biopsy was done to look for the source of her unexplained ascites with elevated alkaline phosphatase, as all other investigations so far were normal. It revealed mild centrilobular scarring, but the rest of the parenchymal architecture was normal, with no evidence of bridging fibrosis or nodular regenerative hyperplasia (Figure 1).

Transjugular measurement of the hepatic vein pressure revealed a hepatic vein pressure gradient of 9 mm Hg, indicating mild portal hypertension. Venography showed widely patent hepatic and portal veins. Her high inflammatory marker levels could have been caused by smoldering rheumatoid arthritis; however, since the patient has had no joint symptoms for 18 years, this is very unlikely. It is more likely to be caused by a plasma cell disorder, as suggested by a monoclonal protein on electrophoresis.

WHAT IS THE DIAGNOSIS?

3. What is the most likely diagnosis in our patient?

• Rheumatoid arthritis
• Cryoglobulinemia
• Capillary leak syndrome
• Hematologic malignancy
• Syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS syndrome)

Rheumatoid arthritis can present with hepatosplenomegaly, lymphadenopathy, ascites, and skin rash, particularly if antinuclear antibody and rheumatoid factor are elevated. Ascites is known to occur in association with rheumatoid arthritis in the setting of Felty syndrome or nodular regenerative hyperplasia of the liver.² However, our patient did not have leukopenia or evidence of regenerative hyperplasia on liver biopsy. Moreover, her rheumatoid arthritis had remained clinically inactive for a long time.

Cryoglobulinemia was possible, given her ascites, neuropathy, and splenomegaly, but her serum hepatic antibody and C4 complement values were normal.³ Also, the appearance of her rash was not typical of cryoglobulinemia.

Capillary leak syndrome was ruled out by the absence of hypotensive episodes, edema of the face or upper extremities, or renal failure.⁴

Lymphoma was excluded by flow cytometry.

A monoclonal protein on serum electrophoresis may suggest multiple myeloma, but this patient had multisystem involvement including organomegaly, endocrinopathy, and skin abnormalities. Thus, POEMS syndrome is the most likely diagnosis.

4. Which test should be done at this time to confirm the diagnosis of POEMS syndrome?

• Bone marrow biopsy
• Vascular endothelial growth factor testing
• Nerve conduction study
• Complete x-ray bone survey

A test for vascular endothelial growth factor should be done. This growth factor is almost always elevated in POEMS, and a positive test helps confirm the diagnosis of POEMS. Our patient’s level was elevated at 1,664 pg/mL (reference range 31–86).

POEMS is thought to be a variant of plasma cell dyscrasia, and all patients with POEMS have a monoclonal protein on electrophoresis. On this background, multiple myeloma is an important consideration.

Our patient underwent bone marrow biopsy, which revealed mild plasmacytosis (< 10%) (Figure 2). A complete bone survey showed generalized osteopenia without blastic or lytic lesions. To complete the workup for POEMS syndrome, a nerve conduction study was done to look for neuropathy; it showed bilateral sensory motor neuropathy with features of both a demyelinating process and axonal loss.

POEMS SYNDROME

POEMS syndrome is a constellation of features such as organomegaly and endocrine and skin abnormalities in association with neuropathy and a monoclonal protein on electrophoresis.⁵ In 2003, Dispenzieri et al⁶ described the major and minor diagnostic criteria based on a retrospective analysis of 99 patients with POEMS syndrome.⁶ Later, elevated vascular endothelial growth factor was added as a confirmatory diagnostic criterion.⁷ This growth factor is also an indicator of prognosis in POEMS syndrome, and its level can be used to monitor the response to treatment.⁷

Our patient met both major criteria for POEMS syndrome, ie, polyneuropathy (based on nerve conduction studies) and a monoclonal protein. Polyneuropathy in POEMS syndrome usually occurs as sensorimotor peripheral neuropathy of insidious onset and is seldom painful. Nerve biopsy study reveals demyelination with features of axonal loss. Interestingly, although our patient had neuropathy as diagnosed by electromyography, she remained clinically asymptomatic.

The monoclonal protein in POEMS syndrome is commonly IgA or IgG. Light chains are always present and are mainly the lambda type; kappa light chains are also reported in rare cases. Our patient had IgG kappa light chains.

Our patient met a number of the minor criteria for POEMS syndrome: ie, organomegaly (hepatosplenomegaly, lymphadenopathy), endocrinopathy (hypothyroidism, diabetes), skin changes (hyperpigmentation and plaques of the lower extremities), edema, pleural effusion, and ascites.

Endocrine disorders in POEMS syndrome

The endocrine abnormalities most often described in POEMS syndrome are hypogonadism, hypothyroidism, and diabetes mellitus. But because hypothyroidism and diabetes are common in the general population, it is debatable whether either of these could constitute the endocrine component of POEMS syndrome. Nevertheless, in three large series,^6,7 occurrences of these two disorders were common, although less specific than adrenal or pituitary involvement.

In the analysis by Dispenzieri et al,⁶ 67% of patients had at least one endocrine abnormality. Our patient had no evidence of an adrenal disorder.

Skin, skeletal, and other changes

The skin changes in POEMS syndrome are often nonspecific and include hyperpigmentation, sclerodema-like thickening, and plaques.

Skeletal changes are noted in up to 97% of patients. A skeletal survey in our patient revealed generalized osteopenia as opposed to osteosclerotic lesions, which are common in POEMS syndrome.

Anemia and thrombocytosis (as in our patient) are usually seen in POEMS syndrome and are induced by cytokines.⁶ POEMS syndrome also leads to increased thrombotic complications from the release of inflammatory cytokines.

Hypoalbuminemia and anasarca including ascites are often seen in POEMS syndrome (prevalence 29% to 89%) and are attributed to cytokine-induced increased vascular permeability. In POEMS syndrome, the serum-ascites albumin gradient is usually less than 1.1 g/dL, as in our patient.

Stepani et al⁸ reported one case of culture-negative neutrocytic ascites with portal hypertension in POEMS syndrome.⁸ (Culture-negative neutrocytic ascites is defined as an ascitic fluid polymorphonuclear count greater than 250/mm³ and a negative ascitic fluid culture in the absence of previous antibiotic therapy.) Chylous ascites has not yet been described in POEMS syndrome. However, chylous ascites is predominantly lymphocytic, whereas our patient had neutrocytic ascites.

We concluded that the cause of our patient’s ascites was multifactorial and included previous surgery and POEMS syndrome.

Nonclassic presentation

In addition to its classic presentation, POEMS syndrome is often reported in association with other “unusual features” such as cardiomyopathy, pulmonary hypertension, and cryoglobulinemia.⁶

So far, very few cases of portal hypertension in POEMS syndrome have been reported. Stepani et al⁸ described a patient who had POEMS syndrome and portal hypertension with extensive portal fibrosis without cirrhosis on liver biopsy. Inoue et al⁹ reported a liver biopsy feature consistent with idiopathic portal hypertension, also noting a case with mild fibrosis and few lymphocytic infiltrates in the portal tract.⁹

The etiopathogenesis of POEMS syndrome is attributed to proangiogenic vascular endothelial growth factor, and other inflammatory cytokines (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha) also play a key role in pulmonary hypertension.^10,11 A similar pathogenesis could also contribute to the development of portal hypertension (Figure 3).

CASE CONCLUDED

We started our patient on oral prednisone 60 mg daily for a month, tapered to a maintenance dose of 15 mg to suppress clonal proliferation of plasma cells. Her symptoms improved. Her vascular endothelial growth factor level decreased from 1,664 to 624 pg/mL. She was enrolled in a National Institutes of Health study to evaluate the effect of a potential new immunomodulator treatment for POEMS syndrome.

In conclusion, POEMS syndrome is rare and can present with many atypical features. A high index of suspicion is needed to detect it in a patient who has noncirrhotic portal hypertension with ascites and multisystem involvement.

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹