Reviews

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:

Click here

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:

Click here

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.

During a routine mammogram, an enlarged lymph node was found in the patient’s armpit. The patient’s primary care physician (PCP) ordered follow-up imaging and referred the patient to a surgeon for possible excisional biopsy. The surgeon suggested that the biopsy could be delayed until additional imaging studies were completed.

The patient transferred her care to another surgeon, who immediately performed the biopsy and found stage IV inoperable breast cancer. The patient underwent aggressive chemotherapy for 3 years, but died 39 months after diagnosis.

ESTATE’S CLAIM The first surgeon was negligent for not immediately performing the biopsy.

DEFENDANTS’ DEFENSE There was no negligence. An earlier biopsy would not have changed the outcome.

VERDICT A $1.5 million Massachusetts verdict was returned.

Treating bowel injury after uterine ablation
Following uterine ablation performed by a gynecologist, a 35-year-old woman suffered severe abdominal pain. Six days later, the gynecologist and a surgeon performed a hysterectomy.

Three days after discharge, the patient returned to the hospital with an abdominal infection and sepsis. During a third operation, a burn hole was found; the injured portion of bowel was resected. The patient has chronic abdominal pain.

PATIENT’S CLAIM Sepsis and infection could have been avoided if either physician had identified the injury during the second hospitalization and surgery. The patient developed psychological issues as a result of chronic pain.

DEFENDANTS’ DEFENSE A settlement was reached with the gynecologist during the trial. The surgeon denied negligence. During the second surgery, he examined her bowel for a possible injury but found none.

VERDICT A $3.5 million Illinois verdict was returned. It included
$1.5 million for past pain and suffering that was reduced by $100,000 due to the patient’s failure to report for psychological counseling. The jury found the gynecologist 65% at fault and the surgeon 35% at fault.

Mother in permanent vegetative state
When a 30-year-old woman went to a hospital in labor, she had gestational hypertension. The next morning, she suffered cardiopulmonary arrest. A healthy baby was born by emergency cesarean delivery, but the mother was left in a permanent vegetative state.

PATIENT’S CLAIM The nurses failed to ensure that the ObGyn came to the hospital and did not report blood pressure data to the ObGyn. Gestational hypertension progressed to preeclampsia. Early delivery should have been induced or magnesium sulfate should have been administered.

DEFENDANTS’ DEFENSE A confidential settlement was reached with the ObGyn before trial.

The nurses were right to rely on the ObGyn to make decisions regarding the patient’s care. They provided appropriate treatment.

VERDICT A New Jersey defense verdict was returned for the hospital.

What caused the child’s brain injuries?
After vaginal delivery, the baby was not breathing and required intubation. He had a seizure and displayed signs of oxygen deprivation, hypoxic ischemic injury, and brain damage. The child uses a special walker and can only communicate using a computer that speaks for him.

PARENTS’ CLAIM The nurses and ObGyn failed to properly assess the baby. The fetal heart-rate monitor electrode should have been placed on the fetal scalp. A cesarean delivery should have been performed.

DEFENDANTS’ DEFENSE The fetal monitor was properly placed. The child’s injury occurred 24 to 72 hours prior to birth due to an umbilical cord accident. A cesarean delivery would have not changed the outcome.  

VERDICT A Georgia defense verdict was returned.

Did a woman’s vaginal infection cause her baby’s death?
At 22 weeks’ gestation, a 26-year-old woman began to leak amniotic fluid and went to the hospital. She was in premature labor. The newborn died 19 minutes after birth.

PARENTS’ CLAIM The ObGyn and nurse midwife who provided prenatal care failed to diagnose and treat a vaginal infection. The infection resulted in premature rupture of membranes, leading to premature birth and the baby’s death.

DEFENDANTS’ DEFENSE A confidential settlement was reached with the ObGyn before trial. The nurse midwife claimed the patient did not have a vaginal infection; she never reported symptoms of a foul-smelling vaginal odor or discharge. Premature rupture of membranes was not caused by a vaginal infection. The newborn’s death was related to an umbilical cord defect, the patient’s delay in coming to the hospital, and the multiple obstetric procedures the mother had undergone before this pregnancy.   

VERDICT A $456,024 New Jersey verdict was returned.

Inadvertent ligation, ureteral obstruction
A 41-year-old woman suffered pelvic pain and had a history of endometriosis. In January 2007, a CT scan revealed a ruptured ovarian cyst; her ObGyn performed laparotomy for a hysterectomy and oophorectomy.

During surgery, a resident working under the supervision of the ObGyn inadvertently ligated the left ureter. The injury was close to the bladder near the ureteral vesicle junction. A few days later, cystoscopy showed ureteral obstruction. The patient underwent operative repair with nephrostomy tube placement. In May 2007, the patient had a third operation to reimplant the ureter. She has chronic flank pain.

PATIENT’S CLAIM The resident and, therefore, the ObGyn, were negligent in the performance of the procedure. Proper bladder dissection would have moved the ureter to a position where it could not have been ligated.

DEFENDANTS’ DEFENSE Ureter injury is a known risk of the procedure.

VERDICT An Illinois defense verdict was returned.

Foot drop after tubal ligatioN?
During tubal ligation, a woman in her 30s was restrained by a belt. Venodyne boots were applied to promote blood circulation.

PATIENT’S CLAIM The belt and/or boot damaged the perineal and tibial nerves in her left leg, causing foot drop. When asked to definitely identify what caused the nerve damage, the patient invoked the doctrine of res ipsa loquitur (presumed negligence during surgery).

DEFENDANTS’ DEFENSE A $400,000 settlement was reached with the hospital before the trial.

The gynecologist and anesthesiologist denied negligence. The Venodyne boots could not have caused the injury, nor could the belt, which was applied in an area that did not involve the perineal or tibial nerves. The patient did not complain of pain after surgery.  

VERDICT A New York defense verdict was returned for the physicians.

Avoid surgical menopause?
After a 10-year history of endometriosis and chronic pelvic pain, a 38-year-old woman underwent bilateral salpingo-oophorectomy. Postoperatively, she suffered surgical menopause that exacerbated pre-existing anxiety and depression.

PATIENT’S CLAIM It was unnecessary to remove the healthy right ovary; having it remain would have avoided early menopause. She would not have consented to the removal of both ovaries had she been properly advised. Alternative treatment was not offered. Her marriage dissolved, her children went to live with their grandparents, and she was unable to work because of complications.

PHYSICIAN’S DEFENSE Proper consent was obtained, including alternatives to surgery. Evidence of ovarian cancer or other medical necessity was not required because full consent was obtained. Removal of the ovaries was proper due to dense pelvic and bowel adhesions, cystic adnexal masses with questionable pathology, and her chronic pelvic pain. The patient’s appendix was adhesed, causing an unreasonable risk of ovarian torsion.

VERDICT A Michigan defense verdict was returned.

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Persistent voiding problems
A 52-year-old woman was given a diagnosis of stage II anterior pelvic organ prolapse, a high transverse fascial defect, stress urinary incontinence, and distal rectocele.

A gynecologist performed robotic supracervical hysterectomy and colposacropexy, with tension-free vaginal tape and perineal repair.

While in the hospital, she required a catheter to void, and was still unable to void 5 days after discharge. The gynecologist identified persistent urinary retention, released the tension-free vaginal tape, and performed a midurethral sling procedure, but the patient continued to have voiding problems.

The gynecologist suspected a neurogenic problem and referred the patient to a neuro-urologist. Continued intermittent catheterization was recommended by the neuro-urologist, but the patient had continued voiding problems and developed a urinary tract infection.

She went to her ObGyn, who performed a sling revision and cysto­scopy and removed all the mesh that could be found. The patient underwent additional treatment, with some improvement.

PATIENT’S CLAIM The gynecologist was negligent for failing to offer further surgery to improve the patient’s condition. 

PHYSICIAN’S DEFENSE There was no negligence. Further dissection in the presence of a neurogenic bladder carried a high risk of incontinence. The patient was told of the risk of urinary retention prior to the first procedure and signed an informed consent.   

VERDICT A Virginia defense verdict was returned.

Did pathologists fail to diagnose early breast cancer?
After A 45-year-old woman underwent mammography in May 2008 at a local hospital, an oncologist noted a suspicious finding in the right breast. The patient had an incisional biopsy interpreted by Dr. A, a pathologist, and a core biopsy interpreted by Dr. B, another pathologist from the same diagnostic medical group. Both pathologists interpreted the mass as atypia, a benign abnormality.

In 2010, the patient went to a university medical center, where the mass was biopsied and the patient was found to have cancer. She underwent a right mastectomy.

PATIENT’S CLAIM The pathologists failed to diagnose her breast cancer at an early stage. Dr. A should have interpreted the 2008 incisional biopsy as malignant. A diagnosis in 2008 would have avoided the need for a mastectomy, allowing her to have a lumpectomy with chemotherapy.

DEFENDANTS’ DEFENSE The 2010 review of the 2008 data was an over-interpretation with hindsight bias; the diagnosis in 2008 was correct.  

VERDICT The case against the local hospital and Dr. B were dismissed. The matter continued against Dr. A and the diagnostic medical group. A California defense verdict was returned.

Brachial plexus injury occurs after admitting physician leaves
A woman sought prenatal care from her family practitioner (FP). The FP admitted the mother to a hospital for induction of labor at 38 weeks’ gestation with concerns of increased uric acid, possible gestational hypertension, and leaking amniotic fluid. Labor progressed and the mother began pushing about 4 pm. After 30 minutes, the FP attempted vacu­um extraction three times; the device popped off during one of the attempts.

The FP then left for a planned trip, and an ObGyn assumed her care. The ObGyn chose to allow the mother to rest. At 6 pm, the mother began to feel the urge to push. The ObGyn attempted vacu­um extraction. Shoulder dystocia was encountered, and McRoberts and corkscrew maneuvers were used to deliver the fetus.

The child has C5–C6 brachial plexus injury with scapular winging and internal shoulder rotation.

PARENTS’ CLAIM A cesarean delivery should have been performed. The ObGyn applied excessive lateral traction, leading to the injury.

DEFENDANTS’ DEFENSE The FP and ObGyn argued that a cesarean ­delivery was not indicated because the fetus was not in distress. Fetal heart-rate monitoring strips were reassuring. The ObGyn denied using excessive lateral traction when freeing the shoulder dystocia. 

VERDICT The hospital settled before trial for $300,000. An Illinois defense verdict was returned for the FP. The jury deadlocked as to the ObGyn’s negligence.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

During a routine mammogram, an enlarged lymph node was found in the patient’s armpit. The patient’s primary care physician (PCP) ordered follow-up imaging and referred the patient to a surgeon for possible excisional biopsy. The surgeon suggested that the biopsy could be delayed until additional imaging studies were completed.

The patient transferred her care to another surgeon, who immediately performed the biopsy and found stage IV inoperable breast cancer. The patient underwent aggressive chemotherapy for 3 years, but died 39 months after diagnosis.

ESTATE’S CLAIM The first surgeon was negligent for not immediately performing the biopsy.

DEFENDANTS’ DEFENSE There was no negligence. An earlier biopsy would not have changed the outcome.

VERDICT A $1.5 million Massachusetts verdict was returned.

Treating bowel injury after uterine ablation
Following uterine ablation performed by a gynecologist, a 35-year-old woman suffered severe abdominal pain. Six days later, the gynecologist and a surgeon performed a hysterectomy.

Three days after discharge, the patient returned to the hospital with an abdominal infection and sepsis. During a third operation, a burn hole was found; the injured portion of bowel was resected. The patient has chronic abdominal pain.

PATIENT’S CLAIM Sepsis and infection could have been avoided if either physician had identified the injury during the second hospitalization and surgery. The patient developed psychological issues as a result of chronic pain.

DEFENDANTS’ DEFENSE A settlement was reached with the gynecologist during the trial. The surgeon denied negligence. During the second surgery, he examined her bowel for a possible injury but found none.

VERDICT A $3.5 million Illinois verdict was returned. It included
$1.5 million for past pain and suffering that was reduced by $100,000 due to the patient’s failure to report for psychological counseling. The jury found the gynecologist 65% at fault and the surgeon 35% at fault.

Mother in permanent vegetative state
When a 30-year-old woman went to a hospital in labor, she had gestational hypertension. The next morning, she suffered cardiopulmonary arrest. A healthy baby was born by emergency cesarean delivery, but the mother was left in a permanent vegetative state.

PATIENT’S CLAIM The nurses failed to ensure that the ObGyn came to the hospital and did not report blood pressure data to the ObGyn. Gestational hypertension progressed to preeclampsia. Early delivery should have been induced or magnesium sulfate should have been administered.

DEFENDANTS’ DEFENSE A confidential settlement was reached with the ObGyn before trial.

The nurses were right to rely on the ObGyn to make decisions regarding the patient’s care. They provided appropriate treatment.

VERDICT A New Jersey defense verdict was returned for the hospital.

What caused the child’s brain injuries?
After vaginal delivery, the baby was not breathing and required intubation. He had a seizure and displayed signs of oxygen deprivation, hypoxic ischemic injury, and brain damage. The child uses a special walker and can only communicate using a computer that speaks for him.

PARENTS’ CLAIM The nurses and ObGyn failed to properly assess the baby. The fetal heart-rate monitor electrode should have been placed on the fetal scalp. A cesarean delivery should have been performed.

DEFENDANTS’ DEFENSE The fetal monitor was properly placed. The child’s injury occurred 24 to 72 hours prior to birth due to an umbilical cord accident. A cesarean delivery would have not changed the outcome.  

VERDICT A Georgia defense verdict was returned.

Did a woman’s vaginal infection cause her baby’s death?
At 22 weeks’ gestation, a 26-year-old woman began to leak amniotic fluid and went to the hospital. She was in premature labor. The newborn died 19 minutes after birth.

PARENTS’ CLAIM The ObGyn and nurse midwife who provided prenatal care failed to diagnose and treat a vaginal infection. The infection resulted in premature rupture of membranes, leading to premature birth and the baby’s death.

DEFENDANTS’ DEFENSE A confidential settlement was reached with the ObGyn before trial. The nurse midwife claimed the patient did not have a vaginal infection; she never reported symptoms of a foul-smelling vaginal odor or discharge. Premature rupture of membranes was not caused by a vaginal infection. The newborn’s death was related to an umbilical cord defect, the patient’s delay in coming to the hospital, and the multiple obstetric procedures the mother had undergone before this pregnancy.   

VERDICT A $456,024 New Jersey verdict was returned.

Inadvertent ligation, ureteral obstruction
A 41-year-old woman suffered pelvic pain and had a history of endometriosis. In January 2007, a CT scan revealed a ruptured ovarian cyst; her ObGyn performed laparotomy for a hysterectomy and oophorectomy.

During surgery, a resident working under the supervision of the ObGyn inadvertently ligated the left ureter. The injury was close to the bladder near the ureteral vesicle junction. A few days later, cystoscopy showed ureteral obstruction. The patient underwent operative repair with nephrostomy tube placement. In May 2007, the patient had a third operation to reimplant the ureter. She has chronic flank pain.

PATIENT’S CLAIM The resident and, therefore, the ObGyn, were negligent in the performance of the procedure. Proper bladder dissection would have moved the ureter to a position where it could not have been ligated.

DEFENDANTS’ DEFENSE Ureter injury is a known risk of the procedure.

VERDICT An Illinois defense verdict was returned.

Foot drop after tubal ligatioN?
During tubal ligation, a woman in her 30s was restrained by a belt. Venodyne boots were applied to promote blood circulation.

PATIENT’S CLAIM The belt and/or boot damaged the perineal and tibial nerves in her left leg, causing foot drop. When asked to definitely identify what caused the nerve damage, the patient invoked the doctrine of res ipsa loquitur (presumed negligence during surgery).

DEFENDANTS’ DEFENSE A $400,000 settlement was reached with the hospital before the trial.

The gynecologist and anesthesiologist denied negligence. The Venodyne boots could not have caused the injury, nor could the belt, which was applied in an area that did not involve the perineal or tibial nerves. The patient did not complain of pain after surgery.  

VERDICT A New York defense verdict was returned for the physicians.

Avoid surgical menopause?
After a 10-year history of endometriosis and chronic pelvic pain, a 38-year-old woman underwent bilateral salpingo-oophorectomy. Postoperatively, she suffered surgical menopause that exacerbated pre-existing anxiety and depression.

PATIENT’S CLAIM It was unnecessary to remove the healthy right ovary; having it remain would have avoided early menopause. She would not have consented to the removal of both ovaries had she been properly advised. Alternative treatment was not offered. Her marriage dissolved, her children went to live with their grandparents, and she was unable to work because of complications.

PHYSICIAN’S DEFENSE Proper consent was obtained, including alternatives to surgery. Evidence of ovarian cancer or other medical necessity was not required because full consent was obtained. Removal of the ovaries was proper due to dense pelvic and bowel adhesions, cystic adnexal masses with questionable pathology, and her chronic pelvic pain. The patient’s appendix was adhesed, causing an unreasonable risk of ovarian torsion.

VERDICT A Michigan defense verdict was returned.

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Persistent voiding problems
A 52-year-old woman was given a diagnosis of stage II anterior pelvic organ prolapse, a high transverse fascial defect, stress urinary incontinence, and distal rectocele.

A gynecologist performed robotic supracervical hysterectomy and colposacropexy, with tension-free vaginal tape and perineal repair.

While in the hospital, she required a catheter to void, and was still unable to void 5 days after discharge. The gynecologist identified persistent urinary retention, released the tension-free vaginal tape, and performed a midurethral sling procedure, but the patient continued to have voiding problems.

The gynecologist suspected a neurogenic problem and referred the patient to a neuro-urologist. Continued intermittent catheterization was recommended by the neuro-urologist, but the patient had continued voiding problems and developed a urinary tract infection.

She went to her ObGyn, who performed a sling revision and cysto­scopy and removed all the mesh that could be found. The patient underwent additional treatment, with some improvement.

PATIENT’S CLAIM The gynecologist was negligent for failing to offer further surgery to improve the patient’s condition. 

PHYSICIAN’S DEFENSE There was no negligence. Further dissection in the presence of a neurogenic bladder carried a high risk of incontinence. The patient was told of the risk of urinary retention prior to the first procedure and signed an informed consent.   

VERDICT A Virginia defense verdict was returned.

Did pathologists fail to diagnose early breast cancer?
After A 45-year-old woman underwent mammography in May 2008 at a local hospital, an oncologist noted a suspicious finding in the right breast. The patient had an incisional biopsy interpreted by Dr. A, a pathologist, and a core biopsy interpreted by Dr. B, another pathologist from the same diagnostic medical group. Both pathologists interpreted the mass as atypia, a benign abnormality.

In 2010, the patient went to a university medical center, where the mass was biopsied and the patient was found to have cancer. She underwent a right mastectomy.

PATIENT’S CLAIM The pathologists failed to diagnose her breast cancer at an early stage. Dr. A should have interpreted the 2008 incisional biopsy as malignant. A diagnosis in 2008 would have avoided the need for a mastectomy, allowing her to have a lumpectomy with chemotherapy.

DEFENDANTS’ DEFENSE The 2010 review of the 2008 data was an over-interpretation with hindsight bias; the diagnosis in 2008 was correct.  

VERDICT The case against the local hospital and Dr. B were dismissed. The matter continued against Dr. A and the diagnostic medical group. A California defense verdict was returned.

Brachial plexus injury occurs after admitting physician leaves
A woman sought prenatal care from her family practitioner (FP). The FP admitted the mother to a hospital for induction of labor at 38 weeks’ gestation with concerns of increased uric acid, possible gestational hypertension, and leaking amniotic fluid. Labor progressed and the mother began pushing about 4 pm. After 30 minutes, the FP attempted vacu­um extraction three times; the device popped off during one of the attempts.

The FP then left for a planned trip, and an ObGyn assumed her care. The ObGyn chose to allow the mother to rest. At 6 pm, the mother began to feel the urge to push. The ObGyn attempted vacu­um extraction. Shoulder dystocia was encountered, and McRoberts and corkscrew maneuvers were used to deliver the fetus.

The child has C5–C6 brachial plexus injury with scapular winging and internal shoulder rotation.

PARENTS’ CLAIM A cesarean delivery should have been performed. The ObGyn applied excessive lateral traction, leading to the injury.

DEFENDANTS’ DEFENSE The FP and ObGyn argued that a cesarean ­delivery was not indicated because the fetus was not in distress. Fetal heart-rate monitoring strips were reassuring. The ObGyn denied using excessive lateral traction when freeing the shoulder dystocia. 

VERDICT The hospital settled before trial for $300,000. An Illinois defense verdict was returned for the FP. The jury deadlocked as to the ObGyn’s negligence.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

During a routine mammogram, an enlarged lymph node was found in the patient’s armpit. The patient’s primary care physician (PCP) ordered follow-up imaging and referred the patient to a surgeon for possible excisional biopsy. The surgeon suggested that the biopsy could be delayed until additional imaging studies were completed.

The patient transferred her care to another surgeon, who immediately performed the biopsy and found stage IV inoperable breast cancer. The patient underwent aggressive chemotherapy for 3 years, but died 39 months after diagnosis.

ESTATE’S CLAIM The first surgeon was negligent for not immediately performing the biopsy.

DEFENDANTS’ DEFENSE There was no negligence. An earlier biopsy would not have changed the outcome.

VERDICT A $1.5 million Massachusetts verdict was returned.

Treating bowel injury after uterine ablation
Following uterine ablation performed by a gynecologist, a 35-year-old woman suffered severe abdominal pain. Six days later, the gynecologist and a surgeon performed a hysterectomy.

Three days after discharge, the patient returned to the hospital with an abdominal infection and sepsis. During a third operation, a burn hole was found; the injured portion of bowel was resected. The patient has chronic abdominal pain.

PATIENT’S CLAIM Sepsis and infection could have been avoided if either physician had identified the injury during the second hospitalization and surgery. The patient developed psychological issues as a result of chronic pain.

DEFENDANTS’ DEFENSE A settlement was reached with the gynecologist during the trial. The surgeon denied negligence. During the second surgery, he examined her bowel for a possible injury but found none.

VERDICT A $3.5 million Illinois verdict was returned. It included
$1.5 million for past pain and suffering that was reduced by $100,000 due to the patient’s failure to report for psychological counseling. The jury found the gynecologist 65% at fault and the surgeon 35% at fault.

Mother in permanent vegetative state
When a 30-year-old woman went to a hospital in labor, she had gestational hypertension. The next morning, she suffered cardiopulmonary arrest. A healthy baby was born by emergency cesarean delivery, but the mother was left in a permanent vegetative state.

PATIENT’S CLAIM The nurses failed to ensure that the ObGyn came to the hospital and did not report blood pressure data to the ObGyn. Gestational hypertension progressed to preeclampsia. Early delivery should have been induced or magnesium sulfate should have been administered.

DEFENDANTS’ DEFENSE A confidential settlement was reached with the ObGyn before trial.

The nurses were right to rely on the ObGyn to make decisions regarding the patient’s care. They provided appropriate treatment.

VERDICT A New Jersey defense verdict was returned for the hospital.

What caused the child’s brain injuries?
After vaginal delivery, the baby was not breathing and required intubation. He had a seizure and displayed signs of oxygen deprivation, hypoxic ischemic injury, and brain damage. The child uses a special walker and can only communicate using a computer that speaks for him.

PARENTS’ CLAIM The nurses and ObGyn failed to properly assess the baby. The fetal heart-rate monitor electrode should have been placed on the fetal scalp. A cesarean delivery should have been performed.

DEFENDANTS’ DEFENSE The fetal monitor was properly placed. The child’s injury occurred 24 to 72 hours prior to birth due to an umbilical cord accident. A cesarean delivery would have not changed the outcome.  

VERDICT A Georgia defense verdict was returned.

Did a woman’s vaginal infection cause her baby’s death?
At 22 weeks’ gestation, a 26-year-old woman began to leak amniotic fluid and went to the hospital. She was in premature labor. The newborn died 19 minutes after birth.

PARENTS’ CLAIM The ObGyn and nurse midwife who provided prenatal care failed to diagnose and treat a vaginal infection. The infection resulted in premature rupture of membranes, leading to premature birth and the baby’s death.

DEFENDANTS’ DEFENSE A confidential settlement was reached with the ObGyn before trial. The nurse midwife claimed the patient did not have a vaginal infection; she never reported symptoms of a foul-smelling vaginal odor or discharge. Premature rupture of membranes was not caused by a vaginal infection. The newborn’s death was related to an umbilical cord defect, the patient’s delay in coming to the hospital, and the multiple obstetric procedures the mother had undergone before this pregnancy.   

VERDICT A $456,024 New Jersey verdict was returned.

Inadvertent ligation, ureteral obstruction
A 41-year-old woman suffered pelvic pain and had a history of endometriosis. In January 2007, a CT scan revealed a ruptured ovarian cyst; her ObGyn performed laparotomy for a hysterectomy and oophorectomy.

During surgery, a resident working under the supervision of the ObGyn inadvertently ligated the left ureter. The injury was close to the bladder near the ureteral vesicle junction. A few days later, cystoscopy showed ureteral obstruction. The patient underwent operative repair with nephrostomy tube placement. In May 2007, the patient had a third operation to reimplant the ureter. She has chronic flank pain.

PATIENT’S CLAIM The resident and, therefore, the ObGyn, were negligent in the performance of the procedure. Proper bladder dissection would have moved the ureter to a position where it could not have been ligated.

DEFENDANTS’ DEFENSE Ureter injury is a known risk of the procedure.

VERDICT An Illinois defense verdict was returned.

Foot drop after tubal ligatioN?
During tubal ligation, a woman in her 30s was restrained by a belt. Venodyne boots were applied to promote blood circulation.

PATIENT’S CLAIM The belt and/or boot damaged the perineal and tibial nerves in her left leg, causing foot drop. When asked to definitely identify what caused the nerve damage, the patient invoked the doctrine of res ipsa loquitur (presumed negligence during surgery).

DEFENDANTS’ DEFENSE A $400,000 settlement was reached with the hospital before the trial.

The gynecologist and anesthesiologist denied negligence. The Venodyne boots could not have caused the injury, nor could the belt, which was applied in an area that did not involve the perineal or tibial nerves. The patient did not complain of pain after surgery.  

VERDICT A New York defense verdict was returned for the physicians.

Avoid surgical menopause?
After a 10-year history of endometriosis and chronic pelvic pain, a 38-year-old woman underwent bilateral salpingo-oophorectomy. Postoperatively, she suffered surgical menopause that exacerbated pre-existing anxiety and depression.

PATIENT’S CLAIM It was unnecessary to remove the healthy right ovary; having it remain would have avoided early menopause. She would not have consented to the removal of both ovaries had she been properly advised. Alternative treatment was not offered. Her marriage dissolved, her children went to live with their grandparents, and she was unable to work because of complications.

PHYSICIAN’S DEFENSE Proper consent was obtained, including alternatives to surgery. Evidence of ovarian cancer or other medical necessity was not required because full consent was obtained. Removal of the ovaries was proper due to dense pelvic and bowel adhesions, cystic adnexal masses with questionable pathology, and her chronic pelvic pain. The patient’s appendix was adhesed, causing an unreasonable risk of ovarian torsion.

VERDICT A Michigan defense verdict was returned.

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Persistent voiding problems
A 52-year-old woman was given a diagnosis of stage II anterior pelvic organ prolapse, a high transverse fascial defect, stress urinary incontinence, and distal rectocele.

A gynecologist performed robotic supracervical hysterectomy and colposacropexy, with tension-free vaginal tape and perineal repair.

While in the hospital, she required a catheter to void, and was still unable to void 5 days after discharge. The gynecologist identified persistent urinary retention, released the tension-free vaginal tape, and performed a midurethral sling procedure, but the patient continued to have voiding problems.

The gynecologist suspected a neurogenic problem and referred the patient to a neuro-urologist. Continued intermittent catheterization was recommended by the neuro-urologist, but the patient had continued voiding problems and developed a urinary tract infection.

She went to her ObGyn, who performed a sling revision and cysto­scopy and removed all the mesh that could be found. The patient underwent additional treatment, with some improvement.

PATIENT’S CLAIM The gynecologist was negligent for failing to offer further surgery to improve the patient’s condition. 

PHYSICIAN’S DEFENSE There was no negligence. Further dissection in the presence of a neurogenic bladder carried a high risk of incontinence. The patient was told of the risk of urinary retention prior to the first procedure and signed an informed consent.   

VERDICT A Virginia defense verdict was returned.

Did pathologists fail to diagnose early breast cancer?
After A 45-year-old woman underwent mammography in May 2008 at a local hospital, an oncologist noted a suspicious finding in the right breast. The patient had an incisional biopsy interpreted by Dr. A, a pathologist, and a core biopsy interpreted by Dr. B, another pathologist from the same diagnostic medical group. Both pathologists interpreted the mass as atypia, a benign abnormality.

In 2010, the patient went to a university medical center, where the mass was biopsied and the patient was found to have cancer. She underwent a right mastectomy.

PATIENT’S CLAIM The pathologists failed to diagnose her breast cancer at an early stage. Dr. A should have interpreted the 2008 incisional biopsy as malignant. A diagnosis in 2008 would have avoided the need for a mastectomy, allowing her to have a lumpectomy with chemotherapy.

DEFENDANTS’ DEFENSE The 2010 review of the 2008 data was an over-interpretation with hindsight bias; the diagnosis in 2008 was correct.  

VERDICT The case against the local hospital and Dr. B were dismissed. The matter continued against Dr. A and the diagnostic medical group. A California defense verdict was returned.

Brachial plexus injury occurs after admitting physician leaves
A woman sought prenatal care from her family practitioner (FP). The FP admitted the mother to a hospital for induction of labor at 38 weeks’ gestation with concerns of increased uric acid, possible gestational hypertension, and leaking amniotic fluid. Labor progressed and the mother began pushing about 4 pm. After 30 minutes, the FP attempted vacu­um extraction three times; the device popped off during one of the attempts.

The FP then left for a planned trip, and an ObGyn assumed her care. The ObGyn chose to allow the mother to rest. At 6 pm, the mother began to feel the urge to push. The ObGyn attempted vacu­um extraction. Shoulder dystocia was encountered, and McRoberts and corkscrew maneuvers were used to deliver the fetus.

The child has C5–C6 brachial plexus injury with scapular winging and internal shoulder rotation.

PARENTS’ CLAIM A cesarean delivery should have been performed. The ObGyn applied excessive lateral traction, leading to the injury.

DEFENDANTS’ DEFENSE The FP and ObGyn argued that a cesarean ­delivery was not indicated because the fetus was not in distress. Fetal heart-rate monitoring strips were reassuring. The ObGyn denied using excessive lateral traction when freeing the shoulder dystocia. 

VERDICT The hospital settled before trial for $300,000. An Illinois defense verdict was returned for the FP. The jury deadlocked as to the ObGyn’s negligence.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.